Abstract POSTER-THER-1419: Chk1 inhibitor (MK8776) enhances cytotoxicity of gemcitabine in select patient-derived ovarian tumorgraft models
Authors: A Kumar, S Weroha, M Becker, X Hou, S Greiner, L Karnitz, P Haluska
Journal: Clinical Cancer Research (2015)

Abstract Purpose: Treatment of recurrent ovarian cancer is limited by low response rates to salvage chemotherapy. Novel small molecule inhibitors to Chk1 (checkpoint kinase 1) have been proposed to potentiate the cytotoxic effect of one such salvage treatment, gemcitabine, by interrupting the DNA damage repair pathway. Patient derived tumorgrafts were characterized by responsiveness to gemcitabine +/- MK8776 (Chk1 inhibitor). Response was correlated with markers of Chk1 activity. Methods: Patient-derived tumorgraft models were created from patients undergoing surgery for epithelial ovarian cancer. Gemcitabine response was characterized in five high-grade serous models (PH044, PH048, PH070, PH080, and PH110). Two models (PH048 and PH080) were treated with gemcitabine monotherapy (240 mg/kg qweek x 4 doses), MK8776 monotherapy (32 mg/kg qweek x 4 doses), and with combination therapy (Gemcitabine 190 mg/kg and MK8776 32 mg/kg qweek x 4 doses). Animals were monitored for cytotoxicity, and tumors were measured weekly with ultrasound. Response to gemcitabine and to combination therapy was correlated to immunohistochemistry of γH2AX and immunoblotting for p345-Chk1 and p296-Chk1. Results: Gemcitabine monotherapy did not affect tumor growth in two models (PH044 and PH048). Significant in vivo response to gemcitabine was seen in PH070 and PH080. Significant growth attenuation but not tumor regression was seen in PH110. MK8776 did not have any effect on tumor growth as monotherapy or in combination with gemcitabine in the gemcitabine resistant model, PH048. In contrast, in a gemcitabine sensitive model, PH080, MK8776 monotherapy significantly attenuated tumor growth, and there was a trend for MK8776 to potentiate the cytotoxic effects of gemcitabine in PH080 (p=0.16). Final tumor weights in the PH080 model after 4 doses of chemotherapy were 1.7 g (90%CI: 1.5-1.9g), 0.3g (90%CI: 0.18-0.35g), and 0.14g (90%CI: 0.08-.19g) in the control, gemcitabine alone, and gemcitabine with MK8776 groups respectively. Decrease in the tumor auto-phosphorylation of Chk1 at Serine-296 was observed in some, but not all models in response to MK8766 treatment. γH2AX increased in response to the addition of MK8776 to gemcitabine. Conclusions: Chk1 inhibition may enhance the activity of gemcitabine in some, but not all ovarian tumors. Further work is needed to find markers that will predict response to Chk1 inhibitors to help select patients for future clinical trials. While pChk1-S296 previously demonstrated potential utility as a biomarker of Chk1 inhibition, in vivo assessments of its differential expression may demonstrate the unreliability of this marker. This work supports the use of patient derived tumorgrafts in drug development for ovarian cancer. Citation Format: A Kumar, S Weroha, M Becker, X Hou, S Greiner, L Karnitz, P Haluska. Chk1 inhibitor (MK8776) enhances cytotoxicity of gemcitabine in select patient-derived ovarian tumorgraft models [abstract]. In: Proceedings of the 10th Biennial Ovarian Cancer Research Symposium; Sep 8-9, 2014; Seattle, WA. Philadelphia (PA): AACR; Clin Cancer Res 2015;21(16 Suppl):Abstract nr POSTER-THER-1419.