› Forums › General Melanoma Community › Diagram of Melanoma Pathways
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CHD.
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- April 19, 2016 at 8:23 pm
With greater treatment options for melanoma, questions about what they all mean and the cellular pathways in which they are supposed to operate become more pressing and often confusing. Where does NRAS, BRAF, MEK, ERK, CDK4 and 6 fit in???? Sometimes a picture is worth a thousand words. I posted this some time ago…but thought it might help some of you….
Wishing you all my best. Celeste
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- April 20, 2016 at 3:01 pm
Ok!!! Celeste this is pretty good, now if you could find the same diagram with the names of the drugs in brackets beside the mutation then I would be very impressed. Thanks for sharing, I think I might just change my desktop background from our new little puppy(Australian sheppard) to your Melanoma science chart. Ed
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- April 20, 2016 at 3:01 pm
Ok!!! Celeste this is pretty good, now if you could find the same diagram with the names of the drugs in brackets beside the mutation then I would be very impressed. Thanks for sharing, I think I might just change my desktop background from our new little puppy(Australian sheppard) to your Melanoma science chart. Ed
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- April 20, 2016 at 3:01 pm
Ok!!! Celeste this is pretty good, now if you could find the same diagram with the names of the drugs in brackets beside the mutation then I would be very impressed. Thanks for sharing, I think I might just change my desktop background from our new little puppy(Australian sheppard) to your Melanoma science chart. Ed
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- April 21, 2016 at 12:40 am
Celeste:
This is good information. I can offer a bit of guidance on this.
A signaling pathway is the way messages are communicated from outside the cell to the cell nucleus. This diagram shows activity that is happening between those two areas, with the activity at the cell membrane being at the top of the diagram and the activity closer to the cell nucleus being at the bottom.
At the top the diagram shows GNAQ/GNA11. These proteins actually sit across the cell membrane, interacting with the outside and the inside. They are the cause of virtually all uveal melanomas, or melanoma in the eye. To my knowledge they are rarely or never mutated in other forms of melanoma.
Also near the top is PTEN (pea-ten). This compound is a tumor suppressor; it inhibits cell growth. It is often affected by sun damage and chronically sun damaged skin will have what are called PTEN deletions. This means the cell is lacking the tumor suppressor function that PTEN normally offers. Some studies have been done with drugs attempting to block the next step in that path–PI3K.
The other item near the top is c-kit. A mutation here is more common in mucosal melanoma, but can also occur in cutaneous. Good c-kit inhibitors are on the market and some people have a positive response.
The red pathway is dominated by BRAF (bee-raf). Zelboraf (vemurafenib) and Tafinlar (dabrafenib) are approved BRAF inhibitors. These inhibitors work best when paired with compounds that block the next step in the path–MEK. MEK inhibitors are Cotellic (cobimetinib) and Mekinist (trametinib).
About half of melanomas have a mutation in BRAF. BRAF mutations actually are present in many benign nevi as well, so clearly a second factor is necessary to move a nevus to being melanoma.
Roughly 20% of melanomas have mutated NRAS (the step above BRAF) but studies to find drugs blocking NRAS have been disappointing.
All of this relates to Targeted Therapy–an attempt to go into the tumor cell and shut down the mechanism that is causing it to grow out of control. A lot of interest still exists around trying to block various compounds in that chart.
Immunotherapy is a very different animal. Rather than trying to kill or shut down the tumor cells, immunotherapy seeks to activate the body's immune system to attack the tumor cells.
And both of these are different from chemotherapy. Chemotherapy basically introduces poison into the body. The cells that grow quickly take up more poison and are killed. The challenge is to give enough poison that the cancer cells are killed, but not so much that normal cells are killed. This only works because cancer cells grow very fast. Of course, so do hair cells and the lining of the stomach, so chemotherapy often leads to nausea and hair loss. Chemotherapy does not work very well in melanoma.
Tim–MRF
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- April 21, 2016 at 12:40 am
Celeste:
This is good information. I can offer a bit of guidance on this.
A signaling pathway is the way messages are communicated from outside the cell to the cell nucleus. This diagram shows activity that is happening between those two areas, with the activity at the cell membrane being at the top of the diagram and the activity closer to the cell nucleus being at the bottom.
At the top the diagram shows GNAQ/GNA11. These proteins actually sit across the cell membrane, interacting with the outside and the inside. They are the cause of virtually all uveal melanomas, or melanoma in the eye. To my knowledge they are rarely or never mutated in other forms of melanoma.
Also near the top is PTEN (pea-ten). This compound is a tumor suppressor; it inhibits cell growth. It is often affected by sun damage and chronically sun damaged skin will have what are called PTEN deletions. This means the cell is lacking the tumor suppressor function that PTEN normally offers. Some studies have been done with drugs attempting to block the next step in that path–PI3K.
The other item near the top is c-kit. A mutation here is more common in mucosal melanoma, but can also occur in cutaneous. Good c-kit inhibitors are on the market and some people have a positive response.
The red pathway is dominated by BRAF (bee-raf). Zelboraf (vemurafenib) and Tafinlar (dabrafenib) are approved BRAF inhibitors. These inhibitors work best when paired with compounds that block the next step in the path–MEK. MEK inhibitors are Cotellic (cobimetinib) and Mekinist (trametinib).
About half of melanomas have a mutation in BRAF. BRAF mutations actually are present in many benign nevi as well, so clearly a second factor is necessary to move a nevus to being melanoma.
Roughly 20% of melanomas have mutated NRAS (the step above BRAF) but studies to find drugs blocking NRAS have been disappointing.
All of this relates to Targeted Therapy–an attempt to go into the tumor cell and shut down the mechanism that is causing it to grow out of control. A lot of interest still exists around trying to block various compounds in that chart.
Immunotherapy is a very different animal. Rather than trying to kill or shut down the tumor cells, immunotherapy seeks to activate the body's immune system to attack the tumor cells.
And both of these are different from chemotherapy. Chemotherapy basically introduces poison into the body. The cells that grow quickly take up more poison and are killed. The challenge is to give enough poison that the cancer cells are killed, but not so much that normal cells are killed. This only works because cancer cells grow very fast. Of course, so do hair cells and the lining of the stomach, so chemotherapy often leads to nausea and hair loss. Chemotherapy does not work very well in melanoma.
Tim–MRF
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- April 21, 2016 at 1:20 pm
This is like getting your parents to do your Science project for you in the 5th grade. Thanks Tim !!!! Celeste bye the way, have you been looking at the American Association for cancer Research information coming out of New Orleans, Michael Postow and Mario Sznol posted some more data. I have been following( At OmidHamidmd) on twitter and if you click on the peerview stuff it is pretty interesting and one extra bonus there are some pretty nice new charts that you can add to your collection. The best chart is titled" Emerging Combination Strategies: What to Choose, When, and for Whom? " presented by Mario Sznol, Mike Postow. Best wishes!!! Ed
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- April 21, 2016 at 1:20 pm
This is like getting your parents to do your Science project for you in the 5th grade. Thanks Tim !!!! Celeste bye the way, have you been looking at the American Association for cancer Research information coming out of New Orleans, Michael Postow and Mario Sznol posted some more data. I have been following( At OmidHamidmd) on twitter and if you click on the peerview stuff it is pretty interesting and one extra bonus there are some pretty nice new charts that you can add to your collection. The best chart is titled" Emerging Combination Strategies: What to Choose, When, and for Whom? " presented by Mario Sznol, Mike Postow. Best wishes!!! Ed
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- April 23, 2016 at 9:52 pm
Hi Maria, if you go to ( @omidhamidmd) then go to his tweet third one down with first name "Naijer Rizvi @ columbia and Ed Garon @ UCLAJCCC——" about half way through the title you will see "@ peer View slides" click on blue Peerview and it will open home page of peer view Press and then look down to diagrams and the first ones are about Immunotherapies and T-Cells and Immune-Related Toxicity Management: Hope this helps!!! If you spend some time looking at some of the other tweets from Dr. Omid Hamid you will also find about 10 tweets down a tweet titled " Hey #AACR16 New Directions # Immunotherapy A Cross- Tumor Exploration Checkpoint Blockade #Rizvi # Garon and Me" click on the link to peer View then slide down to Downloads ( click on slides) and you have about 90 graphs tables charts that Dr.Omid will use in his presentation. Good luck and I hope you could follow my directions.Ed
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- April 23, 2016 at 9:52 pm
Hi Maria, if you go to ( @omidhamidmd) then go to his tweet third one down with first name "Naijer Rizvi @ columbia and Ed Garon @ UCLAJCCC——" about half way through the title you will see "@ peer View slides" click on blue Peerview and it will open home page of peer view Press and then look down to diagrams and the first ones are about Immunotherapies and T-Cells and Immune-Related Toxicity Management: Hope this helps!!! If you spend some time looking at some of the other tweets from Dr. Omid Hamid you will also find about 10 tweets down a tweet titled " Hey #AACR16 New Directions # Immunotherapy A Cross- Tumor Exploration Checkpoint Blockade #Rizvi # Garon and Me" click on the link to peer View then slide down to Downloads ( click on slides) and you have about 90 graphs tables charts that Dr.Omid will use in his presentation. Good luck and I hope you could follow my directions.Ed
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- April 23, 2016 at 9:52 pm
Hi Maria, if you go to ( @omidhamidmd) then go to his tweet third one down with first name "Naijer Rizvi @ columbia and Ed Garon @ UCLAJCCC——" about half way through the title you will see "@ peer View slides" click on blue Peerview and it will open home page of peer view Press and then look down to diagrams and the first ones are about Immunotherapies and T-Cells and Immune-Related Toxicity Management: Hope this helps!!! If you spend some time looking at some of the other tweets from Dr. Omid Hamid you will also find about 10 tweets down a tweet titled " Hey #AACR16 New Directions # Immunotherapy A Cross- Tumor Exploration Checkpoint Blockade #Rizvi # Garon and Me" click on the link to peer View then slide down to Downloads ( click on slides) and you have about 90 graphs tables charts that Dr.Omid will use in his presentation. Good luck and I hope you could follow my directions.Ed
-
- April 21, 2016 at 1:20 pm
This is like getting your parents to do your Science project for you in the 5th grade. Thanks Tim !!!! Celeste bye the way, have you been looking at the American Association for cancer Research information coming out of New Orleans, Michael Postow and Mario Sznol posted some more data. I have been following( At OmidHamidmd) on twitter and if you click on the peerview stuff it is pretty interesting and one extra bonus there are some pretty nice new charts that you can add to your collection. The best chart is titled" Emerging Combination Strategies: What to Choose, When, and for Whom? " presented by Mario Sznol, Mike Postow. Best wishes!!! Ed
-
- April 21, 2016 at 12:40 am
Celeste:
This is good information. I can offer a bit of guidance on this.
A signaling pathway is the way messages are communicated from outside the cell to the cell nucleus. This diagram shows activity that is happening between those two areas, with the activity at the cell membrane being at the top of the diagram and the activity closer to the cell nucleus being at the bottom.
At the top the diagram shows GNAQ/GNA11. These proteins actually sit across the cell membrane, interacting with the outside and the inside. They are the cause of virtually all uveal melanomas, or melanoma in the eye. To my knowledge they are rarely or never mutated in other forms of melanoma.
Also near the top is PTEN (pea-ten). This compound is a tumor suppressor; it inhibits cell growth. It is often affected by sun damage and chronically sun damaged skin will have what are called PTEN deletions. This means the cell is lacking the tumor suppressor function that PTEN normally offers. Some studies have been done with drugs attempting to block the next step in that path–PI3K.
The other item near the top is c-kit. A mutation here is more common in mucosal melanoma, but can also occur in cutaneous. Good c-kit inhibitors are on the market and some people have a positive response.
The red pathway is dominated by BRAF (bee-raf). Zelboraf (vemurafenib) and Tafinlar (dabrafenib) are approved BRAF inhibitors. These inhibitors work best when paired with compounds that block the next step in the path–MEK. MEK inhibitors are Cotellic (cobimetinib) and Mekinist (trametinib).
About half of melanomas have a mutation in BRAF. BRAF mutations actually are present in many benign nevi as well, so clearly a second factor is necessary to move a nevus to being melanoma.
Roughly 20% of melanomas have mutated NRAS (the step above BRAF) but studies to find drugs blocking NRAS have been disappointing.
All of this relates to Targeted Therapy–an attempt to go into the tumor cell and shut down the mechanism that is causing it to grow out of control. A lot of interest still exists around trying to block various compounds in that chart.
Immunotherapy is a very different animal. Rather than trying to kill or shut down the tumor cells, immunotherapy seeks to activate the body's immune system to attack the tumor cells.
And both of these are different from chemotherapy. Chemotherapy basically introduces poison into the body. The cells that grow quickly take up more poison and are killed. The challenge is to give enough poison that the cancer cells are killed, but not so much that normal cells are killed. This only works because cancer cells grow very fast. Of course, so do hair cells and the lining of the stomach, so chemotherapy often leads to nausea and hair loss. Chemotherapy does not work very well in melanoma.
Tim–MRF
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Tagged: cutaneous melanoma
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