The information on this site is not intended or implied to be a substitute for professional medical advice, diagnosis or treatment. Content within the patient forum is user-generated and has not been reviewed by medical professionals. Other sections of the Melanoma Research Foundation website include information that has been reviewed by medical professionals as appropriate. All medical decisions should be made in consultation with your doctor or other qualified medical professional.

If you are BRAF+, Please take notice!!

Forums Cutaneous Melanoma Community If you are BRAF+, Please take notice!!

  • Post
    jim Breitfeller
    Participant

      Killing Drug-Resistant Melanoma Requires Combination Therapy

      If you are BRAF +, The combination Therapy of BRAF + MEK  may be the best treatment available at the present time.  See the Article below.

      I met up Dr. Flaherty in Boston this past week. He is one of the experts on BRAF inhibitors.

      Here is his comments on the the news below

      Jim,

      Nice meeting you as well.

      Killing Drug-Resistant Melanoma Requires Combination Therapy

      If you are BRAF +, The combination Therapy of BRAF + MEK  may be the best treatment available at the present time.  See the Article below.

      I met up Dr. Flaherty in Boston this past week. He is one of the experts on BRAF inhibitors.

      Here is his comments on the the news below

      Jim,

      Nice meeting you as well.

       Dr. Herlyn’s data is not alone. Many groups have seen and published combination strategies that might take us to the next level beyond BRAF inhibition alone. The challenge is not generating the lab data, but getting in a position where the drugs can be accessed and combined. This has been my focus for the past several years and we are making progress. But not quickly enough.

       

      Keith

      =================================================================================

      Killing Drug-Resistant Melanoma Requires Combination Therapy

      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.

      Disclaimer: This article is not intended to provide medical advice, diagnosis or treatment. Views expressed here do not necessarily reflect those of ScienceDaily or its staff.

      Source:http://www.sciencemagnews.com/killing-drug-resistant-melanoma-requires-combination-therapy.html

      Take care

       

      Jimmy B

      Melanoma Missionary

      http://melanomamissionary.blogspot.com/

      Loading spinner
    Viewing 3 reply threads
    • Replies
        jim Breitfeller
        Participant

          Benefits of BRAF Inhibitor Confirmed in Metastatic Melanoma

          Elsevier Global Medical News. 2010 Nov 5, P Wendling

           

          Phase II trial data confirm that an experimental BRAF inhibitor dramatically shrinks tumors and extends time to disease progression in patients with previously treated BRAF V600 mutation-positive metastatic melanoma, according to a report presented Nov. 5 at the seventh international congress of the Society for Melanoma Research in Sydney.

          Of the 132 patients in the BRIM2 trial who received RG7204, also known as PLX4032, 52% responded with tumor shrinkage of at least 30% for at least two consecutive CT scans as assessed by independent review.

          In all, 82% of patients had either a response (complete response in 3 patients, partial response in 66) or stable disease (39 patients). The median duration of response was 6.8 months.

          Median progression-free survival reached 6.2 months, Dr. Jeffrey Sosman said at the meeting. After a median follow-up of approximately 7 months, 38% of patients were still on treatment.

          "I think the response duration being just over 6 months is a very, very significant advance," co-investigator Dr. Rene Gonzalez said in an interview. "The normal time to progression in one of these patients is 6 to 8 weeks, so this is almost a tripling of their progression-free survival."

          Both investigators pointed out that the findings confirm earlier data, published in the New England Journal of Medicine (N. Engl. J. Med. Aug. 26, 2010;363:809-19), in which 81% of patients with the BRAF mutation treated with RG7204 had at least 30% tumor shrinkage. No significant predictors of progression or response were identified, except for original tumor size and number.

          Dr. Gonzalez said he has no doubt RG7204 will be approved; the question is whether the Food and Drug Administration will do so based on the phase II data or wait until completion of the ongoing phase III BRIM3 trial evaluating overall survival with RG7204 vs. the standard of care, dacarbazine, in patients with previously untreated BRAF V600 mutation-positive metastatic melanoma. The primary end point in that trial is overall survival.

          The anti-CTLA4 antibody ipilimumab is also poised for approval after becoming the first drug to show a survival advantage in refractory melanoma in a phase III trial, but it has problems, particularly with toxicity, said Dr. Gonzalez, who worked on trials for both drugs. "I think for a community practitioner, this drug [RG7204], I have no doubt would be the first-line choice, if they had an option," he said.

          In the current trial patients received RG7204 at a dose of 960 mg twice daily. Grade 3 or greater adverse events were abnormal liver function (14%), joint pain/arthritis (11%) and dysphagia/pancreatitis (10%). The most common adverse events were rash, photosensitivity, hair loss, and joint pain, reported Dr. Sosman, director of the melanoma and tumor immunotherapy program, Vanderbilt-Ingram Cancer Center, Nashville, Tenn. The secondary end point of overall survival had not yet been reached.

          RG7204, which is being codeveloped by Roche Pharmaceuticals and Plexxikon, is a small molecule designed to selectively inhibit the mutated form of the BRAF protein. It is estimated that BRAF mutations are present in about half of melanomas, of which 90% are BRAF V600 mutations.

          RG7204 may benefit patients with other BRAF mutations, but there are much less data in this small population, said Dr. Gonzalez, professor of medicine and director of the University of Colorado at Denver Melanoma Research Clinic.

          So far, the Achilles' heel of RG7204 appears to be resistance. "If you have a patient with a duration of 6 months, you do get resistance," Dr. Gonzalez said. Strides have been made to understand the mechanism of resistance, but one logical solution would be to combine RG7204 with an anti-CTLA4-antibody, which tends not to work as fast but has responses that seem to be more durable, he said, adding, "That buys us some time."

          It might also be possible to abrogate resistance by blocking both the RAF and MEK pathways or by using pan-RAF inhibitors like RAF265 (Novartis Oncology) that block not only BRAF, but other RAF genes, he said.

          Pending a decision by the FDA, plans are underway to open an expanded access program to make RG7204 available to patients with BRAF-mutation-positive advanced melanoma who have received at least one prior treatment, according to Dr. Hal Barron, head of Genentech's global product development and chief medical officer.

          "People with advanced melanoma urgently need more options for treatment and we will continue to work with global health authorities to gather the necessary data to bring this medicine to people with this type of cancer," Dr. Barron said in a statement.

          Disclosures: BRIM2 was sponsored by Genentech and Hoffman-La Roche Ltd. Dr. Sosman has received grant support from Roche and Plexxikon.

          Loading spinner
          jim Breitfeller
          Participant

            Benefits of BRAF Inhibitor Confirmed in Metastatic Melanoma

            Elsevier Global Medical News. 2010 Nov 5, P Wendling

             

            Phase II trial data confirm that an experimental BRAF inhibitor dramatically shrinks tumors and extends time to disease progression in patients with previously treated BRAF V600 mutation-positive metastatic melanoma, according to a report presented Nov. 5 at the seventh international congress of the Society for Melanoma Research in Sydney.

            Of the 132 patients in the BRIM2 trial who received RG7204, also known as PLX4032, 52% responded with tumor shrinkage of at least 30% for at least two consecutive CT scans as assessed by independent review.

            In all, 82% of patients had either a response (complete response in 3 patients, partial response in 66) or stable disease (39 patients). The median duration of response was 6.8 months.

            Median progression-free survival reached 6.2 months, Dr. Jeffrey Sosman said at the meeting. After a median follow-up of approximately 7 months, 38% of patients were still on treatment.

            "I think the response duration being just over 6 months is a very, very significant advance," co-investigator Dr. Rene Gonzalez said in an interview. "The normal time to progression in one of these patients is 6 to 8 weeks, so this is almost a tripling of their progression-free survival."

            Both investigators pointed out that the findings confirm earlier data, published in the New England Journal of Medicine (N. Engl. J. Med. Aug. 26, 2010;363:809-19), in which 81% of patients with the BRAF mutation treated with RG7204 had at least 30% tumor shrinkage. No significant predictors of progression or response were identified, except for original tumor size and number.

            Dr. Gonzalez said he has no doubt RG7204 will be approved; the question is whether the Food and Drug Administration will do so based on the phase II data or wait until completion of the ongoing phase III BRIM3 trial evaluating overall survival with RG7204 vs. the standard of care, dacarbazine, in patients with previously untreated BRAF V600 mutation-positive metastatic melanoma. The primary end point in that trial is overall survival.

            The anti-CTLA4 antibody ipilimumab is also poised for approval after becoming the first drug to show a survival advantage in refractory melanoma in a phase III trial, but it has problems, particularly with toxicity, said Dr. Gonzalez, who worked on trials for both drugs. "I think for a community practitioner, this drug [RG7204], I have no doubt would be the first-line choice, if they had an option," he said.

            In the current trial patients received RG7204 at a dose of 960 mg twice daily. Grade 3 or greater adverse events were abnormal liver function (14%), joint pain/arthritis (11%) and dysphagia/pancreatitis (10%). The most common adverse events were rash, photosensitivity, hair loss, and joint pain, reported Dr. Sosman, director of the melanoma and tumor immunotherapy program, Vanderbilt-Ingram Cancer Center, Nashville, Tenn. The secondary end point of overall survival had not yet been reached.

            RG7204, which is being codeveloped by Roche Pharmaceuticals and Plexxikon, is a small molecule designed to selectively inhibit the mutated form of the BRAF protein. It is estimated that BRAF mutations are present in about half of melanomas, of which 90% are BRAF V600 mutations.

            RG7204 may benefit patients with other BRAF mutations, but there are much less data in this small population, said Dr. Gonzalez, professor of medicine and director of the University of Colorado at Denver Melanoma Research Clinic.

            So far, the Achilles' heel of RG7204 appears to be resistance. "If you have a patient with a duration of 6 months, you do get resistance," Dr. Gonzalez said. Strides have been made to understand the mechanism of resistance, but one logical solution would be to combine RG7204 with an anti-CTLA4-antibody, which tends not to work as fast but has responses that seem to be more durable, he said, adding, "That buys us some time."

            It might also be possible to abrogate resistance by blocking both the RAF and MEK pathways or by using pan-RAF inhibitors like RAF265 (Novartis Oncology) that block not only BRAF, but other RAF genes, he said.

            Pending a decision by the FDA, plans are underway to open an expanded access program to make RG7204 available to patients with BRAF-mutation-positive advanced melanoma who have received at least one prior treatment, according to Dr. Hal Barron, head of Genentech's global product development and chief medical officer.

            "People with advanced melanoma urgently need more options for treatment and we will continue to work with global health authorities to gather the necessary data to bring this medicine to people with this type of cancer," Dr. Barron said in a statement.

            Disclosures: BRIM2 was sponsored by Genentech and Hoffman-La Roche Ltd. Dr. Sosman has received grant support from Roche and Plexxikon.

            Loading spinner
            jag
            Participant

              Jim could you make this easier to understand with some flowcharts and cool cartoons?

              Loading spinner
                jim Breitfeller
                Participant
                   
                  Braf movie
                  Loading spinner
                  jim Breitfeller
                  Participant
                     
                    Braf movie
                    Loading spinner
                    jim Breitfeller
                    Participant

                      BRAF + MEK Pathways in a Melanoma Cancer cell

                      BRAF + MEK pathways

                      By doing the combination Therapy of BRAF + MEK it blocks the cellular proliferation and survival of the Melanoma cancer cell. Death of the cells is by apoptosis.

                      The immune system has evolved to respond not only to pathogens, but also to signals released from dying cells. Cell death through necrosis induces inflammation (Danger Signals) which can lead to efficient antitumor response, whereas apoptotic cell death provides an important signal for tolerance induction. This means that there is no danger signal given so if the therapy doesn't kill all, I mean all, the host will relapse in the near future.

                       

                      Contents of sequestered in Apoptotic Bodies never send the "Danger Signals" which are the proinflammatory cytokines needed start the immune response.

                      Loading spinner
                      jim Breitfeller
                      Participant

                        BRAF + MEK Pathways in a Melanoma Cancer cell

                        BRAF + MEK pathways

                        By doing the combination Therapy of BRAF + MEK it blocks the cellular proliferation and survival of the Melanoma cancer cell. Death of the cells is by apoptosis.

                        The immune system has evolved to respond not only to pathogens, but also to signals released from dying cells. Cell death through necrosis induces inflammation (Danger Signals) which can lead to efficient antitumor response, whereas apoptotic cell death provides an important signal for tolerance induction. This means that there is no danger signal given so if the therapy doesn't kill all, I mean all, the host will relapse in the near future.

                         

                        Contents of sequestered in Apoptotic Bodies never send the "Danger Signals" which are the proinflammatory cytokines needed start the immune response.

                        Loading spinner
                      jag
                      Participant

                        Jim could you make this easier to understand with some flowcharts and cool cartoons?

                        Loading spinner
                    Viewing 3 reply threads
                    • You must be logged in to reply to this topic.
                    About the MRF Patient Forum

                    The MRF Patient Forum is the oldest and largest online community of people affected by melanoma. It is designed to provide peer support and information to caregivers, patients, family and friends. There is no better place to discuss different parts of your journey with this cancer and find the friends and support resources to make that journey more bearable.

                    The information on the forum 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.