sCD-3BP: An MCT-1-"gated" therapeutic for pancreatic adenocarcinomaB004

Abstract Metabolic reprogramming is a hallmark of Pancreatic Ductal Adenocarcinomas (PDAC) and offers unique opportunities for therapeutic development. TCGA datasets and pancreatic tissue microarrays reveal that nearly 30% of PDACs exhibit a marked overexpression of Monocarboxylate Transporter 1 (MCT-1), a known lactate/pyruvate transporter. In addition, several clinical studies have correlated MCT-1 expression to poor patient prognosis in other cancers and potential resistance to therapies in PDAC, making MCT-1 an intriguing therapeutic target for pancreatic cancer. In this study, we leverage 3-Bromopyruvate (3BP), a cytotoxic pyruvate analog, to target MCT-1 overexpressing PDACs and optimize it for systemic delivery. First, we establish that the sensitivity of PDAC cells to 3BP correlates to MCT-1 expression. In vitro studies with a panel of pancreatic cancer cell lines highlight that the cytotoxicity of 3BP is limited to PDAC cells with elevated MCT-1 and the mode of action of 3BP is distinctly different from AZD-3965, an MCT-1 inhibitor under clinical investigation. We demonstrate that 3BP exerts its effect on PDAC cells using MCT-1 as gate to enter a cell and then induce cytotoxicity. While 3BP is considered promising, poor serum stability, pharmacokinetics, and excessive in vivo toxicity have hampered its clinical development. We show here, a novel formulation where 3BP is entrapped inside a cyclodextrin cage (sCD-3BP) stabilizes 3BP in vivo, retains its MCT-1 specific activity, and delivers significantly more drug to the tumor with a single dose. Additionally, we show that even short exposures of sCD-3BP are adequate for induction of cell death when compared to current standard-of-care therapeutics such as gemcitabine and components of FOLFIRINOX. Finally, we test our MCT-1 gated approach in multiple in vivo models of pancreatic cancer: an orthotopic pancreatic cancer cell line model and two patient-derived orthotopic xenografts (PDoX) models originating from a primary pancreatic and a metastatic site. Arguably more clinically relevant, the PDoX models used in our study closely mimic clinical features of donor disease, causing significant metastasis to lung and liver, marked invasion into the pancreas, and development of duct-like structures within the tumor. In these models, sCD-3BP significantly reduces pancreatic cancer growth and metastatic spread. In summary, we show that intravenous administration of sCD-3BP is safe, causes no damage to normal tissue and effectively suppresses PDAC tumor growth and reduces metastatic burden. In addition, elucidating the mechanism of action of 3BP allows us to identify potential candidates for this therapy. Our study demonstrates that sCD-3BP can be a powerful therapeutic tool against MCT-1 overexpressed PDACs and present a strong rationale for future human clinical trials. Citation Format: Surojit Sur, Jordina Rincon-Toroella, Marco Dal Molin, Kathleen Gabrielson, Chetan Bettegowda, Shibin Zhou, Ken Kinzler, Bert Vogelstein. sCD-3BP: An MCT-1-“gated” therapeutic for pancreatic adenocarcinoma [abstract]. In: Proceedings of the AACR Special Conference on Pancreatic Cancer; 2022 Sep 13-16; Boston, MA. Philadelphia (PA): AACR; Cancer Res 2022;82(22 Suppl):Abstract nr B004.