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New hope for melanoma
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New hope for melanoma
www.thelancet.com/oncology Vol 11 April 2010
that leads to constitutive activation of the protein and the pathway, and in which a drug is available to inhibit its activity. The newest example is PLX4032 for the mutant BRAF oncogene,” says Herlyn. BRAF was identified in 2002, and mutations occur in over 50% of melanoma patients. Several BRAF inhibitors are now in clinical testing, although PLX4032 is furthest along, having moved into phase 3 clinical trials in December, 2009. However, Herlyn adds that “mutant BRAF alone cannot transform melanocytes, it needs cooperating genes. Those need to be found and then targeted. Thus, a BRAF inhibitor alone will not cure, it needs to be used in combinations, except that we do not yet know which other pathways we need to block, nor how many.” C-KIT comprises a much smaller set of mutations than BRAF, affecting around 1–3% of patients. “It’s a small number of patients but it’s the first proof of principle that you can personalise treatments for melanoma based on the genomics of their tumour”, says F Stephen Hodi (DanaFarber Cancer Institute, Boston, MA, USA). “Even though things look the same under the microscope, when you look at genomics, you’ll find that a patient has the KIT mutation versus other mutations that can suggest a treatment path.” A number of KITactive drugs are being tested for this melanoma subtype. Another broad group of molecules being explored are anti-apoptosis inhibitors, such as ABT-737, which inhibits BCL2 and BCLXL (which stop cells from undergoing cell death). “The drug binds to these inhibitors, and releases proteins that promote cell death. This is more broad spectrum, but it still needs to hit MCL1”, explains Victor Tron (Laboratory for Skin Cancer Biology and Therapeutics, Queen’s University, Kingston, ON, Canada). “More drugs are coming
down the pipeline that will target BCL2, BCLXL, and MCL1. Those may be very promising.” Meanwhile, Hodi is still hopeful that immunotherapy can offer something valuable, the idea that “by pressing down on the accelerator or taking the brakes off of the immune system, you can very selectively take advantage of that. And by figuring out what those molecules do, you can literally steer the immune system in the right direction to try to fight cancer.” Hodi’s team is exploring a cytotoxic T-lymphocyte-associated antigen 4 (CTLA4) antibody, one of a family of immune checkpoints that can limit the potential therapeutic potency of cancer vaccines by suppressing T-cell function. Hodi reports that additional phase 3 results are expected soon. Convinced that no magic bullet will emerge for melanoma, many researchers believe that it may need to follow HIV’s lead: combination therapy. That is the idea that spawned the Melanoma Breakthrough Consortium recently assembled by the Melanoma Research Foundation (MRF), which combines the work of ten academic centres with pharmaceutical companies that have a melanoma research focus. “Its core focus is to do combination studies that aren’t being done anywhere else that we are convinced will be relevant for melanoma patients”, says Tim Turnham (executive director of MRF), and to accelerate the “complicated and slow” drug-development process. Flaherty says that even for the promising PLX4032, they are eyeing combinations for “attacking other mutated genes and enzymes that happen in the same cells as BRAF and can be targeted with drugs”, and moving “toward adjuvant therapy trials in the not-too-distant future with single-agent BRAF inhibition with the hope of curing”.
Science Source/Science Photo Library
Like a sibling trying on cast-offs, no treatment that has worked for other cancers has been a proper fit for melanoma. “Drug therapy for metastatic melanoma or adjuvant therapy for those who have had surgery with curative intent has severe limits with regard to efficacy”, says Keith T Flaherty (Massachusetts General Hospital Cancer Center, Boston, MA, USA). On average, patients with stage IV disease survive for 6–10 months, with fewer than 5% surviving beyond 5 years. The melanoma research community, intent on extending that window significantly, has been struck with infectious optimism fuelled by a growing understanding of the molecular underpinnings of melanoma, the identification of new genetic and immune-system targets, and encouraging results from clinical trials. As the search for melanomaspecific targets continues, however, there is unfortunately no one-sizefits-all approach. “All tumours look and act differently even within the same patient”, says Meenhard Herlyn (Wistar Institute, Philadelphia, PA, USA). “We are distinguishing between a genetic and a biological cancer signature. If we know the ‘drivers’, those genetic alterations that drive the malignancy, we can individualise our therapies and tailor them against those mutant proteins—albeit our repertoire is still limited. We hope that the cancer genome atlas will provide more information to distinguish between drivers and passengers. In the biological signature, we find heterogeneity due to different stages of the cell cycle or due to specific subpopulations, some of which may have special survival skills.” Many research centres are exploring potential targeted therapies, such as BRAF and C-KIT inhibitors. “The most promising are those in which there is a defined mutation in all cancer cells
Angela Pirisi 317
New hope for melanoma
www.thelancet.com/oncology Vol 11 April 2010
that leads to constitutive activation of the protein and the pathway, and in which a drug is available to inhibit its activity. The newest example is PLX4032 for the mutant BRAF oncogene,” says Herlyn. BRAF was identified in 2002, and mutations occur in over 50% of melanoma patients. Several BRAF inhibitors are now in clinical testing, although PLX4032 is furthest along, having moved into phase 3 clinical trials in December, 2009. However, Herlyn adds that “mutant BRAF alone cannot transform melanocytes, it needs cooperating genes. Those need to be found and then targeted. Thus, a BRAF inhibitor alone will not cure, it needs to be used in combinations, except that we do not yet know which other pathways we need to block, nor how many.” C-KIT comprises a much smaller set of mutations than BRAF, affecting around 1–3% of patients. “It’s a small number of patients but it’s the first proof of principle that you can personalise treatments for melanoma based on the genomics of their tumour”, says F Stephen Hodi (DanaFarber Cancer Institute, Boston, MA, USA). “Even though things look the same under the microscope, when you look at genomics, you’ll find that a patient has the KIT mutation versus other mutations that can suggest a treatment path.” A number of KITactive drugs are being tested for this melanoma subtype. Another broad group of molecules being explored are anti-apoptosis inhibitors, such as ABT-737, which inhibits BCL2 and BCLXL (which stop cells from undergoing cell death). “The drug binds to these inhibitors, and releases proteins that promote cell death. This is more broad spectrum, but it still needs to hit MCL1”, explains Victor Tron (Laboratory for Skin Cancer Biology and Therapeutics, Queen’s University, Kingston, ON, Canada). “More drugs are coming
down the pipeline that will target BCL2, BCLXL, and MCL1. Those may be very promising.” Meanwhile, Hodi is still hopeful that immunotherapy can offer something valuable, the idea that “by pressing down on the accelerator or taking the brakes off of the immune system, you can very selectively take advantage of that. And by figuring out what those molecules do, you can literally steer the immune system in the right direction to try to fight cancer.” Hodi’s team is exploring a cytotoxic T-lymphocyte-associated antigen 4 (CTLA4) antibody, one of a family of immune checkpoints that can limit the potential therapeutic potency of cancer vaccines by suppressing T-cell function. Hodi reports that additional phase 3 results are expected soon. Convinced that no magic bullet will emerge for melanoma, many researchers believe that it may need to follow HIV’s lead: combination therapy. That is the idea that spawned the Melanoma Breakthrough Consortium recently assembled by the Melanoma Research Foundation (MRF), which combines the work of ten academic centres with pharmaceutical companies that have a melanoma research focus. “Its core focus is to do combination studies that aren’t being done anywhere else that we are convinced will be relevant for melanoma patients”, says Tim Turnham (executive director of MRF), and to accelerate the “complicated and slow” drug-development process. Flaherty says that even for the promising PLX4032, they are eyeing combinations for “attacking other mutated genes and enzymes that happen in the same cells as BRAF and can be targeted with drugs”, and moving “toward adjuvant therapy trials in the not-too-distant future with single-agent BRAF inhibition with the hope of curing”.
Science Source/Science Photo Library
Like a sibling trying on cast-offs, no treatment that has worked for other cancers has been a proper fit for melanoma. “Drug therapy for metastatic melanoma or adjuvant therapy for those who have had surgery with curative intent has severe limits with regard to efficacy”, says Keith T Flaherty (Massachusetts General Hospital Cancer Center, Boston, MA, USA). On average, patients with stage IV disease survive for 6–10 months, with fewer than 5% surviving beyond 5 years. The melanoma research community, intent on extending that window significantly, has been struck with infectious optimism fuelled by a growing understanding of the molecular underpinnings of melanoma, the identification of new genetic and immune-system targets, and encouraging results from clinical trials. As the search for melanomaspecific targets continues, however, there is unfortunately no one-sizefits-all approach. “All tumours look and act differently even within the same patient”, says Meenhard Herlyn (Wistar Institute, Philadelphia, PA, USA). “We are distinguishing between a genetic and a biological cancer signature. If we know the ‘drivers’, those genetic alterations that drive the malignancy, we can individualise our therapies and tailor them against those mutant proteins—albeit our repertoire is still limited. We hope that the cancer genome atlas will provide more information to distinguish between drivers and passengers. In the biological signature, we find heterogeneity due to different stages of the cell cycle or due to specific subpopulations, some of which may have special survival skills.” Many research centres are exploring potential targeted therapies, such as BRAF and C-KIT inhibitors. “The most promising are those in which there is a defined mutation in all cancer cells
Angela Pirisi 317