Prevalence and Biologic Impact of FGFR3 Genomic Alterations in Bladder Cancer
Abstract
The fiscal year 2022 Peer Reviewed Cancer Research Program (PRCRP) Topic Area to be addressed is bladder cancer. Scientific Objectives and Rationale: Metastatic bladder cancer remains incurable in most patients. Erdafitinib is an oral targeted therapy approved for treating patients with metastatic bladder cancer that harbors genetic changes (mutations or fusions) within the fibroblast growth factor receptor-3 (FGFR3) gene, present in about 20% of patients with metastatic disease. While the drug is effective at shrinking tumors and controlling disease, the median time that patients are on treatment before the disease progresses is less than 6 months. The reasons for this rapid onset of resistance are largely unknown, and the goal of this proposal is to identify these mechanisms. Additionally, bladder cancer is known to have a high degree of genomic heterogeneity, or differences in the profile of mutations, between different stages of tumors and even different portions of the same tumor in individual patients. We will leverage a largest-of-its-kind cohort of patients with bladder cancer who have undergone genetic sequencing of their tumors (including of FGFR3) to identify differences in FGFR3 mutation status between a primary tumor and metastatic biopsies within the same patients to gauge how often FGFR3 mutations are only found in a primary tumor or a metastasis. This work will help answer whether genetic sequencing of a metastatic site may be critical to the accurate identification of patients with FGFR3 mutations who may be eligible for erdafitinib therapy. Recognizing the fact that obtaining biopsies is simply not feasible for many patients, we will also explore the rate of FGFR3 alterations in circulating tumor DNA. Utilizing the same patient cohort with primary and metastatic biopsies available who are being managed at our institution, we will collect plasma for ctDNA isolation at the time of systemic treatment initiation (such as chemotherapy, immunotherapy, or erdafitinib). Following genetic sequencing of ctDNA, we will compare the FGFR3 alteration rate with tumor tissue. In some patients, we expect that FGFR3 alterations may only be detected in ctDNA due to underlying genomic heterogeneity that cannot be captured from single-site biopsies. In a parallel effort, we will perform an in-depth evaluation of FGFR3 mutant mouse models derived from patient tumor biopsies. Specifically, mice injected with patient-derived tumors containing various FGFR3 mutations will be treated with erdafitinib to assess sensitivity to drug as a function of the FGFR3 mutation and the profile of co-alterations within the tumor. We will perform detailed analyses of tumors that grow or recur after initially shrinking to identify mechanisms of resistance to erdafitinib and we will generate erdafitinib- resistant models and study resistance mechanisms using genetic sequencing. We will validate novel mechanisms within the lab. Finding ways to prolong treatment with approved drugs, such as erdafitinib, or combining erdafitinib with other drugs to delay or prevent resistance to therapy, represents an area of critical unmet need. Additionally, accurate identification of patients who are most likely to benefit from erdafitinib therapy is urgently needed. In the current era of precision medicine in which genetic sequencing has been incorporated into the routine management of several cancers, it is even more essential to define the optimal specimen to sequence given the spatial and temporal heterogeneity of therapeutically actionable genetic alterations. In the long-term, several new FGFR inhibitors that are likely to be better tolerated than erdafitinib are about to begin clinical trial development. We plan to open two studies of FGFR3-specific inhibitors at MSKCC, and the proposed work will provide a head start to define resistance mechanisms to these novel agents. This proposal seeks to address the PRCRP Overarching Challe
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Jan 04, 2024
- Source ID
- HT94252310637
Entities
People
- Gopakumar Iyer
Organizations
- Sloan-Kettering Institute
- United States Army