Abstract B167: APX3330 drug development for clinical trials targeting APE1/Ref-1 in pancreatic cancer

Abstract

Abstract Despite recent progress in the treatment of cancer over the past several decades, effective therapeutic options for pancreatic cancer remain as an area of high unmet medical need. Most patients with pancreatic cancer will survive less than six months following diagnosis. Targeted therapies including Gemcitabine (GemzarTM), FOLFIRINOX (5-FU/leucovorin/irinotecan/oxaliplatin), and sustained release, nab-paclitaxel (AbraxaneTM) offer some modest improvement in survival, albeit at an increase in side effects and unwanted toxicities. Data presented here will center on redox factor-1 (Ref-1) and a Ref-1 inhibitor developed in our laboratories, APX3330. Ref-1 regulates multiple transcription factors (TFs) involved in pancreatic cancer cell survival signaling due to its redox-coactivator activity on oxidized TFs including HIF-1α, AP-1, NFkB, and STAT3. High expression levels of Ref-1 also indicate decreased survival in pancreatic ductal adenocarcinoma (PDAC) as well as other cancers. APX3330 has been shown in multiple in vitro and in vivo models of pancreatic cancer to be effective in reducing tumor growth and metastases as a single agent. The mechanism of action has been extensively investigated and characterized and involves APX3330 binding to Ref-1. Furthermore, the safety and dose administration of APX3330 have been established by Eisai pharmaceutical company through a previous development program including toxicology, phase I, and phase II clinical evaluation in non-cancer patients in Japan. We have partnered with ApeX Therapeutics to develop APX3330 for cancer (IND submitted; phase I trial anticipated start date early 2016). Methods: We performed in vivo studies demonstrating single and combination effects of APX3330 with gemcitabine. Additionally, we tested single and combination studies of APX3330 in anex vivo 3-Dimensional tumor-stroma model system using patient derived tumor cells along with patient derived cancer-associated fibroblasts (CAFs). Results: In our ex vivo 3D co-culture system, APX3330 decreases the tumor area and intensity in a dose-dependent manner. We can quantitate the effect on both the tumor and the CAFs as they are labeled with different fluorescent markers. The combination of APX3330 with Gemcitabine (Gem) demonstrated an additive enhancement effect in the tumor. However, the combination treatment did not appear to sensitize CAF cells to Gemcitabine, which suggests that Gem+APX3330 treatment is more specifically targeting tumor cells. This suggests that blocking redox function in both tumor and CAF cells can stop the cross-talk between tumor and fibroblast, therefore sensitizing the tumor cells to Gemcitabine-induced cell killing. Using in vivo animal models, APX3330 has been shown to be effective in reducing tumor volume and metastases as a single agent. APX3330 also reduced the number of lymph node metastatic lesions. In our current combination in vivo study, APX3330 was combined with a standard dose of Gemcitabine and carried out over 63 days. There was a significantly decreased tumor volume in the combination treatments of APX3330 with Gemcitabine compared to the single-agents alone. Based on these findings we are proposing phase I/Ib studies of APX3330 in patients with solid tumors, and in combination with Gemcitabine in patients with advanced pancreatic ductal adenocarcinoma. Citation Format: Melissa L. Fishel, Huiwen Cheng, Safi Shahda, Mark R. Kelley. APX3330 drug development for clinical trials targeting APE1/Ref-1 in pancreatic cancer. [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2015 Nov 5-9; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2015;14(12 Suppl 2):Abstract nr B167.