Targeting key apoptosis regulators to overcome the apoptotic resistance of cancer cells is a highly attractive therapeutic strategy. Pro-apoptotic BAX is a critical member of the BCL-2 protein family, which is composed of opposing pro- and anti-apoptotic members that dictate cellular life and death at the mitochondrial apoptotic pathway. Pro-apoptotic BAX, upon activation, translocates from the cytosol to the mitochondria to execute permeabilization of the outer mitochondrial membrane, the """"""""point of no return"""""""" for mitochondrial apoptosis. The role of BAX in cell death regulation, tumorigenesis and chemotherapy-induced cancer cell death has been well established. Furthermore, significant overexpression of anti-apoptotic BCL-2 members, the inhibitors of BAX, is common in cancer cells and contributes to tumorigenesis and chemoresistance. Therefore, the vast majority of cancer cells contain functional but suppressed BAX. We previously discovered the BAX trigger site that regulates the activation of cytosolic BAX and a small molecule that binds to the trigger site of BAX and induces BAX activation, enabling the direct and rational targeting of this high-profile apoptotic target. Here, we propose to evaluate the potential of the trigger site of BAX as a novel pharmacological strategy to reactivate cancer cell death and investigate BAX activator molecules (BAMs) as promising prototype therapeutics, in the context of resistant Acute Myeloid Leukemia (AML). Specifically, we will 1) characterize novel BAMs in binding, structural and biochemical studies for binding selectively to the BAX trigger site and induction of BAX activation, 2) investigate the direct activation mechanism of BAX to reactivate BAX-mediated apoptosis in human AML cells and genetically modified cancer cells, 3) examine the therapeutic efficacy of direct BAX activation, in human AML xenografts and in vitro and in vivo toxicity studies, using our novel lead compound and 4) synthesize novel BAMs for target validation and improvement of potency, selectivity and pharmacological properties. Thus, we propose a multidisciplinary approach that combines synthetic chemistry, structural biology, biochemistry, cancer cell biology and in vivo efficacy studies to validate a novel small-molecule therapeutic approach to restore cancer cell death and provide BAMs as potential lead structures for cancer therapeutics.
Programmed cell death, or apoptosis, regulates the critical balance between cellular life and death and, when it is deregulated, it can contribute to the pathogenesis, maintenance and chemoresistance of tumors. Pro-apoptotic BAX operates as gateway to apoptosis and recent discoveries about its mechanism of activation promise to enable opportunities for modulating apoptosis for therapeutic benefit. The goal of this proposal is to investigate a novel small-molecule therapeutic approach, by directly targeting pro-apoptotic BAX, to promote selective apoptosis in cancer cells.
|Rocha, Agostinho G; Franco, Antonietta; Krezel, Andrzej M et al. (2018) MFN2 agonists reverse mitochondrial defects in preclinical models of Charcot-Marie-Tooth disease type 2A. Science 360:336-341|
|Galluzzi, Lorenzo; Vitale, Ilio; Aaronson, Stuart A et al. (2018) Molecular mechanisms of cell death: recommendations of the Nomenclature Committee on Cell Death 2018. Cell Death Differ 25:486-541|
|Reyna, Denis E; Gavathiotis, Evripidis (2018) Pulling the BAX trigger for tumor cell death. Oncotarget 9:8204-8205|
|Garner, Thomas P; Lopez, Andrea; Reyna, Denis E et al. (2017) Progress in targeting the BCL-2 family of proteins. Curr Opin Chem Biol 39:133-142|
|Reyna, Denis E; Garner, Thomas P; Lopez, Andrea et al. (2017) Direct Activation of BAX by BTSA1 Overcomes Apoptosis Resistance in Acute Myeloid Leukemia. Cancer Cell 32:490-505.e10|
|Karoulia, Zoi; Gavathiotis, Evripidis; Poulikakos, Poulikos I (2017) New perspectives for targeting RAF kinase in human cancer. Nat Rev Cancer 17:676-691|
|Karoulia, Zoi; Wu, Yang; Ahmed, Tamer A et al. (2016) An Integrated Model of RAF Inhibitor Action Predicts Inhibitor Activity against Oncogenic BRAF Signaling. Cancer Cell 30:485-498|
|Klionsky, Daniel J (see original citation for additional authors) (2016) Guidelines for the use and interpretation of assays for monitoring autophagy (3rd edition). Autophagy 12:1-222|
|Cotto-Rios, Xiomaris M; Gavathiotis, Evripidis (2016) Chemical genetics: Unraveling cell death mysteries. Nat Chem Biol 12:470-1|
|Uchime, Onyinyechukwu; Dai, Zhou; Biris, Nikolaos et al. (2016) Synthetic Antibodies Inhibit Bcl-2-associated X Protein (BAX) through Blockade of the N-terminal Activation Site. J Biol Chem 291:89-102|
Showing the most recent 10 out of 19 publications