Final Report Summary - FUNCTIONAL GENOMICS (DISSECTING GENETIC DEPENDENCIES IN CANCER)
This ERC grant aimed to help improve to lives of cancer patients through two routes. First, we aimed to identify novel potent combinations of “targeted” cancer drugs. Most cancer drugs provoke short-term responses in cancer patients, but ultimately drug resistance develops. Through the use of innovative genetic screens, we searched for effective combinations of cancer drugs that are far more powerful than current therapies based on single agent regimen.
In research funded through this ERC grant, we have identified two very powerful drug combinations for BRAF and KRAS mutant colon cancer, which together has resulted in six clinical studies. Two of these have progressed to phase III registration studies and will likely yield new registered drug combinations in the near future.
Another societal benefit is that the Principal Investigator of this grant has established a spin off company (Qameleon Therapeutics BV) that aims to bring additional powerful drug combinations to the clinic through new insights into functional dependencies in cancer cells.
A second major goal of our research effort was the identification of biomarkers and mechanisms of resistance to targeted cancer drugs. Understanding mechanisms of drug resistance is important to design effective strategies to counter drug resistance. We achieved two major successes in this part of our research.
First, we identified a group of cancers that are driven by activated TGF-beta signalling that fail to respond to both targeted cancer drugs and chemotherapies. Our data suggest that in these cancers a drug that blocks TGF-beta signalling will restore responsiveness to cancer drugs. We have reached agreement with a major pharma company to test this in the clinic starting in the second quarter of 2016.
Second, we have identified a specific acquired vulnerability of BRAF mutant melanomas that is gained upon development of resistance to BRAF and/or MEK inhibitor drugs (one of the current first line treatments for this disease). Our data show that untreated melanomas are insensitive to inhibitors of Histone Deacetylases (HDAC inhibitors), but that melanomas that have acquired resistance to BRAF inhibitors have developed hypersensitivity to these drugs. In animal models HDAC inhibitors are very effective in the treatment of BRAF inhibitor resistant melanoma. I have submitted an ERC POC grant application to test this proposed therapy in the clinic. If funded, this study will start in Q1 2016, making for a total of 8 clinical studies as a direct outcome from this ERC grant.
In research funded through this ERC grant, we have identified two very powerful drug combinations for BRAF and KRAS mutant colon cancer, which together has resulted in six clinical studies. Two of these have progressed to phase III registration studies and will likely yield new registered drug combinations in the near future.
Another societal benefit is that the Principal Investigator of this grant has established a spin off company (Qameleon Therapeutics BV) that aims to bring additional powerful drug combinations to the clinic through new insights into functional dependencies in cancer cells.
A second major goal of our research effort was the identification of biomarkers and mechanisms of resistance to targeted cancer drugs. Understanding mechanisms of drug resistance is important to design effective strategies to counter drug resistance. We achieved two major successes in this part of our research.
First, we identified a group of cancers that are driven by activated TGF-beta signalling that fail to respond to both targeted cancer drugs and chemotherapies. Our data suggest that in these cancers a drug that blocks TGF-beta signalling will restore responsiveness to cancer drugs. We have reached agreement with a major pharma company to test this in the clinic starting in the second quarter of 2016.
Second, we have identified a specific acquired vulnerability of BRAF mutant melanomas that is gained upon development of resistance to BRAF and/or MEK inhibitor drugs (one of the current first line treatments for this disease). Our data show that untreated melanomas are insensitive to inhibitors of Histone Deacetylases (HDAC inhibitors), but that melanomas that have acquired resistance to BRAF inhibitors have developed hypersensitivity to these drugs. In animal models HDAC inhibitors are very effective in the treatment of BRAF inhibitor resistant melanoma. I have submitted an ERC POC grant application to test this proposed therapy in the clinic. If funded, this study will start in Q1 2016, making for a total of 8 clinical studies as a direct outcome from this ERC grant.