Friday, February 6, 2009

Researchers Uncover Gene for Melanoma of the Eye Jim Breitfeller

"If ever a cancer gene were discovered in the right place and at the right time, GNAQ may be it. The gene has been known for years but not linked to cancer. Now researchers say that it is mutated in patients with uveal melanoma and may be an important cause of this rare cancer, which arises from cells that give color to the eye.

The gene is in the right place because it belongs to a pathway that is activated in melanomas of the skin and has been the subject of considerable research. Drug companies are already investigating the pathway, known as the MAP kinase pathway, to develop targeted therapies for cancers other than uveal melanoma.

The time is right because of these investigations, and also because uveal melanoma may be a candidate for emerging RNA-based therapies. For example, the cancer frequently spreads through the bloodstream to the liver, and RNA delivery works particularly well in the liver.

Melanomas of the skin and the eye are biologically distinct diseases, though some of the same pathways are overactive in each. GNAQ mutations are an alternate trigger for the MAP kinase pathway, according to results published online in Nature December 10.

"Mutations in GNAQ activate a critical signaling pathway in melanoma, but it somehow enters the pathway from a different branch than melanoma of the skin," said lead investigator Dr. Boris Bastian of the University of California, San Francisco. "This may explain why the gene has not been found to be mutated in cancer until now."

GNAQ mutations were present in half of the uveal melanoma cases surveyed, and the mutations were not found in surrounding tissues.

The findings are confirmed by a follow-up study in the December Investigative Ophthalmology & Visual Science led by Dr. William Harbour of the Washington University School of Medicine.

"These authors have uncovered a mutation that certainly makes sense as a critically important mutation for uveal melanoma," said Dr. David H. Abramson, chief of ophthalmic oncology at Memorial Sloan-Kettering Cancer Center. "And what's exciting is that the discovery has the potential to go quickly from a lab experiment to a clinical treatment. Drug companies are already looking at this pathway because of other cancers."

About 1,500 cases of uveal melanoma are diagnosed each year in the United States. Although local treatment such as surgery and radiation is somewhat effective in uveal melanoma, half of the patients develop metastases to the liver even if the primary site has been effectively dealt with and controlled.

Given that some patients have metastatic disease at the time of diagnosis, what's desperately needed is a systemic therapy, said Dr. Abramson. The discovery of GNAQ represents an important step in that direction, he added.

GNAQ had been analyzed in large-scale cancer genome projects, but it went undetected as a cancer gene because the collections of melanoma samples have not been sufficiently diverse to include this rare subgroup, Dr. Bastian noted.

The project began serendipitously at a pigment cell biology meeting in 2003. Dr. Bastian heard a talk about mice developed in the laboratory of Dr. Gregory Barsh at Stanford University. The mice had a mutation that caused pigment cells to accumulate in the deep layer of the skin and resulted in bluish-black coloring on their ears and tails.

The coloring reminded Dr. Bastian of a skin condition in humans known as blue nevus, and he wondered whether the same mutations were involved. An analysis of DNA from blue nevi revealed GNAQ mutations in 80 percent of the samples. The mutation turned up only once in skin melanoma samples, however. But because a type of blue nevus is associated with a risk of uveal melanoma, the researchers looked for GNAQ mutations in that disease, and they found them.

"It's fascinating how similar the mice and the humans were in this situation," said Dr. Catherine Van Raamsdonk of the University of British Columbia, who did the analysis. "In each case, the mutations caused pigment cells to accumulate in the deep layer of the skin."

The findings raise an interesting question: Why are GNAQ mutations relatively harmless when they occur in the skin but may cause cancer in the eye? "We don't yet know why that is," said Dr. Van Raamsdonk. Benign nevi can arise within the eye, but researchers do not know whether they also carry the mutation because the nevi are not biopsied.

In recent years Dr. Bastian and others have been making the case that melanoma is actually more than one biologically distinct disease, as has been demonstrated for many cancers. The finding of GNAQ mutations in uveal melanoma and blue nevi potentially identifies them as biologically related subtypes. Mutations have also been reported in melanomas of the mucosa, palms, soles, and nail beds, suggesting that these are biologically distinct.

A critical task for the future, said Dr. Bastian, is to classify melanomas and develop therapies targeted at the genetic features underlying each form of the disease.

His laboratory is collaborating with Alnylam Pharmaceuticals to develop a therapy for silencing GNAQ in the liver. Experiments in cellas showed that introducing a small piece of genetic material (siRNA) to silence the gene caused the cancer cells to die. Alnylam has developed siRNAs for delivery to the liver in animal models, and the goal will now be to develop a panel that could selectively silence GNAQ.

Dr. Abramson praised the new studies as examples of synergy in science that does not happen often enough. "In both cases, excellent basic scientists were collaborating with excellent clinicians in work that is basic science and that could be quickly applicable to humans," he said. "That's a credit to all of them."

Source: NCI Cancer Bulletin:December 16, 2008 • Volume 5 / Number 25

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.

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


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

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.


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..

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.

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!!!



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

How Skin Cancer Develops by " : 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)

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.