Identifying TME-Derived Pathways for Cotargeting with FGFR1 in Mesothelioma
Abstract
This application will explore Mesothelioma, a Fiscal Year 2016 Peer Reviewed Cancer Research Program topic area. In addition, the project will address both military relevance focus areas. Firstly, the studies address a cancer (mesothelioma) arising from a military-relevant risk factor (asbestos). Secondly, the project seeks to fill gaps in cancer treatment that may have a particularly profound impact on the health and well-being of military Service members, Veterans, and their beneficiaries. Mesothelioma is a cancer that arises from the cells lining the pleural cavity surrounding the lungs for which asbestos is the main causative agent. Currently, 2,000-3,000 new mesothelioma cases are diagnosed each year in the United States. While this incidence may be decreasing worldwide, the occurrence of this cancer is expected to persist due to varying asbestos regulation and the very long latency for its clinical presentation (up to 50 years). Current therapy largely depends largely on standard chemotherapies since radiation and surgery prove difficult due to the diffuse nature of the cancer. Despite the best treatments available, survival from mesothelioma remains poor, with median survival ranging from 6 to 13 months. New therapies that are designed to target the cancer-causing cell pathways that drive the altered growth properties of mesothelioma are needed. As with all cancers, mesotheliomas will be driven by distinct oncogenic pathways that require implementation of ?precision medicine? where the therapy is matched with the specific drug vulnerabilities of each tumor. In this regard, our proposal attempts to develop novel therapeutic approaches suited for a specific subset of mesotheliomas. Our proposed studies will explore the involvement of the Fibroblast Growth Factor Receptors (FGFRs) as important proteins that drive the abnormal growth properties of mesothelioma cells. Our completed studies revealed that inhibitors of FGFR1 were highly effective for inhibiting growth of specific mesothelioma cell lines in the Petri dish (in vitro), but exerted only transient growth inhibition when the mesothelioma cell lines were grown as tumors in immune deficient mice. Thus, growth and survival pathways arising from the murine host appear to greatly reduce the sole dependency of mesothelioma cells on FGFRs. Consistent with this latter finding, early phase clinical trials with FGFR inhibitors revealed only modest, partial responses in various FGFR1-expressing cancers. Based on these findings, we hypothesize that inhibiting both FGFRs and the novel host-derived signals will yield clinically relevant anti-cancer activity. This research project is intended to impact treatment options for mesothelioma patients whose tumors bear high expression of a specific FGFR, FGFR1. If successful, the studies could lead to ?targeted therapy? options for this subset of mesothelioma patients. The FGFR inhibitor that we will use has already been tested for clinical benefit and patient safety on distinct cancers in which FGFR1 is known to be overactive. Thus, the patient risks and toxicities have already been identified and in most cases, are clinically manageable. Importantly, early-stage clinical trials show only modest clinical benefit from treatment with these drugs as single agents, or monotherapies. Thus, discovery of one or more signal pathways that serve as auxiliary inputs with FGFR1 may open up avenues for drug combinations in the next phase of clinical trials with these FGFR inhibitors. Because Phase 1 clinical trials with FGFR inhibitors are completed, positive findings with novel drug combinations could be rapidly implemented in mesothelioma patients. Evidence demonstrates that former members of the military, especially U.S. Navy Veterans, are among those most affected by asbestos exposure. Although asbestos was heavily used in all branches of the military from World War II until about 1970, the Navy was the most pro
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Aug 07, 2017
- Source ID
- W81XWH1710344
Entities
People
- Lynn E Heasley
Organizations
- United States Army
- University of Colorado Denver