The translational goal of this project is to conduct mechanistic studies on BRAFmut mCRC patients and patient derived xenografts of BRAFmut mCRC treated with dual BRAF and EGFR inhibition to understand predictive biomarkers and mechanism on resistance through 1) a phase I/Ib trial of vemurafenib, cetuximab and irinotecan 2) a national SWOG randomized phase II trial of the combination. 3) concurrent patient derived xenografts trials. The hypothesis to be tested in this proposal is that the combination of BRAF and EGFR inhibition will prove efficacious in BRAFV600E colorectal cancer, but that innate and adaptive resistance mechanisms exist;biomarkers and parallel preclinical efforts are needed to better characterize these mechanisms of resistance. This hypothesis will be tested in vitro, in vivo, and in patients with mCRC in a clinical trial.
Three specific aims are proposed to test this hypothesis, and include: 1) determine the safety and efficacy of BRAF and EGFR inhibition in patients with mCRC in a phase I/Ib trial and a national phase II randomized trial;2) use patient-derived specimens to define predictive biomarkers and mechanisms of innate resistance to BRAF and EGFR inhibition;3) use co-clinical trials with BRAFmut patient-derived xenografts to identify and target mechanisms of acquired resistance. The long-term goal of this project is to develop an understanding of the mechanisms of resistance to therapy for BRAFmut mCRC so that we can design more effective therapies, identify new drug targets for treatment, and develop biomarkers that identify BRAFmut mCRC patients most likely to have responses to specific therapies. OMB No. 0925-0001/0002 (Rev. 08/12 Approved Through 8/31/2015) Page Continuation Format Page
Metastatic colorectal cancer (mCRC) is the second leading cause of cancer-related deaths in the US. BRAFmut mCRC makes up 10% of mCRC cases in the US and is a highly aggressive form of CRC. Increasing the efficacy and understanding the predictive biomarkers of response and mechanisms of resistance will lead to more effective therapies, and identify new drug targets and biomarkers for selecting BRAFmut mCRC patients most likely to respond to treatment.
|Kanikarla-Marie, Preeti; Kopetz, Scott; Hawk, Ernest T et al. (2018) Bioactive lipid metabolism in platelet ""first responder"" and cancer biology. Cancer Metastasis Rev 37:439-454|
|Loree, Jonathan M; Pereira, Allan A L; Lam, Michael et al. (2018) Classifying Colorectal Cancer by Tumor Location Rather than Sidedness Highlights a Continuum in Mutation Profiles and Consensus Molecular Subtypes. Clin Cancer Res 24:1062-1072|
|Mehrvarz Sarshekeh, Amir; Overman, Michael J; Kopetz, Scott (2018) Nivolumab in the treatment of microsatellite instability high metastatic colorectal cancer. Future Oncol 14:1869-1874|
|Dai, Xinghong; Zhou, Z Hong (2018) Structure of the herpes simplex virus 1 capsid with associated tegument protein complexes. Science 360:|
|Menter, David G; Kopetz, Scott; Hawk, Ernest et al. (2017) Platelet ""first responders"" in wound response, cancer, and metastasis. Cancer Metastasis Rev 36:199-213|
|Loree, Jonathan M; Kopetz, Scott (2017) Recent developments in the treatment of metastatic colorectal cancer. Ther Adv Med Oncol 9:551-564|
|Katsiampoura, Anastasia; Raghav, Kanwal; Jiang, Zhi-Qin et al. (2017) Modeling of Patient-Derived Xenografts in Colorectal Cancer. Mol Cancer Ther 16:1435-1442|
|Sundar, Raghav; Hong, David S; Kopetz, Scott et al. (2017) Targeting BRAF-Mutant Colorectal Cancer: Progress in Combination Strategies. Cancer Discov 7:558-560|
|Korphaisarn, Krittiya; Kopetz, Scott (2016) BRAF-Directed Therapy in Metastatic Colorectal Cancer. Cancer J 22:175-8|
|Hong, David S; Morris, Van K; El Osta, Badi et al. (2016) Phase IB Study of Vemurafenib in Combination with Irinotecan and Cetuximab in Patients with Metastatic Colorectal Cancer with BRAFV600E Mutation. Cancer Discov 6:1352-1365|
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