abt-199 and palbociclib

The addition of a CDK4/6 inhibitor to endocrine therapy improves progression-free and overall survival in women with metastatic estrogen receptor-positive breast cancer. In that setting, CDK4/6 inhibitors induce a potent cell-cycle arrest (which may be accompanied by tumor senescence) but fail to induce apoptotic cell death. Venetoclax is a potent inhibitor of BCL2, a pro-survival protein overexpressed in the majority of estrogen receptor-positive cancers. Pre-clinical findings indicate that venetoclax augments tumor response to the CDK4/6 inhibitor palbociclib by triggering apoptosis, including in senescent cells. The PALVEN phase Ib trial will further examine this finding. The primary objective is to identify the maximum tolerated dose and determine the recommended phase II dose for palbociclib, letrozole and venetoclax combination therapy.. The current ‘gold standard' treatment for estrogen receptor-positive, HER2-negative metastatic breast cancer is endocrine therapy with a CDK4/6 inhibitor. This combination improves tumor response and patient outcomes, primarily by reducing tumor cell growth. Paradoxically, less killing of tumor cells is observed in the presence of a CDK4/6 inhibitor. The authors hypothesize that co-treatment with venetoclax, an inhibitor of the BCL2 survival protein, will help trigger tumor death, thereby further improving tumor responses and patient outcomes. As a first step, combination therapy comprising letrozole, palbociclib and venetoclax will be tested in a phase I trial to identify the recommended doses for subsequent studies.

Topics: Antineoplastic Combined Chemotherapy Protocols; Breast Neoplasms; Bridged Bicyclo Compounds, Heterocyclic; Clinical Trials, Phase I as Topic; Female; Humans; Letrozole; Piperazines; Protein Kinase Inhibitors; Proto-Oncogene Proteins c-bcl-2; Pyridines; Receptor, ErbB-2; Receptors, Estrogen; Sulfonamides

Topics: Animals; Azacitidine; Bridged Bicyclo Compounds, Heterocyclic; Leukemia, Myeloid, Acute; Mice; Piperazines; Protein Kinase Inhibitors; Proto-Oncogene Proteins c-bcl-2; Pyridines; Sulfonamides

BH3 mimetics like venetoclax target prosurvival Bcl-2 family proteins and are important therapeutics in the treatment of hematological malignancies. We demonstrate that endogenous Bfl-1 expression can render preclinical lymphoma tumor models insensitive to Mcl-1 and Bcl-2 inhibitors. However, suppression of Bfl-1 alone was insufficient to fully induce apoptosis in Bfl-1-expressing lymphomas, highlighting the need for targeting additional prosurvival proteins in this context. Importantly, we demonstrated that cyclin-dependent kinase 9 (CDK9) inhibitors rapidly downregulate both Bfl-1 and Mcl-1, inducing apoptosis in BH3-mimetic-resistant lymphoma cell lines in vitro and driving in vivo tumor regressions in diffuse large B-cell lymphoma patient-derived xenograft models expressing Bfl-1. These data underscore the need to clinically develop CDK9 inhibitors, like AZD4573, for the treatment of lymphomas using Bfl-1 as a selection biomarker.

Topics: Animals; Antineoplastic Agents; Bridged Bicyclo Compounds, Heterocyclic; Cell Line, Tumor; Cyclin-Dependent Kinase 9; Cycloheximide; Drug Resistance, Neoplasm; Female; Gene Expression Regulation, Neoplastic; Humans; Leupeptins; Lymphoma, Large B-Cell, Diffuse; Macrocyclic Compounds; Mice; Mice, Inbred NOD; Mice, SCID; Minor Histocompatibility Antigens; Molecular Targeted Therapy; Myeloid Cell Leukemia Sequence 1 Protein; Neoplasm Proteins; Peptide Fragments; Piperazines; Proto-Oncogene Proteins; Proto-Oncogene Proteins c-bcl-2; Pyridines; Sulfonamides; Xenograft Model Antitumor Assays

Breast cancer is the most frequent type of cancer and the major cause of mortality in women. The rapid development of various therapeutic options has led to the improvement of treatment outcomes; nevertheless, one-third of estrogen receptor (ER)-positive patients relapse due to cancer cell acquired resistance. Here, we use dynamic BH3 profiling (DBP), a functional predictive assay that measures net changes in apoptotic priming, to find new effective treatments for ER+ breast cancer. We observed anti-apoptotic adaptations upon treatment that pointed to metronomic therapeutic combinations to enhance cytotoxicity and avoid resistance. Indeed, we found that the anti-apoptotic proteins BCL-xL and MCL-1 are crucial for ER+ breast cancer cells resistance to therapy, as they exert a dual inhibition of the pro-apoptotic protein BIM and compensate for each other. In addition, we identified the AKT inhibitor ipatasertib and two BH3 mimetics targeting these anti-apoptotic proteins, S63845 and A-1331852, as new potential therapies for this type of cancer. Therefore, we postulate the sequential inhibition of both proteins using BH3 mimetics as a new treatment option for refractory and relapsed ER+ breast cancer tumors.

Topics: Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Apoptosis; bcl-X Protein; Breast Neoplasms; Bridged Bicyclo Compounds, Heterocyclic; Cell Line, Tumor; Drug Resistance, Neoplasm; Drug Synergism; Estrogen Receptor alpha; Everolimus; Female; Fulvestrant; Gene Expression Regulation, Neoplastic; Humans; MCF-7 Cells; Myeloid Cell Leukemia Sequence 1 Protein; Piperazines; Protein Isoforms; Proto-Oncogene Proteins c-akt; Pyridines; Pyrimidines; Signal Transduction; Sulfonamides; Thiazoles; Thiophenes