Abstract LB-28: Suppression of ovarian tumor growth and metastasis with a STAT3 inhibitor, HO-3867, in preclinical orthotopic models and ex vivo cultures of ovarian cancer
Authors: Naidu Shan K. , Saini Uksha , ElNaggar Adam C. , Hemant Bid K. , Rath Kellie S. , Wanner Ross , Suarez Adrian , Hays John , Houghton Peter , Cohn David E. , Selvendiran Karuppaiyah 
Published: May 2015

Objective: We previously studied a novel anticancer compound, HO-3867, in in vitro culture and xenograft ovarian tumor models. In our current study, we tested our compound in more clinically relevant preclinical models of ovarian cancer. Our goal is to employ an orthotopic mouse model of ovarian cancer by injecting tumor cells directly into intrabursal space and allow the tumor to grow in its native microenvironment. This model allows the investigator to not only evaluate the efficacy of new drugs in treating the primary tumor mass, but also permits investigation into the potential for prevention and/or treatment of metastatic tumor growth.

Methods: Development of an orthotopic model of ovarian tumor. In vivo antitumor activity of STAT3 inhibitor, body weight measurements, feed intake and tumor weight assessment. Assessment of tumor volume and hypoxia using PET/CT. Tumor excision assays with clonogenic survival endpoints. In vivo analysis was performed on mice administered oral HO-3867 using histopathological analysis and TUNEL assays. In vivo bio-absorption of DAP compounds in tumors and in vivo toxicity evaluation. Bio-absorption analysis by EPR and LCMS.

Results: Treatment with HO-3867 significantly suppressed ovarian tumor growth and metastasis compared with Cisplatin. Markers specific to cell proliferation (Ki-67, Cyclin D1), angiogenesis (VEGF and Kinase array) and apoptosis (caspase-3 activity) were demonstrated to be affected by treatment with HO-3867. In vivo histopathological evaluation of internal organs collected from treated tumor mice revealed no evidence of toxicity specific to HO-3867. Normal and malignant tissues were collected and TUNEL/8-OHdG staining revealed selective apoptotic induction limited to neoplastic cells and concomitant increase in reactive oxygen species within the orthotopic tumor. Suppression of STAT3 and its downstream target proteins (cell proliferative, anti-apoptotic and angiogenic) was confirmed with proteomic array. HO-3867 was also found to have cytotoxic effects on human tumors resulting from pharmacologic intervention in ex vivo culture of freshly collected tumor sections

Conclusion: Our results highlight the clinical anti-cancer potential of HO-3867 using a relevant preclinical model, and provide a rationale for the inclusion of ex vivo tumor slice culture in oncologic drug development processes. This pre-clinical screening of HO-3867 may have a significant impact on patient selection for clinical trials and in predicting response to small-molecule STAT3 inhibitor therapy for ovarian cancer.

Citation Format: Shan K. Naidu, Uksha Saini, Adam C. ElNaggar, Bid K. Hemant, Kellie S. Rath, Ross Wanner, Adrian Suarez, John Hays, Peter Houghton, David E. Cohn, Karuppaiyah Selvendiran. Suppression of ovarian tumor growth and metastasis with a STAT3 inhibitor, HO-3867, in preclinical orthotopic models and ex vivo cultures of ovarian cancer. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr LB-28. doi:10.1158/1538-7445.AM2014-LB-28