BH3 Mimetics in Hematologic Malignancies
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 impr...
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doaj-ec23120be87d498b8670e64573f6add62021-09-26T00:25:43ZengMDPI AGInternational Journal of Molecular Sciences1661-65961422-00672021-09-0122101571015710.3390/ijms221810157BH3 Mimetics in Hematologic MalignanciesPavel Klener0Dana Sovilj1Nicol Renesova2Ladislav Andera3First Department of Internal Medicine‑Hematology, General University Hospital in Prague, 121 08 Prague, Czech RepublicInstitute of Biotechnology CAS/BIOCEV, 252 50 Vestec, Czech RepublicFirst Faculty of Medicine, Institute of Pathological Physiology, Charles University, 121 08 Prague, Czech RepublicInstitute of Biotechnology CAS/BIOCEV, 252 50 Vestec, Czech RepublicHematologic 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 <i>TP53</i> 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 <i>TP53 </i>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.https://www.mdpi.com/1422-0067/22/18/10157apoptosisBH3 mimeticsvenetoclaxhematologic malignanciestargeted therapyresistance |
collection |
DOAJ |
language |
English |
format |
Article |
sources |
DOAJ |
author |
Pavel Klener Dana Sovilj Nicol Renesova Ladislav Andera |
spellingShingle |
Pavel Klener Dana Sovilj Nicol Renesova Ladislav Andera BH3 Mimetics in Hematologic Malignancies International Journal of Molecular Sciences apoptosis BH3 mimetics venetoclax hematologic malignancies targeted therapy resistance |
author_facet |
Pavel Klener Dana Sovilj Nicol Renesova Ladislav Andera |
author_sort |
Pavel Klener |
title |
BH3 Mimetics in Hematologic Malignancies |
title_short |
BH3 Mimetics in Hematologic Malignancies |
title_full |
BH3 Mimetics in Hematologic Malignancies |
title_fullStr |
BH3 Mimetics in Hematologic Malignancies |
title_full_unstemmed |
BH3 Mimetics in Hematologic Malignancies |
title_sort |
bh3 mimetics in hematologic malignancies |
publisher |
MDPI AG |
series |
International Journal of Molecular Sciences |
issn |
1661-6596 1422-0067 |
publishDate |
2021-09-01 |
description |
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 <i>TP53</i> 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 <i>TP53 </i>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. |
topic |
apoptosis BH3 mimetics venetoclax hematologic malignancies targeted therapy resistance |
url |
https://www.mdpi.com/1422-0067/22/18/10157 |
work_keys_str_mv |
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