Targeted therapy for metastatic melanoma: From bench to bedside..Jim Breitfeller

Targeted therapy for metastatic melanoma: From bench to bedside
Author: Wen-Jen Hwu, MD, PhD

Malignant melanoma is well known for its aggressive clinical behavior, propensity for lethal metastasis and therapeutic resistance. However, in the last decade, considerable excitement has been generated by the identification of genetic mutations in various components of signaling pathways involving melanoma initiation and progression, particularly those involved in the MAP and PI3 pathways. Most recently, clinical trials of pharmacological targeting of relevant molecular targets have demonstrated dramatic response even in patients with late-stage melanoma.

The emerging insights into the mechanisms of activation and negative regulation of innate and adaptive immunity to tumors have provided another breakthrough in melanoma therapy. A new family of immune-based agents of monoclonal antibodies that exert their functions by tampering with immune system cell molecules causing an enhancement of antitumor immune responses has entered clinical trials. In general, these new antitumor agents are designed to break down the barriers to tumor tolerance/immunity. This new group of agents holds promise for at least additive effects with conventional therapies, as well as signal transduction pathway targeted therapies.

Targeting signal transduction pathways

Several key genetic lesions governing melanoma initiation and progression have been identified, the earliest and most common being a point mutation (T1799A) in the BRAF proto-oncogene, which is detected in approximately 60% of metastatic melanoma. BRAFT1799A encodes BRAFV600E, a constitutively active protein serine kinase that elicits sustained activation of the BRAF® MEK1/2® ERK1/2 MAP kinase pathway.

In addition to BRAF, RAS oncogene (rat sarcoma viral oncogene homolog) is another constituent of the MAP kinase pathway. RAS mutations (in one of three isoforms) are found in approximately 20% of metastatic melanoma. RAS is capable of turning on several downstream pathways, including BRAF and other components of MAP kinase pathways, the PI3 kinase pathway, and the RAL-GDS pathway. In general, if a RAS mutation is present, there will be no BRAF mutation. However, the combination of mutated BRAF and silencing of PTEN expression is common in human melanoma (~20%). Dankort and colleagues have demonstrated in a preclinical model that “BRAFV600E cooperates with PTEN loss to induce metastatic melanoma.”

The prevalence of RAS/RAF alterations in human cancer has prompted significant efforts in the development of drugs targeting the MAP kinase pathway. Many of these are currently in clinical trials in patients with metastatic melanoma. Studies with the broad spectrum RAF inhibitor sorafenib (Nexavar, Bayer) as a single agent in patients with BRAF mutated melanoma have proved disappointing. What was unclear from these studies was whether the lack of efficacy was because BRAF was not a critical target or because of incomplete blocking of BRAF by sorafenib.

Since 2005, several BRAF inhibitors have entered clinical trials. These inhibitors are grouped in two categories: BRAF selective inhibitors, and broad spectrum multiple kinases inhibitors with high potency against BRAF.

BRAF inhibitors

PLX4032 (Plexxikon, also known as RO5185426) is a selective BRAF inhibitor and is the first of its kind tested in advanced melanoma. A response rate of 70% in 32 BRAF mutated melanoma patients was reported in the phase 2 study. In general, PLX4032 is well tolerated and most common toxicities include mild-to-moderate skin rash, sun sensitivity, fatigue, arthralgia and keratoacanthoma. Currently, there are two ongoing PLX4032 trials.


Wen-Jen Hwu

The first is a phase 2 study of PLX4032 as a single agent in BRAF mutated melanoma patients who have failed standard therapy for metastatic disease. This study will hopefully confirm the high response rates observed in previous phase 1/2 studies. The second is a phase 3 trial comparing PLX4032 with dacarbazine (standard chemotherapy) in chemotherapy-naive patients with BRAF mutated metastatic melanoma. Seven hundred patients will be enrolled; the primary endpoint is OS.

Another BRAF selective inhibitor is GSK2118436 (GlaxoSmithKline). This drug has already shown promising antitumor activity in the phase 1 portion of a study. The phase 2 portion is ongoing. The impressive high level of antitumor activity of BRAF selective inhibitors indicates that both PLX4032 and GSK2118436 have single-agent activity; BRAF is an important target in melanoma.

Currently, there are at least two nonselective BRAF inhibitors. XL281 (Bristol-Myers Squibb) and RAF265 (Novartis) are in phase 1 testing. Results are expected in the near future.

MEK is a kinase and is immediately downstream of BRAF. It is never mutated in cancer but is activated by BRAF and, in turn, activates the rest of the MAP kinase pathway. In the laboratory, MEK inhibitors have shown activity in a number of BRAF mutated cancers. Currently, there are many MEK inhibitors in clinical trials.

AZD6244 (AstraZeneca) is a MEK inhibitor that has been evaluated most extensively in melanoma. A phase 2 study comparing AZD6244 with temozolomide (oral chemotherapy) has found an objective response rate of 12% among 45 BRAF-mutated patients. However, patients in this study who received temozolomide had a similar response rate and PFS.

Melanomas from acral lentiginous, mucosal and chronic sun-damaged sites frequently harbor activating mutations and/or increased copy number in the KIT tyrosine kinase receptor gene, which are very rare in more common cutaneous melanomas. Multiple case reports and early observations from clinical trials suggested that targeting mutant KIT with small molecule KIT inhibitors such as imatinib (Gleevec, Novartis) and/or dasatinib (Sprycel, BristolMyersSquibb) is efficacious.

Although the dramatic clinical activity of BRAF selective inhibitors is a major breakthrough in the treatment of this disease, there are many hurdles to overcome to optimize this targeted therapy approach. Many of the patients who initially responded to PLX4032 have subsequently progressed with a median duration of response of approximately 8 months. The mechanisms that cause resistance are largely unknown.

Recently, a number of preclinical studies have demonstrated that BRAF inhibitors activate MEK and MAP kinases in melanoma cell lines with wild-type BRAF, including cell lines with mutant NRAS. These studies suggest at least one potential mechanism of resistance is through continued activation of the RAS-RAF-MEK-ERK signaling pathway. Thus, combination agents that target multiple components of this pathway have great potential to overcome drug resistance. Several ongoing clinical trials using the combination of BRAF and MEK targeted agents will be able to test this hypothesis.

Targeting tumor immunity barriers

Since the discovery of monoclonal antibodies in the late 1970s, it has become clear that these antibodies, which are of defined specificity and can be produced in large amounts, had potential for the management of various diseases, including malignancies.

The key property of antibodies to be used as therapeutic tools is their behavior as high-avidity ligands to protein or glycoprotein. Most recently, a new group of monoclonal antibodies that enhance the cellular immune response against cancer have entered clinical trials. These agents bind molecules on the surface of immune system cells. They either provide activating signals to lymphocytes and antigen presenting cells or block the action of receptors that normally down-regulate the immune response.

A humanized monoclonal antibodies (MDX-010, Medarex) against cytotoxic T-lymphocyte antigen 4 (CTLA-4) is the first to reach clinical trials. CTLA-4 is only expressed on the cell surface of activated T cells and regulatory CD4+ CD25+ T cells. In murine models, systemic treatment with transplantable immunogenic colon carcinoma cells with anti-CTLA-4 monoclonal antibodies induced complete tumor regression of established tumors through an immune response found to be critically dependent on the activity of cytotoxic T lymphocytes.

Various phase clinical studies have been conducted on the two anti-CTLA-4 monoclonal antibodies, ipilimumab (Bristol-Myers Squibb) and tremilimumab (Pfizer), as monotherpy, in combination with vaccines or other immunotherapies, and in combination with chemotherapies. Blockade by the T-cell inhibitory molecule CTLA-4 results in antitumor response with overall response rates from 10% to 20%. Most adverse events involve autoimmune toxicities, such as dermatitis, uveitis, colitis/enterocolitis, hepatitis and hypophysitis.

4-1BB (CD137) is a surface glycoprotein that belongs to the TNF receptor family. It is expressed by activated, but not resting, T and NK cells. A humanized anti-4-1BB monoclonal antibody (Bristol-Myers Squibb) has been tested in clinical trials. However, the phase 2 study in refractory melanoma was discontinued in May 2009 due to unusually high incidence of grade-4 hepatitis.

Programmed death 1 (PD-1) and its ligands, PD-L1 and PD-L2, deliver inhibitory signals that regulate the balance between T cell activation, tolerance and immunopathology. In vivo studies have shown B7-1 (CD80) is also a binding partner for PD-L1, and their interactions can lead to bidirectional inhibitory response in T cells.

PD-L1 is expressed on many tumors including melanoma and is a component of the immune suppression by the tumor microenvironment. Phase 1/2 experience of the anti-PD-1 monoclonal antibody, MDX-1106 (Medarex, Ono-4538), in refractory or relapsed malignancies was presented at the 2009 ASCO Annual Meeting. Clinical activity against melanoma was observed and, more importantly, no MDX-1106 related severe adverse events were noted.

In 2009, at M.D. Anderson Cancer Center, we participated in a phase 1 study of anti-PD-L1 monoclonal antibody (MDX-1105, Medarex) in refractory metastatic melanoma. MDX-1105 has been tolerated by all patients. Most adverse events were mild and were related to inflammatory responses in the tumors, not immune-related toxicity. Clinical responses were observed at all dose levels (1 mg/kg to 10 mg/kg every 2 weeks). Durable partial responses and stable disease were noted in patients whose disease had progressed after at least one, and as many as five, prior systemic therapies. Based on the low toxicity and impressive clinical activity, a phase 2 study of MDX-1105 in advanced melanoma is warranted.

In summary, the treatment of metastatic melanoma is changing rapidly due to the great success in translational research from bench to bedside. Although such studies, to date, have focused on the treatment of advanced metastatic disease, the approaches of targeting signal transduction pathway, as well as targeting tumor immunity barrier, hold great promise to the development of preventive strategies and personalized therapies in malignant melanoma.

Wen-Jen Hwu, MD, PhD, is a professor in the department of melanoma medical oncology at The University of Texas M.D. Anderson Cancer Center and is a member of the HemOnc Today Editorial Board.

Source:http://www.hemonctoday.com/article.aspx?rid=65856


“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

Follow Up of Dr. Flaherty’s Conference Call on Targeted Therapy Melanoma..Jim Breitfeller

As we all know Melanoma is on the rise in the United States and 65000 will be diagnosed this year alone. 8400 will die of the disease. Despite 30 years of research in Melanoma, we only have two FDA approved drugs at the present for Metastatic Melanoma. One is Dicarbazine also known as DACARBAZINE... NSC-45388, TOSLAB 25071, DICARBAZINE, DACARBAZINE RELATED COMPOUND A 5- AMINOIMIDAZOLE-4-CARBOXAMIDE HCL USP(CRM STANDARD), DACARBAZINE USP STANDARD, (DTIC).

It is usually administered as a single agent and has a clinical response of 5 to 10 percent. Part of the major problem is that the Melanoma Cells can become chemical resistant to the therapy because the cells can morph based on their microenvironment.1

The United States Food and Drug Administration (FDA) officially recognized the efficacy of Interluekin -2 (IL-2) in patients with metastatic melanoma by granting approval for commercial marketing of the drug for that indication in 1998, based on tumor response and survival data generated from clinical trials of the intermittent high-dose bolus regimen.

Today, we are in a new era of therapy. Immunotherapy has come to the forefront of Melanoma Therapy. Researchers are beginning to crack the code and are making great strides inmmunotherapy.

To be able to unravel the “Melanoma Maze” as I call it, we need to know “How Melanoma works.” In this next section, It may get very detailed, but I will try to explain with the help of the experts and a dictionary. I am learning like you so please bear with me.

So here it goes!!!!!

Cancer begins in cells, the building blocks that make up tissues. Tissues make up the organs of the body. Normally, cells grow and divide to form new cells as the body needs them. When cells grow old, they die, and new cells take their place.
Sometimes this orderly process goes wrong and new cells form when the body does not need them, and old cells do not die when they should. These extra cells can form a mass of tissue called a growth or tumor. Not all tumors are cancer.
In Melanoma, the cause is by the uncontrolled, unregulated growth of Melanocytes. The cell cycle proceeds unregulated, and cell growth proliferates.



It has been suggested that there are Five Stages to Metastatic Melanoma .2
Five stages of tumor progression have been suggested:
1) Benign melanocytic nevi- Melanocytic nevi are benign neoplasms or hamartomas composed of melanocytes, the pigment-producing cells that constitutively colonize the epidermis. The malignant analogue of a melanocytic nevus is melanoma. This where Melanoma can start, but can also start at eyes, ears, GI tract, leptomeninges, and oral and genital mucous membranes and even sometimes the primary site is unknown and is called “Occult Primary Melanoma”.

2) Melanocytic nevi with architectural and cytologic atypia (dysplastic nevi) “An atypical nevus, usually larger than 5 millimeters in diameter with variable pigmentation and ill-defined borders, marked by melanocytic dysplasia and associated with an increased risk for the development of nonfamilial cutaneous malignant melanoma. Also called dysplastic nevus3” The Precursor to melanoma.
“The sequence of events in which normal melanocytes transform into melanoma cells, referred to as melanomagenesis, is poorly understood. It likely involves a multistep process of progressive genetic mutations that (1) alter cell proliferation, differentiation, and death and (2) impact susceptibility to the carcinogenic effects of ultraviolet radiation.4”

3) Primary malignant melanoma, radial growth phase
This is early pattern of growth of cutaneous malignant melanoma in which tumor cells spread laterally into the epidermis. This is where if it is identified and removed with surgery, there is 95 % cure rate. The Melanoma Cells have not entered into the lymphatic system.

4) Primary malignant melanoma, vertical growth phase
The late pattern of growth of cutaneous malignant melanoma in which tumor cells spread from the epidermis into the dermis.


Figure 1. Human Skin5

5) Metastatic malignant melanoma
Each step in tumorigenesis is marked by a new clone of cells with growth advantages over the surrounding tissues. The cancer, as it invades in its place of origin, may also work its way into blood vessels. If this occurs, it provides yet another route for the cancer to spread to other organs of the body. When the cancer spreads elsewhere in the body, it has become systemic in extent and the tumor growing elsewhere is known as a metastasis.

What are the different Types of Malignant Melanoma?
1) Superficial spreading melanoma
2) Nodular melanoma
3) Lentigo maligna melanoma
4) Acral melanoma.
5) Ocular Melanoma

Superficial spreading melanoma does just as it sounds. It is on the surface of your skin and spreads horizontally. It is the most common and is a bout 65% of the Melanoma reported cases.

Nodular melanoma is a much less common form of melanoma. It usually starts as a raised lesion that is dark black-blue or bluish-red, however some can lack color. Nodular melanomas account for approximately 15% of cases. It is fast spreading and usually grows vertically in both directions.

Lentigo maligna melanoma is usually found on the palms of the hands, soles of the feet and/or around the toenails. 5-15% of all cases

Acral melanoma is an uncommon type of melanoma. It is the most common type seen in nonwhite individuals. It usually occurs on the palms and soles. Sometimes it occurs on the vulva and vagina. Acral melanoma accounts for 5% of Melanoma cases.

Ocular melanoma occurs in the eye and is estimated that 2% of the total melanoma diagnosed per year is ocular.

So where do we go from here?

Since we now know that the cause for this unregulated growth of Melanocytes is mutation in certain genes, we need to know the signaling pathways that cells took to grow. So researchers like Dr. Smalley, Dr Herlyn and many others have recently identified that the activating mutation in the BRAF gene on chromosome 7 linked to 60% of the cases in Melanoma.6

“This gene encodes a protein belonging to the raf/mil family of serine/threonine protein kinases. This protein plays a role in regulating the MAP kinase/ERKs signaling pathway, which affects cell division, differentiation, and secretion.

Mutations in this gene are associated with cardiofaciocutaneous syndrome, a disease characterized by heart defects, mental retardation and a distinctive facial appearance. Mutations in this gene have also been associated with various cancers, including non-Hodgkin lymphoma, colorectal cancer, malignant melanoma, thyroid carcinoma, non-small cell lung carcinoma, and adenocarcinoma of lung.”7

Our understanding of B-RAF regulation was greatly increased recently when the crystal structure of the B-RAF kinase domain bound to the small molecule inhibitor BAY43-9006 was solved (Wan et al., 2004).

So in 2006, in Cancer Research 66, 1611-1619, February 1, 2006], A research paper came out entitled: The Raf Inhibitor BAY 43-9006 (Sorafenib) Induces Caspase-Independent Apoptosis in Melanoma Cells. David J. Panka1, Wei Wang2, Michael B. Atkins1 and James W. Mier1
1 Division of Oncology, Beth Israel Deaconess Medical Center and Harvard Medical School and 2 Department of Biostatistics and Computational Biology, Dana-Farber Cancer Institute, Boston, Massachusetts
The paper caused excitement among researchers in that Raf Inhibitor was a way to block the pathway and cause apoptosis in Melanoma. This is a form of cell death in which a programmed sequence of events leads to the elimination of cells without releasing harmful substances into the surrounding area.

So what are the signaling pathways known to date?

Figure 2. Signaling pathways affected by the common primary changes in human melanoma, and some inter-relationships8


“Molecules shown in bright red are those clonally amplified or activated in some melanomas; those in bright blue are clonally deleted or inactivated in some melanomas. Pale red and pale blue indicate proteins that are at least secondarily upregulated or downregulated in melanoma, respectively. Rectangles indicate transcription factors. Some components have a larger outline; this is just to emphasize apparently important signaling nodes, and does not reflect molecular size.”
Attempts have been made to focus on pathways known to be present and active in melanoma cells (Dr. Smalley, Dr. Herlyn), although some sections of pathways are derived from the broader literature, and with the help of the pathway maps of Weinberg.9

Figure 3. Schemic of known active signaling pathways in Melanoma
by Dr. Smalley and Dr. Herlyn6




As you can see, from the diagrams, some of these pathways are intertwined and make the research more difficult but not impossible. Careful planning of the experimentations may yield new target therapies down the road. There may be a combo of Chemo and Immunology together to stabilize the Melanoma Beast.

So Now, Where does the Patients come into play?
We need to start by having our Blood typed for Biomarker. A biological marker, or biomarker, is a phenotypic parameter (eg, a substance, structure, or process) that is measured and evaluated as an indicator of normal biological processes, pathogenic processes, or pharmacologic responses to a therapeutic intervention. This step One. Step two is the biopsy of your tumor and getting it typed/mapped. If the Oncologist can get the pathway that is mutated, They will be able to direct to the right therapy base on that mutation.

Example: Kit Mutation
“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, 2008



I believe we are now able to use the molecular profile of disease to deliver the right therapy to the right patient at the right time. But we must first build the infrastructure that will support Targeted Therapy with Personalized Medicine. This will require a Novel approach to the Global Healthcare seen. We would need a seamless communication along with various components including a national tissue repository, molecular diagnostic standards and procedure in place. A network of clinical sites working in collaboration to identify cohorts of patients with similar abnormal molecular profiles that is in a database and is available to Oncologists and Medical Researchers alike, a bioinformatic infrastructure integrating all of these elements.

It may be already here!!!!!!


Big Changes at BiobankCentral

Posted: 27 Jan 2009 10:36 AM CST

by Kate Blenner, Program Analyst, FasterCures10
We at FasterCures are very pleased to announce some big changes to BiobankCentral.org, the Web site we have established to highlight the importance of biobanks to medical research. This site links researchers to resources, encourages the donation of specimens, and educates the public about the benefits of research on banked biospecimens. After interviewing key stakeholders, including patient advocates, biobank operators, and leaders in the field of biospecimen research, we will begin staging some new features and functions that will make Biobankcentral.org even more useful to visitors hoping to learn more about these critical resources.

The first of these new features is the Spotlight on Innovation which will highlight individuals and organizations doing exceptionally innovative work in biobanking. Our first Spotlight focuses on the Susan G. Komen for the Cure® Tissue Bank at the Indiana University Simon Cancer Center, or Komen Tissue Bank (KTB) for short. This bank’s mission is to collect samples of normal, healthy breast tissue and other biospecimens from healthy women for breast cancer research. Yes, you read that correctly—normal tissue. Healthy women.

In its 1998 priorities for cancer research, the National Cancer Institute identified the lack of knowledge about the normal biology and development of the mammary gland as a significant barrier to finding a breast cancer cure. Most research to date has focused on characterizing diseased tissue, but without the frame of reference of how healthy tissue develops and functions opportunities for a cure could be missed. Complicating the issue was a shortage of normal tissue available for study. The NCI’s recommendations to address the ‘tissue issue’ languished for a few years, until some motivated advocates and clinicians at IU Simon Cancer Center decided to form the KTB.

Despite initial skepticism that healthy women would want to go through an invasive collection procedure, KTB put its faith in the motivation of the breast cancer advocacy community—and it paid off. They have collected thousands of samples to date, and communities across the country have asked KTB to set up its collection tent at their local Race for the Cure events. As bank co-founder and patient advocate Connie Rufenbarger told me: “These women have walked, they’ve written checks, they’ve lit candles—they’ve done everything they can to demonstrate they want to help. [The response] really speaks to the fact that there isn’t a whole lot you could ask that women wouldn’t give you to cure this disease.”

I hope you enjoy this first Spotlight of the Komen Tissue Bank as much as I enjoyed speaking with its remarkable founders and staff. If you have a moment, stop by the KTB Web site to find out how you can get involved in their work to find a cure. And, of course, keep an eye on BiobankCentral.org—we have many more exciting new changes to come.



References

1. Cedric Gaggioli and Erik Sahai- Melanoma invasion – current knowledge and future directions Pigment Cell Res. 2007 20; 161–172
2. http://www.clevelandclinicmeded.com/medicalpubs/
3. http://www.answers.com/topic/malignant-melanoma
4. Demierre MF, Nathanson L. Chemoprevention of melanoma: an unexplored strategy. J Clin Oncol. Jan 1 2003;21(1):158-65. [Medline]
5. http://www.mydr.com.au/files/images/categories/skinhair/skinstructure.gif
6. Keiran S.M. Smalley and Meenhard Herlyn Targeting Intracellular Signaling Pathways as a Novel Strategy in Melanoma Therapeutics Ann. N.Y. Acad. Sci. 1059: 1–10 (2005). 2005 New York Academy of Sciences.doi: 10.1196/annals.1339.005
7. http://www.genecards.org/cgi-bin/carddisp.pl?gene=BRAF
8. Dorothy C Bennett- How to make a melanoma: what do we know of the primary clonal events? Division of Basic Medical Sciences, St George's, University of London, Cranmer Terrace, London SW17 0RE, UK.
9. R. A. Weinberg The Biology of Cancer Garland Science, Taylor & Francis Group,. LLC, London, 2007, 864 pp., ISBN-10 0-8153-4078-8/
10. http://www.fastercures.org/

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

Metastatic melanoma—challenges for the community oncologist!! Jim Breitfeller

Michael B. Atkins, MD | Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA

"The outlook for patients with advanced
melanoma is bleak. Patients with stage IV melanoma have a median
survival of 6–9 months,1–3 with 5-year survival rates of 1%–2%.1,4

An estimated 8,000 Americans will die of melanoma in 2008.1,5 Many of these patients are young, with a median age of ~ 50 years, and otherwise healthy.1,5 This loss of life represents a societal burden in excess
of the actual numbers. Although melanoma is the ninth most common cancer in the United States,1,6 it ranks second among solid tumors in terms of years of productive life lost.

Common treatment approaches have included:
cytotoxic chemotherapy; interleukin-2 (IL-2)–based immunotherapy; and combinations of chemotherapy and immunotherapy (so-called biochemotherapy). Although some treatment approaches, most notably, high-dose IL-2 immunotherapy,
have been shown to produce extremely durable tumor responses in a small percentage of patients,4,7,8 no treatment approach has shown a reproducible survival advantage in phase III trials.

There is a critical need for new treatment approaches for patients with advanced melanoma.Recent advances in the understanding of melanoma
biology, immune regulation, and tumor-induced immune suppression are the foundation for new opportunities to improve therapeutic outcomes for patients with advanced melanoma. Studies of melanoma biology have uncovered critical factors that are important for melanoma cell survival, including activating mutations in BRAF, which occur in > 50% of melanomas; mutations in KIT, the gene encoding the c-Kit receptor, which are common in acral lentiginous and mucosal primary melanomas; overexpression of vascular endothelial growth factor, which drives tumor angiogenesis; and an assortment of factors that limit the apoptotic effects of various cytotoxic chemotherapy agents."

Read the rest:

http://www.oncologystat.com/Images/metastatic_melanoma_tcm8-162554.pdf
Metastatic melanoma—challenges for the community oncologist



Jimmy B

One of our family Member asked about C kit testing!!!! jim Breitfeller

This is another important test for patients with c-kit mutation positive melanoma

This from the University of Utah Pathology Department

Targeted Cancer Therapy in Metastatic Malignant Melanoma
last modified 2008-03-06 18:29 — by Dave

Problem:

"When it comes to cancer patients with metastatic melanoma, there is little that can be done on their behalf. But for a few patients, studies are currently underway that could drastically improve their likelihood of survival."



How it all started:

"The research began a few years ago when scientists in the Division of Anatomic Pathology in the Department of Pathology at the University of Utah were studying gastrointestinal stromal tumors (GISTs) with mutations in the c-kit gene. KIT, the protein coded for by the c-kit gene, normally activates cellular signals which tell the cell to grow and divide. In most normal circumstances, the c-kit gene is turned off and KIT is silent. However, it was discovered that GISTs have mutations in the c-kit gene which result in a KIT protein that is activated, or in other words is always turned on. Activation of the KIT protein causes a constant signal for the GIST tumor cells to grow. It has been discovered that GISTs, a tumor which previously had been therapeutically resistant, can be controlled by use of a new drug called Gleevec. Gleevec works as a tyrosine kinase inhibitor that binds to the active site of the mutationally active tyrosine kinase KIT and inhibits the protein. Inhibition of KIT stops cellular signaling and turns off tumor growth. There are several different types of c-kit activating mutations occurring in GISTs and some are more responsive to Gleevec than others. To aid in the treatment of GIST patients, it is now possible, through the research efforts in Anatomic Pathology, to determine the type of c-kit mutation in GISTs."

The rest can be found at their website:


http://www.path.utah.edu/news/targeted-cancer-therapy


targeted-cancer-therapy


This is why it is so important to know your Blood chemistry!!!!!!!! It will help you find the right path to the right therapy.

Patty, thank you for sharing. This is how we all will become self-educated in Melanoma Therapy.

Jimmy B