3118 - ATR Inhibition as a Radiosensitization Strategy in Naturally Occurring Feline Head and Neck Squamous Cell Carcinoma
Presenter(s)
M. W. Nolan1, E. Palyvou1, M. Ravotti2, J. Veliz2, T. Ingkasri1, F. Ahmed1, E. Koseli1, A. R. Thomas2, J. L. Holleran2, J. Guo2, R. A. Parise2, J. H. Beumer2,3, and Y. M. Mowery4; 1North Carolina State University, Raleigh, NC, 2University of Pittsburgh, Pittsburgh, PA, 3Johns Hopkins University, Baltimore, MD, 4Department of Radiation Oncology, UPMC Hillman Cancer Center, Pittsburgh, PA
Purpose/Objective(s): Feline oral/oropharyngeal squamous cell carcinoma (FOSCC) is an aggressive malignancy with limited treatment options. Affected cats are commonly treated with hypofractionated radiotherapy (RT), but tumor responses are typically short-lived. While ATR inhibitors, such as camonsertib (RP3500), may enhance tumor radiosensitivity, their efficacy in FOSCC remains unexplored. This study will evaluate the radiosensitizing effects of camonsertib in vitro and in vivo in a proof-of-concept clinical trial in pet cats with naturally occurring FOSCC.
Materials/Methods: The effect of camonsertib on cell growth with and without radiation therapy (RT; 4 Gy) was assessed in FOSCC cell lines (SCCF1 and SCCF3) using a cell counting kit assays. Clonogenic assays to assess radiosensitization are ongoing. Pharmacokinetics (PK), toxicity, and maximum tolerated dose (MTD) of camonsertib were determined in three healthy cats. A prospective clinical trial is underway, randomizing six FOSCC-affected cats (3 per arm) to receive RT alone (8 Gy × 3, 72-hour interval) or RT plus camonsertib (5 mg/kg subcutaneous [SC], 90 minutes pre-RT). Tumor response and tolerability are being assessed.
Results: Camonsertib demonstrated single-agent in vitro cytotoxic activity that was enhanced by RT; the half-maximal effective concentration (EC50) of camonsertib was 1.81 µM without RT vs. 0.14 µM with RT for SCCF1, and 0.52 µM without RT vs. 0.09 µM with RT for SCCF3. For in vivo studies, camonsertib was formulated in DMSO, PEG400, tween-80, and saline. Pharmacokinetics were consistent between individual healthy (non tumor-bearing) cats. After SC injection, the maximum concentration occurred between 2-4 hours, with a half-life of 2 hours, and excellent bioavailability. Reversible anemia, neutropenia, elevated alanine aminotransferase, and elevated temperature were the most common adverse events, and the MTD was 5 mg/kg SC. Clinically, five tumor-bearing cats have been enrolled (RT alone: n=3; RT + camonsertib: n=2). No unexpected toxicities have been observed. Evaluation of tumor responses and survival is ongoing. Interestingly, one cat in the RT-alone arm progressed 3 weeks after treatment but then crossed over to RT + camonsertib (off-trial), resulting in a complete response which has thus far lasted three months.
Conclusion: Preliminary data suggest that camonsertib enhances radiosensitivity in FOSCC, with promising in vitro and in vivo clinical findings. This clinical trial design mirrors a pending phase I clinical trial for humans with recurrent head and neck squamous cell carcinoma, with the added benefit of tissue acquisition after the first RT dose in the feline trial. Further enrollment, follow-up, and correlative studies will clarify camonsertib’s therapeutic potential as a radiosensitizer in feline and comparative oncology.