ME3BP-7 is a targeted cytotoxic agent that rapidly kills pancreatic cancer cells expressing high levels of monocarboxylate transporter MCT1
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Curated by eLife
eLife assessment
This study presents a valuable finding and developed ME3BP-7 as a novel microencapsulated form of 3BP targeting MCT1 overexpressing PDAC cells, demonstrating its specificity and efficacy in vitro and in PDAC mouse models with significant anti-tumor effects and improved serum stability. The evidence supporting the claims of the authors is solid; however, the study calls for additional comparative in vivo data to enhance its translational significance.
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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.
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eLife assessment
This study presents a valuable finding and developed ME3BP-7 as a novel microencapsulated form of 3BP targeting MCT1 overexpressing PDAC cells, demonstrating its specificity and efficacy in vitro and in PDAC mouse models with significant anti-tumor effects and improved serum stability. The evidence supporting the claims of the authors is solid; however, the study calls for additional comparative in vivo data to enhance its translational significance.
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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 …
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.
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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 …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. -
