› Forums › General Melanoma Community › Vemurafenib (PLX4032) promotes epigenetic changes in melanoma cells leading to development of more invasive metastatic disease
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- October 31, 2011 at 12:43 am
An abstract of one of the presentations at
8th International Congress of The Society for Melanoma Research
November 9–11, 2011The 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, 2011The 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.
- Replies
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- October 31, 2011 at 8:30 am
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.
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- November 8, 2011 at 1:20 am
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
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- November 8, 2011 at 1:20 am
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
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- November 8, 2011 at 1:20 am
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
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- October 31, 2011 at 8:30 am
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.
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- October 31, 2011 at 8:30 am
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.
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- October 31, 2011 at 4:06 pm
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".
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- October 31, 2011 at 4:33 pm
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?
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- October 31, 2011 at 4:33 pm
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?
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- October 31, 2011 at 4:33 pm
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?
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- November 10, 2011 at 9:46 pm
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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- November 11, 2011 at 12:56 am
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
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- November 11, 2011 at 12:56 am
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
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- November 11, 2011 at 12:56 am
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
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- November 10, 2011 at 9:46 pm
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.
-
- November 10, 2011 at 9:46 pm
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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