Abstract
Nearly 30% of Pancreatic ductal adenocarcinoma (PDAC)s exhibit a marked overexpression of Monocarboxylate Transporter 1 (MCT1) offering a unique opportunity for therapy. However, biochemical inhibitors of MCT1 have proven unsuccessful in clinical trials. In this study we present an alternative approach using 3-Bromopyruvate (3BP) to target MCT1 overexpressing PDACs. 3BP is a cytotoxic agent that is known to be transported into cells via MCT1, but its clinical usefulness has been hampered by difficulties in delivering the drug systemically. We describe here a novel microencapsulated formulation of 3BP (ME3BP-7), that is effective against a variety of PDAC cells in vitro and remains stable in serum. Furthermore, systemically administered ME3BP-7 significantly reduces pancreatic cancer growth and metastatic spread in multiple orthotopic models of pancreatic cancer with manageable toxicity. ME3BP-7 is, therefore, a prototype of a promising new drug, in which the targeting moiety and the cytotoxic moiety are both contained within the same single small molecule.
One Sentence Summary ME3BP-7 is a novel formulation of 3BP that resists serum degradation and rapidly kills pancreatic cancer cells expressing high levels of MCT1 with tolerable toxicity in mice.
Competing Interest Statement
The Johns Hopkins University has filed patent applications related to technologies described in this paper on which JRT, MDM, NP, KWK, BV, SZ & SS are listed as inventors, including: Encapsulated agents that bind to MCT1 (WO2022055748A1), Cyclodextrin compositions encapsulating a selective ATP inhibitor and uses thereof (US20190328666A1), Methods of treating liver fibrosis by administering 3-bromopyruvate (US10751306B2). BV, KWK, & NP are founders of Thrive Earlier Detection, an Exact Sciences Company. KWK & NP are consultants to Thrive Earlier Detection. BV, KWK, NP, and SZ hold equity in Exact Sciences. BV, KWK, SS, NP, and SZ are founders of, or consultants to and own equity in ManaT Bio., Haystack Oncology, Neophore, CAGE Pharma, and Personal Genome Diagnostics. NP is consultant to Vidium. BV is a consultant to and holds equity in Catalio Capital Management. SZ has a research agreement with BioMed Valley Discoveries, Inc. CB is a consultant to Depuy-Synthes, Bionaut Labs, Haystack Oncology and Galectin Therapeutics. CB is a co-founder of OrisDx and Belay Diagnostics. The companies named above, as well as other companies, have licensed previously described technologies related to the work described in this paper from Johns Hopkins University. BV, KWK, NP are inventors on some of these technologies. Licenses to these technologies are or will be associated with equity or royalty payments to the inventors as well as to Johns Hopkins University. Patent applications on the work described in this paper may be filed by Johns Hopkins University. The terms of all these arrangements are being managed by Johns Hopkins University in accordance with its conflict of interest policies.
