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Bcl-2 pathway inhibition in solid tumors: a review of clinical trials.

ABSTRACT: Due to their key role in the pathogenesis of cancer through the regulation of apoptosis, the B-cell leukemia/lymphoma-2 (BCL-2) family proteins have been an attractive target for cancer therapy for the past decades. Throughout the years, many Bcl-2 family inhibitors have been developed, with Venetoclax being now successfully used in treating hematological malignancies. Although their effectiveness in the treatment of solid tumors is yet to be established, some preclinical evidence indicates their possible clinical application. This review aims to summarize current data from completed clinical trials that used Bcl-2 protein family inhibitors as monotherapy or in combination with other agents for the treatment of solid malignancies. We managed to include clinical trials of various phases which analyze the pharmacokinetics and pharmacodynamics of the drugs, as well as the effectiveness and adverse effects. Active and recruiting clinical trials are also briefly presented and future prospects and challenges are discussed.

SUBMITTER: Ploumaki I

PROVIDER: S-EPMC10203027 | biostudies-literature | 2023 Jun

REPOSITORIES: biostudies-literature

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Bcl-2 pathway inhibition in solid tumors: a review of clinical trials.

Ploumaki Ioanna I Triantafyllou Efthymios E Koumprentziotis Ioannis-Alexios IA Karampinos Konstantinos K Drougkas Konstantinos K Karavolias Ioannis I Trontzas Ioannis I Kotteas Elias A EA

Clinical & translational oncology : official publication of the Federation of Spanish Oncology Societies and of the National Cancer Institute of Mexico 20230113 6

Due to their key role in the pathogenesis of cancer through the regulation of apoptosis, the B-cell leukemia/lymphoma-2 (BCL-2) family proteins have been an attractive target for cancer therapy for the past decades. Throughout the years, many Bcl-2 family inhibitors have been developed, with Venetoclax being now successfully used in treating hematological malignancies. Although their effectiveness in the treatment of solid tumors is yet to be established, some preclinical evidence indicates thei ...[more]

PMID: 36639602

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Project description:PurposeNovel antitumor therapies against the PI3K-AKT-mTOR pathway are increasingly used to treat cancer, either as single agents or in combination with chemotherapy or other targeted therapies. Although these agents are not known to be myelosuppressive, an increased risk of infection has been reported with rapamycin analogues. However, the risk of infection with new inhibitors of this pathway such as PI3K, AKT, mTORC 1/2, or multikinase inhibitors is unknown.Experimental designIn this retrospective case-control study, we determined the incidence of infection in a group of 432 patients who were treated on 15 phase I clinical trials involving PI3K-AKT-mTOR pathway inhibitors (cases) versus a group of 100 patients on 10 phase I clinical trials of single agent non-PI3K-AKT-mTOR pathway inhibitors (controls) which did not involve conventional cytotoxic agents. We also collected data from 42 patients who were treated with phase I trials of combinations of PI3K-AKT-mTOR inhibitors and MEK inhibitors and 24 patients with combinations of PI3K-AKT-mTOR inhibitors and cytotoxic chemotherapies.ResultsThe incidence of all grade infection was significantly higher with all single-agent PI3K-AKT-mTOR inhibitors compared with the control group [27% vs. 8%, respectively, OR, 4.26; 95% confidence intervals (CI), 1.9-9.1, P = 0.0001]. The incidence of grade 3 and 4 infection was also significantly higher with PI3K-AKT-mTOR inhibitors compared with the control group (10.3% vs. 3%, OR, 3.74; 95% CI, 1.1-12.4; P = 0.02). Also, the combination of PI3K-AKT-mTOR inhibitors and chemotherapy was associated with a significantly higher incidence of all grade (OR, 4.79; 95% CI, 2.0-11.2; P = 0.0001) and high-grade (OR, 2.87; 95% CI, 1.0-7.6; P = 0.03) infection when compared with single-agent PI3K-AKT-mTOR inhibitors.ConclusionsInhibitors of the PI3K-AKT-mTOR pathway can be associated with a higher risk of infection. Combinations of PI3K-AKT-mTOR inhibitors and cytotoxic chemotherapy significantly increase the risk of infection. This should be taken into consideration during the design and conduct of trials involving PI3K-AKT-mTOR pathway inhibitors, particularly when combined with chemotherapy or myelosuppressive agents.

Dataset Information

Bcl-2 pathway inhibition in solid tumors: a review of clinical trials.

Publications

Bcl-2 pathway inhibition in solid tumors: a review of clinical trials.

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