MPIP: Melanoma Patients Information Page

The MPIP is the oldest and largest community of people affected by melanoma hosted through the Melanoma Research Foundation. It is designed to provide support and information to caregivers, patients, family and friends. Once you have been touched by melanoma—either as a patient or as a family member or friend of a patient—you become part of a community. It is not a community anyone joins willingly. But if you must be part of this group, you will find no better place to find the tools you need in your journey with this cancer, and the friends who can make that journey more bearable.

The information on the bulletin board is open and accessible to everyone. To add a new topic or to post a reply, you must be a registered user. Please note that you will be able to post both topics and replies anonymously even though you are logged in. All posts must abide by MRF posting policies.

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Hawaii Bob's picture
Replies 1
Last reply 1/20/2011 - 5:57am
Replies by: Kim K

This past summer saw a revolution in melanoma therapy. Patients whose melanoma lesions contain a mutation in the BRAF gene were successfully treated with a BRAF-specific inhibitor, PLX4032. Reports of the drug trial described shrinking tumors and improved health. Yet seven months after therapy began the tumors returned and resumed growing. Now, scientists at The Wistar Institute explain why: the tumor learns to signal around the blocked gene by adjusting its molecular wiring. They also show how to overcome resistance by simultaneously targeting multiple signaling pathways.

The researchers see this as further evidence that some cancers must be treated with multiple targeted drugs at the outset of treatment. Their findings are published in the December 14 issue of the journal Cancer Cell.

"The evidence suggests that targeting mutant BRAF can kill cancer cells, but it is not enough by itself to finish off melanoma," said Meenhard Herlyn, D.V.M., D.Sc., director of The Wistar Institute Melanoma Research Center and leader of Wistar's Molecular and Cellular Oncogenesis program. "The good news is that drugs are being developed to work in combination with BRAF inhibitors, which our data clearly shows is our best option if we intend to beat advanced melanoma."

Melanoma is the deadliest, most aggressive form of skin cancer. While surgical treatment of early melanoma leads to 90 percent cure rates, advanced melanoma is notoriously resistant to chemotherapy and has a tendency to metastasize, or spread, throughout the body. According to the World Health Organization, cases of the disease continue to rise, which has helped spur research into therapies such as BRAF inhibitors.

To study how melanoma responds to BRAF inhibitors, the Herlyn lab took melanoma cells with the BRAF mutation and tested them against a variety of anti-mutant BRAF drugs. When exposed to the drugs, the cells died off dramatically only to grow back again. In fact, cells that became resistant to one type of BRAF drug became resistant to all of them, which suggests that the cells were biochemically "rewired" in such a way that they no longer needed BRAF to form tumors.

"Cells are complex machines that work, essentially, through chains of biochemical reactions that we refer to as signaling pathways," said Jessie Villanueva, Ph.D., senior author on the study and staff scientist in the Herlyn laboratory. "Knocking out mutant BRAF shuts a major pathway down, but if some cells can use an alternate pathway, then they can survive."

To find out which alternate pathways the drug-resistant cells use, Villanueva and her colleagues looked for signs of increased activation among proteins along the pathways BRAF uses, as well as other pathways.

Their hunt turned up two paths that worked together to aid survival. First, they found that resistant cells used a protein similar to BRAF to carry the signal down the chain. Second, they found these cells received an additional boost from the IGF-1 receptor, a protein that sits on the surface of cells and sends signals that prevent cells from being killed. The resistant cells re-route the signal around BRAF by switching to an alternate protein (CRAF or ARAF), which promotes tumor cell growth, while IGF-1R signaling promotes survival of the resistant cells.

Fortunately, there are a number compounds in clinical development that could block signals along both these pathways. So-called MEK inhibitors target a protein along the same pathway as BRAF, and IGF-1 receptor inhibitors (and inhibitors of P13K, a protein that can be activated by the IGF-1 receptor pathway) block the cancer-enabling survival signal. To test these drug combinations in the BRAF-inhibitor resistant cells, the Herlyn laboratory used a tool they developed to simulate the real-world environment of human cells: 3-D melanoma tumor spheroids. Their 3-D tissue cultures allow melanoma cells to grow in all directions, much like a new melanoma tumor would grow after metastasis. As predicted, a combination of these two inhibitors killed BRAF-resistant melanoma cells in the Wistar 3-D model.

Moreover, the Herlyn laboratory confirmed in tissue samples from patients in the PLX4032 trial taken both before treatment and after they developed resistance that an increased expression of the IGF-1 receptor is associated with resistance to BRAF inhibitors. None of the laboratory-generated cell lines or the post-relapse patient's tumor samples analyzed had new mutations in the BRAF, NRAS, or c-Kit genes.

Additionally, the researchers noted an association between the loss of a tumor suppressor called PTEN, and resistance to BRAF inhibitors in melanoma cell lines. The scientists found that the relapsed tumor of one patient included in the study lost the PTEN gene, even though it was present before treatment. These findings suggest that loss of PTEN could be an additional way that melanoma cells gain resistance to BRAF inhibitors. The Wistar group continues to investigate these and other mechanisms of resistance, as they expect that several will likely arise given the heterogeneous nature of melanoma.

"Tumors are efficient engines of evolution they are going to find a way around most treatments, so we want to kill all the malignant cells from the very beginning," said Villanueva. "By targeting both pathways simultaneously you hit these cells with two punches from which they cannot recover."

"If you do this at the outset of treatment, we reason, it will prevent melanoma survival and hopefully improve patient outcomes," Villanueva added.

Support for this study was provided by grants from the National Cancer Institute and the Dr. Miriam and Sheldon G. Adelson Medical Research Foundation.

Wistar co-authors in this study include Adina Vultur, Ph.D.; John T. Lee, Ph.D.; Rajasekharan Somasundaram, Ph.D.; Mizuho Fukunaga-Kalabis, M.D., Ph.D.; Angela K. Cipolla; James E. Hayden; and Ademi E. Santiago-Walker, Ph.D. University of Pennsylvania School of Medicine co-authors include Katherine L. Nathanson, M.D.; Xiaowei Xu, M.D., Ph.D.; Phyllis A. Gimotty, Ph.D.; Bradley Wubbenhorst; Richard Letrero; Kurt D'Andrea; and Anitha Pushparajan. Other authors included Grant A. McArthur, M.B., B.S., Ph.D.; and Damien Kee, MBBS, FRACP, of the Peter MacCallum Cancer Centre in Victoria, Australia; Jeffrey A. Sosman, M.D., and Kimberly Dahlman Brown of the Vanderbilt University Medical Center; and Sylvie Laquerre, Ph.D., of GlaxoSmithKline's division of Oncology Biology in Collegeville, Pa.

Source: Wistar Institute

 

Article URL: http://www.medicalnewstoday.com/articles/211315.php

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Not sure if this qualifies as a "major breakthroug" as the original article's title states, but it is interesting and adds to the community's base of knowledge about melanoma genetics ...... Hawaii Bob, Stage IIA, Oahu, USA.......BTW, from the website "MedicalNewsToday" ......

Link at the bottom......

In a breakthrough that could lead to new treatments for patients with malignant melanoma, researchers from Mount Sinai School of Medicine have discovered that a particular protein suppresses the progression of melanoma through regulation of an oncogene, or gene responsible for cancer growth. The study is published in Nature.

Researchers studied the natural progression of melanoma using mouse and human cells, as well as patient samples and determined that the presence of a specific histone variant, which is a protein that helps package DNA, was directly related to the growth of melanoma. In all instances, researchers observed that as the melanoma became more aggressive, the presence of the histone variant macroH2A decreased. Researchers then manipulated macroH2A levels in melanoma and found that when they removed it in the early stages of the disease, the melanoma progressed more aggressively both in growth and metastasis. Adding macroH2A to late-stage aggressive melanoma cells created the opposite effect.

"We wanted to determine whether macroH2A is a passenger in this process or if it's crucial in the progression of melanoma," said Emily Bernstein, PhD, Assistant Professor of Oncological Sciences and Dermatology, Mount Sinai School of Medicine, and lead author of the study. When further investigating macroH2A function in melanoma, the researchers found that it regulates CDK8, a known oncogene for colorectal cancer. "CDK8 is highly expressed in aggressive melanoma, suggesting it also plays a major role in the process," Dr. Bernstein explained.

Through further functional studies, researchers found that eliminating macroH2A led to an increase in CDK8 expression, and the elimination of CDK8 in metastatic melanoma cells impaired their proliferation. These results suggest that macroH2A suppresses melanoma progression, at least in part, through the regulation of CDK8.

"Very little is known about melanoma epigenetics or the histone-mediated epigenetic changes in cancer in general, so these findings are a major step forward in our research. As we move ahead, we would like to determine how to inhibit CDK8 function, thereby inhibiting the growth of melanoma, as well as identify additional epigenetic changes in melanoma progression." said Dr. Bernstein. "What these discoveries really highlight is the need for further studies into the epigenetic code of cancer."

 

http://www.medicalnewstoday.com/articles/212399.php

 

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New US National Comprehensive Cancer Network Guidelines for Melanoma Patients
"The National Comprehensive Cancer Network® (NCCN®) aims to provide people with cancer and the general public state-of-the-art cancer treatment information in easy-to-understand language. The NCCN Guidelines for Patients™, based on the NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines™), are meant to help you when you talk with your doctor about treatment options that are best for you. These guidelines do not replace the expertise and clinical judgment of your doctor.

NCCN is pleased to present the new NCCN Guidelines for Patients™ on Melanoma. This 72 page PDF file is available for download at the link below. I believe newly diagnosed patients will find this booklet to be a very valuable source in understanding their specific melanoma, treatment options, etc., in a handy, "one stop shop" format.....

V/R

Hawaii Bob
Stage IIA
NED 2 years & 5 months (but who's counting)

http://www.nccn.com/images/patient-g...f/melanoma.pdf

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LynnLuc's picture
Replies 5
Last reply 1/20/2011 - 1:45pm

I wanted to share this..it was released today...http://www.nih.gov/news/health/jan2011/nci-19.htm

 

Embargoed for Release
Wednesday, January 19, 2011
1 p.m. EST

Contact:
NCI Office of Media Relations
301-496-6641

NIH study in mice uncovers pathway critical for UV-induced melanoma

Scientists have made an unanticipated discovery in mice that interferon-gamma, a type of protein primarily used by the immune system for intercellular communication, acts as a promoter for the deadly form of skin cancer known as melanoma. This finding resulted from a series of experiments designed to understand how solar ultraviolet (UV) radiation causes melanoma. The results of this study suggest that interferon-gamma, which has been thought to contribute to an innate defense system against cancer, under some circumstances may promote melanoma and incite the development of tumors. The work, led by researchers from the National Cancer Institute (NCI), part of the National Institutes of Health, appeared online in Nature, Jan. 19, 2011.

Cutaneous melanoma is a highly aggressive and frequently drug-resistant cancer with rising incidence rates. The major environmental risk factor for melanoma is UV radiation exposure, usually from the sun, with the highest risk associated with intermittent burning doses, especially during childhood.

Over the past 10 years, the researchers used genetically engineered mice first to prove, and then to try to understand, the connection between exposure to UV radiation and the initiation of melanoma. The current work was the latest attempt to define the molecular mechanisms of this cause and effect relationship. The results of this study offer the possibility that the inhibition of interferon-gamma immediately after sunburn might block the carcinogenic activation of the skin’s pigment-producing cells, known as melanocytes, making it a potentially effective preventive strategy against UV radiation-induced melanoma, according to the scientists.

The key to the experiments, led by Glenn Merlino, Ph.D., Laboratory of Cancer Biology and Genetics, NCI, and research fellow and first author M. Raza Zaidi, Ph.D., was the development of a unique genetically engineered mouse in which the melanocytes were exclusively labeled with a green fluorescent protein. This fluorescent tag allowed visual tracking and specific purification of melanocytes from the mouse skin. For the first time this enabled researchers to evaluate the response of melanocytes to UV radiation exposure while residing in the natural skin environment of a living animal.

The researchers observed that UV radiation doses equivalent to what would cause sunburn in human skin resulted in increased numbers and movement of melanocytes within the mouse skin. A detailed analysis of gene expression changes associated with this melanocyte activation revealed abnormal expression of a number of genes known to be responsive to interferon-gamma.

When the function of interferon-gamma was inhibited at the time of UV radiation, the number of melanocytes and their movement remained normal, suggesting that interferon-gamma was responsible for the UV radiation-induced activation of the melanocytes.

The source of interferon-gamma within the skin was determined to be macrophages — cells that normally protect against infection — that had infiltrated the skin after UV exposure. The pro-melanoma potential of these macrophages was revealed when they were found to enhance the growth of melanomas when transplanted under the skin of mice.

This effect was abolished when interferon-gamma was blocked, corroborating its importance in promoting melanoma development. Moreover, when the scientists examined human melanoma tissue samples, they found interferon-gamma-producing macrophages in 70 percent of the tumors, supporting the idea that these macrophages can significantly contribute to the initiation and/or progression of human melanoma.

"We anticipate that this discovery may change how interferons are used in the clinic as anticancer agents," said Merlino. "Our findings raise the possibility that targeting the interferon-gamma pathway may represent a novel, less toxic therapeutic alternative for effective treatment of malignant melanoma patients, who currently have poor cure rates."

These studies were made possible through long-term collaborations with Edward De Fabo, Ph.D., and Frances Noonan, Ph.D., of George Washington University Medical Center, Washington, D.C.

NCI leads the National Cancer Program and the NIH effort to dramatically reduce the burden of cancer and improve the lives of cancer patients and their families, through research into prevention and cancer biology, the development of new interventions, and the training and mentoring of new researchers. For more information about cancer, please visit the NCI Web site at www.cancer.gov or call NCI's Cancer Information Service at 1-800-4-CANCER (1-800-422-6237).

The National Institutes of Health (NIH) — The Nation's Medical Research Agency — includes 27 Institutes and Centers and is a component of the U.S. Department of Health and Human Services. It is the primary federal agency for conducting and supporting basic, clinical and translational medical research, and it investigates the causes, treatments, and cures for both common and rare diseases. For more information about NIH and its programs, visit www.nih.gov.

Reference: Zaidi MR, et al., Interferon-gamma links ultraviolet radiation to melanomagenesis in mice, Nature, Jan. 27, 2010, DOI: 10.1038/nature09666.

 

 

Advocate for your own treatment.. Stage 4 Melanoma NED Surgery,Radiation, Temodar 300Mg July 2009-March 2010, then Thorocotomy...now "Phase I Study of Anti-PD-1 Human Monoclonal Antibody MDX-1106 and Vaccine Therapy"

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Tim--MRF's picture
Replies 12
Last reply 1/24/2011 - 4:16pm

Roche/Genentech/Plexxikon just announced that their BRAF inhibitor that has been so much in the news hit it's primary endpoints in a Phase III study.  They have gathered enough data to show that the drug provides both Progression-Free Survival (PFS) and Overall Survival (OS). 

The best I can tell, here is what we know about this drug:

--it is applicable only to patients who have BRAF V600 mutation, which is about half of all melanoma patients;

--of the patients who have the mutation, about 60% will respond to the drug (vs. 14% who respond to IL-2, for example); and,

--the average duration of response is about 7 months.

This is a major win for patients, but also demonstrates how much more has to be done in this field.  We need to find ways to extend the duration of response (probably through combining this drug with another drug) and also to find more options for patients who do not have the BRAF mutation.  Several early-stage trials are ongoing that address these two needs.

Here is the press release:  http://www.roche.com/media/media_releases/med-cor-2011-01-19.htm

 

Tim--MRF

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ockelly's picture
Replies 2
Last reply 1/20/2011 - 11:17am
Replies by: EmilyandMike, MaryD

A friend just sent me this link.  The article is very interesting... click the link to cancercommons at the end.... then Melanoma Therapy App.
http://wtop.com/?nid=104&sid=2236525

Kelly

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Browneyes's picture
Replies 4
Last reply 1/19/2011 - 8:34am
Replies by: Browneyes, lhaley, Janner

Hi, I'm new to this board. I watched a mole grow for - I don't even know how long- maybe a year. It was kind of cute - a heart shape, oddly over the top my left breast kind of where you think of your heart being. It started to itch last summer. My husband told me to get it checked. This was denial on my part, I put it off. I went in a couple weeks ago to my family doctor and asked him for a full body scan for skin cancer. He looked at the mole and agreed - set me up with a Derm in the same clinic. I got the full body look-over and then asked the Derm if he was taking it off - he said Oh yeah. I asked if he thought it was Melanoma and he looked me in the eye and said yes. He did a excision biopsy and I waited for 5 days to hear about the biopsy and did pretty well waiting. Luckily I had done some reading the night before, so I was prepared for 'Melanoma' and the excision. They called yesterday and said yes, it's Melanoma. I had to ask what stage and the clerk said 0 - In Situ. I asked some other questions and she didn't say much but I will have WLE and she set up a 3 month appointment. She did say there would not be any other tests. 

I've done ok with this considering how much I read over the weekend. I decided not to be upset until I found out the stage at least, but that didn't prevent moments of abject fear. I have read extensively (including some on this board and I'm sorry to everyone who has to go through worse stages of this cancer) and it is scary. I feel very lucky for this diagnosis and VERY nervous about the rest of my skin and future health. I'm just past 50, a smoker so I have plenty of other stuff to worry about. And I'm in the process of quitting that. 

I am composing a list of questions for Friday when I get the stitches out and will be asking for copies of the biopsy report and office visit. So my question to anyone here - is this all standard? They tell you yeah, you have Melanoma, but you're stage 0 so there's nothing to worry about and then turn you loose after a wide excision?    Aside from asking the depth, the stage, the spread and what the WLE entails, what else should I be asking the Dermatologist? Something that really bugs me is... if you get Melanoma once even if it's stage 0, why is it not standard to do extensive testing right off the bat to see if you have it anywhere else? Like why don't they give all new patients a PET scan or something? It seems from some stories here that extra testing early might help catch some tumors in earlier stages. ? I don't get it. 

Thanks for reading this. My hub went away on business for the rest of the week and I'm kinda sitting here worrying about various things like what vitamins you can take that won't make the cancers grow more, are the UV rays coming in thru the skylights in the room where I sit every day, should I have some other moles taken off, should I ask for a chest xray, etc. Thanks for any replies. 

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Linda/Kentucky's picture
Replies 6
Last reply 1/18/2011 - 10:23pm

Although it has been a while since I have been on here due to things taking a bad turn, I just wanted to post one last post in memory of my loving husband John.  John was carried by angels to his home in heaven Tues Jan. 11, 2011 at 11:15 p.m.  He struggled with this ugly disease almost 14 months.  We said in the beginning of treatments that we would pray about what direction to take and never look back and wish we had changed something or done differently because we KNOW  God led us the way He wanted us to go.  Our faith stood strong throughout as John never complained or shifted blame on the Lord as to "why" this was happening to him, his response when diagnosed was "why not me, I'm no different than anyone else"  That was the kind of man he was.  I, however did question from time to time.  He only took two different treatments.  The first was high dose IL-2 which didn't do anything for him and the Ipi compassionate trial which also did not do anything for him.  I hope by him participating in this clinical trial it helped in someway with getting it approved.  I know it can/will be a successful drug for others.  It just was not meant to be for John.  As far as the side effects he felt from ???? cancer/treatment throughout was severe total fatigue/exaustion.  Even though he had the cancer in his lungs, liver, throughout his bones he took ibuprofen up until about 2 months ago.  And uncontrollable pain for 1 day.  We truly feel blessed by this.  I pray daily for all those going through this unfortunate journey and will continue to remember you all.  It's a journey nobody should have to take but if you know the Lord as your personal savior you know you have a home waiting for you in heaven with a glorified body.  The physicians on earth may not have been able to heal John but the Great Physician in heaven has wiped out every cancer cell in his body and restored him to what he was meant to be.  Again my prayers are with you all, good luck with any treatment you take, keep your head up and be encouraged that all things are possible with God~~~ 

Linda/Kentucky

Please know my intent on this post was not to discourage anybody but to encourage them to never give up hope.  I didn't!!!

  

I can do ALL things through Christ who strengthens me! Phillipians 4:13

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djpayn's picture
Replies 2
Last reply 1/22/2011 - 10:18am
Replies by: EricNJill, Amy Busby

im hoping that someone can give me advice about using fentanyl patches. i have been using one (100mcg/h) for about 6 months now. in the past few weeks,  i have begun to notice that by the second day of wearing the patch, my pain becomes stronger and i have wierd sensations in my legs - almost like restless legs but not quite as severe. i start taking my breakthrough meds on the second day which helps with the pain, but also relieves the sensations in my legs. i hafta take the pills the second and third day of the the patch, but once i change the patch on the 3rd day, i feel fine again.... for abt 2 days.

dont know if anyone has experienced this before but im hoping someone has some advice. i have been on a wide assortment of pain meds in the past 2.5yrs, and feel the patch works best, but am wondering if this will get worse over time. im not opposed to talking with my pain specilist about a med change, i just really dont want to. the patch has been instrumental in makin my pain and life manageable and feels like im back to my old self.

thanks for any help.

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paleskinisin's picture
Replies 6
Last reply 1/19/2011 - 9:38pm

A melanoma warrior has moved to NC due to husbands military orders.  She is stage IV and in desperate need of a good doctor.  I was hoping to find some recommendations for her.

Thank you!

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There is a new application created by Marty Tenenbaum, an E-commerce guy who has melanoma. Here is the link to the article as well as the application...looks interesting!

http://www.washingtonpost.com/wp-dyn/content/article/2011/01/16/AR201101...

http://therapy.collabrx.com/

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Anonymous's picture
Anonymous
Replies 4
Last reply 1/20/2011 - 11:49pm

I have some new liver mets and was wondering what are the most effective treatments for liver mets.  I do not think they are good candidates for surgical removal, it is more multiple areas of uptake spread throughout the liver.

Any ideas?

I continue to praise God in this storm, counting my blessings & enjoying my "bonus time!"

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Linda J's picture
Replies 2
Last reply 1/18/2011 - 8:59pm
Replies by: Carmon in NM, LynnLuc

I just was about to start th braf/mek combo trial this week when the routine MRI showed 5 small brain mets-the biggest is 1cm (is that still small)? The pet scan also showed activity in my bones, spine and nodes, along with the 20 subqs that i have been getting since mid December. The plan right now is WBR this weekend, then chemo until the braf trial that targets the brain as well opens up in Canada in six weeks.
Is it a good sign that the Mel isn't in any organs other than the brain? Are bone mets bad? I feel like the Mel went totally crazy within the past few months as I had a clear pet scan in august. Am I too far gone? Can I still slow it down and beat it?? I am 31 and have a 2yr old miracle son. I told my doctors that I am going to be one of those miracle patients that they tell their other patients about.
I would really really love to hear some success stories from those of you who have had brain and bone mets. I need some reassurance that I can still beat this despite how aggressive it seems to have become.

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Insert Generic Inspirational Motto Here

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