Radiation and Cancer Biology

PD 07 - Biology 3 - Poster Discussion

1061 - Molecular Profiling of Head and Neck Cancer Patient Derived Xenografts Identifies FGFR As a Target for Radiosensitization.

Monday, October 22
4:51 PM - 4:57 PM
Location: Room 217 C/D

Molecular Profiling of Head and Neck Cancer Patient Derived Xenografts Identifies FGFR As a Target for Radiosensitization.
A. M. Baschnagel1, M. Fisher2, M. Miller3, L. Able3, C. Li3, S. Brennan3, G. Iyer3, P. M. Harari2, and R. J. Kimple4; 1Department of Human Oncology, University of Wisconsin Hospital and Clinics, Madison, WI, 2Department of Human Oncology, University of Wisconsin, Madison, WI, 3University of Wisconsin, Madison, WI, 4University of Wisconsin School of Medicine and Public Health, Department of Human Oncology, Madison, WI

Purpose/Objective(s): The fibroblast growth factor receptors (FGFR1, FGFR2, FGFR3) are frequently altered or overexpressed in head and neck squamous cell carcinomas (HNSCC). Amplification of FGFR1 has been reported to be as high as 17% in this disease. FGFRs activate multiple pathways involved in the radiation response including RAS/RAF/MAPK, PI3K/AKT and STAT. AZD4547 is a potent and selective tyrosine kinase inhibitor of the FGFR family and is currently being investigated in clinical trials. We therefore examined the anti-tumor effects of AZD4547 in combination with radiation in HNSCC model systems.

Materials/Methods: HNSCC patient derived xenografts were screened using FGFR1 and FGFR2 RNA in situ hybridization. A panel of HNSCC cell lines were screened for FGFR1/2 protein and RNA expression and response to AZD4547. Immunoblots were used to examine the effect of AZD4547 on downstream signaling proteins. Radiation clonogenic survival assays and xenograft growth delays experiments were performed to investigate radiosensitization.

Results: Out of the 22 HNSCC patient derived xenografts examined, three were found to have FGFR1/2 expression. This included one p16 negative tumor and two p16 positive tumors. Nine cell lines demonstrated varying degree of FGFR1/2 protein and RNA expression. The half-maximal inhibitory concentration (IC50) of AZD4547 in these cell lines ranged from 0.05 to 42.2 uM. Sensitivity to AZD4547 did not directly correlate with protein or RNA expression. In sensitive cell lines, AZD4547 inhibited p-MAPK in a time dependent manner. In vitro clonogenic survival assays showed enhancement in radiosensitivity with AZD4547 in two HNSCC cell lines. AZD4547 induced significant growth inhibition in a FGFR1 expressing patient derived xenograft. Significant tumor growth delay was observed with the combination of radiation and AZD4547 compared to radiation or drug alone in a FGFR2 expressing cell line HNSCC xenograft model.

Conclusion: These findings suggest that AZD4547 can augment the response of radiation HNSCC in vivo model systems. FGFR1 and FGFR2 expression may provide a potential target for radiosensitization in HNSCC. Additional studies are underway to understand the mechanism of radiosensitization.

Author Disclosure: A.M. Baschnagel: None. M. Fisher: None. L. Able: None. C. Li: None. S. Brennan: None. P.M. Harari: Member; ASTRO Board of Directors. R.J. Kimple: Employee; University of Wisconsin. Research Grant; Threshold Pharmaceuticals, Peloton Therapeutics, American Cancer Society, National Institute of Health, V Foundation for Cancer Research.

Andrew Baschnagel, MD

Disclosure:
Employment
University of Wisconsin: Assistant Professor: Employee

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