Research Abstract

As a gastrointestinal oncologist with a primary interest in translational oncology research, my work focuses on targeted therapies directed against specific mutations commonly found in human cancers, with a focus on BRAF and KRAS mutant gastrointestinal cancers. My work explores the hypothesis that the optimal therapy for individual tumors may vary widely based on the genetic alterations present, and that prior knowledge of these genetic changes and an understanding of the signaling pathways involved will allow selection of an optimal targeted agent or combination of agents capable of inhibiting the critical survival signals within a given tumor.

My work on BRAF mutant cancers has focused on determinants of resistance to BRAF and MEK inhibitors. We have identified BRAF amplification as a potential cause of acquired and de novo resistance in BRAF mutant colorectal cancers (Science Signaling, 2010), and have shown that combined BRAF and MEK inhibition can overcome resistance. We have also demonstrated that combined BRAF and MEK inhibition leads to increased efficacy in treatment-naïve BRAF mutant colorectal cancer models, leading to the development of a clinical trial assessing combined BRAF and MEK inhibition in patients with BRAF mutant colorectal (ASCO Abstract, 2012; ASCO Abstract, 2013). Additionally, we have found that EGFR-mediated reactivation of MAPK signaling contributes to the relative insensitivity of BRAF mutant colorectal cancers to BRAF inhibition, compared to BRAF mutant melanomas, and that combined BRAF and EGFR inhibition can overcome resistance, leading to tumor regressions in BRAF mutant colorectal xenografts (Cancer Discovery, 2012). Clinical trials based on this concept are currently enrolling patients. We are also focused on identifying additional causes of de novo and acquired resistance in BRAF mutant cancers using a combination of preclinical models and patient tumor specimens. (Cancer Discovery, 2015). Simultaneously, we are developing biomarkers to predict response to therapy (Cancer Discovery, 2011), including real-time pharmacodynamic assessment of signaling changes in on-treatment patient tumor biopsies (Science Translational Medicine, 2013), and combination therapy strategies to overcome resistance.

In KRAS mutant cancers, we have demonstrated the effectiveness of combination therapies involving inhibition of the PI3K and MEK pathways in mouse models of KRAS mutant cancers (J Clinical Investigation, 2011) and have evaluated the role of STAT3 in KRAS-induced pancreatic tumorigenesis (Cancer Research, 2011). Our current work focuses on identifying new combination therapy approaches to KRAS mutant cancers in an effort to identify novel target pathways. Recently, we identified combined targeting of BCL-XL and MEK as a promising therapeutic strategy that leads to dramatic tumor regressions in KRAS mutant xenografts and in KRAS-driven genetically-engineered mouse tumor models (Cancer Cell, 2013). A clinical trial based on this concept and funded by NCI/CTEP is currently enrolling patients, for which I am principal investigator. By identifying and understanding key mechanisms of response and resistance to targeted therapies, we hope to devise and validate potential clinical strategies for BRAF and KRAS mutant cancers.