The centra] theme of this Drug Discovery Group is to use knowledge of apoptosis targets and mechanisms for generating small molecule drugs for the improved treatment of cancer. Defects in programmed cell death (apoptosis) mechanisms play important roles in many aspects of tumor pathogenesis and progression. For example, apoptosis defects allow neoplastic cells to survive beyond their normally intended life-spans, subverting the need for exogenous survival factors, providing protection from hypoxia and oxidative stress as tumor mass expands, and allowing time for accumulative genetic alterations that deregulate cell proliferation, interfere with differentiation, promote angiogenesis, and increase cell motility and invasiveness during tumor progression (1). In fact, apoptosis defects are recognized as an important complement to proto-oncogene activation, as many deregulated oncoproteins that drive cell division also trigger apoptosis (e.g. Myc; Ela; Cyclin-Dl) (2). Similarly, defects in DNA repair and chromosome segregation normally trigger cell suicide as a defense mechanism for eradicating genetically unstable cells, and thus apoptosis defects permit survival of the genetically unstable cells, providing opportunities for selection of progressively aggressive clones (3). Apoptosis defects also facilitate metastasis by allowing epithelial cells to survive in a suspended state, without attachment to extracellular matrix (4). They also promote resistance to the immune system, in as much as many of the weapons cytolytic T-cells (CTLs) and Natural Killer (NK) cells use for attacking tumors depend on integrity of the apoptosis machinery (5). .Finally, cancer-associated defects in apoptosis play a role in chemoresistance and radioresistance, increasing the threshold for cell death, and thereby requiring higher doses for tumor killing (6). Thus, defective apoptosis regulation is a fundamental aspect of the biology of cancer. Because apoptosis defects permit a wide-variety of aberrant cellular behaviors, as exhibited in cancer cells, therapeutic strategies that negate the apoptosis advantage for tumors are predicted to selectively kill cancer cells as opposed to normal cells. Fundamentally, cancer cells should be more dependent on apoptosis defense mechanisms than normal cells, and thus proportionally more sensitive to interventions that target apoptosis proteins and genes. To date, efforts to bring apoptosis-based strategies into animal models or human clinical trials have provided support for this concept of selective vulnerability of neoplastic as opposed to normal cells. A solid knowledge-base now exists about the mechanisms of apoptosis regulation, the proteins involved, their 3-dimensional structures, and biochemical mechanisms. Over the past two decades, a clearer understanding has emerged of the defects in expression or function of apoptosis-regulating genes and proteins as pertains to cancer. This knowledge-base can now be exploited for devising strategies for small molecule drug discovery, towards the goal of revolutionary new treatments for cancer and leukemia.
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