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Vemurafenib (PLX4032) promotes epigenetic changes in melanoma cells leading to development of more invasive metastatic disease

Forums General Melanoma Community Vemurafenib (PLX4032) promotes epigenetic changes in melanoma cells leading to development of more invasive metastatic disease

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    CaliforniaCaregiver
    Participant

      An abstract of one of the presentations at

      8th International Congress of The Society for Melanoma Research
      November 9–11, 2011

      The Pennsylvania State University College of Medicine, Hershey, PA,

      An abstract of one of the presentations at

      8th International Congress of The Society for Melanoma Research
      November 9–11, 2011

      The Pennsylvania State University College of Medicine, Hershey, PA,

      PLX4032, clinically known as vemurafenib, is a V600EBRAF selective
      inhibitor. It is effective in patients containing V600EBRAF protein,
      leading to an ~80% partial or complete anti-tumor response rate
      during the first 2 month treatment cycle. An average regression
      period of 2–18 and 6.2 months progression-free survival is observed
      but all patients eventually relapse developing drug resistant invasive
      disease. Recurrence can be caused by secondary BRAF mutations,
      alternate pathways of MAPK reactivation, or activation of compensating
      alternative survival pathways. The mechanisms promoting
      disease recurrence to BRAF targeting agents are an extremely
      important area of research for the clinical management of melanoma,
      which remains to be completely unraveled and the epigenetic
      contribution to this process in unknown. Once the mechanisms are
      completely elucidated, this information would be useful for designing
      better approaches to prevent resistance and disease recurrence.

      This study demonstrates that an acquired more invasive resistant phenotype
      can occur following treatment with BRAF inhibitors by increasing
      methyl transferases activity to promote epigenetic silencing of genes
      regulating this process.

      Vemurafenib treatment led to promoter
      methylation and silencing of the invasion suppressor CD82 in
      melanoma cells. Lack of CD82 in turn increased the invasive potential
      of the cells, promoting migration through vessel and capillary walls,
      thereby aiding development of metastases. Invasive metastatic
      disease mediated by silencing of CD82 could be reversed using
      5-aza-2¢-deoxycytidine (5AzaC), clinically known as decitabine, which
      then decreased the invasive phenotype mediated by these agents.
      These observations suggest that combining BRAF targeting with DNA
      demethylating agents might be one clinically effective approach to
      overcome the development of resistant invasive melanoma following
      treatment with agents such as vemurafenib.

    Viewing 8 reply threads
    • Replies
        JerryfromFauq
        Participant

          Interesting.  We definitely need something to attack the next step after"PLX-4032" stops being effective.  Wish they were freer with the reports from this meeting. 

            FormerCaregiver
            Participant

              Jerry, I agree. Hopefully we can get more info soon. I have read that Dr Roger Lo has been researching this area, with MRF support.

              Take care

              Frank from Australia

              FormerCaregiver
              Participant

                Jerry, I agree. Hopefully we can get more info soon. I have read that Dr Roger Lo has been researching this area, with MRF support.

                Take care

                Frank from Australia

                FormerCaregiver
                Participant

                  Jerry, I agree. Hopefully we can get more info soon. I have read that Dr Roger Lo has been researching this area, with MRF support.

                  Take care

                  Frank from Australia

                JerryfromFauq
                Participant

                  Interesting.  We definitely need something to attack the next step after"PLX-4032" stops being effective.  Wish they were freer with the reports from this meeting. 

                  JerryfromFauq
                  Participant

                    Interesting.  We definitely need something to attack the next step after"PLX-4032" stops being effective.  Wish they were freer with the reports from this meeting. 

                    MichaelFL
                    Participant

                      This is nothing new. Researchers have been aware of this for several years now. As the article states, they're working on it by "designing better approaches to prevent resistance and disease recurrence".

                        killmel
                        Participant

                          The statment: "This study demonstrates that an acquired more invasive resistant phenotype
                          can occur following treatment with BRAF inhibitors by increasingmethyl transferases activity to promote epigenetic silencing of genesregulating this process."

                          I think that the "new" information from the researcher is that once BRAF stops working that acquired  "more invasive" resistant phenotype can occur following treatment with BRAF inhibitors. In other words, ones Braf stops working, the tumor/mel  is more invasive resistant to treatment.

                          My interpretation could be wrong, anyone else have a opinion?

                          killmel
                          Participant

                            The statment: "This study demonstrates that an acquired more invasive resistant phenotype
                            can occur following treatment with BRAF inhibitors by increasingmethyl transferases activity to promote epigenetic silencing of genesregulating this process."

                            I think that the "new" information from the researcher is that once BRAF stops working that acquired  "more invasive" resistant phenotype can occur following treatment with BRAF inhibitors. In other words, ones Braf stops working, the tumor/mel  is more invasive resistant to treatment.

                            My interpretation could be wrong, anyone else have a opinion?

                            MichaelFL
                            Participant

                              Yeah, I guess that is why some patients say it comes back with a vengeance.

                              MichaelFL
                              Participant

                                Yeah, I guess that is why some patients say it comes back with a vengeance.

                                MichaelFL
                                Participant

                                  You gonna post that at MIF too?

                                  MichaelFL
                                  Participant

                                    You gonna post that at MIF too?

                                    MichaelFL
                                    Participant

                                      You gonna post that at MIF too?

                                      MichaelFL
                                      Participant

                                        Yeah, I guess that is why some patients say it comes back with a vengeance.

                                        killmel
                                        Participant

                                          The statment: "This study demonstrates that an acquired more invasive resistant phenotype
                                          can occur following treatment with BRAF inhibitors by increasingmethyl transferases activity to promote epigenetic silencing of genesregulating this process."

                                          I think that the "new" information from the researcher is that once BRAF stops working that acquired  "more invasive" resistant phenotype can occur following treatment with BRAF inhibitors. In other words, ones Braf stops working, the tumor/mel  is more invasive resistant to treatment.

                                          My interpretation could be wrong, anyone else have a opinion?

                                        MichaelFL
                                        Participant

                                          This is nothing new. Researchers have been aware of this for several years now. As the article states, they're working on it by "designing better approaches to prevent resistance and disease recurrence".

                                          MichaelFL
                                          Participant

                                            This is nothing new. Researchers have been aware of this for several years now. As the article states, they're working on it by "designing better approaches to prevent resistance and disease recurrence".

                                            Bailey
                                            Participant

                                              Seems to raise issues to be discussed with clinicians in deciding on treatment strategies:  if both Yervoy and Zelboraf are options, should Yervoy be the first option and Zelboraf the backup, especially if mets are not extensive when treatment for newly-diagnosed patients at Stage IV begins?  Is there a current back-up to Zelboraf when Zelboraf is no longer effective?  Is that realistically Yervoy, since Yervoy apparently takes some months to evoke an effective immunological response even in patients who do respond to it?  Asked this last question of a prominent medical oncologist who has been actively involoved in research on both drugs; response was "that's a good question."  Probably is, but it's also the patient's quality of life and the patient's survival time, and if the order in which treatments are used potentially impacts time of survival, it's an important question in the near term, until an effective way to block the relapses is developed.

                                                mombase
                                                Participant

                                                  My onc and I discussed this prior to deciding the order of treatments. After comparing a new scan with a baseline scan (3 months apart), he asked me what I thought based on my several weeks of research. I told him Yervoy followed by Zelboraf based on the a) fairly low tumor load, b) history of brain tumors, and c) stability of tumors since the last scan. He was in total agreement. I feel pretty fortunate that the answer was so obvious and straight-forward for me!

                                                  Cristy, Stage IV

                                                  mombase
                                                  Participant

                                                    My onc and I discussed this prior to deciding the order of treatments. After comparing a new scan with a baseline scan (3 months apart), he asked me what I thought based on my several weeks of research. I told him Yervoy followed by Zelboraf based on the a) fairly low tumor load, b) history of brain tumors, and c) stability of tumors since the last scan. He was in total agreement. I feel pretty fortunate that the answer was so obvious and straight-forward for me!

                                                    Cristy, Stage IV

                                                    mombase
                                                    Participant

                                                      My onc and I discussed this prior to deciding the order of treatments. After comparing a new scan with a baseline scan (3 months apart), he asked me what I thought based on my several weeks of research. I told him Yervoy followed by Zelboraf based on the a) fairly low tumor load, b) history of brain tumors, and c) stability of tumors since the last scan. He was in total agreement. I feel pretty fortunate that the answer was so obvious and straight-forward for me!

                                                      Cristy, Stage IV

                                                    Bailey
                                                    Participant

                                                      Seems to raise issues to be discussed with clinicians in deciding on treatment strategies:  if both Yervoy and Zelboraf are options, should Yervoy be the first option and Zelboraf the backup, especially if mets are not extensive when treatment for newly-diagnosed patients at Stage IV begins?  Is there a current back-up to Zelboraf when Zelboraf is no longer effective?  Is that realistically Yervoy, since Yervoy apparently takes some months to evoke an effective immunological response even in patients who do respond to it?  Asked this last question of a prominent medical oncologist who has been actively involoved in research on both drugs; response was "that's a good question."  Probably is, but it's also the patient's quality of life and the patient's survival time, and if the order in which treatments are used potentially impacts time of survival, it's an important question in the near term, until an effective way to block the relapses is developed.

                                                      Bailey
                                                      Participant

                                                        Seems to raise issues to be discussed with clinicians in deciding on treatment strategies:  if both Yervoy and Zelboraf are options, should Yervoy be the first option and Zelboraf the backup, especially if mets are not extensive when treatment for newly-diagnosed patients at Stage IV begins?  Is there a current back-up to Zelboraf when Zelboraf is no longer effective?  Is that realistically Yervoy, since Yervoy apparently takes some months to evoke an effective immunological response even in patients who do respond to it?  Asked this last question of a prominent medical oncologist who has been actively involoved in research on both drugs; response was "that's a good question."  Probably is, but it's also the patient's quality of life and the patient's survival time, and if the order in which treatments are used potentially impacts time of survival, it's an important question in the near term, until an effective way to block the relapses is developed.

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