Dysregulation of fibroblast growth factor receptor 1 (FGFR1) has been associated with pathogenesis and disease progression of a number of human malignancies. The aggressive 8p11 myeloproliferative syndrome (EMS) is associated with several recurrent translocations involving the region p11.2-11.1 of chromosome 8, which have been associated with two distinct clinical hematopoietic malignancies: acute myeloid leukemia (AML) or stem-cell myeloproliferative disorder (MPD). The major translocations include t(8;13)(p11;q12), t(8;9)(p11;q33), t(6;8)(q27;p11) and t(8;22)(p11;q11) that result in fusion of distinct partners to FGFR1 gene on 8p11, including ZNF198, CEP110, FOP and BCR, respectively. In each case, the fusion FGFR1 tyrosine kinase is constitutively activated by the N-terminal partner containing self-association motif, and plays a pathogenic role. However, despite of the advances in understanding of molecular basis of 8p11 EMS, current empirically-derived cytotoxic chemotherapy is inadequate treatment of this disease. Patients with MPD are characterized by myeloid hyperplasia that aggressively progresses to AML within a year of the original diagnosis; and cure requires allogeneic stem cell transplantation. Therefore, there is a compelling need to develop effective molecularly targeted therapies in treatment of 8p11 EMS, where the pathogenic role of FGFR1 fusions makes them an attractive target. These therapies may also apply to solid tumors where overexpression of FGFR1 was identified in breast cancer and pancreatic adenocarcinomas. In this proposal, we will characterize the signaling properties and pathophysiologic significance of oncogenic FGFR1 and its fusions in murine disease models of leukemia and solid tumors. Moreover, we will test the therapeutic effects of strategies targeting FGFR1 or downstream signaling effectors, including FGFR inhibitors, PKC412 and CHIR-258 in preclinical translational studies.
In Specific Aim 1, we will characterize the role of putative critical signaling effectors including STAT5 and PI3K in hematopoietic transformation by diverse FGFR1 fusions in vitro and in vivo.
In Specific Aim 2, we will characterize the transforming activity of a spectrum of clinically reported FGFR1 fusions in vitro and in vivo, and determine the therapeutic efficacy of FGFR1 inhibitors in preclinical animal models of diseases.
This aim builds on our previous studies that a small molecule tyrosine kinase inhibitor PKC412 is a potent inhibitor of FGFR1.
Specific Aim 3 will focus on development of alternative strategies to inhibit FGFR1, and overcome drug resistance. We will test stable expression of siRNA in mammalian cells using a novel approach we have developed, and small molecule inhibitors of downstream effectors identified in Specific Aim 1 both alone, and in combination with FGFR1 inhibitors. In summary, this proposal will provide detailed information about signaling and transforming properties of FGFR1 fusions, and explore therapeutic strategies to treat FGFR1-associated malignancies. ? ? ? ?
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