Date of Award
Fall 2023
Document Type
Dissertation
Degree Name
Doctor of Philosophy (PhD)
Department
Pharmacology
First Advisor
Anderson, Karen
Abstract
FGFR genomic alterations have been implicated in a number of cancers as oncogenesis driver genes. However, despite the approval of several FGFR inhibitors as targeted therapies for the treatment of cancer patients with FGFR aberrations in recent years, durable responses for FGFR inhibitors are still uncommon and most patients relapse to metastatic disease. In particular, FGFR2 fusions have been detected in ~15% of intrahepatic cholangiocarcinoma (ICC) patients. ICC is a highly aggressive bile duct carcinoma, with a dismal 5-year overall survival rate for patients at advanced stages. Therefore, there is a desperate and urgent need for the development of new therapeutic strategies. Given the necessity to further improve targeted therapy, in this study, we reported the establishment of a novel ICC patient-derived FGFR2 fusion-positive preclinical model system, including a cell line, organoid, and PDX model, which were extensively characterized genomically, histologically, and phenotypically. We then examined their sensitivities to FGFR inhibitors and standard-of-care chemotherapies and also leveraged these models to illustrate the additivity between FGFR inhibitors and cytotoxic chemotherapies. To further improve the efficacy of FGFR targeted therapy, we next performed an unbiased small molecule high-throughput screening which revealed that FGFR inhibitors are synergistic with HDAC inhibitors. The combinational effects of FGFR and HDAC inhibitors were further verified in all of our patient-derived cell line, organoid, and xenograft models. Furthermore, we also demonstrated that this combination can have a broader application to other FGFR fusion-positive cancers. FGFR genomic alterations have also been particularly prevalent in bladder cancer (BC). Thus, we sought to further investigate this novel combination in BC with FGFR3 fusions. Our studies confirmed the synergy between FGFR and HDAC inhibitors in vitro and validated the benefits of this combination in vivo as well for FGFR3 fusion-positive BC. Studies to examine the molecular mechanisms for the synergy in BC revealed that HDAC inhibitors might achieve the synergy with FGFR inhibitors by sensitizing BC cells to FGFR inhibitors through the downregulation of FGFR3 and HDGF expression. Additionally, we also demonstrated the generality of this FGFR/HDAC synergistic combination in breast cancer with FGFR3 fusions and bladder cancer with FGFR3 activating mutations. This study discovers a new avenue for treatment of cancer patients with FGFR aberrations, especially patients with FGFR fusions, as well as uncovers novel mechanistic insights. These preclinical studies present the proof-of-principle and thus, pave the way for a direct translation of this combination into early phase clinical trials.
Recommended Citation
Wang, Zechen, "Tackling FGFR Fusion-Positive Cancers with a Novel Synergistic Combination of FGFR and HDAC Inhibitors" (2023). Yale Graduate School of Arts and Sciences Dissertations. 1146.
https://elischolar.library.yale.edu/gsas_dissertations/1146
