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Published on: July 12, 2018
KAT/3BP: A Metabolism-Targeting Agent with Single and Combination Activity in Aggressive B-Cell Lymphomas
Chiara Tarantelli1, Filippo Spriano1, Elisa Civanelli1
1Institute of Oncology Research, Faculty of Biomedical Sciences, Università Della Svizzera Italiana, 6500 Bellinzona, Switzerland.
Background/Objectives:
Reprogramming of the cellular metabolism is a hallmark of cancer, offering therapeutic opportunities to target cancer cell vulnerabilities for therapeutic purposes. 3-Bromopyruvate (3BP) is a small alkylating agent that functions as an anti-metabolite, targeting key substrates in cancer metabolism and demonstrating antitumor activity across multiple cancer types. However, unformulated 3BP is associated with significant toxicity. This study investigates the efficacy of KAT/3BP, a clinical derivative of 3BP currently in phase 1 trials for hepatocellular carcinoma, in preclinical lymphoma models.
Results:
In vitro, KAT/3BP exhibited cytotoxic activity across 12 lymphoma cell lines-including diffuse large B-cell lymphoma and mantle cell lymphoma-with a median IC50 of 3.7 μM. It also remained effective against lymphoma cell lines with acquired resistance to FDA-approved therapies. In vivo, treatment with KAT/3BP led to reduced tumor size in a syngeneic mouse model, with the combination of oral and intratumoral administration showing the greatest efficacy. Furthermore, KAT/3BP demonstrated synergistic activity when combined with standard lymphoma therapies such as bendamustine and R-CHOP.
Conclusions:
Our findings highlight the potential of KAT/3BP as a novel therapeutic option, either as a single agent or in combination regimens, for treating lymphomas.
Insights
KAT/3BP, a 3-Bromopyruvate (3BP) derivative, shows potent anti-lymphoma activity in preclinical models. It is effective alone and synergizes with standard therapies, offering a promising new treatment strategy for lymphomas.
Area of Science:
- Oncology
- Cancer Metabolism
- Drug Development
Background:
- Cancer cells exhibit metabolic reprogramming, presenting therapeutic targets.
- 3-Bromopyruvate (3BP) is an anti-metabolite with antitumor activity but significant toxicity.
- KAT/3BP is a clinical 3BP derivative investigated for safety and efficacy.
Purpose of the Study:
- To evaluate the efficacy of KAT/3BP in preclinical lymphoma models.
- To assess KAT/3BP as a single agent and in combination therapies.
- To determine if KAT/3BP overcomes resistance to existing lymphoma treatments.
Main Methods:
- In vitro cytotoxicity assays across 12 lymphoma cell lines.
- In vivo efficacy studies in a syngeneic mouse lymphoma model.
- Combination studies with standard lymphoma chemotherapies (bendamustine, R-CHOP).
Main Results:
- KAT/3BP demonstrated significant in vitro cytotoxicity (median IC50 3.7 μM) against diverse lymphoma types.
- Effective against cell lines resistant to current FDA-approved therapies.
- Reduced tumor size in vivo, with combined oral/intratumoral administration being most effective.
- Showed synergistic activity with bendamustine and R-CHOP.
Conclusions:
- KAT/3BP exhibits promising therapeutic potential for lymphomas.
- It can be used as a single agent or in combination regimens.
- Represents a novel therapeutic option for lymphoma treatment.
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