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.
Small molecule inhibitors of the cellular pro-survival BCL-2 family proteins, termed 'BH3-mimetics', have entered clinical trials for blood cancers with the BCL-2 inhibitor venetoclax already approved for treatment of therapy refractory chronic lymphocytic leukaemia and acute myeloid leukaemia in the elderly.
Finally, we provide a perspective on how therapies targeting BCL-2 family proteins may be optimally implemented into future therapeutic regimens for 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).
Venetoclax (ABT-199) is a Bcl-2-specific BH3-mimetic that has shown significant promise in certain subtypes of CLL as well as in several other hematologic malignancies.
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.
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.
New targeted therapies for hematological malignancy include chimeric antigen receptor T cells (CAR T cells), Bi-specific T-cell Engager (BiTE) blinatumomab, and the antibody-drug conjugate (ADC) of calicheamicin inotuzumab ozogamicin for acute lymphoblasic leukemia (ALL) and lymphoma; the Bruton's tyrosine kinase (BTK) inhibitor ibrutinib and phosphatidylinositol 3-kinase (PI3Kδ) inhibitor idelalisib for lymphoma and graft-versus-host disease (GVHD); FMS-like tyrosine kinase 3 (FLT3) inhibitors, such as midostaurin, sorafenib and gilteritinib for acute myeloid leukemia (AML); and the BCL-2 inhibitor venetoclax for a range of hematological malignancies including lymphoma and leukemia.
Accordingly, efforts have lately been focused on the development of drugs targeting Bcl-2 proteins with considerable therapeutic success, particularly in hematologic malignancies.
The BCL-2-selective inhibitor venetoclax has been approved for use in chronic lymphocytic leukemia and is now being studied in a number of other hematologic malignancies.
BH3 mimetics are promising drugs for hematologic malignancies that trigger cell death by promoting the release of proapoptotic BCL2 family members from antiapoptotic proteins.
<b>Purpose:</b> Clinically available BH3 mimetic drugs targeting BCLXL and/or BCL2 (navitoclax and venetoclax, respectively) are effective in some hematologic malignancies, but have limited efficacy in solid tumors.
BFL1 is a relatively understudied member of the BCL2 protein family which has been implicated in the pathogenesis and chemoresistance of a variety of human cancers, including hematological malignancies and solid tumours.
Inhibitors of BCL-2 family proteins (BH3 mimetics) are under investigation or in clinical practice for several hematological malignancies and show promise in solid tumors.