The utility of targeting BCL-2 in hematological malignancies has become evident in early-phase studies, with remarkable clinical responses seen in heavily pretreated patients.
IDH1- and IDH2-mutant primary human AML cells were more sensitive than IDH1/2 wild-type cells to ABT-199, a highly specific BCL-2 inhibitor that is currently in clinical trials for hematologic malignancies, both ex vivo and in xenotransplant models.
Here, we discuss the biology of the intrinsic pathway of apoptosis, an assay known as BH3 profiling that can interrogate this pathway, early attempts to target BCL-2 clinically, and the recent promising results with the BCL-2 antagonist venetoclax (ABT-199) in clinical trials in hematologic malignancies.
Here, we identify Bcl2-like 13 (Bcl2L13), an atypical member of the Bcl-2 family, as a therapy susceptibility gene with elevated expression in solid and blood cancers, including glioblastoma (GBM).
Accordingly, efforts have lately been focused on the development of drugs targeting Bcl-2 proteins with considerable therapeutic success, particularly in hematologic malignancies.
Hopefully, in the next future, BCL2 inhibitors (alone or in combination with immuno- and/or chemo-therapeutic agents) will represent target-specific drugs expanding our therapeutic armamentarium in the fight against hematologic malignancies.
BCL2L12 is a recently identified gene belonging to the BCL2 family, members of which are implicated in hematologic malignancies, including chronic lymphocytic leukemia (CLL).
Taken together, these findings suggest that small molecule Bcl-2 inhibitors may represent a promising class of alternative agents for the treatment of Bcl-2 overexpressed refractory or recurrent hematological malignancies when conventional chemotherapy fails.
As a strategy for blocking Bcl-2 for enhancement of the chemotherapeutic effect, antisense Bcl-2 (AS Bcl-2; G3139, oblimersen sodium, Genasense) has shown promise, and there are several ongoing clinical studies with hematological malignancies as well as solid tumors.
Constitutive overexpression of Bcl-2 or unchanged expression after treatment with anticancer drugs confers drug resistance not only to hematologic malignancies but also to solid tumors.
Bax protein, a member of the Bcl-2 family, regulates the apoptotic pathway that involves both Bcl-2 and p53. bax mutations are found in hematological malignancies, colon cancer with microsatellite mutator phenotype, and some other cancers.
The present study focuses on the quantitation of resistance to increasing doses of 1-beta-d-arabinofuranosylcytosine (Ara-C) by using hematological tumors expressing different levels of bcl-2.