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Really down and need a pick me up

Forums General Melanoma Community Really down and need a pick me up

  • Post
    Linda J
    Participant

    Hi survivor family

    I'm six weeks out of surgery that removed 10 lymph nodes (5 positive) and a larger tumor around my hip/bum.  I have had local reoccurances since the surgery and I am freaking out.  I have a CT scan and a brain MRI this week but I am in a complete funk while I'm in the "in between". 

    I have all kinds of weird feelings and pains and twinges that I'm now thinking is the cancer spreading all over – my body is a stranger to me. 

    Hi survivor family

    I'm six weeks out of surgery that removed 10 lymph nodes (5 positive) and a larger tumor around my hip/bum.  I have had local reoccurances since the surgery and I am freaking out.  I have a CT scan and a brain MRI this week but I am in a complete funk while I'm in the "in between". 

    I have all kinds of weird feelings and pains and twinges that I'm now thinking is the cancer spreading all over – my body is a stranger to me. 

    I will likely start a some kind of clinical trial in the new year but I am feeling like I'm finding a new subq like every 4 days and what if my body doesn't make it until the new year?! 

    I'm BRaf positive and my PET scan in September was clear (minus the tumors in my groin/butt they already knew about). 

    I'm trying to hold it together for my son (2 years old) and family over the holidays but I really really just need some positive stories to know that it is possible for me to make it to treatment and then beat this devil disease once I'm in treatment. 

    If there is hopeful stories out there, please send them my way!

    Thanks!

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  • Replies
      Fen
      Participant

      Linda – you said it perfectly when you said "my body is a stranger to me".  I remember feeling the same way between the time I was diagnosed and my PET/CT scan. I had all sorts of aches and pains and weird symptoms – they turned out to be the result of stress and worry.  Scanxiety does strange things to us all and you are in the added position of not knowing what treatment you'll be doing soon.    Our tendency is always to assume the worst – but many times that's not the case.   

      My symptoms disappeared after my pet scan and a treatment plan was in place.  Do the best you can over the holidays. I hope that some of the people on the board who have had similar situations will chime in.   

      Fen

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      Fen
      Participant

      Linda – you said it perfectly when you said "my body is a stranger to me".  I remember feeling the same way between the time I was diagnosed and my PET/CT scan. I had all sorts of aches and pains and weird symptoms – they turned out to be the result of stress and worry.  Scanxiety does strange things to us all and you are in the added position of not knowing what treatment you'll be doing soon.    Our tendency is always to assume the worst – but many times that's not the case.   

      My symptoms disappeared after my pet scan and a treatment plan was in place.  Do the best you can over the holidays. I hope that some of the people on the board who have had similar situations will chime in.   

      Fen

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      killmel
      Participant

      I totally understand what you are going through. I am having scans & think the worse because I have a tumor growing daily. I too am depressed because I donot think the treatment available are all that good.Just a band aid waiting for another recurrence.

      Even with scans, you cannot always believe the radiologist read the scans correctly.I have heard of horror stories of missed tumors. Have happened to me too. Your scans are only asgood as the radiologist that reads them

      Wish I could give you a happy story.Can only says I know exactly how you feel. Hope your story has a happy ending!

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      killmel
      Participant

      I totally understand what you are going through. I am having scans & think the worse because I have a tumor growing daily. I too am depressed because I donot think the treatment available are all that good.Just a band aid waiting for another recurrence.

      Even with scans, you cannot always believe the radiologist read the scans correctly.I have heard of horror stories of missed tumors. Have happened to me too. Your scans are only asgood as the radiologist that reads them

      Wish I could give you a happy story.Can only says I know exactly how you feel. Hope your story has a happy ending!

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      King
      Participant

      Hi Linda,

      I clicked on your name but it brought me to a profile of another Linda J.  One of the most important pieces of advice that I have to give is to be certain that you are being treated at a well respected melanoma center if at all possible.  Do you know if clear margins were obtained after your WLE?  I credit a big part of my survival to my surgeon who was very aggressive.  I guess i'm wondering about these local recurrences possibly being a result of not getting enough tissue at the time of surgery.

      The waiting time is tough and I can't guarantee that will get any better with time.  I would think a 2 year old can get your mind off of it some (or cause more worry, I guess).

      Being BRAF positive has to be a plus.  And I'm not certain that we ever adjust completely to our new body and battle scars.

      This is my story of hope.  I was diagnosed at Stage III with an unknown primary site in 2004 (over 6 years ago!).  I had a groin lymph node removal followed by the full 12 months of Interferon.  Ten weeks later on a routine scan, a mass was discovered on my liver.  I was told that without an effective treatment that my life expectancy was 6 months or less (that was 5 years ago!).  I had a liver resection (70% of my liver removed..that's the maximum amount of liver tissue that can be removed) followed by 12 months in a Phase II clinical trial of GM-CSF (trial results have recently been published and this has shown to be of no benefit).  In 2008, melanoma was back in 2 locations…around my pancreas and a subq in my butt/hip area.  Things were not looking good at all.  After considering the few options that existed, my surgeon agreed to try once again to surgically remove the mass.  He told us that there was a 50-50 chance of being able to remove it (he knew the subq could be removed).  He did it once again!  This was even a longer and more tedious surgery than the liver resection but it brought me back to NED (no evidence of disease) once again.  I have had no recurrences since.  Yes, I do live with after effects from these surgeries but I am still alive and well in my opinion.

      Hang onto hope!  Do your research, pick your treatment and believe in it.

      Please keep us posted.  Try real hard to enjoy these holidays…don't let melanoma steal your joy.

      Stay Strong
      King

      Stage IV 7/05 Liver mets

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      King
      Participant

      Hi Linda,

      I clicked on your name but it brought me to a profile of another Linda J.  One of the most important pieces of advice that I have to give is to be certain that you are being treated at a well respected melanoma center if at all possible.  Do you know if clear margins were obtained after your WLE?  I credit a big part of my survival to my surgeon who was very aggressive.  I guess i'm wondering about these local recurrences possibly being a result of not getting enough tissue at the time of surgery.

      The waiting time is tough and I can't guarantee that will get any better with time.  I would think a 2 year old can get your mind off of it some (or cause more worry, I guess).

      Being BRAF positive has to be a plus.  And I'm not certain that we ever adjust completely to our new body and battle scars.

      This is my story of hope.  I was diagnosed at Stage III with an unknown primary site in 2004 (over 6 years ago!).  I had a groin lymph node removal followed by the full 12 months of Interferon.  Ten weeks later on a routine scan, a mass was discovered on my liver.  I was told that without an effective treatment that my life expectancy was 6 months or less (that was 5 years ago!).  I had a liver resection (70% of my liver removed..that's the maximum amount of liver tissue that can be removed) followed by 12 months in a Phase II clinical trial of GM-CSF (trial results have recently been published and this has shown to be of no benefit).  In 2008, melanoma was back in 2 locations…around my pancreas and a subq in my butt/hip area.  Things were not looking good at all.  After considering the few options that existed, my surgeon agreed to try once again to surgically remove the mass.  He told us that there was a 50-50 chance of being able to remove it (he knew the subq could be removed).  He did it once again!  This was even a longer and more tedious surgery than the liver resection but it brought me back to NED (no evidence of disease) once again.  I have had no recurrences since.  Yes, I do live with after effects from these surgeries but I am still alive and well in my opinion.

      Hang onto hope!  Do your research, pick your treatment and believe in it.

      Please keep us posted.  Try real hard to enjoy these holidays…don't let melanoma steal your joy.

      Stay Strong
      King

      Stage IV 7/05 Liver mets

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      Erica A
      Participant

      My husband had a very agressive melanoma and went stage IV with 17 tumors throughout his body – that was 5.5 years ago and he has been cancer-free ever since.  (all details in profile)  There is a lot of hope and new treatments are popping up every day – there are lots of reasons to be positive.

      With all that said, it's hard to stay positive all the time and one of my husband's complaints when he was in the middle of his treatments was that no one would let him be scared and talk about his feelings that he needed to deal with.  It was obviously hard for his family to hear him talk about his insecurities because we always felt like we had to "cheer him up".  I think you need someone that can listen to how scared you are, because even if there is a lot of hope – it's still scary.  This community helps, but an outside voice might help as well.

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      Erica A
      Participant

      My husband had a very agressive melanoma and went stage IV with 17 tumors throughout his body – that was 5.5 years ago and he has been cancer-free ever since.  (all details in profile)  There is a lot of hope and new treatments are popping up every day – there are lots of reasons to be positive.

      With all that said, it's hard to stay positive all the time and one of my husband's complaints when he was in the middle of his treatments was that no one would let him be scared and talk about his feelings that he needed to deal with.  It was obviously hard for his family to hear him talk about his insecurities because we always felt like we had to "cheer him up".  I think you need someone that can listen to how scared you are, because even if there is a lot of hope – it's still scary.  This community helps, but an outside voice might help as well.

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      Ninja
      Participant

      Hi Linda,

      I think I understand what you are going through. My husband was diagnosed 6 years ago (stage IIIa  – 2 sentinel nodes positive).  It is hard and very scary at times. And I also want to tell you that my husband too, felt all kinds of aches and pains, specially the first year after being diagnosed…luckily every time it turned out to be nothing!!!

      As another person wrote to you on this board, try to find someone that listens to you  and don't keep everything inside!!!!!

      As I said, my husband was diagnosed 6 years ago and he has been NED since and there are so many other long term survivors on this board…you will be one of them!!!!!

      Consuelo

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      Ninja
      Participant

      Hi Linda,

      I think I understand what you are going through. My husband was diagnosed 6 years ago (stage IIIa  – 2 sentinel nodes positive).  It is hard and very scary at times. And I also want to tell you that my husband too, felt all kinds of aches and pains, specially the first year after being diagnosed…luckily every time it turned out to be nothing!!!

      As another person wrote to you on this board, try to find someone that listens to you  and don't keep everything inside!!!!!

      As I said, my husband was diagnosed 6 years ago and he has been NED since and there are so many other long term survivors on this board…you will be one of them!!!!!

      Consuelo

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      Carmon in NM
      Participant

      I think everyone here understands what you are going through and how incredibly hard the waiting is. We all do so much better when we can feel like we are doing something!

      I was diagnosed 3b 9/2008 and was on a 'wait and watch' protocol. After almost two whole years of clear scans, we were beginning to feel pretty positive when an unseen brain tumor began bleeding into my brain last June. One emergency craniotomy later and Gamma Knife Surgery on *two* brain tumors and I had been uncerimoniously kicked up to Stage 4.

      The good news had been the full body CT done at the time of the brain bleed showed no other mets anywhere. Then a follow up scan in September showed a 2.4X2.4 centimeter tumor on my right adrenal gland. It had gotten that big in three months and was causing me terrible pain.

      We decided on a clinical trial rather than immediate surgery to see if we could use it as 'the canary in the coal mine' to find something that will work on my brand of mel. I am on a phase II trial of carboplatin/carbotaxil/temodar and here is the Oh So Happy News! After only two infusions, the adrenal tumor has shrunk by better than 50% and no new tumors!!!

      So don't give up hope and never stop fighting! I was pretty down and my husband I both felt like the rug had been jerked out from under us too many times,  I was dreading the idea of more surgery and almost welcomed the respite of a drug trial for six months first.

      I have lots and lots of odd nerve pains all through my body from damage done to major nerves during surgeries and I imagine that is what you are experiencing too since they went so deep. One suggestion I have for you is to find a good acupuncturist with experience in working with cancer patients. They can do wonders to calm down those damaged nerve meridians and help to keep your body in balance. Your spirits too.  If you start a drug trial, they can also help to keep your red blood cell levels in a good range.

      You will be in my praryers and I hope you find some peace for Christmas – Carmon

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      Carmon in NM
      Participant

      I think everyone here understands what you are going through and how incredibly hard the waiting is. We all do so much better when we can feel like we are doing something!

      I was diagnosed 3b 9/2008 and was on a 'wait and watch' protocol. After almost two whole years of clear scans, we were beginning to feel pretty positive when an unseen brain tumor began bleeding into my brain last June. One emergency craniotomy later and Gamma Knife Surgery on *two* brain tumors and I had been uncerimoniously kicked up to Stage 4.

      The good news had been the full body CT done at the time of the brain bleed showed no other mets anywhere. Then a follow up scan in September showed a 2.4X2.4 centimeter tumor on my right adrenal gland. It had gotten that big in three months and was causing me terrible pain.

      We decided on a clinical trial rather than immediate surgery to see if we could use it as 'the canary in the coal mine' to find something that will work on my brand of mel. I am on a phase II trial of carboplatin/carbotaxil/temodar and here is the Oh So Happy News! After only two infusions, the adrenal tumor has shrunk by better than 50% and no new tumors!!!

      So don't give up hope and never stop fighting! I was pretty down and my husband I both felt like the rug had been jerked out from under us too many times,  I was dreading the idea of more surgery and almost welcomed the respite of a drug trial for six months first.

      I have lots and lots of odd nerve pains all through my body from damage done to major nerves during surgeries and I imagine that is what you are experiencing too since they went so deep. One suggestion I have for you is to find a good acupuncturist with experience in working with cancer patients. They can do wonders to calm down those damaged nerve meridians and help to keep your body in balance. Your spirits too.  If you start a drug trial, they can also help to keep your red blood cell levels in a good range.

      You will be in my praryers and I hope you find some peace for Christmas – Carmon

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      Sharyn
      Participant

      Hi Linda,

      It's always horrible feeling like that, but Christmas time seems to accentuate everything. When I was diagnosed, they gave me 3 mos to 3 yrs max. That was 5 years ago. I have had about 25 sub-qs excised, and a considerable number of treatments. You can see them all listed below my signature. When they discovered brain mets in Oct/09, they gave me 6 mos. I'm still here, and furthermore, if you ever met me, you would never know there's anything wrong with me. As a matter of fact, I went to the gym yesterday to see about a membership so my husband can give it to me for Christmas. One thing to which I credit my continued good health (mel aside) is this forum. I have fiercely researched melanoma, and taken control of my own treatments (like, I find a clinical trial, I tell my Dr I want to do it, and he supports me). But most of my knowledge and links to helpful articles have come from the members on this board — a truly incredible bunch!. I also credit my own ability to stay positive, even when I continue to advance. Getting bad news doesn't throw me into depression, but rather it fuels my determination to keep this disease under control, and I seek new trials. I know I will never be cured, but if I can keep it reigned in as a chronic disease for as long as possible, I'm alright with that.

      Please, Linda, do calm down, take a deep breath, and enjoy every moment with your precious little boy. You are a long way off from dying, and in the meantime, there a many, many treatment options out there. And with every day that passes, new treatments are being discovered. Right now I am in the compassionate use ipilimumab trial, and it is the first treatment I have had to date that is showing positive results.

      I do hope you can be at peace with this. I wish you a wonderful Christmas, and a healthy, positive 2011.

      Hugs

      Sharyn, Stage IV 

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      Sharyn
      Participant

      Hi Linda,

      It's always horrible feeling like that, but Christmas time seems to accentuate everything. When I was diagnosed, they gave me 3 mos to 3 yrs max. That was 5 years ago. I have had about 25 sub-qs excised, and a considerable number of treatments. You can see them all listed below my signature. When they discovered brain mets in Oct/09, they gave me 6 mos. I'm still here, and furthermore, if you ever met me, you would never know there's anything wrong with me. As a matter of fact, I went to the gym yesterday to see about a membership so my husband can give it to me for Christmas. One thing to which I credit my continued good health (mel aside) is this forum. I have fiercely researched melanoma, and taken control of my own treatments (like, I find a clinical trial, I tell my Dr I want to do it, and he supports me). But most of my knowledge and links to helpful articles have come from the members on this board — a truly incredible bunch!. I also credit my own ability to stay positive, even when I continue to advance. Getting bad news doesn't throw me into depression, but rather it fuels my determination to keep this disease under control, and I seek new trials. I know I will never be cured, but if I can keep it reigned in as a chronic disease for as long as possible, I'm alright with that.

      Please, Linda, do calm down, take a deep breath, and enjoy every moment with your precious little boy. You are a long way off from dying, and in the meantime, there a many, many treatment options out there. And with every day that passes, new treatments are being discovered. Right now I am in the compassionate use ipilimumab trial, and it is the first treatment I have had to date that is showing positive results.

      I do hope you can be at peace with this. I wish you a wonderful Christmas, and a healthy, positive 2011.

      Hugs

      Sharyn, Stage IV 

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        killmel
        Participant

        Sharyn

        So happy to see your positive. You attitude is remarkable.

        How about an update-Did you get the results of the scans yet.

        How is has IPI effected your mel…any shrinkage, etc.

        Wishing you & your family a wonderful holiday.

        Jan

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        killmel
        Participant

        Sharyn

        So happy to see your positive. You attitude is remarkable.

        How about an update-Did you get the results of the scans yet.

        How is has IPI effected your mel…any shrinkage, etc.

        Wishing you & your family a wonderful holiday.

        Jan

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      jim Breitfeller
      Participant

      Linda,

      Christmas is a time for sharing, so I am going to share with you some information. It is time to play the BRAF card. Mid December I wen to Boston to meet up a another Melanoma patient  and to See the "Wizzard of BRAF" Dr. Keith Flaherty at MGH. I have been told that the Combination of GSK's BRAF and MEK therapy is showing great responses.

      Also, Just out is a paper called " Targeting BRAF for patients with melanoma"

       from the British Journal of Cancer advance online publication, 7 December 2010.

      Then some research has just been published by Dr. Meenhard Herlyn at the Wistar

      "Killing Drug-Resistant Melanoma Requires Combination Therapy" (BRAF + MEK) in the December 14 issue of the journal Cancer Cell

       

      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

       

      So jump on the Clinical trials website and look for GSK Braf and MEK

       

      Investigate Safety, Pharmacokinetics and Pharmacodynamics of GSK2118436 & GSK1120212
      This study is currently recruiting participants.
      Verified by GlaxoSmithKline, July 2010
       
      Contacts and Locations

      Please refer to this study by its ClinicalTrials.gov identifier: NCT01072175

      Contacts
      Contact: US GSK Clinical Trials Call Center 877-379-3718  

      Locations
      United States, Florida
      GSK Investigational Site Recruiting
      Tampa, Florida, United States, 33612
      Principal Investigator: Jeffrey Weber            
      United States, Massachusetts
      GSK Investigational Site Not yet recruiting
      Boston, Massachusetts, United States, 02114
      Principal Investigator: Keith T Flaherty            
      United States, Tennessee
      GSK Investigational Site Recruiting
      Nashville, Tennessee, United States, 37203
      Principal Investigator: Jeffrey R Infante            
      United States, Texas
      GSK Investigational Site Recruiting
      Houston, Texas, United States, 77030
      Principal Investigator: Gerald Falchook            

      Sponsors and Collaborators
      GlaxoSmithKline

      Investigators
      Study Director: GSK Clinical Trials GlaxoSmithKline

       

      Melanoma Missionary

      Take care and Merry Christmas!!!!!

       

      Jimmy B

       

       

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      jim Breitfeller
      Participant

      Linda,

      Christmas is a time for sharing, so I am going to share with you some information. It is time to play the BRAF card. Mid December I wen to Boston to meet up a another Melanoma patient  and to See the "Wizzard of BRAF" Dr. Keith Flaherty at MGH. I have been told that the Combination of GSK's BRAF and MEK therapy is showing great responses.

      Also, Just out is a paper called " Targeting BRAF for patients with melanoma"

       from the British Journal of Cancer advance online publication, 7 December 2010.

      Then some research has just been published by Dr. Meenhard Herlyn at the Wistar

      "Killing Drug-Resistant Melanoma Requires Combination Therapy" (BRAF + MEK) in the December 14 issue of the journal Cancer Cell

       

      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

       

      So jump on the Clinical trials website and look for GSK Braf and MEK

       

      Investigate Safety, Pharmacokinetics and Pharmacodynamics of GSK2118436 & GSK1120212
      This study is currently recruiting participants.
      Verified by GlaxoSmithKline, July 2010
       
      Contacts and Locations

      Please refer to this study by its ClinicalTrials.gov identifier: NCT01072175

      Contacts
      Contact: US GSK Clinical Trials Call Center 877-379-3718  

      Locations
      United States, Florida
      GSK Investigational Site Recruiting
      Tampa, Florida, United States, 33612
      Principal Investigator: Jeffrey Weber            
      United States, Massachusetts
      GSK Investigational Site Not yet recruiting
      Boston, Massachusetts, United States, 02114
      Principal Investigator: Keith T Flaherty            
      United States, Tennessee
      GSK Investigational Site Recruiting
      Nashville, Tennessee, United States, 37203
      Principal Investigator: Jeffrey R Infante            
      United States, Texas
      GSK Investigational Site Recruiting
      Houston, Texas, United States, 77030
      Principal Investigator: Gerald Falchook            

      Sponsors and Collaborators
      GlaxoSmithKline

      Investigators
      Study Director: GSK Clinical Trials GlaxoSmithKline

       

      Melanoma Missionary

      Take care and Merry Christmas!!!!!

       

      Jimmy B

       

       

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