PARP inhibition in combination with radiation therapy for the treatment of feline oral squamous cell carcinoma
Feline oral squamous cell carcinoma (FOSCC) is a devastating tumor frequently palliated with radiation therapy (RT). Disappointingly, RT typically exerts marginal and transient tumor regression and new strategies to enhance RT efficacy are needed. Poly (ADP-ribose) polymerase (PARP) is a key molecule involved in single stranded DNA break repair. PARP inhibitors (PARPi) are predicted to amplify RT-induced lethal DNA damage, and combinatorial strategies with PARPi and RT are being investigated for treating human solid tumors. We hypothesized that Olaparib, an orally bioavailable PARPi, combined with RT will improve therapeutic outcomes in FOSCC. Three feline squamous cell carcinoma (SCC) cell lines (SCCF1, SCCF2 and SCCF3), and a human SCC cell line (HN31) were used to characterize the radiobiologic activities of Olaparib and RT. Changes in DNA damage were studied using nuclear γH2AX via confocal microscopy with different treatment combinations. Colony formation assays were performed to evaluate cell survival in various treatment settings. Clonogenic survival fraction was quantified and displayed with digital imaging. A dose escalation study in healthy cats was performed assessing Olaparib safety and pharmacokinetics, and these preclinical findings guided a comparative clinical trial combining Olaparib and stereotactic radiotherapy (SRT) in 20 cats with OSCC. Olaparib enhanced DNA damage induced by RT in vitro across all cell lines. In healthy cats, Olaparib is safe and demonstrated dose-dependent pharmacokinetics. In OSCC cats, Olaparib could be combined with SRT and radiologic responses were achieved in the majority of cats treated, and proved to be superior in comparison with cats treated with SRT alone. Combinatorial strategies with PARPi and RT hold promise for improving the management of solid tumors such as OSCC, however, additional studies are required to optimize dose schedule and sequence.
FOSCC, PARP inhibitor, BRCA-1, double strand DNA breaks, olaparib, Radiation therapy, HNSCC
University of Illinois - Urbana-Champaign
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