Abstract 2853: TP-6379, an investigational TGFBR1 inhibitor, shows improvement in survival and enhances activity of standard of care in preclinical ovarian cancer models

Abstract

Abstract Ovarian cancer is still associated with poor prognosis and remains amongst the leading causes of cancer related deaths in females. High recurrence rates, resistance to chemotherapy, and meager outcome highlight the need for improved therapies that stem from understanding the complex and multifactorial etiology of ovarian malignancies. Transforming growth factor-β (TGF-β) signaling can regulate both oncogenesis and metastasis in ovarian cancer (Kumri et al. 2021). This, in part, is done by affecting apoptosis and survival mechanisms, epithelial to mesenchymal transition, immune cell recruitment and response. Inhibition of the TGF-β signaling pathway is a potential pharmaceutical approach for treating ovarian malignancies.TP-6379 is a potent and orally available investigational TGF-β receptor 1 (TGFBR1) inhibitor and is currently in preclinical development at Sumitomo Pharma Oncology, Inc. (SMP Oncology). We hypothesized that TP-6379 may inhibit the TGF-β signaling pathway and show activity in preclinical ovarian cancer models. TP-6379 was observed to inhibit TGFBR1 potently in a biochemical kinase assay. Dose dependent increase in compound concentration was observed in ES-2 tumor burdened animals treated with TP-6379. Preclinical data showed TP-6379 (150 mg/kg, BID) treatment significantly improved overall survival compared to vehicle treatment in an ES-2 mouse xenograft model of clear cell carcinoma. We hypothesize this result was, in part, due to alleviation of ovarian cancer induced cachexia, as animals treated with TP-6379 showed retention of muscle mass in their hind limbs compared to the vehicle treated animals. To investigate a combination effect with the standard of care in ovarian cancer, a SK-OV-3 ovarian cancer adenocarcinoma cell line was treated in vitro with TP-6379 and paclitaxel. Class III β-tubulin (TUBB3), a potential resistance mechanism to paclitaxel, showed induced expression in response to TGF-β, paclitaxel or both, after 24 hr treatment, and this effect was observed to be inhibited by TP-6379 treatment. In a SK-OV-3 xenograft model, TP-6379 (150 mg/kg, BID) treatment showed the trend of tumor growth inhibition (TGI) as a monotherapy and showed enhanced TGI in combination with paclitaxel (7.5 mg/kg, QW) when compared to vehicle treatment. Combination treatment in this xenograft model showed significant reduction of TUBB3 mRNA compared to paclitaxel treatment alone. In conclusion, our preliminary preclinical studies have shown promising activity for TP-6379 in ovarian malignancies as monotherapy and/or in combination with standard of care. TP-6379 may be a viable therapeutic option by targeting the TGF-β pathway in ovarian cancer. Citation Format: Tetyana V. Forostyan, David A. Kircher, Richard E. Heinz, Curtis Allred, Sal Sommakia, Yuta Matsumura, Adam Siddiqui, Jason M. Foulks, Steven L. Warner. TP-6379, an investigational TGFBR1 inhibitor, shows improvement in survival and enhances activity of standard of care in preclinical ovarian cancer models [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 2853.