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BH3 Mimetics in Hematologic Malignancies

Klener, Pavel, Sovilj, Dana, Renesova, Nicol, Andera, Ladislav·2021·International Journal of Molecular Sciences
DOI 10.3390/ijms221810157PMC PMC8466478
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Abstract

Hematologic malignancies (HM) comprise diverse cancers of lymphoid and myeloid origin, including lymphomas (approx. 40%), chronic lymphocytic leukemia (CLL, approx. 15%), multiple myeloma (MM, approx. 15%), acute myeloid leukemia (AML, approx. 10%), and many other diseases. Despite considerable improvement in treatment options and survival parameters in the new millennium, many patients with HM still develop chemotherapy‑refractory diseases and require re-treatment. Because frontline therapies for the majority of HM (except for CLL) are still largely based on classical cytostatics, the relapses are often associated with defects in DNA damage response (DDR) pathways and anti-apoptotic blocks exemplified, respectively, by mutations or deletion of the TP53 tumor suppressor, and overexpression of anti-apoptotic proteins of the B-cell lymphoma 2 (BCL2) family. BCL2 homology 3 (BH3) mimetics represent a novel class of pro-apoptotic anti-cancer agents with a unique mode of action—direct targeting of mitochondria independently of TP53 gene aberrations. Consequently, BH3 mimetics can effectively eliminate even non-dividing malignant cells with adverse molecular cytogenetic alterations. Venetoclax, the nanomolar inhibitor of BCL2 anti-apoptotic protein has been approved for the therapy of CLL and AML. Numerous venetoclax-based combinatorial treatment regimens, next-generation BCL2 inhibitors, and myeloid cell leukemia 1 (MCL1) protein inhibitors, which are another class of BH3 mimetics with promising preclinical results, are currently being tested in several clinical trials in patients with diverse HM. These pivotal trials will soon answer critical questions and concerns about these innovative agents regarding not only their anti-tumor efficacy but also potential side effects, recommended dosages, and the optimal length of therapy as well as identification of reliable biomarkers of sensitivity or resistance. Effective harnessing of the full therapeutic potential of BH3 mimetics is a critical mission as it may directly translate into better management of the aggressive forms of HM and could lead to significantly improved survival parameters and quality of life in patients with urgent medical needs.

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Metadata

Authors
Klener, P., Sovilj, D., Renesova, N., & Andera, L.
Venue
International Journal of Molecular Sciences
Publisher
MDPI AG
Published
2021-09-21
Volume
22
Issue
18
Pages
10157
ISSN
1422-0067
DOI
10.3390/ijms221810157
PMC
PMC8466478
Cited by
31
References
12
Language
en
Licence
creativecommons.org/licenses/by/4.0/ (vor)
Funders
  • Agentura Pro Zdravotnický Výzkum České Republiky (AZV NU21-03-00386)
  • Grantová Agentura České Republiky (GACR17-14007S and GACR19-08772S)
  • Univerzita Karlova v Praze (Center of Excellence UNCE/MED/016)
  • Ministerstvo Školství, Mládeže a Tělovýchovy (PROGRES Q26/LF1 and PROGRES Q28/LF1)

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