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Dissecting and Targeting Deregulated Mitochondrial Apoptosis in Human Cancer

Loren David Walensky

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National Institutes of Health (NIH)
The BCL-2 family of apoptotic proteins regulates the critical balance between cellular life and death. Deregulation of this essential signal transductio network drives the development, maintenance, and chemoresistance of a broad spectrum of human cancers. My laboratory is addressing the questions of just how interactions among BCL-2 family proteins regulate their structural changes and signaling functions during homeostasis and malignant transformation. Because BCL-2 protein interactions determine whether the cell will live or die in response to stress, we believe these structure-function studies will both infor basic biological mechanisms and opportunities to pharmacologically modulate them. Thirty years of BCL-2 family research has led to the first small molecule drug to reactive apoptosis in BCL-2 dependent cancer. Despite this remarkable scientific progress and the renewed promise of targeting BCL-2 proteins in cancer, fundamental questions remain about how this complex protein family regulates mitochondrial apoptosis. Indeed, their predominant membrane localization has made BCL-2 family proteins remarkably challenging to study. How the activated forms of BAX and BAK self-assemble into toxic oligomeric pores - the very death channels that mediate apoptosis - is unknown. How anti-apoptotic proteins such as BCL-2 change their structure within the membrane to block the various steps of BAX/BAK activation is unknown. Indeed, the full spectrum of contact surfaces between the many conserved domains of BCL-2 proteins is unknown. Perhaps the most perplexing question of how such structurally similar proteins can have diametrically opposite functions, as either inhibitors or activators of cell deat, remains essentially unknown. We address these mechanistic questions with broad experimental approaches, spanning chemistry, structural biology, proteomics, biochemistry, cell biology, mouse modeling, and pharmacology. For example, we have developed new chemical tools to dissect and target BCL-2 family protein interactions, advanced new methods to rapidly and accurately identify interaction sites using photoreactive structured peptides and mass spectrometry, and are currently applying hydrogen- deuterium exchange mass spectrometry to study BCL-2 family conformational changes in the membrane in real-time for the first time. Our goals for this R35 cancer research program include defining the conformational activation and homo-oligomerization mechanism(s) of BAX and BAK, characterizing a novel mechanism for BAX and BAK suppression by the BH4 domains of anti-apoptotic BCL-2 proteins, and investigating a new allosteric mechanism that controls the apoptotic functionalities of BCL-2 proteins. In each case, the structure- function insights will be harnessed to develop new approaches for targeting apoptotic resistance in cancer. As a chemical biologist and practicing pediatric oncologist, I have dedicated my research laboratory to deciphering BCL-2 family-mediated cancer mechanisms so that fresh insights into their protein interaction biology can inform the next generation of pro-apoptotic therapies for human cancer.

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