Wednesday, January 28, 2009

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.

Photobucket
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

Photobucket
“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
Photobucket



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/

No comments:

Post a Comment

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.



Kenny B




Jimmy and Dee

Carepage: Jimmybreitfeller
Jimmy Breitfeller


My Profile as of 2009

My Photo
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

Disclaimer

The information contained within this Blog is not meant to replace the examination or advice of your Oncologist or Medical Team. The educational material that is covered here or Linked to, does not cover every detail of each disorder discussed.

Only your physician/Oncologist can make medical decisions and treatment plans that are appropriate for you. But, An Educated Consumer is a Smart consumer.

As Dr. Casey Culberson Said:

"The BEST melanoma patient is an ACTIVE PARTICIPANT in his or her treatment
(not a PASSIVE RECIPIENT)"

Melanoma and the “Magic Bullet” (Monoclonal Antibodies)

Just to let you know I posted the first draft of the Melanoma and the “Magic Bullet” (Monoclonal Antibodies). on Melanoma Missionary In the Shared File Section. you can download it for 19.95 (Only kidding) it is Free for the taking.


It is 33 pages long and may help you in your quest for the Yellow Brick Broad. Just to let you know it is only the first draft. Revisions are sure to come. I wanted to get it to the people that need it the most, the Melanoma Patients.

Preview:

So, where does Interluekin-2 (IL-2) come into play? According to Byung-Scok et al and recent reports, IL-2 is not needed for developmental CD4+ CD25+ Treg cells in the thymus but does play an important role in the maintenance and function in the peripheral.18 Peripheral is defines as secondary system outside the bone marrow and thymus. It entails the site of antigen, immune system interaction. IL-2 is required for the peripheral generation of Tregs based Abbas’s and colleagues research.19

IL-2 prevents the spontaneous apoptosis of the CD4+ CD25+ Treg cells. It has been reported that patients with multiple advance-stage tumors have elevated levels of Tregs within the tumor microenviroment.20 Interluekin-2 is the survival factor for CD4+ CD25+ Treg cells.21 If the addition of IL-2 is on or before the maximum propagation of the CD4+ T cells, the Tregs population can increase 5-fold in a 96 hour period based on certain growth mediums.

By controlling the addition of the endogenous IL-2, one has a knob to turn and can lead to the control of the expansion of the Tregs. When you combined this control with the anti-CTLA-4 blockage, you can shift the balance of the immune response.

Now here is the catch. The maintenance and function of the CD8+ T-cells require CD4+ cells which secrete IL-2. So we don’t want to deplete the CD4+ cells, we want to control the expansion of the Tregs which are a subset of the CD4+ cells. It has been postulated by some researchers that the Anti-CTLA-4 blockage also suppresses the Treg function in a different mechanism. By using IL-2 as the rate limiting factor, we can suppress the CD4+ CD25+ Treg cell expansion by controlling the concentration and timing of the Inerluekin-2 at the tumor microenvironment.


The Interluekin-2 plays another role in this Melanoma Maze. In a study by Janas et al, Il-2 increases the expressions of the perforin and granzyme A, B and C genes in the CD8+ T-cells. This increase expression causes the CD8+ T-cells to mature into Cytoxic T Lymphocytes (CTLs). The exogenous IL-2 is required for the granzyme proteins. As stated previously, CTLs have cytoplasmic granules that contain the proteins perforin and granzymes. A dozen or more perforin molecules insert themselves into the plasma membrane of target cells forming a pore that enables granzymes to enter the cell. Once in the tumor cell, these enzymes are able to breakup (lyse) the cell and destroy it. This is the beginning of the end for the cancer cells. The tumors begin to shrink and the rest is history,



On the other hand, prolong therapy with Il-2 can result in causing apoptotic death of the tumor- specific CD8+ T-cells.23

Clearly in a clinical setting, timing, dose, and exposure to these drugs play a major roll in the immunotherapy, and can have dramatic effects on the outcome.

All it takes is that one magic bullet to start the immune reaction..

https://app.box.com/shared/kjgr6dkztj

Melanoma And The Magic Bullet (Monoclonal Antibodies)

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


For the Warriors




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!!!

Photobucket

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!!!

Photobucket

Sincerely,

Jimmy Breitfeller
Turn off Music before you "Click to Play"
Signs of Melanoma Carcinoma Skin Cancer

How Skin Cancer Develops by "About.com : Dermatology"

Call for Patients with Unresectable Liver Metastases Due to Melanoma



Delcath Systems Granted Orphan-Drug Designations for Cutaneous and Ocular Melanoma


Delcath is actively enrolling patients in a Phase III clinical trial testing its proprietary drug delivery system, known as Percutaneous Hepatic Perfusion (“PHP”), with melphalan for the treatment of ocular and cutaneous melanoma metastatic to the liver.

This NCI-led trial is enrolling patients at leading cancer centers throughout the United States. Commenting on these orphan-drug designations, Richard L. Taney, President and CEO of Delcath, stated, “These favorable designations are important steps in our efforts to secure Delcath’s commercial position upon conclusion of our pivotal Phase III trial for metastatic melanoma. We remain steadfast in our commitment to become the leader in the regional treatment of liver cancers and we continue to enroll patients in this study, and advance our technology and the promise that it offers to patients with these deadly forms of melanoma and other cancers of the liver, all with limited treatment options.”

Orphan drug designation, when granted by the FDA’s Office of Orphan Products Development, allows for up to seven years of market exclusivity upon FDA approval, as well as clinical study incentives, study design assistance, waivers of certain FDA user fees, and potential tax credits.


Current Trial Centers


Phase I Study of Hepatic Arterial Melphalan Infusion and Hepatic Venous Hemofiltration Using
Percutaneously Placed Catheters in Patients With Unresectable Hepatic Malignancies



James F. Pingpank, Jr., MD, FACS
Associate Professor of Surgery
Division of Surgical Oncology
Suite 406, UPMC Cancer Pavillion
5150 Centre Avenue
Pittsburgh, PA 15232
412-692-2852 (Office)
412-692-2520 (Fax)
PingpankJF@UPMC.edu


Blog Archive

Call For Melanoma Patients!!!!

Call For Melanoma Patients!!!!

Dr. Rosenberg Has a New Clinical Trial.

Our latest treatment has a 72% objective response rate with 36% complete responses.

We are currently recruiting patients for our latest trial.

Is there some way to post this “Call for Patients” on the web site?

Steve Rosenberg

Dr. Rosenberg's Clinical Trials



(For a copy of the research paper.. see My Shared files)

The news headlines shown above for Melanoma / Skin Cancer are provided courtesy of Medical News Today.