Mutation of the BRAF oncogene is a common event in colorectal cancer (CRC). These mutations are associated with adverse outcome and insensitivity to epidermal growth factor receptor (EGFR) based therapy. Whereas RAF inhibitors have been successful in the treatment of BRAF-mutant malignant melanoma, response rates in BRAF-mutant CRC are surprisingly low. The basis for these disparate treatment outcomes remains incompletely understood. Preliminary studies from our groups found that suppression of the MAPK pathway by PLX4720 is incomplete in CRC lines. In some cases, this may be due to augmented EGFR-dependent signaling, but this does not explain all resistance in this setting. Our objective is to identify mechanisms operant in BRAF-mutant colorectal cancer that confer de novo resistance to RAF inhibitors, in hopes of enabling more efficacious therapeutics. First, differentially expressed genes linked to BRAF-mutant CRC will be identified by analysis of the TCGA dataset;these genes will be integrated with those that modify response to MAPK pathway inhibitors based on ongoing systematic functional screens. Top-ranking genes will be subjected to mechanistic studies to elucidate the molecular basis by which they confer resistance, in parallel, ongoing functional screens will be expanded to identify genes that are synthetic lethal with RAF inhibition in BRAF-mutant colorectal cells. Here, validation of leading candidates will be prioritized for genes that are potentially druggable-several candidates have already been nominated. Rational combinations of targeted agents with RAF inhibitors will be explored in cell culture and in xenograft models. Finally, clinical trials of combined RAF and MEK inhibitors will be performed at DF/HCC in an attempt to improve efficacy by enhancing suppression of the MAPK pathway and possibly prevent the emergence of drug-resistance. Tumor biopsies will be collected pre-treatment, on-treatment and post-progression, and whole exome and transcriptome sequencing will be used to identify genomic alterations that may drive resistance. Altogether, this work should provide a rigorous analysis of resistance to MAPK inhibitors and new therapeutic approaches to overcome them.
The survival colorectal cancer patients whose tumors harbor BRAF mutations is dramatically worse than those with wildtype BRAF;the benefit of certain chemotherapy drugs is similarly poor. Therefore, It Is essential that novel therapeutic approaches are developed to address this unmet medical need. We will utilize state of the art technologies and experimental approaches together with a rational clinical trial to forge a new treatment framework for this lethal subtype of colorectal cancer.
|Ananthakrishnan, Ashwin N; Du, Mengmeng; Berndt, Sonja I et al. (2015) Red meat intake, NAT2, and risk of colorectal cancer: a pooled analysis of 11 studies. Cancer Epidemiol Biomarkers Prev 24:198-205|
|Song, Mingyang; Gong, Jian; Giovannucci, Edward L et al. (2015) Genetic variants of adiponectin and risk of colorectal cancer. Int J Cancer 137:154-64|
|Lochhead, Paul; Chan, Andrew T; Nishihara, Reiko et al. (2015) Etiologic field effect: reappraisal of the field effect concept in cancer predisposition and progression. Mod Pathol 28:14-29|
|Inamura, Kentaro; Yamauchi, Mai; Nishihara, Reiko et al. (2015) Prognostic significance and molecular features of signet-ring cell and mucinous components in colorectal carcinoma. Ann Surg Oncol 22:1226-35|
|Serrano, César; Wang, Yuexiang; Mariño-Enríquez, Adrián et al. (2015) KRAS and KIT Gatekeeper Mutations Confer Polyclonal Primary Imatinib Resistance in GI Stromal Tumors: Relevance of Concomitant Phosphatidylinositol 3-Kinase/AKT Dysregulation. J Clin Oncol 33:e93-6|
|Rosenthal, Michael H; Kim, Kyung Won; Fuchs, Charles S et al. (2015) CT predictors of overall survival at initial diagnosis in patients with stage IV colorectal cancer. Abdom Imaging 40:1170-6|
|Arteaga, Carlos L; Engelman, Jeffrey A (2014) ERBB receptors: from oncogene discovery to basic science to mechanism-based cancer therapeutics. Cancer Cell 25:282-303|
|Wu, Chen; Kraft, Peter; Stolzenberg-Solomon, Rachael et al. (2014) Genome-wide association study of survival in patients with pancreatic adenocarcinoma. Gut 63:152-60|
|Ma, Tianle; Jang, Eun Jeong; Zukerberg, Lawrence R et al. (2014) Recurrences are common after endoscopic ampullectomy for adenoma in the familial adenomatous polyposis (FAP) syndrome. Surg Endosc 28:2349-56|
|Blaszkowsky, L S; Ryan, D P; Szymonifka, J et al. (2014) Phase I/II study of neoadjuvant bevacizumab, erlotinib and 5-fluorouracil with concurrent external beam radiation therapy in locally advanced rectal cancer. Ann Oncol 25:121-6|
Showing the most recent 10 out of 259 publications