2015 — 2016 |
Saha, Supriya K |
K08Activity Code Description: To provide the opportunity for promising medical scientists with demonstrated aptitude to develop into independent investigators, or for faculty members to pursue research aspects of categorical areas applicable to the awarding unit, and aid in filling the academic faculty gap in these shortage areas within health profession's institutions of the country. |
Novel Targeted Therapies For Isocitrate Dehydrogenase Mutant Cholangiocarcinoma @ Massachusetts General Hospital
? DESCRIPTION (provided by applicant): 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.
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0.909 |
2016 — 2019 |
Saha, Supriya K |
K08Activity Code Description: To provide the opportunity for promising medical scientists with demonstrated aptitude to develop into independent investigators, or for faculty members to pursue research aspects of categorical areas applicable to the awarding unit, and aid in filling the academic faculty gap in these shortage areas within health profession's institutions of the country. |
Novel Targeted Therapies For Isocitrate Dehydrogenase Mutantcholangiocarcinoma @ Fred Hutchinson Cancer Research Center
? DESCRIPTION (provided by applicant): 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.
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0.903 |
2018 — 2019 |
Saha, Supriya K |
R21Activity Code Description: To encourage the development of new research activities in categorical program areas. (Support generally is restricted in level of support and in time.) |
Exploring Immune Surveillance in Isocitrate Dehydrogenase Mutant Cholangiocarcinoma @ Fred Hutchinson Cancer Research Center
PROJECT SUMMARY/ABSTRACT Intrahepatic cholangiocarcinoma (ICC) is a deadly liver cancer which has been rising in incidence over several decades. Unfortunately, immunomodulatory therapies which have revolutionized clinical paradigms in many other cancers, have thus far demonstrated only limited efficacy in a small fraction of ICC patients. We hypothesize that a better understanding of the mechanisms by which this disease evades immune recognition will allow for the development of therapeutic strategies that improve antitumoral immunity. To address these questions, we have developed the first and only genetically-engineered mouse model (GEMM) of isocitrate dehydrogenase (IDH) mutant ICC, which represents the most common genetic subset of ICC (20-25% of patients). While pharmacologic inhibitors of mutant IDH (IDH*) are currently being evaluated in clinical trials and appear to provide some clinical benefit with minimal toxicity, these effects are only transient, suggesting that combinatorial strategies are needed to induce durable remissions. Intriguingly, recent reports have suggested that IDH* may also suppress immune responses, thus contributing to immune evasion. For instance, the presence of IDH* in a syngeneic model of glioma resulted in a dramatic suppression of chemotaxis and immune cell infiltration into tumors. Moreover, the upregulation of immune-response related genes in patients with IDH* ICC seems to correlate with clinical response. Here, we propose to use our GEMM of IDH* ICC to characterize the impact of IDH* on immune surveillance in the normal and injured murine liver. We will then determine whether IDH* inhibition may enhance immune cell infiltration or activation in established IDH* ICC tumors. These preliminary studies will pave the way for future mechanistic work where we functionally interrogate the role of individual cell types and cytokines and explore how IDH* subverts their normal activity, with the ultimate goal of identifying therapeutic strategies that may effectively combine IDH* inhibition with immunomodulatory therapy for ICC and other IDH* cancers.
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0.903 |
2019 — 2020 |
Saha, Supriya K |
R21Activity Code Description: To encourage the development of new research activities in categorical program areas. (Support generally is restricted in level of support and in time.) |
Evaluating Novel Targeted Therapies in Cholangiocarcinoma Using Tumor Slice Cultures @ Fred Hutchinson Cancer Research Center
PROJECT SUMMARY/ABSTRACT Intrahepatic cholangiocarcinoma (ICC) is a deadly liver cancer which has been rising in incidence over several decades. The overarching goal of this proposal is to evaluate novel therapeutic strategies for the subset of ICC harboring mutations in isocitrate dehydrogenase 1 (IDH1), the most common oncogenic driver in this disease. In early phase clinical trials, pharmacologic inhibitors of mutant IDH provided clinical benefit in some patients, but their mechanism of action remains poorly understood due to a paucity of on-treatment biopsy tissue and relevant model systems. To overcome this hurdle, a protocol to maintain the viability and original architecture of resected ICC tumors as `tumor slice cultures' (TSCs) and evaluate their response to targeted therapies within their native microenvironment has been developed. In the proposal attached, 100 TSCs will be generated for each of the ~50 resected ICCs over the next two years, anticipating 10-15 IDH mutant ICC tumors. We will then assess their response to mutant IDH inhibition by monitoring proliferation, apoptosis, viability and the expression of relevant biomarkers. Finally, we will evaluate possible combinatorial strategies based on top `hits' from unbiased drug screens of IDH mutant preclinical models. Responses will be correlated with underlying tumor genetics and compared to those of IDH wild-type tumors. Overall, these data will serve as proof of concept for a long-term study exploiting ICC TSCs to elucidate the mechanisms underlying IDH inhibition in ICC, identify predictive biomarkers of response and resistance and establish effective combinatorial strategies for subsequent evaluation in a clinical trial setting.
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0.903 |