Targeting FGFR2 Fusions with Novel Antibody Therapeutics in Cholangiocarcinoma
Abstract
Principle Investigator: My past experiences and current postdoctoral research have motivated me to pursue a career investigating liver cancers. My long-term aspirations are to conduct research with a focus on genetic mutations that drive liver cancer initiation and progression and to discover ways to target those mutations using innovative therapeutics. My graduate studies provided me with a solid foundation in studying liver development, repair, and carcinogenesis. For my postdoctoral research, I am applying this background to mammalian systems using patient-derived models to develop and evaluate new antibody-based therapeutics. Through the completion of the proposed research, the Horizon Award will allow me to gain the expertise and skill sets necessary to achieve my ultimate goal of becoming an independent investigator in the liver cancer field. Dr. Sellers is a world-expert in the development of cancer therapeutics. As a postdoctoral researcher, I joined Dr. Sellers’ lab not only for his subject matter expertise but also his strong mentorship record, having successfully nurtured the careers of postdocs to become established independent scientists in leading research institutions. Dr. Sellers strives to bring together researchers with diverse backgrounds and expertise while fostering a collaborative and friendly research environment. In this setting, I will have opportunities to enhance my scientific, leadership, and communication skills. The Broad Institute, where the Sellers lab resides is also home to numerous exceptional and collaborative cancer research scientists. The commitment to mentorship, along with unparalleled resources and skilled collaborators, will allow me to successfully carry out the proposed research questions and to achieve my career goals. Scientific Objective and Rationale: Liver cancers are the fourth leading cause of cancer-related death worldwide. Our research focuses on one of the major types of liver cancers, intrahepatic cholangiocarcinoma (ICC), a cancer arising from the bile ducts of the liver. ICC is among the most aggressive liver cancers, and it has been steadily rising in incidence over the past four decades. Surgery is curative in some cases; however, most patients are diagnosed with unresectable advanced stage disease. These advanced stage patients are left with few treatment options, and survival is typically less than 1 year. Therefore, novel therapeutics to combat ICC are critically needed. Fibroblast Growth Factor 2 (FGFR2) gene mutations occur frequently in ICC, causing over-activation of a critical growth promoting pathway. This finding has led to the successful testing of new drugs targeting FGFR in preclinical and clinical trials. Nevertheless, studies have found drug resistance and adverse effects in patients treated with FGFR inhibitors, suggesting that FGFR inhibitors alone may not be sufficient to cure ICC patients. A better understanding of FGFR2 in these cancers and alternative therapeutic approaches are therefore critically needed and are the focus of this proposal. Here, we propose to explore antibody-based treatment strategies that we believe will lead to higher efficacy and lower toxicity and also have the ability to overcome resistance. We will test these antibodies in cell line models of this cancer type as well as in animal models. We will further utilize novel technologies to engineer and improve current antibodies such that they may have enhanced therapeutic impact in ICC patients. The anticipated results from this proposal will enhance our understanding of FGFR2 in the progression of ICC biology and lead to new insights, enabling the effective deployment of our proposed new treatments. If successful, this research may take 3-5 years to translate into human clinical trials, or potentially less time if the tested antibody therapeutics have previously been evaluated in humans. The discoveries of this new therapeutics and their impact are not limited to IC
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Mar 10, 2021
- Source ID
- W81XWH2010325
Entities
People
- Saireudee Chaturantabut
Organizations
- Broad Institute
- United States Army