-Author name in bold denotes the presenting author
-Asterisk * with author name denotes a Non-ASH member
Clinically Relevant Abstract denotes an abstract that is clinically relevant.

PhD Trainee denotes that this is a recommended PHD Trainee Session.

Ticketed Session denotes that this is a ticketed session.

2792 Synergistic Antitumor Effect of a Novel First-in-Class Small Molecule OPB-111077 That Inhibits Mitochondrial Oxidative Phosphorylation in Combination with Alkylating Agent

Program: Oral and Poster Abstracts
Session: 605. Molecular Pharmacology and Drug Resistance: Lymphoid Neoplasms: Poster II
Hematology Disease Topics & Pathways:
Research, Translational Research
Sunday, December 8, 2024, 6:00 PM-8:00 PM

Emiri Omori Takaki* and Naoto Ohi, PhD*

Osaka Research Center for Drug Discovery, Otsuka Pharmaceutical Co., Ltd., Osaka, Japan

Background:

Cancer cells are known to exhibit Warburg effect, but it has been recently reported that mitochondrial oxidative phosphorylation (OXPHOS) is also important for tumor cell proliferation, and that metabolic reprogramming from glycolysis to OXPHOS is one of the resistance mechanisms to antitumor drugs. OPB-111077, synthesized by Otsuka Pharmaceutical Co., Ltd., is a novel orally available small molecule compound that inhibits mitochondrial respiratory chain complex I, suppressing energy production through OXPHOS. OPB-111077 showed antitumor effects against various human hematological and solid tumors in cultured cells and cell line-derived xenograft (CDX) models. Here, we report the combination therapeutic strategy based on the cancer energy metabolism of OPB-111077. Currently, we are conducting a combination therapy of OPB-111077 with bendamustine and rituximab in Phase 1 clinical trial for relapsed/refractory DLBCL in Japan and Korea (NCT04049825), and we have reported the preliminary results from dose-escalation stage in ASH 2023 (DOI:10.1182/blood-2023-179716).

Method:

The combined growth inhibitory effects of OPB-111077 and the alkylating agent bendamustine were evaluated in lymphoma cell lines. The combined antitumor effects and tumor growth delay effects were evaluated in diffuse large B cell lymphoma (DLBCL) CDX models and lymphoma patient-derived xenograft (PDX) models. To elucidate the mechanism of the combination effect, we measured the oxygen consumption rate (OCR), an indicator of OXPHOS, and the extracellular acidification rate (ECAR), an indicator of glycolysis. Furthermore, metabolome analysis using the DLBCL CDX model was conducted.

Results:

Studies using cultured cell lines, CDX models and PDX models revealed that OPB-111077 has a synergistic antitumor effect in DLBCL when combined with bendamustine. OCR and ECAR measurements showed that OPB-111077 inhibited OXPHOS while increasing glycolysis, but when combined with bendamustine, the increase in glycolysis was suppressed. We also found that bendamustine reprogrammed cancer cells to OXPHOS, suggesting that the tumor environment becomes more conducive to the antitumor effects of OPB-111077 when combined with bendamustine. Metabolome analysis using the DLBCL CDX model confirmed a decrease in TCA cycle-related metabolites in tumor tissues after OPB-111077 administration, thus comprehensive analysis showed that OPB-111077 inhibited OXPHOS and caused changes in various downstream metabolites.

Conclusions:

OPB-111077 is an OXPHOS inhibitor and bendamustine, an alkylating agent, is used as standard therapies for B-cell lymphoma. In this study, we found that OPB-111077 exhibits a synergistic antitumor effect in combination with bendamustine. We propose a novel anticancer therapeutic strategy that combines OXPHOS inhibitors with alkylating agents. OPB-111077 could be treated in a wide range of applications as a combination therapy with the alkylating agents for lymphoma.

Disclosures: Takaki: Otsuka Pharmaceutical Co., Ltd.: Current Employment. Ohi: Otsuka Pharmaceutical Co., Ltd.: Current Employment.

*signifies non-member of ASH