Enhanced Preprints

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

  1. Jordina Rincon-Torroella
  2. Marco Dal Molin
  3. Brian Mog
  4. Gyuri Han
  5. Evangeline Watson
  6. Nicolas Wyhs
  7. Shun Ishiyama
  8. Taha Ahmedna
  9. Il Minn
  10. Nilofer S. Azad
  11. Chetan Bettegowda
  12. Nickolas Papadopoulos
  13. Kenneth W. Kinzler
  14. Shibin Zhou
  15. Bert Vogelstein author has email address
  16. Kathleen Gabrielson author has email address
  17. Surojit Sur author has email address
  1. Ludwig Center, Sidney Kimmel Comprehensive Cancer Center, The Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA
  2. Department of Neurosurgery, The Johns Hopkins University School of Medicine, MD 21205, USA
  3. Department of Oncology, The Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA
  4. Department of Surgery, University of Maryland School of Medicine, Baltimore, MD, USA
  5. Howard Hughes Medical Institute, Chevy Chase, MD 20815, USA
  6. Lustgarten Pancreatic Cancer Research Laboratory, Sidney Kimmel Comprehensive Cancer Center, The Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA
  7. Department of Biomedical Engineering, Johns Hopkins University, Baltimore, MD 21218, USA
  8. Department of Pathology, The Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA
  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, 601 North Caroline Street, JHOC 3223, Baltimore, MD, 21287, USA
  11. Bloomberg∼Kimmel Institute for Cancer Immunotherapy, Sidney Kimmel Comprehensive Cancer Center, Baltimore, MD 21287, USA

Editors

  • Reviewing Editor
    Sendurai Mani
    Brown University, Providence, Rhode Island, United States of America
  • Senior Editor
    Wafik El-Deiry
    Brown University, Providence, United States of America

Reviewer #1 (Public Review):

Summary:
In the present study, Rincon-Torroella et al. developed ME3BP-7, a microencapsulated formulation of 3BP, as an agent to target MCT1 overexpressing PDACs. They provided evidence showing the specific killing of PDAC cells with MCT1 overexpressing in vitro, along with demonstrating the safety and anti-tumor efficacy of ME3BP-7 in PDAC orthotopic mouse models.

Strengths:
* Developed a novel agent.
* Well-designed experiments and an organized presentation of data that support the conclusions drawn.

Weaknesses:
There are some minor issues that could enhance the clarity and completeness of the study:

(1) Statistical results should be visually presented in Figure 4 and Figure S1.

(2) Given the tumor heterogeneity and the identification of focal high expression of MCT1 in Figure 7 and Figure S5B, it is suggested that the authors include the results of immunohistochemical (IHC) analysis of MCT1 expression in both control and ME3BP-7 treated tumor tissues. This addition may offer insight into whether the remaining tumors are composed of PDAC cells with negative MCT1 expression, while the cells with relatively high levels of MCT1 expression were eliminated by ME3BP-7 treatment.

(3.)The authors are encouraged to discuss the future directions for improving the efficacy of this study. For example, exploring the combination of ME3BP-7 with a glutaminase-1 inhibitor (PMID 37891897) could be a valuable avenue for further research.

Reviewer #2 (Public Review):

Summary:
In the manuscript by Rincon-Torroella et al, the authors evaluated the therapeutic potential of ME3BP-7, a microencapsulated formulation of 3BP which specifically targets MCT-1 high tumor cells, in pancreatic cancer models. The authors showed that, compared to 3BP, ME3BP-7 exhibited much-enhanced stability in serum. In addition, the authors confirmed the specificity of ME3BP-7 toward MCT-1 high tumor cells and demonstrated the in vivo anti-tumor effect of ME3BP-7 in orthotopic xenograft of human PDAC cell line and PDAC PDX model.

Strengths:
(1) The study convincingly demonstrated the superior stability of ME3BP-7 in serum.
(2) The specificity of ME3BP-7 and 3BP toward MCT-1 high PDAC cells was clearly demonstrated with CRISPR-mediated knockout experiments.

Weaknesses:
The advantage of ME3BP-7 over 3BP under an in vivo situation was not fully established.

  1. Howard Hughes Medical Institute
  2. Wellcome Trust
  3. Max-Planck-Gesellschaft
  4. Knut and Alice Wallenberg Foundation