This proposal seeks support for the training of Dr. Supriya Saha, a medical oncologist at the Massachusetts General Hospital (MGH) Cancer Center, toward his goal of becoming an independent physician-scientist with a focused clinical practice in hepatobiliary cancers and a research laboratory dedicated to the study of cholangiocarcinoma. Dr. Saha will be mentored by Dr. Nabeel Bardeesy, a leader in mouse models of gastrointestinal cancer, and Dr. Andrew Zhu, a clinical expert in hepatobiliary cancers. Intrahepatic Cholangiocarcinoma (ICC) has an average survival of < 1 year and has been increasing in incidence for several decades. With no effective targeted therapies or methods for prevention or early detection currently available, there is an urgent need for a greater focus on basic and translational ICC research. Recent studies have identified missense mutations in the metabolic enzymes isocitrate dehydrogenase 1 or 2 (IDH1/2) as the most common genetic alterations in ICC. Mutant IDH (IDH*) has been proposed to contribute to tumorigenesis through an intriguing mechanism whereby the IDH* enzyme produces an `oncometabolite', 2-hydroxglutarate (2HG), that inhibits a family of enzymes requiring alpha-ketoglutarate as a co-factor. Unfortunately, the lack of animal models of IDH*-driven ICC or human cell lines with endogenous IDH mutations has hindered elucidation of the oncogenic mechanisms and of effective therapies against IDH* disease. Over the last 3 years, Dr. Saha has worked in Dr. Bardeesy's laboratory to overcome these hurdles by defining the mechanism by which IDH* promotes ICC and generating the first genetically engineered mouse model of IDH* ICC. Simultaneously, Dr. Saha designed and implemented a clinical protocol to obtain fresh patient samples to generate a rich panel of human ICC cell lines and patient-derived xenografts. In collaboration with Dr. Cyril Benes, these tools were subjected to a high-throughput drug screen to identify a class of kinase inhibitors with potent and specific efficacy against IDH* ICC. During the award period, Dr. Saha will complete studies required for the effective translation of his work into an early phase clinical trial. This includes evaluating the se of targeted kinase inhibition in an autochthonous mouse model of IDH* ICC, using proteomic approaches to identify the specific targets and mechanism of action of kinase inhibition in ICC and exploring the potential mechanisms of resistance that may develop in this disease. This work will benefit from the breadth of expertise at MGH, which houses leading research groups in cancer genetics, molecular biology, signal transduction and cancer therapeutics, and was the first institution to identify IDH mutations in ICC. Given his extensive background in laboratory research, promising preliminary results and the superb mentorship he will receive, Dr. Saha anticipates applying for independent funding within the third year of this award.
Intrahepatic cholangiocarcinoma (ICC) is a deadly liver cancer that has been increasing in incidence for several decades and is among the most lethal of all human malignancies with an average survival of less than 1 year. As we have no effective measures for screening, prevention or early detection, we set out to identify new therapies for this disease through high-throughput drug screens. Our preliminary results show that a subset of ICC tumors with mutations in isocitrate dehydrogenase (IDH) may be extremely susceptible to an oral medication called dasatinib, which has been used safely for years to treat some types of leukemia. This proposal aims to understand why these tumors are sensitive to dasatinib and to explore how best to deploy dasatinib as a novel targeted therapy for patients with IDH mutant ICC.
|Goyal, Lipika; Saha, Supriya K; Liu, Leah Y et al. (2017) Polyclonal Secondary FGFR2 Mutations Drive Acquired Resistance to FGFR Inhibition in Patients with FGFR2 Fusion-Positive Cholangiocarcinoma. Cancer Discov 7:252-263|
|Kugel, Sita; Sebastián, Carlos; Fitamant, Julien et al. (2016) SIRT6 Suppresses Pancreatic Cancer through Control of Lin28b. Cell 165:1401-1415|
|Saha, Supriya K; Gordan, John D; Kleinstiver, Benjamin P et al. (2016) Isocitrate Dehydrogenase Mutations Confer Dasatinib Hypersensitivity and SRC Dependence in Intrahepatic Cholangiocarcinoma. Cancer Discov 6:727-39|
|Saha, Supriya K; Zhu, Andrew X; Fuchs, Charles S et al. (2016) Forty-Year Trends in Cholangiocarcinoma Incidence in the U.S.: Intrahepatic Disease on the Rise. Oncologist 21:594-9|