Abstract 5771: Targeting EphA2 in bladder cancer using a novel antibody-directed nanotherapeutic

Abstract

Abstract Ephrin receptor A2 (EphA2) is a member of the Ephrin-Ephrin receptors cell to cell signaling family of molecules and plays a key role in proliferation, differentiation, and migration. EphA2 is overexpressed in a broad range of cancers, including bladder cancer, and is associated with increased metastasis and poor prognosis. Several potential EphA2-targeted therapies were developed and showed promising preclinical activity which failed to translate clinically due to narrow therapeutic window. we propose to use a novel antibody-directed nanotherapeutic (ADN) approach to target EphA2 for the treatment of bladder cancer. This work characterizes the expression of EphA2 in bladder cancer patients, evaluates its prognostic power, and tests an EphA2-targeted ADN, MM-310, in patient-derived xenograft (PDX) models. EphA2 expression in tumors was investigated using a validated immunohistochemistry assay performed in 147 bladder cancer samples, enabling analysis of prevalence and prognostic power. Whole sections of primary and metastatic tumor resections were used to assess EphA2 expression in tumor-associated vessels and tumor cells. Four EphA2+ PDX models were used to evaluate the activity of MM-310 compared to free docetaxel, alone or in combination with gemcitabine. EphA2 was expressed in tumor cells and tumor-associated blood vessels in primary and metastatic lesions. EphA2 overexpression was seen in 80%-100% of tumors and correlated with shorter survival. In the PDX models, MM-310 controlled tumor growth, mediated greater regression, and was more active than free docetaxel at equitoxic dosing (Table). Additionally, the combination of MM-310 and gemcitabine controlled tumor growth better than each drug alone, and outperformed the combination of free docetaxel and gemcitabine in the single PDX model where it was compared. Thus, in bladder cancer models, a docetaxel-based ADN as a monotherapy and in combination with gemcitabine targeted EphA2 and led to significant tumor regression. Maximum tumor regression (%) & Time to regrowth (days)Model NameControlDocetaxelMM-310p valueBL0293-2% & 3 days-58% & 55 days-100% & 120 days<.05 & <.001BL03820% & 3 days-16% & 34 days-100% & 106 days<.001 & <.001BL04400% & 7 days-43% & 41 days-84% & 67 days<.01 & <.01BL4173620% & 5 days-47% & 69 days-100% & 121 days<.05 & <.05 Citation Format: Walid Kamoun, Elden Swindell, Christine Pien, Lia Luus, Jason Cain, Irawati Kandela, Richard Huang, Suresh Tipparaju, Dmitri Kirpotin, Wiam Bshara, Vasileios Askoxylakis, Carl Morrison, Daryl Drummond. Targeting EphA2 in bladder cancer using a novel antibody-directed nanotherapeutic [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 5771.