FGFR Pathway as a Lead Therapeutic Vulnerability in Pediatric Ependymoma
Abstract
Our proposal aligns with the fiscal year 2022 (FY22) Peer Reviewed Cancer Research Program (PRCRP) Topic Areas of (i) brain cancer, and (ii) pediatric brain tumors; and with the FY22 PRCRP Military Health Focus Area Gaps in cancer research that may affect mission readiness. The lead scientific investigators of this proposal, Drs. Mack and Filbin, study a type of aggressive pediatric brain tumor called ependymoma. Treatment for ependymoma has not changed in the last 20 years. In independent lab studies, Drs. Mack and Filbin identified a key druggable pathway, called the FGFR pathway, that may be important for treating these diseases. Based upon these findings, a national clinical trial consortium, called the Pacific Pediatric Neuro-Oncology Consortium (PNOC), prioritized targeting the FGFR pathway as the lead concept to advance to ependymoma clinical trials (see Letter of Support: Sabine Mueller, M.D., Ph.D.). However, before launching this clinical trial, several key pieces of data in animal mouse models are needed and which we seek to accomplish in our grant proposal. Our overall objectives are to rigorously test drugs that block the FGFR pathway across several ependymoma animal models and identify new drug combinations that may be rapidly advanced to clinical trial. Our research will help children with a type of pediatric brain tumor called ependymoma. However, more broadly, scientific findings from our research have the potential to inform treatment of other cancer types driven by the same pathway. In addition, novel computational methods we have developed and incorporated in this grant for drug discovery have the potential to impact findings outside pediatric brain tumors including adult cancers. The goal of our research is to take findings from each of our objectives, and directly translate these to a clinical trial in patients within PNOC. As members of the PNOC consortium, Drs. Mack and Filbin will be directly engaged in the scientific components of this prospective clinical trial to test FGFR drugs in patients. Because there are zero targeted therapies available to these patients, our research proposal has potential to have an immediate impact. Based upon findings and outcomes of our research, we would anticipate translating these findings to clinical trials in patients in approximately 5 years. Our anticipated clinical trial in humans will help both pediatric and adolescent patients. It will provide patients and their families an option to enroll in a clinical trial that evaluates FGFR therapy. This is particularly relevant since there are so few clinical trials open across the U.S. for this patient population, and even fewer ependymoma-focused trials. Our proposal will address the specific FY22 PRCRP overarching challenge to Transform cancer treatment through the identification of new targets, especially for advanced disease and metastasis. FGFR pathway is a novel target that we have discovered in ependymoma using distinct methods. Our research proposal seeks to rigorously test FGFR drugs, find the disease types that respond effectively, and to identify rationale drug combinations so we can target drug resistant cells with alternate therapies. Our research grant would directly affect the FY22 PRCRP Military Health Focus Area Gaps in cancer research that may affect mission readiness, specifically the treatment and health of Service Members, Veterans, their beneficiaries, and the general public. Our research focuses on the topic of pediatric brain tumors; however, several elements of our proposal have potential to impact other tumor types driven by FGFR alterations. Furthermore, our strategy to identify combination therapy using single-cell transcriptomic profiling has potential to broadly apply to the study of other cancer types and improve our understanding of cancer toward new therapeutic development.
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Jan 04, 2024
- Source ID
- HT94252310865
Entities
People
- Stephen Mack
Organizations
- United States Army