ME3BP-7 is a targeted cytotoxic agent that rapidly kills pancreatic cancer cells expressing high levels of monocarboxylate transporter MCT1

Author:

Rincon-Torroella Jordina123,Molin Marco Dal4,Mog Brian1567,Han Gyuri1,Watson Evangeline1,Wyhs Nicolas1368,Ishiyama Shun9,Ahmedna Taha9,Minn Il10,Azad Nilofer S.3,Bettegowda Chetan1211,Papadopoulos Nickolas13611,Kinzler Kenneth W.136118,Zhou Shibin13611,Vogelstein Bert135611,Gabrielson Kathleen398,Sur Surojit13611

Affiliation:

1. Ludwig Center, Sidney Kimmel Comprehensive Cancer Center, The Johns Hopkins University School of Medicine

2. Department of Neurosurgery, The Johns Hopkins University School of Medicine

3. Department of Oncology, The Johns Hopkins University School of Medicine

4. Department of Surgery, University of Maryland School of Medicine

5. Howard Hughes Medical Institute

6. Lustgarten Pancreatic Cancer Research Laboratory, Sidney Kimmel Comprehensive Cancer Center, The Johns Hopkins University School of Medicine

7. Department of Biomedical Engineering, Johns Hopkins University

8. Department of Pathology, The Johns Hopkins University School of Medicine

9. Department of Molecular and Comparative Pathobiology, The Johns Hopkins University School of Medicine; Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University

10. Division of Nuclear Medicine and Molecular Imaging, The Russell H. Morgan Department of Radiology and Radiological Science, The Johns Hopkins University School of Medicine

11. Bloomberg∼Kimmel Institute for Cancer Immunotherapy, Sidney Kimmel Comprehensive Cancer Center

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.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.

Publisher

eLife Sciences Publications, Ltd

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