Ryan Corcoran, MD, PhD
Assistant Professor of Medicine
Harvard Medical School
The Corcoran laboratory focuses on developing new and effective therapies for gastrointestinal cancers, such as colorectal and pancreatic cancers, by targeting the specific survival signals that are active in a given patient’s cancer. Our research utilizes targeted therapies, which are drugs that inhibit signaling pathways activated by the specific mutations that drive individual tumors. Since cancer cells often become resistant to these targeted therapies by activating alternative signaling pathways, we focus on identifying these key resistance signals in cancer cells. We utilize this information to devise effective combinations of targeted therapies that anticipate and ultimately overcome these mechanisms of drug resistance. Overall, our goal is to develop promising therapeutic strategies that can be evaluated in clinical trials for patients whose cancers are driven by specific mutations.
Ryan Corcoran, MD, PHD
Jason Godfrey, MS
Targeted therapy strategies for gastrointestinal cancers
Our laboratory focuses on targeted therapies directed against specific mutations commonly found in human gastrointestinal cancers, with a focus on BRAF and KRAS mutant cancers. Our 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 us to select an optimal targeted agent or combination of agents capable of inhibiting the critical survival signals within a given tumor. Knowing that cancers often activate parallel or redundant signaling pathway to become resistant to specific targeted therapies, our laboratory also focuses on identifying these critical resistance signals and using this information to devise combinations of targeted agents that can overcome or even prevent resistance.
BRAF mutant colorectal cancer
BRAF mutations occur in 10-15% of colorectal cancers and confer poor prognosis. Interestingly, while BRAF inhibitors have shown dramatic anti-tumor activity in the ~50% of melanomas that harbor BRAF mutations, these agents have been largely ineffective in BRAF mutant colorectal cancers. Therefore, our laboratory has focused on determinants of resistance to BRAF inhibitors in BRAF mutant colorectal cancers. 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. 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 cancer models in mice (Cancer Discovery, 2012). We are also focused on identifying additional causes of de novo resistance in BRAF mutant cancers using a combination of preclinical models and patient tumor specimens. 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.
KRAS mutant cancers
KRAS is the most commonly mutated oncogene in human cancer and is mutated in ~20% of all cancers, with particularly high frequency in pancreatic (~90%) and colorectal cancers (~40%). However, currently no effective therapies exist for KRAS mutant cancers, likely because KRAS itself has proven difficult to target directly with small molecules. Our current work focuses on identifying novel target pathways in KRAS mutant cancers though hypothesis-based and large-scale pooled RNA interference screening approaches, with the goal of developing new targeted therapycombination approaches for KRAS mutant cancers. Recently, through a pooled RNA interference drug screen, we identified combined targeting of BCL-XL and MEK as a promising therapeutic strategy that leads to dramatic tumor regressions in KRAS mutant mouse tumor models (Cancer Cell, 2013). We are currently expanding these approaches to identify other potentially effective targets and therapeutic strategies in KRAS mutant cancers.
The overall goal of our research is to develop improved treatments for patients with gastrointestinal cancers and to identify molecular markers that may help us identify those patients most likely to respond to a given therapy. As such, our laboratory takes a highly translational approach with a central focus bringing new therapeutic strategies into the clinic for evaluation in novel clinical trials. Based on our observation that combined BRAF and MEK inhibition can overcome certain resistance mechanisms in leads BRAF mutant colorectal cancer models, we developed and completed a clinical trial assessing combined BRAF and MEK inhibition in patients with BRAF mutant colorectal cancer, which showed promising activity in a subset of patients. (ASCO abstract, J ClinOncol, 2013). Based on our observations that EGFR may contribute to resistance in many BRAF mutant colorectal cancers, we are currently enrolling patients to clinical trials evaluating the combination of BRAF and EGFR inhibitors. Finally, we are developing a clinical trial combining the BCL-XL/BCL-2 inhibitor navitoclax with the MEK inhibitor trametinib in KRAS mutant cancers.
1.) Corcoran RB*, Rothenberg SM*, Hata A, Piris A, Nazarian R, Brown RD, Godfrey JT, Winokur D, Walsh J, Mino-Kenudson M, Maheswaran S, Settleman J, Wargo JA, Flaherty KT, Haber DA, Engelman JA. TORC1 suppression predicts responsiveness to vemurafenib in BRAF mutant melanoma. Science Translational Medicine5: 196ra98 (2013). (* denotes equal contribution)
2.) Corcoran RB, Cheng KA, Ebi H, Hata A, Faber AC, Coffee EM, Greninger P, Brown RD, Godfrey JT,Cohoon TJ, Song Y, Lifshits E, Hung KE, Shioda T, Dias-Santagata D, Singh A, Settleman J, Benes CH, Mino-Kenudson M, Wong KK, Engelman JA. Synthetic lethal interaction of combined BCL-XL and MEK inhibition promotes tumor regressions in KRAS mutant cancer models. Cancer Cell, 23: 121-8(2013).
3.) Corcoran RB, Falchook GS, Infante JR, Hamid O, Messersmith W,Daud A,Kwak EL, Ryan DP, Kurzrock R, Atreya CE, Luan J, Sun P, Allred A, Schaeffer M, Motwani M, Bleam M, Moy CH, Patel K, Orford KW, Kopetz S, Venook AP. Pharmacodynamic and efficacy analysis of the BRAF inhibitor dabrafenib in combination with the MEK inhibitor trametinib in patients with BRAFV600 mutant colorectal cancer. J Clinical Oncology 31, suppl;abstr 3507 (2013).
4.) Corcoran RB*, Ebi H*, Turke AB, Coffee EM, Nishino M, Cogdill AP, Brown RD, Della Pelle P, Dias-Santagata D, Hung KE, Flaherty KT, Piris A, Wargo JA, Settleman J, Mino-Kenudson M, Engelman JA. EGFR-mediated reactivation of MAPK signaling contributes to insensitivity of BRAF mutant colorectal cancers to RAF inhibition. Cancer Discovery 2: 227-235 (2012). PMCID:3308191. (* denotes equal contribution)
5.) Faber AC*, Corcoran RB*, Ebi, H*, Sequist LV, Waltman BA, Chung E, Incio J, Digumarthy S, Pollock S, Song Y, Lifshits E, Roberge S, Coffman EJ, Benes CH, Gomez H, Baselga J, Arteaga C, Rivera MN, Dias-Santagata D, Jain R,Engelman JA.BIM expression in treatment naïve cancers predicts responsiveness to kinase inhibitors. Cancer Discovery 1: 352-65 (2011). PMCID:3229203.(* denotes equal contribution)
6.) Corcoran RB, Dias-Santagata D, Bergethon K, Iafrate AJ, Settlemen J, Engelman JA. BRAF gene amplification can promote acquired resistance to MEK inhibitors in cancer cells harboring the BRAF V600E mutation. Science Signaling3: ra84 (2010). PMCID:21098728.