Massachusetts General Hospital Cancer Center
149 13th St, 7th floor
Boston, MA 02129
Ryan Corcoran, MD, PhD
Associate Professor of Medicine
Harvard Medical School
Center for Cancer Research
Explore the Corcoran Lab
The Corcoran laboratory focuses on developing new and effective therapies for gastrointestinal cancers, including colorectal, pancreatic, stomach, and esophageal 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.
Targeted therapy strategies for gastrointestinal cancers
Historically, the standard clinical approach for patients with advanced cancers has been to treat all patients with the same tumor type with the same generalized chemotherapy strategy. However, even among patients with the same type of tumor, the genetic mutations driving tumor growth in each individual patient can be vastly different. As an alternative approach, by identifying the key gene mutations present in an individual patient’s tumor, we can “personalize” therapy by matching each patient with specific therapies that target those mutations essential for tumor growth. Our laboratory focuses on developing targeted therapy strategies directed against specific mutations commonly found in gastrointestinal cancers, including cancers with BRAF and KRAS mutations. However, while targeted therapy strategies can lead to dramatic tumor responses, clinical benefit is often limited by the ability of tumor cells to evolve and develop resistance to therapy. By identifying and understanding the key signals driving resistance, our laboratory aims 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. While BRAF inhibitors have shown dramatic anti-tumor activity in melanomas harboring BRAF mutations, these agents are 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 found that reactivation of the MAPK signaling pathway (often mediated through EGFR), contributes to the relative insensitivity of BRAF mutant colorectal cancers to BRAF inhibition. However, we found that combining BRAF inhibitors with EGFR and/or MEK inhibitors can overcome resistance, leading to improved efficacy (Cancer Discovery, 2012). We have also identified multiple mechanisms of resistance that can arise to these newer BRAF inhibitor combinations, and are utilizing this information to develop therapeutic strategies to surmount resistance (Cancer Discovery, 2015; Cancer Discovery, 2018).
KRAS is the most commonly mutated oncogene in human cancer, mutated in ~20% of all cancers, including pancreatic (~90%) and colorectal cancers (~40%). 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 through hypothesis-based and large-scale pooled RNA interference screening approaches, with the goal of developing new targeted therapy combination approaches for KRASmutant 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 KRASmutant mouse tumor models. We have also identified adaptive feedback signals that impede the ability of MEK inhibitors to suppress MAPK signaling. We have expanded these approaches to identify other potentially effective targets 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 to bringing new therapeutic strategies into the clinic for evaluation in novel clinical trials. Based on our observations, we have launched several clinical trials of BRAF inhibitor combinations in BRAF-mutant colorectal cancers that are showing increased efficacy (J Clinical Oncology, 2015). We have also developed a clinical trial combining the BCL-XL/BCL-2 inhibitor navitoclax with the MEK inhibitor trametinib in KRAS-mutant cancers.
To guide our laboratory investigations, we are utilizing key clinical specimens, including tumor biopsies and patient-derived tumor models to understand how tumors become resistant to therapy. We also utilize serial blood collections for circulating tumor DNA analysis to monitor the tumor heterogeneity and clonal dynamics associated with the emergence of therapeutic resistance (Cancer Discovery 2015, Nature Medicine 2015, Cancer Discovery 2016, Cancer Discovery 2017, Cancer Discovery 2018.)
Postdoctoral Research Position
A postdoctoral position is available in the laboratory of Dr. Ryan Corcoran at the Massachusetts General Hospital Cancer Center/Harvard Medical School. Our research 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 based on its mutational profile. Since cancer cells often become resistant to targeted therapies by activating alternative signaling pathways, we focus on identifying these key resistance signals and utilizing this information to devise effective combinations of targeted therapies to overcome resistance and provide novel strategies for evaluation in clinical trials.
Current projects in the laboratory include: synthetic lethal RNAi-drug screens to identify novel targeted therapy combinations for KRAS mutant cancers; modeling resistance to RAF inhibitor combinations in BRAF mutant colorectal cancers and understanding key changes in signal transduction; and whole exome sequencing of paired pre-treatment and post-progression biopsies from patients with GI cancers who progress after an initial response to a targeted therapy regimen, in order to identify key alterations involved in clinical acquired resistance to therapy.
Applicants should be highly motivated, must have an PhD or MD or equivalent, and no more than three years of postdoctoral experience.
To apply, email a cover letter, CV, and three letters of recommendation to:
Ryan B. Corcoran, MD PhD
Massachusetts General Hospital Cancer Center
149 13th St, 7th floor
Boston, MA 02129
Parikh AR*, Leshchiner I*, Elagina L*, Goyal L, Levovitz C, Siravegna G , Livitz D, Rhrissorrakrai K, Martin EE, Van Seventer EE, Hanna M, Slowik K, Utro F, Pinto CJ, Wong A, Danysh BP, Fece de la Cruz F, Fetter IJ, Nadres B, Shahzade HA, Allen JN, Blaszkowsky LS, Clark JW, Giantonio B, Murphy JE, Nipp RD, Roeland E, Ryan DP, Weekes CD, Kwak EL, Faris JE, Wo JY, Aguet F, Dey-Guha I, Hazar-Rethinam M, Dias-Santagata D, Ting DT, Zhu AX , Hong TS, Golub TR, Iafrate AJ, Adalsteinsson VA, Bardelli A, Parida L, Juric D, Getz G, Corcoran RB. Liquid versus tissue biopsy for detecting acquired resistance and tumor heterogeneity in gastrointestinal cancers. Nature Medicine, in press (2019).
Corcoran RB, André T,Atreya CE, Schellens JHM, Yoshino T,Bendell JC, Hollebecque A, McRee AJ,SienaS, Middleton G, Muro K, Gordon MS, Tabernero J,Yaeger R, O’Dwyer J, Humblet Y, De Vos F, Jung AS, Brase JC, Jaeger S, Bettinger S, Mookerjee B, Rangwala F,Van Cutsem E. Combined BRAF, EGFR, and MEK Inhibition in Patients with BRAFV600E-Mutant Colorectal Cancer. Cancer Discovery. 2018, 8: 428-443.
Hazar-Rethinam M, Kleyman M, Han GC, Liu D, Ahronian LG, Shahzade HA, Chen L, Parikh AR, Allen JN, Clark JW, Kwak EL, Faris JE, Murphy JE, Hong TS, Van Seventer EE, Nadres B, Hong CB, Gurski JM Jr., Jessop NA, Dias-Santagata D, Iafrate AJ, Van Allen EM, Corcoran RB. Convergent therapeutic strategies to overcome the heterogeneity of acquired resistance in BRAFV600E colorectal cancer. Cancer Discovery. 2018, 8: 417-427.
Strickler JH, Loree JM, Ahronian LG, Parikh AR, Niedzwiecki D, Pereira AAL, McKinney M, Korn WM, Atreya CE, Banks KC, Nagy RJ, Meric-Bernstam F, Lanman RB, Talasaz A, Tsigelny IF, Corcoran RB, Kopetz S. Genomic Landscape of Cell-Free DNA in Patients with Colorectal Cancer. Cancer Discovery. 2018; 8: 164-173.
Goyal L, Saha SK, Liu LY, Siravegna G, Leshchiner I, Ahronian LG, Lennerz JK, Vu P, Desphande V, Kambadakone A, Mussolin B, Reyes S, Henderson L, Sun JE, Van Seventer EE, Gurski JM Jr., Baltschukat S, Schacher-Engstler B, Barys L, Furet P, Ryan DP, Stone JR, Iafrate AJ, Getz G, Porta DG, Tiedt R, Bardelli A, Juric D, Corcoran RB*, Bardeesy N*, Zhu AX*. Polyclonal secondary FGFR2 mutations drive acquired resistance to FGFR inhibition in FGFR2 fusion-positive cholangiocarcinoma patients. Cancer Discovery, 7: 252-263 (2017).
Russo M, Siravegna G, Blaszkowsky LS, Corti G, Crisafulli G, Ahronian LG, Mussolin B, Kwak EL, Buscarino M, Lazzari L, Valtorta E, Truini M, Jessop NA, Robinson HE, Hong TS, Mino-Kenudson M, Di Nicolantonio F, Thabet A, Aartore-Bianchi A, Siena S, Iafrate AJ, Bardelli A, Corcoran RB. Tumor heterogeneity and lesion-specific response to targeted therapy in colorectal cancer. Cancer Discovery,6: 147-53 (2016).
*Denotes equal contribution
Response and resistance in BRAF-mutant colorectal cancer. (Left) Example of a dramatic tumor response in a patient treated with the combination of a BRAF and a MEK inhibitor. (Right) KRAS amplification (red probes) can lead to BRAF inhibitor resistance in BRAF mutant colorectal cancer patients.
Ryan Corcoran, MD, PhDPrincipal Investigator
- William Bradford
- Ferran Fece de la Cruz, PhD
- Isobel Fetter
- Stephanie McQueen
- Sarah Phat
- Meagan Ryan, PhD
- Heather Shahzade
- Deepinder Singh
- Giulia Siravegna, PhD
- Noritaka Tanaka, PhD
- Jun Tian, PhD
- Edmond Wong