Abstract 3855: Preclinical investigation of novel ALDH1A1 inhibitors in pancreatic cancer

Abstract

Introduction: Pancreatic adenocarcinoma remains a devastating disease, with a predicted 5-year survival at the time of diagnosis of less than 10%, and likely the number 2 cause of U.S. cancer deaths in the next decade. The lack of effective therapies and resistance to cytotoxic agents contribute to the poor outcomes in this patient population. Aldehyde dehydrogenases (ALDHs) are a family of enzymes that play important biological and metabolic roles in the human body. ALDH activity has been identified in many human malignancies as a marker of tumor initiating cells. In pancreatic cancer, ALDH1A1 has been shown to be upregulated in cancer stem cells (CSCs) and has been attributed to tumorigenesis and chemotherapeutic resistance. Methods: Six novel ALDH1A1 inhibitor drugs from the National Center for Advancing Translational Sciences (NCATS) were screened on human pancreatic cancer cell lines using the Cell Titer-Glo Assay. Proliferation assays were also performed with the three best performing inhibitors on a total of eight human pancreatic cancer cell lines. The best performing ALDH1A1 inhibitor drug were chosen and tested in combination with gemcitabine and paclitaxel on patient-derived tumor organoids (PDTOs). The combination effects were assessed over a 7-day period using the IncuCyte ZOOM live cell imager and CellTiter-Glo 3D Assay. Results: We assessed the anti-proliferative effects of 6 novel ALDH1A1 inhibitors on 4 pancreatic cancer cell lines. Two out of 4 pancreatic cell lines showed moderate treatment effects to 3 ALDH1A1 inhibitors. Further evaluation of one of the ALDH1A1 inhibitor on 8 additional pancreatic cancer cell lines revealed similar results. While several pancreatic cell lines showed some moderate activity at higher levels of drug exposure, most of the pancreatic cancer cell lines treated were more resistant. We next investigated the treatment effects of ALDH1A1 inhibitor in combination with gemcitabine or paclitaxel on PDTO 269 and 272. A combination effect with the ALDH1A1 inhibitor and paclitaxel was observed after 72 hours of drug exposure in both PDTO 269 and 272. In contrast, treatment with the ALDH1A1 inhibitor with gemcitabine did not further decrease growth when compared to single agent ALDH1A1 and gemcitabine. Conclusions: Although single agent activity of novel ALDH1A1 inhibitors is limited at significantly reducing cellular proliferation, inhibition of ALDH1A1 in combination with paclitaxel appears to have potent anti-tumor activity in PDTOs. These findings support further investigation of this combinational therapy for the treatment of pancreatic cancer. Additional studies are currently underway to evaluate this combinational activity in more preclinical pancreatic cancer models and to elucidate the underlying mechanisms whereby the inhibition of ALDH1A1 enhances the anti-tumor potential of paclitaxel. Citation Format: Betelehem W. Yacob, John J. Arcaroli, Maraake Taddese, Todd M. Pitts, Stacey M. Bagby, Sarah J. Hartman, S.Lindsey Davis, Christopher H. Lieu, Alexis D. Leal, Wells A. Messersmith. Preclinical investigation of novel ALDH1A1 inhibitors in pancreatic cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 3855.