Showing posts with label molecular profiling. Show all posts
Showing posts with label molecular profiling. Show all posts
Friday, September 21, 2012
Legislation for Combinatorial Therapy >> Melanoma ..Jim Breitfeller
Congressman Bilbray, and Congresswomen Maloney and DeLaura are submitting legislation today that, if passed, will provide extended patent protection for investigational drugs that are tested in combination. This will provide a major financial incentive for industry to do the kinds of studies they now find difficult but which offer the best hope for melanoma patients.
This legislation came out of meetings MRF had with Congressman Bilbray, whose daughter has Stage III melanoma. We proposed the idea to the Congressman and provided a background document showing how similar action in pediatrics and some infectious diseases has resulted in tremendous progress in drug development.
Most doctors agree that real advances in effective treatments will only come through combining two or more drugs together. If these drugs are already approved, doing studies like this are relatively easy. If they are not yet approved--still in clinical trials--they are very difficult. Companies worry that any side effects that arise from a combination study will "taint" the data of their drug and hurt its chances of approval. And they are reluctant to collaborate with other companies on these studies. This legislation will add a "carrot" to the mix and will help accelerate these important studies.
“It is not the strongest of the species that survives, nor the most intelligent, but the one most responsive to change.”
~Charles Darwin~
Take Care,
Jimmy B
Thursday, August 13, 2009
Genetic Profiling Of Tumors Could Have 'Immediate Impact' On Treating Cancer..Melanoma Jim Breitfeller
Genetic Profiling Of Tumors Could Have 'Immediate Impact' On Treating Cancer
Main Category: Cancer / Oncology
Also Included In: Genetics
Article Date: 08 Aug 2009 - 0:00 PDT
New work by MIT cancer biologists shows that the interplay between two key genes that are often defective in tumors determines how cancer cells respond to chemotherapy.
The findings should have an immediate impact on cancer treatment, say Michael Hemann and Michael Yaffe, the two MIT biology professors who led the study. The work could help doctors predict what types of chemotherapy will be effective in a particular tumor, which would help tailor treatments to each patient.
"This isn't something that's going to take five years to do," says Yaffe, who, along with Hemann is a member of the David H. Koch Institute for Integrative Cancer Research at MIT. "You could begin doing this tomorrow."
The work could also guide the development of new chemotherapy drugs targeted to tumors with specific genetic mutations.
Hemann, Yaffe, and their colleagues report their results in the Aug. 15 issue of the journal Genes and Development. Koch Institute postdoctoral associates Hai Jiang and H. Christian Reinhardt are lead authors of the study, which the researchers say is one of the first examples of how genetic profiling of tumors can translate to improvements in patient treatment.
"There's a huge amount of genetic information available, but it hasn't made its way into clinical practice yet," says Hemann.
Genetic mystery
The research team focused on two proteins often involved in cancer, p53 and ATM. One of the first tumor suppressor genes discovered, p53 serves a watchdog function over a cell's genome, activating repair systems when DNA is damaged and initiating cell death if the damage is irreparable.
ATM is also involved in controlling the cell's response to DNA damage and is known to help regulate p53.
Mutations in p53, ATM or both are often seen in tumor cells. (ATM mutations occur in about 15 percent of cancers, and p53 is mutated in about 30 percent.)
Scientists have long tried to pin down a relationship between mutations in these genes and the effectiveness of DNA-damaging chemotherapy agents, but published studies have produced conflicting reports.
"It's been unclear whether the loss of p53 made tumors easier to treat or harder to treat. You could find examples of either case in the clinical literature," says Yaffe, adding that the same holds true for ATM.
The new study, conducted with human cancer cells, shows that tumors in which both p53 and ATM are defective are highly susceptible to chemotherapy agents that damage DNA. The double mutation prevents tumor cells from being able to repair DNA, and the cells commit suicide.
However, in cells where p53 is mutated but ATM is not, that type of chemotherapy is less effective. Remarkably, tumors where ATM is mutated but p53 is not turn out to be highly resistant to those types of chemotherapy.
With this new information, doctors could choose chemotherapy treatments based on the status of the p53 and ATM genes in a patient's tumor. Traditional DNA-damaging chemotherapy would be a good option for patients with both p53 and ATM mutations, but not for those with normal p53 and mutated ATM.
For patients who have normal ATM and mutated p53, other options might be better: New drugs that inhibit ATM, now in clinical trials, could improve tumors' susceptibility to chemotherapy in those patients.
The study shows the importance of studying cancer genes as a network, rather than trying to predict outcomes based on the status of single genes such as p53, says Robert Abraham, director of the cancer drug discovery program at Wyeth Pharmaceuticals.
Once ATM inhibitors are approved, "understanding the combined status of ATM and p53 should allow physicians to identify patients who should be treated with ATM inhibitors and chemotherapy and those for whom such a therapy could potentially be harmful," Abraham says.
In patients with normal p53 and mutated ATM, doctors could use drugs that target alternative DNA repair pathways. In their Genes and Development paper, the MIT researchers showed that treating such tumors with a drug that targets DNA-PK, another protein involved in DNA repair, renders them vulnerable to chemotherapy.
The MIT researchers collaborated with scientists from the Centre for Genotoxic Stress Research in Denmark, Helsinki University Central Hospital in Finland, and Uppsala University Hospital in Sweden.
The research was funded by the National Institutes of Health, the David H. Koch Fund, the Deutsche Forschungsgemeinschaft, the Deutsche Nierenstiftung, the Danish Cancer Society, the European Community, the Czech Ministry of Education and the Helsinki University Central Hospital Research Fund.
Source:
Jen Hirsch
Massachusetts Institute of Technology
Where did I hear about Genomic Profiling? It was right here on carepages.
Take Care,
Jimmy B
Main Category: Cancer / Oncology
Also Included In: Genetics
Article Date: 08 Aug 2009 - 0:00 PDT
New work by MIT cancer biologists shows that the interplay between two key genes that are often defective in tumors determines how cancer cells respond to chemotherapy.
The findings should have an immediate impact on cancer treatment, say Michael Hemann and Michael Yaffe, the two MIT biology professors who led the study. The work could help doctors predict what types of chemotherapy will be effective in a particular tumor, which would help tailor treatments to each patient.
"This isn't something that's going to take five years to do," says Yaffe, who, along with Hemann is a member of the David H. Koch Institute for Integrative Cancer Research at MIT. "You could begin doing this tomorrow."
The work could also guide the development of new chemotherapy drugs targeted to tumors with specific genetic mutations.
Hemann, Yaffe, and their colleagues report their results in the Aug. 15 issue of the journal Genes and Development. Koch Institute postdoctoral associates Hai Jiang and H. Christian Reinhardt are lead authors of the study, which the researchers say is one of the first examples of how genetic profiling of tumors can translate to improvements in patient treatment.
"There's a huge amount of genetic information available, but it hasn't made its way into clinical practice yet," says Hemann.
Genetic mystery
The research team focused on two proteins often involved in cancer, p53 and ATM. One of the first tumor suppressor genes discovered, p53 serves a watchdog function over a cell's genome, activating repair systems when DNA is damaged and initiating cell death if the damage is irreparable.
ATM is also involved in controlling the cell's response to DNA damage and is known to help regulate p53.
Mutations in p53, ATM or both are often seen in tumor cells. (ATM mutations occur in about 15 percent of cancers, and p53 is mutated in about 30 percent.)
Scientists have long tried to pin down a relationship between mutations in these genes and the effectiveness of DNA-damaging chemotherapy agents, but published studies have produced conflicting reports.
"It's been unclear whether the loss of p53 made tumors easier to treat or harder to treat. You could find examples of either case in the clinical literature," says Yaffe, adding that the same holds true for ATM.
The new study, conducted with human cancer cells, shows that tumors in which both p53 and ATM are defective are highly susceptible to chemotherapy agents that damage DNA. The double mutation prevents tumor cells from being able to repair DNA, and the cells commit suicide.
However, in cells where p53 is mutated but ATM is not, that type of chemotherapy is less effective. Remarkably, tumors where ATM is mutated but p53 is not turn out to be highly resistant to those types of chemotherapy.
With this new information, doctors could choose chemotherapy treatments based on the status of the p53 and ATM genes in a patient's tumor. Traditional DNA-damaging chemotherapy would be a good option for patients with both p53 and ATM mutations, but not for those with normal p53 and mutated ATM.
For patients who have normal ATM and mutated p53, other options might be better: New drugs that inhibit ATM, now in clinical trials, could improve tumors' susceptibility to chemotherapy in those patients.
The study shows the importance of studying cancer genes as a network, rather than trying to predict outcomes based on the status of single genes such as p53, says Robert Abraham, director of the cancer drug discovery program at Wyeth Pharmaceuticals.
Once ATM inhibitors are approved, "understanding the combined status of ATM and p53 should allow physicians to identify patients who should be treated with ATM inhibitors and chemotherapy and those for whom such a therapy could potentially be harmful," Abraham says.
In patients with normal p53 and mutated ATM, doctors could use drugs that target alternative DNA repair pathways. In their Genes and Development paper, the MIT researchers showed that treating such tumors with a drug that targets DNA-PK, another protein involved in DNA repair, renders them vulnerable to chemotherapy.
The MIT researchers collaborated with scientists from the Centre for Genotoxic Stress Research in Denmark, Helsinki University Central Hospital in Finland, and Uppsala University Hospital in Sweden.
The research was funded by the National Institutes of Health, the David H. Koch Fund, the Deutsche Forschungsgemeinschaft, the Deutsche Nierenstiftung, the Danish Cancer Society, the European Community, the Czech Ministry of Education and the Helsinki University Central Hospital Research Fund.
Source:
Jen Hirsch
Massachusetts Institute of Technology
Where did I hear about Genomic Profiling? It was right here on carepages.
Take Care,
Jimmy B
Thursday, April 2, 2009
Gene Screen Could Help Spot Melanoma Jim Breitfeller
Date:3/31/2009
"Activity of key proteins separate cancer from benign mole, scientists say
TUESDAY, March 31 (HealthDay news) -- Identifying the differences between melanoma skin cancer and a harmless mole can still be a tough call for even trained specialists. But scientists say differences in levels of certain genetic markers may help distinguish between the two lesions.
Melanoma is the deadliest form of skin cancer. Standard microscopic examinations of tissue biopsies can be ambiguous, so using this new technique along with standard practice could help clarify difficult-to-diagnosis cases, according to researchers from the University of California, San Francisco.
They found that both the level and the pattern of activity of five proteins can distinguish benign moles from melanoma. Testing the diagnostic technique on 693 previously diagnosed tissue samples, they found that it correctly diagnosed 91 percent of melanomas and 95 percent of benign moles. The technique also correctly diagnosed 75 percent of the most difficult cases that had previously been misdiagnosed."
Source:http://www.bio-medicine.org/medicine-news-1/Gene-Screen-Could-Help-Spot-Melanoma-41161-1/
Gene Screen Could Help Spot Melanoma
Jimmy B
"Activity of key proteins separate cancer from benign mole, scientists say
TUESDAY, March 31 (HealthDay news) -- Identifying the differences between melanoma skin cancer and a harmless mole can still be a tough call for even trained specialists. But scientists say differences in levels of certain genetic markers may help distinguish between the two lesions.
Melanoma is the deadliest form of skin cancer. Standard microscopic examinations of tissue biopsies can be ambiguous, so using this new technique along with standard practice could help clarify difficult-to-diagnosis cases, according to researchers from the University of California, San Francisco.
They found that both the level and the pattern of activity of five proteins can distinguish benign moles from melanoma. Testing the diagnostic technique on 693 previously diagnosed tissue samples, they found that it correctly diagnosed 91 percent of melanomas and 95 percent of benign moles. The technique also correctly diagnosed 75 percent of the most difficult cases that had previously been misdiagnosed."
Source:http://www.bio-medicine.org/medicine-news-1/Gene-Screen-Could-Help-Spot-Melanoma-41161-1/
Gene Screen Could Help Spot Melanoma
Jimmy B
Wednesday, March 25, 2009
Genomic and Molecular Profiling Predicts Response toTemozolomide in Melanoma Jim Breitfeller
Temozolomide (brand names Temodar and Temodal Schering-Plough Corporation) is an oral alkylating agent which can be used for the treatment of Grade IV astrocytoma -- an aggressive brain tumor, also known as glioblastoma multiforme. The agent was developed by Malcolm Stevens and his team at Aston University in Birmingham, UK.[1] A derivative of imidazotetrazine, temozolomide is the prodrug of MTIC (3-methyl-(triazen-1-yl)imidazole-4-carboxamide). It has been available in the US since August 1999, and in other countries since the early 2000s.
A 2005 study has showed that its benefits depend on the epigenetic silencing of the MGMT gene; MGMT encodes a protein that removes alkyl groups from the O-6 position of guanine
Source: Wikipedia
When I came across this Research paper "Genomic and Molecular Profiling Predicts Response to Temozolomide in Melanoma", I contacted Dr. Christina Augustine.
Christina Augustine, PhD
Assistant Professor
Department of Surgery
Duke University Medical Center
Box 3118 Med Ctr
Durham NC 27710
(919) 286.0411 x 5191
christi.augustine@duke.edu
Temozolomide is the only chemo drug of it's kind to cross over the Brain/blood barrier. If you could predict which patients will
respond to Temozolomide, then you could help those with the right genotype.
"With the increasing incidence of melanoma and the historicallypoor
response rates to traditional chemotherapy, it is important
to develop tools that can be used prospectively to
characterize apatient’s tumor with regard to chemoresistance
pathways.The findings in this study show striking differences
in terms of DNA repair pathway efficiency and temozolomide
response across a broad sampling of melanoma cell lines and
that, in melanoma, resistance to temozolomide is conferred
largely by the activity of the DNA repair enzyme O6-methylguanine-
DNA methyltransferase (MGMT). Our results suggest that MGMT expression could potentially be a useful tool for personalizing treatment strategies in melanoma patients by identifying those patients most likely to respond to temozolomide and those patients for whom combination therapy
or alternative chemotherapeutic reagentsmight be desirable."
I will post the paper on Melanoma Missionary
Jimmy B
A 2005 study has showed that its benefits depend on the epigenetic silencing of the MGMT gene; MGMT encodes a protein that removes alkyl groups from the O-6 position of guanine
Source: Wikipedia
When I came across this Research paper "Genomic and Molecular Profiling Predicts Response to Temozolomide in Melanoma", I contacted Dr. Christina Augustine.
Christina Augustine, PhD
Assistant Professor
Department of Surgery
Duke University Medical Center
Box 3118 Med Ctr
Durham NC 27710
(919) 286.0411 x 5191
christi.augustine@duke.edu
Temozolomide is the only chemo drug of it's kind to cross over the Brain/blood barrier. If you could predict which patients will
respond to Temozolomide, then you could help those with the right genotype.
"With the increasing incidence of melanoma and the historicallypoor
response rates to traditional chemotherapy, it is important
to develop tools that can be used prospectively to
characterize apatient’s tumor with regard to chemoresistance
pathways.The findings in this study show striking differences
in terms of DNA repair pathway efficiency and temozolomide
response across a broad sampling of melanoma cell lines and
that, in melanoma, resistance to temozolomide is conferred
largely by the activity of the DNA repair enzyme O6-methylguanine-
DNA methyltransferase (MGMT). Our results suggest that MGMT expression could potentially be a useful tool for personalizing treatment strategies in melanoma patients by identifying those patients most likely to respond to temozolomide and those patients for whom combination therapy
or alternative chemotherapeutic reagentsmight be desirable."
I will post the paper on Melanoma Missionary
Jimmy B
Thursday, February 26, 2009
Jay Tenenbaum Urges Collaboration To Treat the Long Tail of Disease Melanoma..Jim Breitfeller
By Kevin Davies
February 26, 2009 SAN FRANCISCO—In the powerful opening keynote at CHI’s Molecular Medicine Tri-Conference on Wednesday, Jay “Marty” Tenenbaum, founder and chairman of CollabRx, urged members of the life sciences community to share their resources to empower personalized research and help satisfy the unmet medical needs of the “long tail” of disease. “As a patient… I want to tap all of the world’s knowledge and all of the world’s resources into curing my disease,” Tenenbaum said.
Tenenbaum, a highly successful Internet entrepreneur in the 1990s, is a cancer survivor. Ten years ago, suffering from metastatic melanoma, he was given 12 months to live. He researched various experimental drug treatments, and credits a failed cancer vaccine, among other drugs, for saving his life. Through the company he founded, CollabRx, Tenenbaum aims to leverage the extraordinary untapped expertise and resources across the industry to empower individual patient healthcare through personalized research.
This sounds Familiar!!!!!!!!!
Source:http://www.bio-itworld.com/2009/02/26/tenenbaum-mmtc-keynote.html
Jay Tenenbaum Urges Collaboration To Treat the Long Tail of Disease
http://podcast.mktw.net/wsj/audio/20080728/pod-wsjmarcus/pod-wsjmarcus.mp3
Jay Tenenbaum Urges Collaboration Podcast
Take care
Jimmy B
February 26, 2009 SAN FRANCISCO—In the powerful opening keynote at CHI’s Molecular Medicine Tri-Conference on Wednesday, Jay “Marty” Tenenbaum, founder and chairman of CollabRx, urged members of the life sciences community to share their resources to empower personalized research and help satisfy the unmet medical needs of the “long tail” of disease. “As a patient… I want to tap all of the world’s knowledge and all of the world’s resources into curing my disease,” Tenenbaum said.
Tenenbaum, a highly successful Internet entrepreneur in the 1990s, is a cancer survivor. Ten years ago, suffering from metastatic melanoma, he was given 12 months to live. He researched various experimental drug treatments, and credits a failed cancer vaccine, among other drugs, for saving his life. Through the company he founded, CollabRx, Tenenbaum aims to leverage the extraordinary untapped expertise and resources across the industry to empower individual patient healthcare through personalized research.
This sounds Familiar!!!!!!!!!
Source:http://www.bio-itworld.com/2009/02/26/tenenbaum-mmtc-keynote.html
Jay Tenenbaum Urges Collaboration To Treat the Long Tail of Disease
http://podcast.mktw.net/wsj/audio/20080728/pod-wsjmarcus/pod-wsjmarcus.mp3
Jay Tenenbaum Urges Collaboration Podcast
Take care
Jimmy B
Wednesday, February 4, 2009
Are The Europeans ahead of us in the War Against Melanoma? Jim Breitfeller
Genetics
European Organization for Research and Treatment of Cancer
EORTC Melanoma Group Genetics Committee
The mission of this sub-group is to develop genetics based translational research within the EORTC Melanoma group.
The sub-group has strong links with the melanoma genetics consortium GenoMEL @ www.genomel.org
Committee members
- Julia Newton Bishop, Chairman
- Veronique Bataille
- Brigitte Bressac
- Florence Demenais
- Giovanna Bianchi Scarra
- Dirk Schadendorf
- Johan Hansson
- Nelleke Gruis
- Susana Puig
Ongoing Studies
1. A Cohort Study of Patients with a positive sentinel node biopsy (SNB)
This study will commence recruitment in the early Autumn of 2006. Patients with a positive SNB will be offered participation in the cohort study in EORTC centres in France, Italy, the UK, Germany and Spain. The study is designed to
• Identify the histological, environmental, and genetic predictors of relapse in patients with a positive SNB so that a risk algorithm can be developed
• Increase our understanding of the biology of metastasis in melanoma patients and the genetic and environmental modifiers of that process
• Identify gene expression profiles in the primary tumour which are predictive of relapse in SNB positive patients
Participating patients will be asked to complete a questionnaire, give a blood sample from which DNA can be extracted and allow their paraffin embedded tumour tissue to be used for immunohistochemical, genetic and gene expression studies.
2. A study of inherited variation in immune response genes as modifiers of outcome in melanoma patients
Melanoma is an immunogenic tumour and it is postulated that there is inherited variation in the host’s response to the tumour, moderated by inheritance of polymorphisms in genes such as cytokine genes and the vitamin D receptor gene. Melanoma patients participating in EORTC adjuvant therapeutic trials will be asked to participate in these translational genetic studies. Consenting patients will be asked to complete a one page questionnaire based upon family history and previous medical history and to give a blood sample from which DNA can be extracted. DNA will be extracted and stored at Leiden University Medical Center, and analysed in the CR-UK Genetic Epidemiology Laboratory in Leeds and other GenoMEL laboratories. A candidate gene approach will be taken to the identification of genes hypothesized to modulate the host response to the tumour via immune processes or angiogenesis.
http://www.melanomagroup.eu/content/view/45/53/
EORTC Melanoma Group Genetics Committee
Jimmy B
European Organization for Research and Treatment of Cancer
EORTC Melanoma Group Genetics Committee
The mission of this sub-group is to develop genetics based translational research within the EORTC Melanoma group.
The sub-group has strong links with the melanoma genetics consortium GenoMEL @ www.genomel.org
Committee members
- Julia Newton Bishop, Chairman
- Veronique Bataille
- Brigitte Bressac
- Florence Demenais
- Giovanna Bianchi Scarra
- Dirk Schadendorf
- Johan Hansson
- Nelleke Gruis
- Susana Puig
Ongoing Studies
1. A Cohort Study of Patients with a positive sentinel node biopsy (SNB)
This study will commence recruitment in the early Autumn of 2006. Patients with a positive SNB will be offered participation in the cohort study in EORTC centres in France, Italy, the UK, Germany and Spain. The study is designed to
• Identify the histological, environmental, and genetic predictors of relapse in patients with a positive SNB so that a risk algorithm can be developed
• Increase our understanding of the biology of metastasis in melanoma patients and the genetic and environmental modifiers of that process
• Identify gene expression profiles in the primary tumour which are predictive of relapse in SNB positive patients
Participating patients will be asked to complete a questionnaire, give a blood sample from which DNA can be extracted and allow their paraffin embedded tumour tissue to be used for immunohistochemical, genetic and gene expression studies.
2. A study of inherited variation in immune response genes as modifiers of outcome in melanoma patients
Melanoma is an immunogenic tumour and it is postulated that there is inherited variation in the host’s response to the tumour, moderated by inheritance of polymorphisms in genes such as cytokine genes and the vitamin D receptor gene. Melanoma patients participating in EORTC adjuvant therapeutic trials will be asked to participate in these translational genetic studies. Consenting patients will be asked to complete a one page questionnaire based upon family history and previous medical history and to give a blood sample from which DNA can be extracted. DNA will be extracted and stored at Leiden University Medical Center, and analysed in the CR-UK Genetic Epidemiology Laboratory in Leeds and other GenoMEL laboratories. A candidate gene approach will be taken to the identification of genes hypothesized to modulate the host response to the tumour via immune processes or angiogenesis.
http://www.melanomagroup.eu/content/view/45/53/
EORTC Melanoma Group Genetics Committee
Jimmy B
Genomic and Molecular Profiling Predicts Response to Temozolomide in Melanoma!! Jim Breitfeller
Christina K. Augustine1,5, Jin Soo Yoo1, Anil Potti2,4, Yasunori Yoshimoto1,5, Patricia A. Zipfel1,5, Henry S. Friedman1, Joseph R. Nevins3,4, Francis Ali-Osman1 and Douglas S. Tyler1,5
Authors' Affiliations: Departments of 1 Surgery, 2 Medicine, and 3 Molecular Genetics and Microbiology, and 4 Duke Institute for Genome Sciences and Policy, Duke University Medical Center and 5 Durham VA Medical Center, Durham, North Carolina
Requests for reprints: Christina K. Augustine, Box 3118, Medical Center, Duke University Medical Center, Durham, NC 27710. Phone: 919-286-0411, ext. 5191; Fax: 919-684-6044; E-mail: Christi.augustine@duke.edu.
Purpose: Despite objective response rates of only 13%, temozolomide remains one of the most effective single chemotherapy agents against metastatic melanoma, second only to dacarbazine, the current standard of care for systemic treatment of melanoma. The goal of this study was to identify molecular and/or genetic markers that correlate with, and could be used to predict, response to temozolomide-based treatment regimens and that reflect the intrinsic properties of a patient's tumor.
Experimental Design: Using a panel of 26 human melanoma-derived cell lines, we determined in vitro temozolomide sensitivity, O6-methylguanine-DNA methyltransferase (MGMT) activity, MGMT protein expression and promoter methylation status, and mismatch repair proficiency, as well as the expression profile of 38,000 genes using an oligonucleotide-based microarray platform.
Results: The results showed a broad spectrum of temozolomide sensitivity across the panel of cell lines, with IC50 values ranging from 100 µmol/L to 1 mmol/L. There was a significant correlation between measured temozolomide sensitivity and a gene expression signature–derived prediction of temozolomide sensitivity (P < 0.005). Notably, MGMT alone showed a significant correlation with temozolomide sensitivity (MGMT activity, P < 0.0001; MGMT expression, P 0.0001). The promoter methylation status of the MGMT gene, however, was not consistent with MGMT gene expression or temozolomide sensitivity. Conclusions: These results show that melanoma resistance to temozolomide is conferred predominantly by MGMT activity and suggest that MGMT expression could potentially be a useful tool for predicting the response of melanoma patients to temozolomide therapy. Source: Clinical Cancer Research 15, 502-510, January 15, 2009. doi: 10.1158/1078-0432.CCR-08-1916 http://clincancerres.aacrjournals.org/cgi/content/short/15/2/502
Authors' Affiliations: Departments of 1 Surgery, 2 Medicine, and 3 Molecular Genetics and Microbiology, and 4 Duke Institute for Genome Sciences and Policy, Duke University Medical Center and 5 Durham VA Medical Center, Durham, North Carolina
Requests for reprints: Christina K. Augustine, Box 3118, Medical Center, Duke University Medical Center, Durham, NC 27710. Phone: 919-286-0411, ext. 5191; Fax: 919-684-6044; E-mail: Christi.augustine@duke.edu.
Purpose: Despite objective response rates of only 13%, temozolomide remains one of the most effective single chemotherapy agents against metastatic melanoma, second only to dacarbazine, the current standard of care for systemic treatment of melanoma. The goal of this study was to identify molecular and/or genetic markers that correlate with, and could be used to predict, response to temozolomide-based treatment regimens and that reflect the intrinsic properties of a patient's tumor.
Experimental Design: Using a panel of 26 human melanoma-derived cell lines, we determined in vitro temozolomide sensitivity, O6-methylguanine-DNA methyltransferase (MGMT) activity, MGMT protein expression and promoter methylation status, and mismatch repair proficiency, as well as the expression profile of 38,000 genes using an oligonucleotide-based microarray platform.
Results: The results showed a broad spectrum of temozolomide sensitivity across the panel of cell lines, with IC50 values ranging from 100 µmol/L to 1 mmol/L. There was a significant correlation between measured temozolomide sensitivity and a gene expression signature–derived prediction of temozolomide sensitivity (P < 0.005). Notably, MGMT alone showed a significant correlation with temozolomide sensitivity (MGMT activity, P < 0.0001; MGMT expression, P 0.0001). The promoter methylation status of the MGMT gene, however, was not consistent with MGMT gene expression or temozolomide sensitivity. Conclusions: These results show that melanoma resistance to temozolomide is conferred predominantly by MGMT activity and suggest that MGMT expression could potentially be a useful tool for predicting the response of melanoma patients to temozolomide therapy. Source: Clinical Cancer Research 15, 502-510, January 15, 2009. doi: 10.1158/1078-0432.CCR-08-1916 http://clincancerres.aacrjournals.org/cgi/content/short/15/2/502
Tuesday, February 3, 2009
Cambridge University Research Group Employs Fluidigm’s EP1 System for Cancer and Disease Association Studies Melanoma Jim Breitfeller
Monday, February 2, 2009; South San Francisco, CA; Cambridge, UK – Fluidigm Corporation today announced that the Cancer Research UK Centre for Genetic Epidemiology, University of Cambridge, based at Strangeways Research Laboratory in the United Kingdom, has purchased the company’s EP1 System to conduct cancer research and disease association studies. The Fluidigm EP1 system combines the efficiencies of integrated fluidic circuit (IFC)-based high-throughput genotyping in a desktop-sized configuration, with a very affordable system price.
The Centre for Genetic Epidemiology is using high-throughput SNP genotyping to identify and verify genetic variants that can underlie susceptibility to various cancers. Cancers that are being investigated include breast, ovarian, colorectal, prostate, and melanoma. The lab uses an automated process with sample tracking and quality control. The Centre has successfully completed its validation experiments on the EP1 system using real samples and will now move forward using the system in its large genotyping studies.
“With a high-throughput genotyping lab already in place here at Strangeways, Fluidigm’s integrated fluidic circuits offered us an exciting new technology where we could use reliable TaqMan® chemistry with the added ability of assaying 96 SNPs at a time,” said Craig Luccarini, Senior Technical Officer, Strangeways Research Laboratory. “Piloting of the EP1 system generated data of good quality and the system fitted well in our lab as a robust process, capable of genotyping thousands of DNA samples, all at a competitive cost per genotype.”
“The Centre for Genetic Epidemiology is undertaking important research focusing on understanding the determinants of common disease and how to prevent them. Their work can make a noteworthy difference in people’s lives,” said Gajus Worthington, Fluidigm president and chief executive officer. “We believe the attributes of our EP1 system can help them speed toward the answers they seek.”
Strangeways Research Laboratory is known for its exploration surrounding identification and prevention of common diseases with a genetic component. They use a wide range of disciplines relevant to a given field, and bring together researchers in epidemiology, molecular genetics, bioinformatics, statistics and public health. This interdisciplinary approach is a particular strength of Strangeways Research Laboratory.
Fluidigm’s EP1 system, combined with the company’s IFCs called dynamic arrays, provide superior data quality, a fast and easy workflow, and significant cost savings for high-throughput SNP genotyping studies. The EP1 system delivers the highest quality SNP genotyping results on the market with better than 99 percent call rates and 99.75 percent or greater accuracy. All of this is achieved with an easy-to-use, high-throughput workflow that can provide up to 9,216 data points per IFC with results in just four hours.
The EP1 system, which includes the IFC Controller, Stand-Alone Thermal Cycler and End Point Reader, provides over 27,000 genotypes a day. By adding more IFC controllers and thermal cyclers to be used in conjunction with a single EP1 Reader, laboratories can generate more than 200,000 genotypes in a day using TaqMan chemistries.
About Fluidigm
Fluidigm develops, manufactures and markets proprietary Integrated Fluidic Circuit (IFC) systems that significantly improve productivity in life science research. Fluidigm’s IFCs enable the simultaneous performance of thousands of sophisticated biochemical measurements in extremely minute volumes. These “integrated circuits for biology” are made possible by miniaturizing and integrating liquid handling components on a single microfabricated device (chip). Fluidigm’s IFC systems, consisting of instrumentation, software and single-use IFCs, increase throughput, decrease costs and enhance sensitivity compared to conventional laboratory systems. Fluidigm products have not been cleared or approved by the Food and Drug Administration for use as a diagnostic and are only available for research use.
http://www.fluidigm.com/
Fluidigm.com
The Centre for Genetic Epidemiology is using high-throughput SNP genotyping to identify and verify genetic variants that can underlie susceptibility to various cancers. Cancers that are being investigated include breast, ovarian, colorectal, prostate, and melanoma. The lab uses an automated process with sample tracking and quality control. The Centre has successfully completed its validation experiments on the EP1 system using real samples and will now move forward using the system in its large genotyping studies.
“With a high-throughput genotyping lab already in place here at Strangeways, Fluidigm’s integrated fluidic circuits offered us an exciting new technology where we could use reliable TaqMan® chemistry with the added ability of assaying 96 SNPs at a time,” said Craig Luccarini, Senior Technical Officer, Strangeways Research Laboratory. “Piloting of the EP1 system generated data of good quality and the system fitted well in our lab as a robust process, capable of genotyping thousands of DNA samples, all at a competitive cost per genotype.”
“The Centre for Genetic Epidemiology is undertaking important research focusing on understanding the determinants of common disease and how to prevent them. Their work can make a noteworthy difference in people’s lives,” said Gajus Worthington, Fluidigm president and chief executive officer. “We believe the attributes of our EP1 system can help them speed toward the answers they seek.”
Strangeways Research Laboratory is known for its exploration surrounding identification and prevention of common diseases with a genetic component. They use a wide range of disciplines relevant to a given field, and bring together researchers in epidemiology, molecular genetics, bioinformatics, statistics and public health. This interdisciplinary approach is a particular strength of Strangeways Research Laboratory.
Fluidigm’s EP1 system, combined with the company’s IFCs called dynamic arrays, provide superior data quality, a fast and easy workflow, and significant cost savings for high-throughput SNP genotyping studies. The EP1 system delivers the highest quality SNP genotyping results on the market with better than 99 percent call rates and 99.75 percent or greater accuracy. All of this is achieved with an easy-to-use, high-throughput workflow that can provide up to 9,216 data points per IFC with results in just four hours.
The EP1 system, which includes the IFC Controller, Stand-Alone Thermal Cycler and End Point Reader, provides over 27,000 genotypes a day. By adding more IFC controllers and thermal cyclers to be used in conjunction with a single EP1 Reader, laboratories can generate more than 200,000 genotypes in a day using TaqMan chemistries.
About Fluidigm
Fluidigm develops, manufactures and markets proprietary Integrated Fluidic Circuit (IFC) systems that significantly improve productivity in life science research. Fluidigm’s IFCs enable the simultaneous performance of thousands of sophisticated biochemical measurements in extremely minute volumes. These “integrated circuits for biology” are made possible by miniaturizing and integrating liquid handling components on a single microfabricated device (chip). Fluidigm’s IFC systems, consisting of instrumentation, software and single-use IFCs, increase throughput, decrease costs and enhance sensitivity compared to conventional laboratory systems. Fluidigm products have not been cleared or approved by the Food and Drug Administration for use as a diagnostic and are only available for research use.
http://www.fluidigm.com/
Fluidigm.com
Wednesday, January 28, 2009
State of the Science Lecture Series On Melanoma ..Jim Breitfeller
If you want, you can dive into these Lectures on Melanoma
http://www.webtie.org/SOTS/Meetings/Melanoma/05-05-2003/lectures.htm
State of the Science Lecture Series On Melanoma
Jimmy B
http://www.webtie.org/SOTS/Meetings/Melanoma/05-05-2003/lectures.htm
State of the Science Lecture Series On Melanoma
Jimmy B
Thursday, January 22, 2009
Summary of the Conference Call with Dr. Flaherty on 1/21/2008 Melanoma.. Jim Breitfeller
Topic: Targeted Therapy
WHAT IS TARGETED THERAPY?
Targeted therapy is a term that refers to a drug or combination of drugs that targets a specific pathway in the growth and development of a tumor. By attacking or blocking these important targets, the therapy helps to fight the tumor itself. The targets themselves are typically various small molecules in the body that are known or suspected to induce cancer formation.
HOW ARE TARGETED THERAPIES NAMED?
The names of the major classes of targeted therapies typically include the word "anti-", or "inhibitor", together with the name of the target itself. This means that the drug blocks, (is "anti"), that particular target. Then within each class of inhibitors, there is/are the actual drug(s).
It is important to realize that a single drug can have several names, including a generic name and a brand name. This can be confusing because often the generic and brand names are used interchangeably in the literature and the media. This means you need to the names to follow the pathways.
What are the different classes of targeted therapy? In other words, what are the different targets?
There are several pathways that have been studied quite intensively and they are:
Kinase: Defintion …Any of various enzymes (proteins) that catalyze the transfer of a phosphate group from a donor, such as ADP or ATP, to an acceptor
1) Map Kinase : Mitogen-activated protein (MAP) kinases (EC 2.7.11.24) are serine/threonine-specific protein kinases that respond to extracellular stimuli (mitogens) and regulate various cellular activities, such as gene expression, mitosis, differentiation, and cell survival/apoptosis
It was studied early on in the Melanoma Research.
2) PI3-Kinase: PI 3-kinases have been linked to an extraordinarily diverse group of cellular functions, including cell growth, proliferation, differentiation, motility, survival and intracellular trafficking. Many of these functions relate to the ability of class I PI 3-kinases to activate protein kinase B (PKB, aka Akt). The class IA PI 3-kinase p110α is mutated in many cancers. Many of these mutations cause the kinase to be more active. The PtdIns(3,4,5)P3 phosphatase PTEN which antagonises PI 3-kinase signalling is absent from many tumours. Hence, PI 3-kinase activity contributes significantly to cellular transformation and the development of cancer. The p110δ and p110γ isoforms regulate different aspects of immune responses. PI 3-kinases are also a key component of the insulin signaling pathway. Hence there is great interest in the role of PI 3-kinase signaling in Diabetes mellitus.).
Another pathway was the c-Kit: Receptor tyrosine kinases, such as c-Kit, are proteins whose function it is to transduce signals from the environment into the cell leading to complex behaviors such as proliferation, migration, survival and differentiation. Many of these behaviors are deregulated in cancer, which is characterized by uncontrolled proliferation, insensitivity towards death stimuli, migration of tumor cells away from the primary tumor site and in some cases also block of cellular differentiation leaving the cell in an immature proliferative state. To be able to target these processes it is vital to have a detailed understanding of the receptor function and the downstream pathways activated.
Well, they developed A c-Kit antigen:
.
Example of Targeted Therapy:
THURSDAY, April 17 2008 (HealthDay News) -- The cancer drug Gleevec has forced metastatic melanoma into remission for the first time, report researchers at the Dana-Farber Cancer Institute in Boston.
The case involves a 79-year-old woman with melanoma tumors in several parts of her abdomen. The tumor cells carried an abnormality in a gene called KIT, so the patient was enrolled in a clinical trail of the drug imatinib (Gleevec), which targets the KIT gene.
Four weeks after the woman started therapy, there was dramatic reduction in tumor size and metabolism. Two of the tumor masses had vanished, and several others were much smaller. After four months, the tumors were still in check and, nine months later, the women was still taking the drug and her condition remained stable.
The report was published in the April 20 issue of the Journal of Clinical Oncology .
"This is the first proof of principle that we can find an Achilles' heel in melanoma and by targeting that gene with a drug, cause the [tumor cells] to die. It is especially exciting because there haven't been any effective treatments for melanoma patients with metastatic disease," study author Dr. Stephen Hodi said in a prepared statement.
He said this case may involve just one patient, but should inspire new hope in the fight against melanoma. Because previous research failed to identify any genetic weak point that could be targeted to stop melanoma cell growth, some researchers believed that no such Achilles' heel existed for melanoma cells. The discovery of this one suggests there may be others.
SOURCE: Dana-Farber Cancer Institute, news release, April 17, 2008Melanoma Mutations:
Strategies for attacking melanoma may soon involve a personalized approach based on the genetic characteristics of the patient’s tumor. Recently, scientists have begun to uncover genetic mutations that drive the unchecked growth of melanoma cells. By determining the pathways that caused the mutation, they hope to create drugs that better target the specific problem.
A common genetic mutation in melanoma creates an overactive version of a protein called BRAF, which instigates cell growth and division. Other mutations activate a related protein, called N-RAS, also resulting in unchecked cell division. Drugs designed to block these overactive proteins kill melanoma cells in laboratory tests, but so far they have shown only some promise in patients. So they are starting personalize the therapy base on patient’s tumor genetics.
Near term goal is to control the progression until they can find the silver bullet. So they will use Chemo and Biological to control the Beast for now.
So, hold on to your hats and make sure that if you have a tumor that can be harvested, you should ask your oncologist to get genetic mapping/typing of the tumor. It could send you down the YELLOW BRICK ROAD to the Emerald City.
Another take away is that a cure may be based on personalized therapy. So there might not be just one cure, but many based on genetics.
Source:Oncolink and the Dictionary
Take Care
jimmy B
WHAT IS TARGETED THERAPY?
Targeted therapy is a term that refers to a drug or combination of drugs that targets a specific pathway in the growth and development of a tumor. By attacking or blocking these important targets, the therapy helps to fight the tumor itself. The targets themselves are typically various small molecules in the body that are known or suspected to induce cancer formation.
HOW ARE TARGETED THERAPIES NAMED?
The names of the major classes of targeted therapies typically include the word "anti-", or "inhibitor", together with the name of the target itself. This means that the drug blocks, (is "anti"), that particular target. Then within each class of inhibitors, there is/are the actual drug(s).
It is important to realize that a single drug can have several names, including a generic name and a brand name. This can be confusing because often the generic and brand names are used interchangeably in the literature and the media. This means you need to the names to follow the pathways.
What are the different classes of targeted therapy? In other words, what are the different targets?
There are several pathways that have been studied quite intensively and they are:
Kinase: Defintion …Any of various enzymes (proteins) that catalyze the transfer of a phosphate group from a donor, such as ADP or ATP, to an acceptor
1) Map Kinase : Mitogen-activated protein (MAP) kinases (EC 2.7.11.24) are serine/threonine-specific protein kinases that respond to extracellular stimuli (mitogens) and regulate various cellular activities, such as gene expression, mitosis, differentiation, and cell survival/apoptosis
It was studied early on in the Melanoma Research.
2) PI3-Kinase: PI 3-kinases have been linked to an extraordinarily diverse group of cellular functions, including cell growth, proliferation, differentiation, motility, survival and intracellular trafficking. Many of these functions relate to the ability of class I PI 3-kinases to activate protein kinase B (PKB, aka Akt). The class IA PI 3-kinase p110α is mutated in many cancers. Many of these mutations cause the kinase to be more active. The PtdIns(3,4,5)P3 phosphatase PTEN which antagonises PI 3-kinase signalling is absent from many tumours. Hence, PI 3-kinase activity contributes significantly to cellular transformation and the development of cancer. The p110δ and p110γ isoforms regulate different aspects of immune responses. PI 3-kinases are also a key component of the insulin signaling pathway. Hence there is great interest in the role of PI 3-kinase signaling in Diabetes mellitus.).
Another pathway was the c-Kit: Receptor tyrosine kinases, such as c-Kit, are proteins whose function it is to transduce signals from the environment into the cell leading to complex behaviors such as proliferation, migration, survival and differentiation. Many of these behaviors are deregulated in cancer, which is characterized by uncontrolled proliferation, insensitivity towards death stimuli, migration of tumor cells away from the primary tumor site and in some cases also block of cellular differentiation leaving the cell in an immature proliferative state. To be able to target these processes it is vital to have a detailed understanding of the receptor function and the downstream pathways activated.
Well, they developed A c-Kit antigen:
.
Example of Targeted Therapy:
THURSDAY, April 17 2008 (HealthDay News) -- The cancer drug Gleevec has forced metastatic melanoma into remission for the first time, report researchers at the Dana-Farber Cancer Institute in Boston.
The case involves a 79-year-old woman with melanoma tumors in several parts of her abdomen. The tumor cells carried an abnormality in a gene called KIT, so the patient was enrolled in a clinical trail of the drug imatinib (Gleevec), which targets the KIT gene.
Four weeks after the woman started therapy, there was dramatic reduction in tumor size and metabolism. Two of the tumor masses had vanished, and several others were much smaller. After four months, the tumors were still in check and, nine months later, the women was still taking the drug and her condition remained stable.
The report was published in the April 20 issue of the Journal of Clinical Oncology .
"This is the first proof of principle that we can find an Achilles' heel in melanoma and by targeting that gene with a drug, cause the [tumor cells] to die. It is especially exciting because there haven't been any effective treatments for melanoma patients with metastatic disease," study author Dr. Stephen Hodi said in a prepared statement.
He said this case may involve just one patient, but should inspire new hope in the fight against melanoma. Because previous research failed to identify any genetic weak point that could be targeted to stop melanoma cell growth, some researchers believed that no such Achilles' heel existed for melanoma cells. The discovery of this one suggests there may be others.
SOURCE: Dana-Farber Cancer Institute, news release, April 17, 2008Melanoma Mutations:
Strategies for attacking melanoma may soon involve a personalized approach based on the genetic characteristics of the patient’s tumor. Recently, scientists have begun to uncover genetic mutations that drive the unchecked growth of melanoma cells. By determining the pathways that caused the mutation, they hope to create drugs that better target the specific problem.
A common genetic mutation in melanoma creates an overactive version of a protein called BRAF, which instigates cell growth and division. Other mutations activate a related protein, called N-RAS, also resulting in unchecked cell division. Drugs designed to block these overactive proteins kill melanoma cells in laboratory tests, but so far they have shown only some promise in patients. So they are starting personalize the therapy base on patient’s tumor genetics.
Near term goal is to control the progression until they can find the silver bullet. So they will use Chemo and Biological to control the Beast for now.
So, hold on to your hats and make sure that if you have a tumor that can be harvested, you should ask your oncologist to get genetic mapping/typing of the tumor. It could send you down the YELLOW BRICK ROAD to the Emerald City.
Another take away is that a cure may be based on personalized therapy. So there might not be just one cure, but many based on genetics.
Source:Oncolink and the Dictionary
Take Care
jimmy B
Friday, January 9, 2009
Letter to Dr. Steven Rosenberg at the National Cancer Institute from Jim Breitfeller
Dr.Rosenberg, Friday, January 09, 2009
We’ve been communicating off and on since 2006 through your research staff on my Melanoma situation. I want to personally thank you and you staff for all the knowledge that you have generated over years and have shared with me and others. I been trying to follow your research through abstracts and online papers. Thank you for publishing your results. They are a Godsend to the patients and researchers alike.
Now, Let me get back to my situation. I am under the care of your friend and colleague, Dr, John Kirkwood. As you might know , I did a combo regiment but not like the
Tumor Regression and Autoimmunity in Patients Treated With
Cytotoxic T Lymphocyte–Associated Antigen 4 Blockade and
Interleukin 2: A Phase I/II Study
See, I only did one course of CTLA-4 and then I jumped to high dose interlukin-2 for three courses but on the forth course, I has a mild heart attack and the stopped the treatment.
On September 6th, I had another CT scan and MRI for the next trial which was Anti-CTLA-4. On September 13 I had my first infusion. On October 8, 2006 My wife noticed two new growths on my back. It was confirmed on October 11th it was new tumors.
Dr. John Kirkwood has decided that IL-2 Interleukin 2 would be next course of action. I have completed another round of tests (CT scan, Pulmonary Function, and a Nuclear Stress Test). The CT scans shows 40+ nodules in my lungs ranging from 15mm to less than 5mm.
I am slated to be High dosage IL-2 on November 1st 2006.
I am presently washed out an IL-2 clinical trial that started in November 1, 2006. On the fourth cycle I had a heart attack and the doctors determined to abort the IL-2 on February 2, 2007. On August 23 2007 there was no change to the tumors in my back or lungs but also no growth. In October 24 2007 I got the word that the tumors and the lung nodules were shrinking. In April 14, 2008, the 40 + nodules in my lungs decrease to 2. In July 2008, the nodules in my lungs were undetectable and the ones on my back were all but one gone. Presently, CT and MRI
In November 2008 show no signs cancerous activity.
I am stabilized for the time being.
The Melanoma type that I have is nodular. Dr. Kirkwood has taken one of the tumors and stored it cryogenically.
Now here comes the thousand dollar question.
With your expert knowledge, would molecular profiling or mapping of the tumor aid in your research? If so, Please contact me and/or Dr. Kirkwood.
See, as a researcher myself for Eastman Kodak Research Labs in the field of “Surface Science” I believe there is some value in what made my tumor tic. Since we know that the CTLA-4 -IL-2 worked for me, it may be specific to Nodular Melanoma. And if that is the case, when people get diagnosed, they may a have one line of defense lined up. So please, let me know what you think.
Thank for you time and again, thank you for all the great research you are doing on the behalf of the Melanoma Patient. We surely appreciate it.
Sincerely,
James M.Breitfeller
We’ve been communicating off and on since 2006 through your research staff on my Melanoma situation. I want to personally thank you and you staff for all the knowledge that you have generated over years and have shared with me and others. I been trying to follow your research through abstracts and online papers. Thank you for publishing your results. They are a Godsend to the patients and researchers alike.
Now, Let me get back to my situation. I am under the care of your friend and colleague, Dr, John Kirkwood. As you might know , I did a combo regiment but not like the
Tumor Regression and Autoimmunity in Patients Treated With
Cytotoxic T Lymphocyte–Associated Antigen 4 Blockade and
Interleukin 2: A Phase I/II Study
See, I only did one course of CTLA-4 and then I jumped to high dose interlukin-2 for three courses but on the forth course, I has a mild heart attack and the stopped the treatment.
On September 6th, I had another CT scan and MRI for the next trial which was Anti-CTLA-4. On September 13 I had my first infusion. On October 8, 2006 My wife noticed two new growths on my back. It was confirmed on October 11th it was new tumors.
Dr. John Kirkwood has decided that IL-2 Interleukin 2 would be next course of action. I have completed another round of tests (CT scan, Pulmonary Function, and a Nuclear Stress Test). The CT scans shows 40+ nodules in my lungs ranging from 15mm to less than 5mm.
I am slated to be High dosage IL-2 on November 1st 2006.
I am presently washed out an IL-2 clinical trial that started in November 1, 2006. On the fourth cycle I had a heart attack and the doctors determined to abort the IL-2 on February 2, 2007. On August 23 2007 there was no change to the tumors in my back or lungs but also no growth. In October 24 2007 I got the word that the tumors and the lung nodules were shrinking. In April 14, 2008, the 40 + nodules in my lungs decrease to 2. In July 2008, the nodules in my lungs were undetectable and the ones on my back were all but one gone. Presently, CT and MRI
In November 2008 show no signs cancerous activity.
I am stabilized for the time being.
The Melanoma type that I have is nodular. Dr. Kirkwood has taken one of the tumors and stored it cryogenically.
Now here comes the thousand dollar question.
With your expert knowledge, would molecular profiling or mapping of the tumor aid in your research? If so, Please contact me and/or Dr. Kirkwood.
See, as a researcher myself for Eastman Kodak Research Labs in the field of “Surface Science” I believe there is some value in what made my tumor tic. Since we know that the CTLA-4 -IL-2 worked for me, it may be specific to Nodular Melanoma. And if that is the case, when people get diagnosed, they may a have one line of defense lined up. So please, let me know what you think.
Thank for you time and again, thank you for all the great research you are doing on the behalf of the Melanoma Patient. We surely appreciate it.
Sincerely,
James M.Breitfeller
Thursday, January 8, 2009
Second response from Molecular Profiling for Jim Breitfeller's Melanoma Tumor
Second response from Molecular Profiling for Jim Breitfeller's Melanoma Tumor
Hi Jim:
Our “counterpart” companies that do research that we are able to utilize in our profiling programs are TGen (Transgenomics) and IGC (International Genomics Consortium). To oversimplify but give you an idea of how it works, initial research is done at IGC. That research is shared with and translated by TGen, who then takes it, further studies, and coordinates clinical trials based on the research and evidence. Once the research and evidence are found to be solid, and we are able to confidently recommend treatment to an oncologist based on that, the information is shared with Caris who incorporates that into our molecular profiling test reporting.
So essentially, the research is done prior to Caris’ involvement in the process, so if you are interested in being profiled for the purpose of allowing your results to be used for research/academic purposes, I would recommend speaking with someone at TGen who would be able to direct you further. If this is the case, let me know and I will try and find an appropriate contact there for you.
As far as cost of the profiling if done by us, the cost depends on if there is frozen tissue available from your biopsy or just paraffin-embedded tissue. If frozen tissue is available, the cost of the full profile as billed to insurance is close to $6k, for paraffin-embedded tissue it’s roughly $4k. For many plans, the test is billed under laboratory services & fees, which typically have a very high percentage of coverage, if not covered at a full 100%.
Michele Hudson
Caris Client Services
445 N. 5th Street, Third Floor
Phoenix, AZ 85004
602.358.8977 - Phone
602.358.8920 - Fax
mhudson@carismpi.com
The Train is leaving the station: "ALL ABOARD!!!!"
"NEXT STOP TGen" "PLEASE HAVE YOUR BOARDING PASSES READY"
Hi Jim:
Our “counterpart” companies that do research that we are able to utilize in our profiling programs are TGen (Transgenomics) and IGC (International Genomics Consortium). To oversimplify but give you an idea of how it works, initial research is done at IGC. That research is shared with and translated by TGen, who then takes it, further studies, and coordinates clinical trials based on the research and evidence. Once the research and evidence are found to be solid, and we are able to confidently recommend treatment to an oncologist based on that, the information is shared with Caris who incorporates that into our molecular profiling test reporting.
So essentially, the research is done prior to Caris’ involvement in the process, so if you are interested in being profiled for the purpose of allowing your results to be used for research/academic purposes, I would recommend speaking with someone at TGen who would be able to direct you further. If this is the case, let me know and I will try and find an appropriate contact there for you.
As far as cost of the profiling if done by us, the cost depends on if there is frozen tissue available from your biopsy or just paraffin-embedded tissue. If frozen tissue is available, the cost of the full profile as billed to insurance is close to $6k, for paraffin-embedded tissue it’s roughly $4k. For many plans, the test is billed under laboratory services & fees, which typically have a very high percentage of coverage, if not covered at a full 100%.
Michele Hudson
Caris Client Services
445 N. 5th Street, Third Floor
Phoenix, AZ 85004
602.358.8977 - Phone
602.358.8920 - Fax
mhudson@carismpi.com
The Train is leaving the station: "ALL ABOARD!!!!"
"NEXT STOP TGen" "PLEASE HAVE YOUR BOARDING PASSES READY"
The Response to Molecular Profiling Jim Breitfeller's Melanoma Tumor
Good morning, Mr. Breitfeller:
First, I was so happy to read of the excellent response you’ve had with your two biological therapies!
As you can see, Arlet has asked me to coordinate possible molecular profiling of your previous tumor biopsy.
Obviously, we would be happy to profile your tumor, however, I wanted to be sure that you’re aware that Caris does not do any sort of research at our facility - all of our testing is designed for use in a patient’s continued care. What this means to you is that we would be required to bill your insurance for the cost of the test, with you being responsible for any co-pay or deductible as per your insurance policy. The test also needs to be ordered by an MD, so your oncologist would need to sign off on the requisition. The results would then also be given to your oncologist for his/her reference.
If this is something you would like to proceed with, please let me know, and I would be happy to coordinate all the necessary arrangements to get the profiling completed.
Warm regards,
Michele Hudson
Caris Client Services
445 N. 5th Street, Third Floor
Phoenix, AZ 85004
602.358.8977 - Phone
602.358.8920 - Fax
mhudson@carismpi.com
I SEE ROAD BLOCKS!!!!!!
1) MY INSURANCE WILL MOST LIKELY NOT WANT TO FOOT THE BILL
2) I NEED DR.KIRKWOODS SIGN OFF
3) IF THEY DON'T DO RESEARCH, WHAT DO THEY DO!!!!!!
I guess I need to come at this at a different angle.
I may have to make a cyber visit to the National Cancer Institute
and tap in to Dr. Roesenberg Himself.
All I am tring is to "FOLLOW THE YELLOW BRICK ROAD"
SO I AM OFF TO SEE "THE WIZARD". Wish me Luck
jimmy B
First, I was so happy to read of the excellent response you’ve had with your two biological therapies!
As you can see, Arlet has asked me to coordinate possible molecular profiling of your previous tumor biopsy.
Obviously, we would be happy to profile your tumor, however, I wanted to be sure that you’re aware that Caris does not do any sort of research at our facility - all of our testing is designed for use in a patient’s continued care. What this means to you is that we would be required to bill your insurance for the cost of the test, with you being responsible for any co-pay or deductible as per your insurance policy. The test also needs to be ordered by an MD, so your oncologist would need to sign off on the requisition. The results would then also be given to your oncologist for his/her reference.
If this is something you would like to proceed with, please let me know, and I would be happy to coordinate all the necessary arrangements to get the profiling completed.
Warm regards,
Michele Hudson
Caris Client Services
445 N. 5th Street, Third Floor
Phoenix, AZ 85004
602.358.8977 - Phone
602.358.8920 - Fax
mhudson@carismpi.com
I SEE ROAD BLOCKS!!!!!!
1) MY INSURANCE WILL MOST LIKELY NOT WANT TO FOOT THE BILL
2) I NEED DR.KIRKWOODS SIGN OFF
3) IF THEY DON'T DO RESEARCH, WHAT DO THEY DO!!!!!!
I guess I need to come at this at a different angle.
I may have to make a cyber visit to the National Cancer Institute
and tap in to Dr. Roesenberg Himself.
All I am tring is to "FOLLOW THE YELLOW BRICK ROAD"
SO I AM OFF TO SEE "THE WIZARD". Wish me Luck
jimmy B
Do You Recall the paper I posted? "Adapting life sciences technologies to IVDs"
Do you Recall the paper I posted.
Adapting life sciences technologies to IVDs
Technological advances in life sciences can feed the early-stage assay development pipeline and can be transitioned into the clinical diagnostics setting.
Sara J. Agee and Quynh Anh Lu
Well I contacted Sara Agee to see is if they needed Help on our end "THE PATIENT".
Here is the reply:
Hi James,
Thanks for sending me your personal story, it is always nice to put a real name behind the cause. We do not have any trials for which we are currently enrolling, but I will keep your email for any future prospects. Glad you found the article so fascinating!
My best wishes to you,
--Sara
This is how to make contacts in the medical world.
"You always keep the door open"
By the way, this article was found by Larry.
Jimmy B
Adapting life sciences technologies to IVDs
Technological advances in life sciences can feed the early-stage assay development pipeline and can be transitioned into the clinical diagnostics setting.
Sara J. Agee and Quynh Anh Lu
Well I contacted Sara Agee to see is if they needed Help on our end "THE PATIENT".
Here is the reply:
Hi James,
Thanks for sending me your personal story, it is always nice to put a real name behind the cause. We do not have any trials for which we are currently enrolling, but I will keep your email for any future prospects. Glad you found the article so fascinating!
My best wishes to you,
--Sara
This is how to make contacts in the medical world.
"You always keep the door open"
By the way, this article was found by Larry.
Jimmy B
Wednesday, January 7, 2009
I got an Epiffany Last Night!!!!! Melanoma.. Jim Breitfeller
Epiffany:
a. A sudden manifestation of the essence or meaning of something.
b. A comprehension or perception of reality by means of a sudden intuitive realization
I have a KEY!!!!!!!!
Dr. Arlet Alarcon, I contacted you in 2006 about a possible profiling of my tumor, Well I have some good news, I ended up a stage IV Melanoma patient with 40+ nodules in my lungs. I did a combo therapy not at the same time and got a complete response with the two biological therapies. I believe Dr Kirkwood still has a tumor. I would think that it would be extremely important to profile that tumor since we know that the two pathways that worked. Please give me a call or e-mail me. I hope that this may be a break in Melanoma Research. Adding this to your database may help save lives.
Sincerely,
James M. Breitfeller
Note sent this Morning.
The posts are in my carepages in 2006 somewhere.
If you go to Melanoma Missionary you can search on Molecular Profiling
and it should retrieve the posts.
Melanoma_Missionary
Then I fired a note to Myriad Genetics : Personalized Medicine Products
I thought that my Blood my be of some value to them. See they can take my blood chemistry and make a generic Diagnostic test. Since we Know the biologicals, they can develope a test and use my blood chemistry as a control.
It seem to make sense to me. But again, I may be ahead of the times.
Jimmy B
a. A sudden manifestation of the essence or meaning of something.
b. A comprehension or perception of reality by means of a sudden intuitive realization
I have a KEY!!!!!!!!
Dr. Arlet Alarcon, I contacted you in 2006 about a possible profiling of my tumor, Well I have some good news, I ended up a stage IV Melanoma patient with 40+ nodules in my lungs. I did a combo therapy not at the same time and got a complete response with the two biological therapies. I believe Dr Kirkwood still has a tumor. I would think that it would be extremely important to profile that tumor since we know that the two pathways that worked. Please give me a call or e-mail me. I hope that this may be a break in Melanoma Research. Adding this to your database may help save lives.
Sincerely,
James M. Breitfeller
Note sent this Morning.
The posts are in my carepages in 2006 somewhere.
If you go to Melanoma Missionary you can search on Molecular Profiling
and it should retrieve the posts.
Melanoma_Missionary
Then I fired a note to Myriad Genetics : Personalized Medicine Products
I thought that my Blood my be of some value to them. See they can take my blood chemistry and make a generic Diagnostic test. Since we Know the biologicals, they can develope a test and use my blood chemistry as a control.
It seem to make sense to me. But again, I may be ahead of the times.
Jimmy B
This one goes out to Family Members ... MELARIS®
I promise the is the last post of the night.
So tuck those little ones in,and give them a Big Kiss for Jimmy B.
Myriad Genetics One of Sixth Personalized Medicine Products
MELARIS® is a predictive medicine test for inherited susceptibility to melanoma and pancreatic cancer. This test detects inherited mutations in the p16 gene (also called CDKN2A or INK4A), which occur in up to 40% of families with hereditary melanoma. Patient survival is excellent when melanoma is detected at an early stage; however, prognosis is very poor (15% 5-year survival) when melanoma has spread at the time of diagnosis.
Early detection of melanoma is perhaps the best approach to improve outcome.
Jimmy B
So tuck those little ones in,and give them a Big Kiss for Jimmy B.
Myriad Genetics One of Sixth Personalized Medicine Products
MELARIS® is a predictive medicine test for inherited susceptibility to melanoma and pancreatic cancer. This test detects inherited mutations in the p16 gene (also called CDKN2A or INK4A), which occur in up to 40% of families with hereditary melanoma. Patient survival is excellent when melanoma is detected at an early stage; however, prognosis is very poor (15% 5-year survival) when melanoma has spread at the time of diagnosis.
Early detection of melanoma is perhaps the best approach to improve outcome.
Jimmy B
While we are on the subject of Personalized Therapy.. Melanoma
Myriad Genetics Launches Sixth Personalized Medicine Product, Prezeon -- to Reveal PTEN Status
December 22, 2008: 06:30 AM ET
Myriad Genetics, Inc. (NASDAQ: MYGN) (www.myriad.com) announced today that it is launching its sixth molecular diagnostic product, Prezeon(TM). The product will be marketed to researchers and physicians to assist them in understanding the status of the PTEN gene, which plays a major role in critical cell-signaling pathways. These pathways have been implicated in cancer progression and provide important information that may guide therapeutic decisions. The price per Prezeon test is $500.
PTEN Gene Associated With Cancer Prognosis and Choice of Chemotherapy
Do I here A UUUUUUUUUUUUUUUU?
What does it spell, HUURRY!!!!!!!!!!!!!!!!!!
jimmy B.
December 22, 2008: 06:30 AM ET
Myriad Genetics, Inc. (NASDAQ: MYGN) (www.myriad.com) announced today that it is launching its sixth molecular diagnostic product, Prezeon(TM). The product will be marketed to researchers and physicians to assist them in understanding the status of the PTEN gene, which plays a major role in critical cell-signaling pathways. These pathways have been implicated in cancer progression and provide important information that may guide therapeutic decisions. The price per Prezeon test is $500.
PTEN Gene Associated With Cancer Prognosis and Choice of Chemotherapy
Do I here A UUUUUUUUUUUUUUUU?
What does it spell, HUURRY!!!!!!!!!!!!!!!!!!
jimmy B.
2008 Year in Review Continued ...Melanoma
The University of California, San Francisco
School of Pharmacy
"•The National Cancer Institute awarded a $5 million grant to UCSF’s School of Pharmacy’s Center for Translational and Policy Research on Personalized Medicine to investigate how genomic information and pharmacogenomics can best be translated into clinical practice. The grant is the first major NCI funding to focus on health policy issues relating to drugs that are geared to individual genetic differences, often referred to as “personalized medicine.” Many doctors are not yet aware of tests to see if targeted drugs will work for particular patients, or how best to use them."
It is call Molecular Profiling, I tried back on:
Wednesday, October 25, 2006
10/25/2006 Major Set Back!!!!!
Yesterday while at the Rochester Oncologist (Dr. Pandya) office we received bad news. The cancer is spreading in my lungs quite rapidly according to the CT scans. There are now over 40 nodules ranging from 15 mm down to < 5 mm. No wonder I been having shortness of breath. I thought it was my lack of exercise. Dr. Pandya gives my prognosis a poor rating. I guess I won’t be getting a raise this year.
I have started the long term disability process with disbelief. My fight is not over for a long shot. I just need to speed up my trials to find the right one. I will be contacting Dr. Kirkwood today to see where we stand on the Molecular Profiling route. I feel I am in the race of life and second place is not an option. I am going for the Gold.
Stay tune things may get very interesting.
Take care
Jimmy B.
Posted by jimmy_B at 6:10 AM 0 comments Links to this post
Labels: CT Scan, Lungs, molecular profiling
Wednesday, October 18, 2006
This is the first step forward!!!!
An email from Arlet Alarcon to Kirkwood
Hello Dr. Kirkwood,
Please call me at your earliest convenience at any of the numbers below, so that we can discuss how to best help Mr. Jim Breitfeller.
Thank you,
Arlet
Arlet Alarcon, M.D.
Manager, Target Now/Horizon
Molecular Profiling Institute (MP)
445 N. 5th Street, 3rd Floor
Phoenix, AZ. 85004
(602) 358-8982 (direct)
(602) 358-8920 (fax)
(602) 909-7667 (cellular)
Posted by jimmy_B at 12:58 PM 0 comments Links to this post
Labels: dr. kirkwood, dr.Arlet Alarcon, molecular profiling
Molecular Profiling Institute
Jimmy B
Tuesday, October 17, 2006
10/17/2006 The Molecular Profiling Institute Called Yeh!!!!!!
I just received a call from Dr. Arlet Alarcon from the Molecular Profiling Institute. She is the clinical coordinator at the Institute. She gave me some background on what they do and how it would pertain to my situation.
Here the Deal: They would take a biopsy of my tumor and run a genomic sequence on it to determine the pathways that the tumor is using to nourish itself with the blood supply using the supercomputer. Once they determine the pathways, they try to figure out what chemotherapy or drugs would shut down the pathways choking off the blood supply to the tumors. The tumors would slowly die. Easier said than done.
It sounds like Science Fiction.
All I need is to get buy in from Dr. Kirkwood.
Luke Skywalker Here I come!!!!!!!!
Jimmy B. Signing off
Posted by jimmy_B at 12:44 PM 0 comments Links to this post
Labels: dr. kirkwood, dr.Arlet Alarcon, molecular profiling
At that time, Dr. Kirkwood was just tring to stabilize me.
I saw the potential but it was in is infancy. I was too ahead the times.
THAT WAS IN 2006!!
That was three years ago!!
TALK ABOUT BEING AHEAD OF YOUR TIME!!!
As you see HOMEWORK IS EVERYTHING!!!!!
Jimmy B.
School of Pharmacy
"•The National Cancer Institute awarded a $5 million grant to UCSF’s School of Pharmacy’s Center for Translational and Policy Research on Personalized Medicine to investigate how genomic information and pharmacogenomics can best be translated into clinical practice. The grant is the first major NCI funding to focus on health policy issues relating to drugs that are geared to individual genetic differences, often referred to as “personalized medicine.” Many doctors are not yet aware of tests to see if targeted drugs will work for particular patients, or how best to use them."
It is call Molecular Profiling, I tried back on:
Wednesday, October 25, 2006
10/25/2006 Major Set Back!!!!!
Yesterday while at the Rochester Oncologist (Dr. Pandya) office we received bad news. The cancer is spreading in my lungs quite rapidly according to the CT scans. There are now over 40 nodules ranging from 15 mm down to < 5 mm. No wonder I been having shortness of breath. I thought it was my lack of exercise. Dr. Pandya gives my prognosis a poor rating. I guess I won’t be getting a raise this year.
I have started the long term disability process with disbelief. My fight is not over for a long shot. I just need to speed up my trials to find the right one. I will be contacting Dr. Kirkwood today to see where we stand on the Molecular Profiling route. I feel I am in the race of life and second place is not an option. I am going for the Gold.
Stay tune things may get very interesting.
Take care
Jimmy B.
Posted by jimmy_B at 6:10 AM 0 comments Links to this post
Labels: CT Scan, Lungs, molecular profiling
Wednesday, October 18, 2006
This is the first step forward!!!!
An email from Arlet Alarcon to Kirkwood
Hello Dr. Kirkwood,
Please call me at your earliest convenience at any of the numbers below, so that we can discuss how to best help Mr. Jim Breitfeller.
Thank you,
Arlet
Arlet Alarcon, M.D.
Manager, Target Now/Horizon
Molecular Profiling Institute (MP)
445 N. 5th Street, 3rd Floor
Phoenix, AZ. 85004
(602) 358-8982 (direct)
(602) 358-8920 (fax)
(602) 909-7667 (cellular)
Posted by jimmy_B at 12:58 PM 0 comments Links to this post
Labels: dr. kirkwood, dr.Arlet Alarcon, molecular profiling
Molecular Profiling Institute
Jimmy B
Tuesday, October 17, 2006
10/17/2006 The Molecular Profiling Institute Called Yeh!!!!!!
I just received a call from Dr. Arlet Alarcon from the Molecular Profiling Institute. She is the clinical coordinator at the Institute. She gave me some background on what they do and how it would pertain to my situation.
Here the Deal: They would take a biopsy of my tumor and run a genomic sequence on it to determine the pathways that the tumor is using to nourish itself with the blood supply using the supercomputer. Once they determine the pathways, they try to figure out what chemotherapy or drugs would shut down the pathways choking off the blood supply to the tumors. The tumors would slowly die. Easier said than done.
It sounds like Science Fiction.
All I need is to get buy in from Dr. Kirkwood.
Luke Skywalker Here I come!!!!!!!!
Jimmy B. Signing off
Posted by jimmy_B at 12:44 PM 0 comments Links to this post
Labels: dr. kirkwood, dr.Arlet Alarcon, molecular profiling
At that time, Dr. Kirkwood was just tring to stabilize me.
I saw the potential but it was in is infancy. I was too ahead the times.
THAT WAS IN 2006!!
That was three years ago!!
TALK ABOUT BEING AHEAD OF YOUR TIME!!!
As you see HOMEWORK IS EVERYTHING!!!!!
Jimmy B.
Saturday, January 3, 2009
Adjuvant Therapy in Melanoma: New Combination Cytokine and Other Strategies
Introduction
Melanoma is the leading cause of death among all types of skin cancer and is the fifth most common type of cancer in men in the United States. The incidence of melanoma is increasing; in 2008, the incidence of this disease is expected to exceed 60,000, with 8000 deaths.[1] Fortunately, up to 95% of patients will present with either local or regional disease, which is potentially curable.[2] Although the causes of this increased incidence of melanoma are debated, it is thought that increased exposure to ultraviolet radiation interacts in some manner with genetic factors to initiate melanoma.[3]
Histologically, melanoma is characterized by proliferation of transformed melanocytes.[4] These long-lived cells are normally present at the dermo-epidermal junction and impart pigment to the skin; they are typically resistant to DNA damage and apoptosis, a characteristic of melanoma as well. The principal subtypes of cutaneous melanoma are superficial spreading, nodular, lentigo maligna, and acral lentiginous; rarer noncutaneous primary sites include the mucosal membranes and the pigmented epithelium of the eye. Most types of melanoma are more common among whites, although acral lentiginous melanoma occurs with equal frequency in nonwhites.
Several pathologic and clinical factors are predictive of the risk of recurrence and death in persons with melanoma. The clinical factors include age, sex, location, and lymph node or distant organ involvement, whereas pathologically, the tumor depth (Breslow depth), ulceration, mitotic rate, and presence of microsatellites can determine the risk for recurrence or spread.[5] The recent revision of the American Joint Committee on Cancer staging system for melanoma incorporates many of these factors. Some pathologic features, such as involvement of skin layers (Clark levels) and the presence of tumor regression, have not stood up to rigorous multivariate analysis and are no longer used clinically to determine the risk for recurrence or the current staging classification.[6] Over 60% of melanomas have mutations in the B-type RAF-1 kinase (BRAF).[7,8] About 80% of these mutations are found at exon 15, at a single amino acid residue, usually a substitution for valine by glutamic acid, V599E (now referred to as V600E). This mutation causes increased kinase activation and signaling through the mitogen-activated protein (MAP) kinase pathway.[9,10] Surprisingly, this event occurs with high frequency in benign nevi as well as in melanoma.[11] An additional 15% to 20% of melanomas have mutations in N-Ras, which lies upstream of BRAF.[12] Both of these genes code for proteins that are part of the ERK-MAP kinase pathway. A small proportion of melanomas, especially those originating in sun-damaged skin, the palms and soles, and mucous membranes, have mutations or amplifications in the c-kit gene.[13]
Recent reports suggest that integration of molecular profiling with pathologic and clinical features may result in a better prognostic profile and help to more precisely determine an individual's risk for recurrence.[14] It has been suggested, for example, that the melanoma arising from sun-exposed skin in older persons is more likely to have c-kit mutations than the truncal melanoma arising in younger patients, which is more likely to have BRAF mutations.[14]
Surgical excision with wide margins and sentinel lymph node biopsy (for a melanoma whose depth is ≥ 1 mm) is the treatment of choice for primary melanoma. Several large clinical trials have helped to define the width of margins needed to resect melanoma and reduce the risk for recurrence.[15-17]
Currently, melanoma of ≤ 1 mm thickness is resected with surgical margins of 1 cm, whereas melanoma ≥ 2 mm is resected with margins of 2 cm, and intermediate-thickness melanoma is resected with 1- to 2-cm margins. Mapping the draining sentinel lymph node with use of a tracer and careful histologic examination of this node is now a standard of care for melanoma ≥ 1 mm in thickness.[18] High-risk melanoma, defined as stages IIB, IIC, and III, often recurs after excision and is associated with a 40% to 80% chance of death.[2] Given the high risk for recurrence (and subsequent mortality), there is an obvious need for reduction of recurrence risk. This review will address several treatment approaches that have been employed as adjuvant therapy following primary surgical excision.
Interferon Therapy
The interferons (IFNs) can produce antitumor effects through upregulation of the immune system. In humans, IFNs are structurally divided into 2 classes: type I and type II. The type I family, which is used clinically for the treatment of several diseases, includes alpha (alfa), beta, and omega; the type II family has only 1 member, IFN gamma. The various subtypes are further subdivided for pharmaceutical preparations, eg, IFN alfa-2a, IFN gamma-1b.[19] IFNs can stimulate both the innate and adaptive arms of the immune system; for example, they can enhance major histocompatibility complex (MHC) class I antigen presentation, increasing innate immunity and maturation of dendritic cells and leading to enhanced adaptive immunity. They also have antiangiogenic and direct cytotoxic effects on some malignant cells. However, the exact mechanism by which they produce antitumor effects is unclear.
Two large randomized trials have shown that high-dose IFN-alfa-2b significantly reduces the risk for recurrence compared with observation alone in patients with resected cutaneous melanoma.[20,21] A third large randomized trial has shown a significant improvement in overall survival with high-dose IFN-alfa-2b compared with the GM2 ganglioside conjugated to keyhole limpet hemocyanin (KLH) melanoma vaccine in patients with resected stage IIB-III melanoma.[22] In the first trial, ECOG 1684, patients with thick primary melanoma (≥ 4 mm depth) or lymph node-positive disease were randomized to receive IFN-alfa-2b 20 MIU/m2/day intravenously for 4 weeks followed by 10 MIU/m2 subcutaneously 3 times per week for 48 weeks or to observation. Patients who received IFN-alfa-2b had improved relapse-free survival (RFS) (5-year RFS 37% vs 26%; P = .0023) and overall survival (OS) (5-year OS 46% vs 37%; P = .0237) compared with the observation arm. This led to the approval by the US Food and Drug Administration of IFN-alfa-2b for the treatment of high-risk melanoma after surgical resection. Because this high dose appeared to be effective, the next ECOG trial was conducted to determine whether a lower dose of IFN might be as effective as that studied in ECOG 1684. Therefore, ECOG 1690 randomized patients with thick or node-positive melanoma to 1 of 3 arms: (1) high-dose IFN-alfa-2b (20 MIU/m2/day intravenously for 4 weeks followed by 10 MIU/m2 subcutaneously 3 times per week for 48 weeks) for 1 year; (2) low-dose IFN-alfa-2b (3 MIU/m2 3 times per week subcutaneously for 2 years); and (3) observation. Five-year RFS in the 3 arms was 44%, 40%, and 35%, respectively. The difference between high-dose IFN and observation was statistically significant (P = .05), but the difference between low-dose IFN and observation was not. Of note, no improvement in overall survival was noted between either of the treatment arms and observation.
The GM2 ganglioside vaccine had shown promising results in small phase 1 and 2 trials and was brought forward for further clinical testing.[23,24] The gangliosides are complex carbohydrates found on the outer cell membrane that can be as immunogenic as protein antigens. The resulting trial, ECOG 1694,[22] was different from the 2 prior studies because it compared high-dose IFN to GM2-KLH/21 vaccine in patients with resected stage IIB and III melanoma. High-dose IFN improved both RFS (hazard ratio [HR] 1.49; P = .00045) and OS (HR 1.38; P = .023) compared with GM2 vaccine, and this trial was halted early by the data safety monitoring committee. The benefit attributed to IFN was seen in patients with node-positive disease as well as those with node-negative disease.
Because the findings of these trials and others conducted by European and American investigators were inconsistent, several meta-analyses have been performed to assess the data globally. An authoritative meta-analysis performed by Wheatley and colleagues[25] examined 12 randomized controlled trials and found that RFS was highly significantly improved with IFN-alfa by 17% (HR 0.83; P = .000003). The benefit on OS associated with IFN-alfa trended toward a 7% improvement but was not statistically significant (HR 0.93; confidence interval [CI], 0.85-1.02; P = .1). The investigators subsequently have updated their meta-analysis and shown a slightly better outcome for IFN-alfa in terms of OS.
Inasmuch as IFN-alfa has a short half-life necessitating frequent injection and resulting in side effects from rapid variation in blood levels, it has been modified to reduce clearance and increase its half-life.[19] One such modification is the addition of a 12,000-dalton polyethylene glycol chain, which results in pegylated IFN (PEG-IFN). In the treatment of viral hepatitis, PEG-IFN appears to be as efficacious as IFN with reduced toxicity.[26] To determine whether PEG-IFN was effective in melanoma, the European Organization for Research and Treatment of Cancer (EORTC) conducted a large trial, EORTC 18991, which randomized more than 1300 patients with node-positive melanoma postoperatively to either PEG-IFN for a maximum of 5 years or observation. The 4-year RFS was 45.6% and 35.9% (P = .01) in the PEG-IFN and observation groups, respectively. No difference in OS was noted.[27] The greatest benefit appeared to be in patients with microscopic nodal disease. Overall, patients appeared to tolerate this treatment relatively well.
The major issue limiting the use of IFN in patients with melanoma has been its toxicity. IFN is associated with a characteristic and sometimes debilitating constellation of signs and symptoms that can make its use challenging.
Commonly, patients experience fatigue, myalgia, anorexia, altered taste sensation, fevers, chills, loss of concentration and short-term memory, and other neuropsychiatric abnormalities. Significant depression has been reported in some patients. Laboratory abnormalities associated with use of IFN include elevations in transaminase levels, neutropenia and thrombocytopenia, increased creatinine levels, and anemia. Commonly, patients are dehydrated and need to be encouraged to increase their fluid intake and maintain their activity levels. Given the modest benefit of IFN in terms of reducing the risk for recurrence and death from melanoma, its significant toxicity profile has made it an option for only a select subpopulation of patients at high risk for melanoma recurrence.[19]
Granulocyte-Macrophage - Colony-Stimulating Factor
Although granulocyte-macrophage - colony-stimulating factor (GM-CSF; sargramostim) was initially identified as a colony-stimulating factor for myeloid cells in the bone marrow, it was also found to induce differentiation of dendritic cells (DCs).[28] The DCs, sometimes referred to as antigen-presenting cells, display tumor antigens to the immune system in the appropriate context and are increasingly recognized as a vital afferent arm of the immune system. Both quantitative and functional defects in DCs have been described in patients with cancer. These defects may contribute to "tumor escape" of immune surveillance. Specifically, GM-CSF increases the mobilization, differentiation, and function of DCs[29,30] and hence enhanced antigen presentation to CD4 and CD8 T cells.
GM-CSF appeared to be effective in increasing tumor-specific immunity when used as an adjuvant for vaccines.[30] In the metastatic disease setting, GM-CSF has been injected intralesionally and intrahepatically (with use of a hepatic artery catheter) and administered as an inhalational treatment. A GM-CSF-producing adenovirus appears to induce regression of metastatic melanoma when injected into lesions.[31] GM-CSF inhaled as an aerosol resulted in regression of pulmonary metastasis from melanoma in a phase 1 study.[32] In a phase 1 study of patients with metastatic melanoma, a 32% response rate was noted in patients with liver metastases following hepatic arterial infusion of large doses of GM-CSF.[33]
On the basis of these data, Spitler and colleagues[34] evaluated the role of GM-CSF in patients with high-risk (stage IIIB, IIIC, or IV) resected melanoma. Patients received GM-CSF 125 µg/m2 subcutaneously daily for 2 weeks every month for 1 year. The median survival of patients in this study was 37.5 months and far exceeded the median survival of 12.2 months in historical controls. The limitations of the study included the lack of a placebo arm and heterogeneity between the historical control and study groups. Overall, GM-CSF was well tolerated.
To confirm the findings of this trial and to examine the effect of GM-CSF on DCs, Daud and coworkers conducted a study with essentially the same dose and schedule in a similar patient population.[35,36] OS and RFS were 65 months and 5.6 months, respectively. GM-CSF treatment caused an increase in mature DCs, first identified after 2 weeks of treatment and normalizing by 4 weeks. Patients with decreased DCs at baseline had significant increases in DC number and function compared with those with "normal" parameters at baseline (Figure 1).[36] No change was observed in the number of myeloid-derived suppressor cells (MDSCs). Early recurrence (< 90 days) correlated with a decreased effect of GM-CSF on host DCs, compared with late or no (evidence of) recurrence (Figure 2).[36] Therefore, greater increase of DCs was associated with remission or delayed recurrence. Although this study lacked a control group, the survival data for the GM-CSF-treated patients does appear impressive. The benefits of GM-CSF appear to be greater in those with reduced DCs, but inasmuch as these analyses were exploratory, further investigation is warranted.
GM-CSF is currently being actively investigated in combination with other immunologic agents and chemotherapy. GM-CSF with the anti-CTLA-4 antibody ipilumimab has been explored in a phase 1 trial[37] (L. Fong, personal communication) and has shown some promising activity in prostate cancer. In addition, it has been explored as a component of combination therapy[38-40] and also as a maintenance or consolidation regimen in patients with metastatic melanoma who have benefited to some extent from chemotherapy.[41] There is also an ongoing trial with high-dose IL-2 in combination with GM-CSF (J. Lutzky, personal communication).
Anti-CTLA-4 Antibodies
The use of monoclonal antibodies to inhibit cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4) is a novel strategy in melanoma. These antibodies have been found to induce tumor regression and improve long-term survival in tumor-bearing mice.[42-44] Early preclinical studies showed that CTLA-4 serves as a natural braking mechanism for T-cell activation, allowing a return to homeostasis after an immune response. Inhibition of CTLA-4 upregulates several downstream targets, including T helper (Th) 1- and 2- produced cytokines (ie, interleukin 1 and 2) and cell cycle machinery (CDK-4, cyclin D3), leading to a more robust antitumor immune response. Two anti-CTLA-4 antibodies are currently in phase 2 and 3 trials: ipilimumab (also known as MDX-010) and tremelimumab (also known as CP 675,206).
Prolonged, but sometimes delayed, responses have been seen in patients with melanoma who have received either of the anti-CTLA-4 antibodies.[45,46] Similar to the effect seen with IFN therapy, immune-related adverse events correlate with more positive outcomes in patients with metastatic melanoma who receive anti-CTLA-4 therapy, including prolonged time to relapse.[47] Recently, it has been reported that tremelimumab was no better than standard dacarbazine (DTIC) or temozolomide for the up-front treatment of metastatic melanoma.[48] Results of an ongoing trial of ipilimumab and DTIC vs DTIC alone in the setting of metastatic melanoma are expected soon. Because anti-CTLA-4 antibodies appear to be effective in the phase 2 setting in metastatic disease, they are also being considered for use in the adjuvant setting. Currently, an ongoing EORTC study is examining ipilimumab vs observation in patients with high-risk melanoma, and combinations of anti-CTLA-4 antibody with GM-CSF and IFN are promising for evaluation because different parts of the immune system may be stimulated.
Vaccines
Tumor cells can express novel antigens or quantitatively different antigens compared with "normal" or nondividing cells. Harnessing the immune system to destroy malignant cells by recognizing these antigens is a major goal of tumor immunotherapy. Tumor antigens upregulated in melanoma include MART-1 (Melan A), gp100, and tyrosinase; other investigators have focused on the cancer-testis antigens, which are upregulated in tumor cells but present only in human germ cells in the body. Although early studies of therapeutic vaccines against melanoma showed some promise, [49,50] randomized, prospective, placebo-controlled clinical trials have failed to prove a benefit. An allogeneic melanoma vaccine not only failed to improve either DFS or OS, but the study arm actually showed worsened survival.[51] Similarly, although the GM2 ganglioside vaccine showed promise in phase 2 trials,[23] a recent randomized study showed worsened survival in the vaccine population compared with an observation group.[52] Although these signals may be confined to these particular vaccines and not necessarily to peptide or DC vaccines, caution is needed when interpreting vaccine studies given these data.
Chemotherapy
Historically, DTIC has been the standard chemotherapy for patients with high-risk melanoma.[53] The use of chemotherapy in the adjuvant setting in melanoma has been tested in randomized trials and has shown no benefit.[54-56] At this time, chemotherapy should not be administered in the adjuvant setting outside of a clinical trial. Whether chemotherapeutic agents may be effective when used in combination with immune-modulating agents is still under investigation.
Other Novel Therapies
As more details are elucidated about the biology of melanoma, new pharmacologic targets are being identified. Among these are immunologic targets such as programmed death (PD)-1, anti-CD40, and anti-41BB (CD137) antibodies, which are currently in phase 1 and 2 trials.[35] PD-1, a member of the tumor necrosis factor family, has shown promising results in murine trials and is currently in phase 1 investigation. CD40 is a receptor expressed on B cells and DCs; it is bound by CD40 ligand found on activated T cells. Phase 1 trials[57] have demonstrated a modest dose-related benefit (0.3 vs 0.2 mg/kg) that has prompted ongoing phase 2 trials. Also under investigation is adoptive cell transfer after lymphoid depletion (homeostatic lymphoid proliferation).[58] A very interesting proof-of-concept study showed that CD4 T cells directed against NY-ESO-1 antigen were able to produce a response in melanoma.[59]
Targeted agents directed against a growth pathway specific to melanoma are also in development. Sorafenib, a multikinase inhibitor with multiple targets including VEGF, has had modest activity when studied as monotherapy, with a 19% rate of stable disease.[60,61] Src inhibitors such as dasatinib, VEGF kinase antagonists such as sunitinib, and c-kit inhibitors such as imatinib are all under investigation in melanoma.[62].Although these agents are currently not known to be effective in the metastatic setting, they may hold promise for early-stage disease.
Conclusion
Currently, only a few adjuvant therapies show any effectiveness in terms of decreasing the mortality rate in patients with high-risk melanoma. IFN is the only agent that has been proven to reduce recurrences after surgery, although its benefit on survival is likely very modest. However, this modest benefit must be weighed against the toxicities, and hence candidates for adjuvant IFN therapy must be chosen carefully.
Among the newer agents, GM-CSF shows promise: two phase 2 studies have shown that GM-CSF administered subcutaneously may be associated with prolonged survival. Currently a major randomized trial is under way to determine the degree, if any, of this benefit. The combination of GM-CSF with other immune modifiers, such as anti-CTLA-4 antibody or IFN, may be the next step in clinical trials, although no trial data are yet available with these combinations. Vaccines have an extensive history in melanoma, but to date no vaccine preparation has shown a survival or recurrence benefit in melanoma, and recent data even indicate a potential for harm. Other agents are on the horizon, including targeted therapies directed toward the specific mutations present in certain melanomas, which could be used in the adjuvant setting. Some exciting cell-based therapies have been shown to work in proof-of-concept clinical trials; more data are awaited prior to studying these agents in the adjuvant setting.
This activity is supported by an independent educational grant from Bayer HealthCare Pharmaceuticals.
Melanoma is the leading cause of death among all types of skin cancer and is the fifth most common type of cancer in men in the United States. The incidence of melanoma is increasing; in 2008, the incidence of this disease is expected to exceed 60,000, with 8000 deaths.[1] Fortunately, up to 95% of patients will present with either local or regional disease, which is potentially curable.[2] Although the causes of this increased incidence of melanoma are debated, it is thought that increased exposure to ultraviolet radiation interacts in some manner with genetic factors to initiate melanoma.[3]
Histologically, melanoma is characterized by proliferation of transformed melanocytes.[4] These long-lived cells are normally present at the dermo-epidermal junction and impart pigment to the skin; they are typically resistant to DNA damage and apoptosis, a characteristic of melanoma as well. The principal subtypes of cutaneous melanoma are superficial spreading, nodular, lentigo maligna, and acral lentiginous; rarer noncutaneous primary sites include the mucosal membranes and the pigmented epithelium of the eye. Most types of melanoma are more common among whites, although acral lentiginous melanoma occurs with equal frequency in nonwhites.
Several pathologic and clinical factors are predictive of the risk of recurrence and death in persons with melanoma. The clinical factors include age, sex, location, and lymph node or distant organ involvement, whereas pathologically, the tumor depth (Breslow depth), ulceration, mitotic rate, and presence of microsatellites can determine the risk for recurrence or spread.[5] The recent revision of the American Joint Committee on Cancer staging system for melanoma incorporates many of these factors. Some pathologic features, such as involvement of skin layers (Clark levels) and the presence of tumor regression, have not stood up to rigorous multivariate analysis and are no longer used clinically to determine the risk for recurrence or the current staging classification.[6] Over 60% of melanomas have mutations in the B-type RAF-1 kinase (BRAF).[7,8] About 80% of these mutations are found at exon 15, at a single amino acid residue, usually a substitution for valine by glutamic acid, V599E (now referred to as V600E). This mutation causes increased kinase activation and signaling through the mitogen-activated protein (MAP) kinase pathway.[9,10] Surprisingly, this event occurs with high frequency in benign nevi as well as in melanoma.[11] An additional 15% to 20% of melanomas have mutations in N-Ras, which lies upstream of BRAF.[12] Both of these genes code for proteins that are part of the ERK-MAP kinase pathway. A small proportion of melanomas, especially those originating in sun-damaged skin, the palms and soles, and mucous membranes, have mutations or amplifications in the c-kit gene.[13]
Recent reports suggest that integration of molecular profiling with pathologic and clinical features may result in a better prognostic profile and help to more precisely determine an individual's risk for recurrence.[14] It has been suggested, for example, that the melanoma arising from sun-exposed skin in older persons is more likely to have c-kit mutations than the truncal melanoma arising in younger patients, which is more likely to have BRAF mutations.[14]
Surgical excision with wide margins and sentinel lymph node biopsy (for a melanoma whose depth is ≥ 1 mm) is the treatment of choice for primary melanoma. Several large clinical trials have helped to define the width of margins needed to resect melanoma and reduce the risk for recurrence.[15-17]
Currently, melanoma of ≤ 1 mm thickness is resected with surgical margins of 1 cm, whereas melanoma ≥ 2 mm is resected with margins of 2 cm, and intermediate-thickness melanoma is resected with 1- to 2-cm margins. Mapping the draining sentinel lymph node with use of a tracer and careful histologic examination of this node is now a standard of care for melanoma ≥ 1 mm in thickness.[18] High-risk melanoma, defined as stages IIB, IIC, and III, often recurs after excision and is associated with a 40% to 80% chance of death.[2] Given the high risk for recurrence (and subsequent mortality), there is an obvious need for reduction of recurrence risk. This review will address several treatment approaches that have been employed as adjuvant therapy following primary surgical excision.
Interferon Therapy
The interferons (IFNs) can produce antitumor effects through upregulation of the immune system. In humans, IFNs are structurally divided into 2 classes: type I and type II. The type I family, which is used clinically for the treatment of several diseases, includes alpha (alfa), beta, and omega; the type II family has only 1 member, IFN gamma. The various subtypes are further subdivided for pharmaceutical preparations, eg, IFN alfa-2a, IFN gamma-1b.[19] IFNs can stimulate both the innate and adaptive arms of the immune system; for example, they can enhance major histocompatibility complex (MHC) class I antigen presentation, increasing innate immunity and maturation of dendritic cells and leading to enhanced adaptive immunity. They also have antiangiogenic and direct cytotoxic effects on some malignant cells. However, the exact mechanism by which they produce antitumor effects is unclear.
Two large randomized trials have shown that high-dose IFN-alfa-2b significantly reduces the risk for recurrence compared with observation alone in patients with resected cutaneous melanoma.[20,21] A third large randomized trial has shown a significant improvement in overall survival with high-dose IFN-alfa-2b compared with the GM2 ganglioside conjugated to keyhole limpet hemocyanin (KLH) melanoma vaccine in patients with resected stage IIB-III melanoma.[22] In the first trial, ECOG 1684, patients with thick primary melanoma (≥ 4 mm depth) or lymph node-positive disease were randomized to receive IFN-alfa-2b 20 MIU/m2/day intravenously for 4 weeks followed by 10 MIU/m2 subcutaneously 3 times per week for 48 weeks or to observation. Patients who received IFN-alfa-2b had improved relapse-free survival (RFS) (5-year RFS 37% vs 26%; P = .0023) and overall survival (OS) (5-year OS 46% vs 37%; P = .0237) compared with the observation arm. This led to the approval by the US Food and Drug Administration of IFN-alfa-2b for the treatment of high-risk melanoma after surgical resection. Because this high dose appeared to be effective, the next ECOG trial was conducted to determine whether a lower dose of IFN might be as effective as that studied in ECOG 1684. Therefore, ECOG 1690 randomized patients with thick or node-positive melanoma to 1 of 3 arms: (1) high-dose IFN-alfa-2b (20 MIU/m2/day intravenously for 4 weeks followed by 10 MIU/m2 subcutaneously 3 times per week for 48 weeks) for 1 year; (2) low-dose IFN-alfa-2b (3 MIU/m2 3 times per week subcutaneously for 2 years); and (3) observation. Five-year RFS in the 3 arms was 44%, 40%, and 35%, respectively. The difference between high-dose IFN and observation was statistically significant (P = .05), but the difference between low-dose IFN and observation was not. Of note, no improvement in overall survival was noted between either of the treatment arms and observation.
The GM2 ganglioside vaccine had shown promising results in small phase 1 and 2 trials and was brought forward for further clinical testing.[23,24] The gangliosides are complex carbohydrates found on the outer cell membrane that can be as immunogenic as protein antigens. The resulting trial, ECOG 1694,[22] was different from the 2 prior studies because it compared high-dose IFN to GM2-KLH/21 vaccine in patients with resected stage IIB and III melanoma. High-dose IFN improved both RFS (hazard ratio [HR] 1.49; P = .00045) and OS (HR 1.38; P = .023) compared with GM2 vaccine, and this trial was halted early by the data safety monitoring committee. The benefit attributed to IFN was seen in patients with node-positive disease as well as those with node-negative disease.
Because the findings of these trials and others conducted by European and American investigators were inconsistent, several meta-analyses have been performed to assess the data globally. An authoritative meta-analysis performed by Wheatley and colleagues[25] examined 12 randomized controlled trials and found that RFS was highly significantly improved with IFN-alfa by 17% (HR 0.83; P = .000003). The benefit on OS associated with IFN-alfa trended toward a 7% improvement but was not statistically significant (HR 0.93; confidence interval [CI], 0.85-1.02; P = .1). The investigators subsequently have updated their meta-analysis and shown a slightly better outcome for IFN-alfa in terms of OS.
Inasmuch as IFN-alfa has a short half-life necessitating frequent injection and resulting in side effects from rapid variation in blood levels, it has been modified to reduce clearance and increase its half-life.[19] One such modification is the addition of a 12,000-dalton polyethylene glycol chain, which results in pegylated IFN (PEG-IFN). In the treatment of viral hepatitis, PEG-IFN appears to be as efficacious as IFN with reduced toxicity.[26] To determine whether PEG-IFN was effective in melanoma, the European Organization for Research and Treatment of Cancer (EORTC) conducted a large trial, EORTC 18991, which randomized more than 1300 patients with node-positive melanoma postoperatively to either PEG-IFN for a maximum of 5 years or observation. The 4-year RFS was 45.6% and 35.9% (P = .01) in the PEG-IFN and observation groups, respectively. No difference in OS was noted.[27] The greatest benefit appeared to be in patients with microscopic nodal disease. Overall, patients appeared to tolerate this treatment relatively well.
The major issue limiting the use of IFN in patients with melanoma has been its toxicity. IFN is associated with a characteristic and sometimes debilitating constellation of signs and symptoms that can make its use challenging.
Commonly, patients experience fatigue, myalgia, anorexia, altered taste sensation, fevers, chills, loss of concentration and short-term memory, and other neuropsychiatric abnormalities. Significant depression has been reported in some patients. Laboratory abnormalities associated with use of IFN include elevations in transaminase levels, neutropenia and thrombocytopenia, increased creatinine levels, and anemia. Commonly, patients are dehydrated and need to be encouraged to increase their fluid intake and maintain their activity levels. Given the modest benefit of IFN in terms of reducing the risk for recurrence and death from melanoma, its significant toxicity profile has made it an option for only a select subpopulation of patients at high risk for melanoma recurrence.[19]
Granulocyte-Macrophage - Colony-Stimulating Factor
Although granulocyte-macrophage - colony-stimulating factor (GM-CSF; sargramostim) was initially identified as a colony-stimulating factor for myeloid cells in the bone marrow, it was also found to induce differentiation of dendritic cells (DCs).[28] The DCs, sometimes referred to as antigen-presenting cells, display tumor antigens to the immune system in the appropriate context and are increasingly recognized as a vital afferent arm of the immune system. Both quantitative and functional defects in DCs have been described in patients with cancer. These defects may contribute to "tumor escape" of immune surveillance. Specifically, GM-CSF increases the mobilization, differentiation, and function of DCs[29,30] and hence enhanced antigen presentation to CD4 and CD8 T cells.
GM-CSF appeared to be effective in increasing tumor-specific immunity when used as an adjuvant for vaccines.[30] In the metastatic disease setting, GM-CSF has been injected intralesionally and intrahepatically (with use of a hepatic artery catheter) and administered as an inhalational treatment. A GM-CSF-producing adenovirus appears to induce regression of metastatic melanoma when injected into lesions.[31] GM-CSF inhaled as an aerosol resulted in regression of pulmonary metastasis from melanoma in a phase 1 study.[32] In a phase 1 study of patients with metastatic melanoma, a 32% response rate was noted in patients with liver metastases following hepatic arterial infusion of large doses of GM-CSF.[33]
On the basis of these data, Spitler and colleagues[34] evaluated the role of GM-CSF in patients with high-risk (stage IIIB, IIIC, or IV) resected melanoma. Patients received GM-CSF 125 µg/m2 subcutaneously daily for 2 weeks every month for 1 year. The median survival of patients in this study was 37.5 months and far exceeded the median survival of 12.2 months in historical controls. The limitations of the study included the lack of a placebo arm and heterogeneity between the historical control and study groups. Overall, GM-CSF was well tolerated.
To confirm the findings of this trial and to examine the effect of GM-CSF on DCs, Daud and coworkers conducted a study with essentially the same dose and schedule in a similar patient population.[35,36] OS and RFS were 65 months and 5.6 months, respectively. GM-CSF treatment caused an increase in mature DCs, first identified after 2 weeks of treatment and normalizing by 4 weeks. Patients with decreased DCs at baseline had significant increases in DC number and function compared with those with "normal" parameters at baseline (Figure 1).[36] No change was observed in the number of myeloid-derived suppressor cells (MDSCs). Early recurrence (< 90 days) correlated with a decreased effect of GM-CSF on host DCs, compared with late or no (evidence of) recurrence (Figure 2).[36] Therefore, greater increase of DCs was associated with remission or delayed recurrence. Although this study lacked a control group, the survival data for the GM-CSF-treated patients does appear impressive. The benefits of GM-CSF appear to be greater in those with reduced DCs, but inasmuch as these analyses were exploratory, further investigation is warranted.
GM-CSF is currently being actively investigated in combination with other immunologic agents and chemotherapy. GM-CSF with the anti-CTLA-4 antibody ipilumimab has been explored in a phase 1 trial[37] (L. Fong, personal communication) and has shown some promising activity in prostate cancer. In addition, it has been explored as a component of combination therapy[38-40] and also as a maintenance or consolidation regimen in patients with metastatic melanoma who have benefited to some extent from chemotherapy.[41] There is also an ongoing trial with high-dose IL-2 in combination with GM-CSF (J. Lutzky, personal communication).
Anti-CTLA-4 Antibodies
The use of monoclonal antibodies to inhibit cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4) is a novel strategy in melanoma. These antibodies have been found to induce tumor regression and improve long-term survival in tumor-bearing mice.[42-44] Early preclinical studies showed that CTLA-4 serves as a natural braking mechanism for T-cell activation, allowing a return to homeostasis after an immune response. Inhibition of CTLA-4 upregulates several downstream targets, including T helper (Th) 1- and 2- produced cytokines (ie, interleukin 1 and 2) and cell cycle machinery (CDK-4, cyclin D3), leading to a more robust antitumor immune response. Two anti-CTLA-4 antibodies are currently in phase 2 and 3 trials: ipilimumab (also known as MDX-010) and tremelimumab (also known as CP 675,206).
Prolonged, but sometimes delayed, responses have been seen in patients with melanoma who have received either of the anti-CTLA-4 antibodies.[45,46] Similar to the effect seen with IFN therapy, immune-related adverse events correlate with more positive outcomes in patients with metastatic melanoma who receive anti-CTLA-4 therapy, including prolonged time to relapse.[47] Recently, it has been reported that tremelimumab was no better than standard dacarbazine (DTIC) or temozolomide for the up-front treatment of metastatic melanoma.[48] Results of an ongoing trial of ipilimumab and DTIC vs DTIC alone in the setting of metastatic melanoma are expected soon. Because anti-CTLA-4 antibodies appear to be effective in the phase 2 setting in metastatic disease, they are also being considered for use in the adjuvant setting. Currently, an ongoing EORTC study is examining ipilimumab vs observation in patients with high-risk melanoma, and combinations of anti-CTLA-4 antibody with GM-CSF and IFN are promising for evaluation because different parts of the immune system may be stimulated.
Vaccines
Tumor cells can express novel antigens or quantitatively different antigens compared with "normal" or nondividing cells. Harnessing the immune system to destroy malignant cells by recognizing these antigens is a major goal of tumor immunotherapy. Tumor antigens upregulated in melanoma include MART-1 (Melan A), gp100, and tyrosinase; other investigators have focused on the cancer-testis antigens, which are upregulated in tumor cells but present only in human germ cells in the body. Although early studies of therapeutic vaccines against melanoma showed some promise, [49,50] randomized, prospective, placebo-controlled clinical trials have failed to prove a benefit. An allogeneic melanoma vaccine not only failed to improve either DFS or OS, but the study arm actually showed worsened survival.[51] Similarly, although the GM2 ganglioside vaccine showed promise in phase 2 trials,[23] a recent randomized study showed worsened survival in the vaccine population compared with an observation group.[52] Although these signals may be confined to these particular vaccines and not necessarily to peptide or DC vaccines, caution is needed when interpreting vaccine studies given these data.
Chemotherapy
Historically, DTIC has been the standard chemotherapy for patients with high-risk melanoma.[53] The use of chemotherapy in the adjuvant setting in melanoma has been tested in randomized trials and has shown no benefit.[54-56] At this time, chemotherapy should not be administered in the adjuvant setting outside of a clinical trial. Whether chemotherapeutic agents may be effective when used in combination with immune-modulating agents is still under investigation.
Other Novel Therapies
As more details are elucidated about the biology of melanoma, new pharmacologic targets are being identified. Among these are immunologic targets such as programmed death (PD)-1, anti-CD40, and anti-41BB (CD137) antibodies, which are currently in phase 1 and 2 trials.[35] PD-1, a member of the tumor necrosis factor family, has shown promising results in murine trials and is currently in phase 1 investigation. CD40 is a receptor expressed on B cells and DCs; it is bound by CD40 ligand found on activated T cells. Phase 1 trials[57] have demonstrated a modest dose-related benefit (0.3 vs 0.2 mg/kg) that has prompted ongoing phase 2 trials. Also under investigation is adoptive cell transfer after lymphoid depletion (homeostatic lymphoid proliferation).[58] A very interesting proof-of-concept study showed that CD4 T cells directed against NY-ESO-1 antigen were able to produce a response in melanoma.[59]
Targeted agents directed against a growth pathway specific to melanoma are also in development. Sorafenib, a multikinase inhibitor with multiple targets including VEGF, has had modest activity when studied as monotherapy, with a 19% rate of stable disease.[60,61] Src inhibitors such as dasatinib, VEGF kinase antagonists such as sunitinib, and c-kit inhibitors such as imatinib are all under investigation in melanoma.[62].Although these agents are currently not known to be effective in the metastatic setting, they may hold promise for early-stage disease.
Conclusion
Currently, only a few adjuvant therapies show any effectiveness in terms of decreasing the mortality rate in patients with high-risk melanoma. IFN is the only agent that has been proven to reduce recurrences after surgery, although its benefit on survival is likely very modest. However, this modest benefit must be weighed against the toxicities, and hence candidates for adjuvant IFN therapy must be chosen carefully.
Among the newer agents, GM-CSF shows promise: two phase 2 studies have shown that GM-CSF administered subcutaneously may be associated with prolonged survival. Currently a major randomized trial is under way to determine the degree, if any, of this benefit. The combination of GM-CSF with other immune modifiers, such as anti-CTLA-4 antibody or IFN, may be the next step in clinical trials, although no trial data are yet available with these combinations. Vaccines have an extensive history in melanoma, but to date no vaccine preparation has shown a survival or recurrence benefit in melanoma, and recent data even indicate a potential for harm. Other agents are on the horizon, including targeted therapies directed toward the specific mutations present in certain melanomas, which could be used in the adjuvant setting. Some exciting cell-based therapies have been shown to work in proof-of-concept clinical trials; more data are awaited prior to studying these agents in the adjuvant setting.
This activity is supported by an independent educational grant from Bayer HealthCare Pharmaceuticals.
Wednesday, October 25, 2006
10/25/2006 Major Set Back!!!!!
Yesterday while at the Rochester Oncologist (Dr. Pandya) office we received bad news. The cancer is spreading in my lungs quite rapidly according to the CT scans. There are now over 40 nodules ranging from 15 mm down to < 5 mm. No wonder I been having shortness of breath. I thought it was my lack of exercise. Dr. Pandya gives my prognosis a poor rating. I guess I won’t be getting a raise this year.
I have started the long term disability process with disbelief. My fight is not over for a long shot. I just need to speed up my trials to find the right one. I will be contacting Dr. Kirkwood today to see where we stand on the Molecular Profiling route. I feel I am in the race of life and second place is not an option. I am going for the Gold.
Stay tune things may get very interesting.
Take care
Jimmy B.
I have started the long term disability process with disbelief. My fight is not over for a long shot. I just need to speed up my trials to find the right one. I will be contacting Dr. Kirkwood today to see where we stand on the Molecular Profiling route. I feel I am in the race of life and second place is not an option. I am going for the Gold.
Stay tune things may get very interesting.
Take care
Jimmy B.
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Greetings to One and All
This Blog is dedicated My Brother Kenny B. who passed away in the late 1970's with Cancer before the Internet.
It was he, who showed me How to live and give back. He was wise beyond his years.
Jimmy and Dee
Carepage: Jimmybreitfeller
Jimmy Breitfeller
It was he, who showed me How to live and give back. He was wise beyond his years.
Jimmy and Dee
Carepage: Jimmybreitfeller
Jimmy Breitfeller
My Profile as of 2009
- jimmy_B
- Last July (2005)I was riding my bicycle to work at the Eastman Kodak Research Labs about 3 miles from home. I was wearing a knapsack to carry my things to and from the labs. I started noticing an ache on my back. So I decide to go to the dermatologist. To make the long story short, it was cancer. I knew from my research that I would be needing adjuvant therapy. So I started communicating with Sloan Kettering, University of Pittsburgh Cancer Center, and a couple of others including the Wilmot Cancer Center at Strong. I realized that by telling my story, I might help someone else out there in a similar situation. So to all who are linked by diagnosis or by relation to someone with melanoma, I wish you well. Stay positive, read as much as you can (information helps to eliminate the fear associated with the unknown), and live for today, as no one can predict what tomorrow may bring. Jimmy B. posted 12/15/08
Public Service Announcement
A call for Melanoma Patients by Dr. Steven A Rosenberg
"We continue to see a high rate of clinical responses in our cell transfer immunotherapy treatments for patients with metastatic melanoma", Dr. Rosenberg said.
"We are actively seeking patients for these trials and any note of that on a patient-directed web site would be appreciated."
If you would like to apply for his trials, here is the website and information.
Dr. Rosenberg's information
Dr. Rosenberg's Clinical Trials
The Melanoma Research Alliance has partnered with Bruce Springsteen, the E Street Band, and the Federici family to alleviate suffering and death from melanoma. Please view Bruce Springsteen’s public service announcement inspired by Danny Federici. Danny was the E Street Band’s organist and keyboard player. He died on April 17, 2008 at Memorial Sloan-Kettering Cancer Center in New York City after a three year battle with melanoma.
http://www.melanomaresearchalliance.org/news/PSA/
Source Fastcures blog
"We continue to see a high rate of clinical responses in our cell transfer immunotherapy treatments for patients with metastatic melanoma", Dr. Rosenberg said.
"We are actively seeking patients for these trials and any note of that on a patient-directed web site would be appreciated."
If you would like to apply for his trials, here is the website and information.
Dr. Rosenberg's information
Dr. Rosenberg's Clinical Trials
The Melanoma Research Alliance has partnered with Bruce Springsteen, the E Street Band, and the Federici family to alleviate suffering and death from melanoma. Please view Bruce Springsteen’s public service announcement inspired by Danny Federici. Danny was the E Street Band’s organist and keyboard player. He died on April 17, 2008 at Memorial Sloan-Kettering Cancer Center in New York City after a three year battle with melanoma.
http://www.melanomaresearchalliance.org/news/PSA/
Source Fastcures blog
Join the Relay for Life!!!
Dear Family and Friends,
I’ve decided to take a stand and fight back against cancer by participating in the American Cancer Society Relay For Life® event right here in my community! Please support me in this important cause by making a secure, tax-deductible donation online using the link below.
To donate on line now, click here to visit my personal page.
Jimmy B AKA Melanoma_Missionary
Relay For Life® is a life-changing event that brings together more than 3.5 million people worldwide to:
CELEBRATE the lives of those who have battled cancer. The strength of survivors inspires others to continue to fight.
REMEMBER loved ones lost to the disease. At Relay, people who have walked alongside people battling cancer can grieve and find healing.
FIGHT BACK. We Relay because we have been touched by cancer and desperately want to put an end to the disease.
Whatever you can give will help - it all adds up! I greatly appreciate your support and will keep you posted on my progress.
Keep the Fire Burning!!!
Sincerely,
Jimmy Breitfeller