8.4.1 ABSTRACT: TUMOR BIOLOGY AND PROGRESSION, The Tumor Biology and Progression program, led by James McCarthy, Ph.D., has 27 members, : representing 16 departments and five schools. As of October 1, 2007, these members have a total of $6.5 million in peer-reviewed, funded research projects for the current budget period. Since June 2003, their research has resulted in 172 publications, of which 14% were intra-programmatic and 15% were interprogrammatic. Research within the Tumor Biology and Progression Program focuses on molecular and cellular mechanisms associated with the progression of malignant tumors. The program has three major scientific focus areas or themes. First, program members are studying the biology of tumor growth/survival and evaluating important contributions of the tumor microenvironment in progression. The role of heat shock protein 70 in the therapeutic resistance of pancreatic cancer cells and identification of specific inhibitors to improve therapy are being pursued. New protocols using neoadjuvant therapies for pancreatic cancer are being developed and tested in orthotopic animal models of the disease. Newly recrujted faculty are studying the importance of macrophage infiltration to early progression associated events in a transgenic animal model of breast cancer. Studies are also in progress to examine mechanisms of action Of defined antiangiogenic agents, including novel engineered nonpeptide mimetic inhibitors of angiogenesis. Second, there is a prostate cancer focus group that consists of clinincal investigators and basic scientists.Projects being pursued include determining how androgen receptors regulate the growth of hormone refractory disease, how intracellular kinases such as CK2 confer survival, and how hyaluronan within the microenvironment facilitates progression. These studies are being extended to evaluate feasibility of delivering RNA interference based therapies using sub 50nm nanocapsules. Synthetic peptides that disrupt hyaluronan/ tumor cell interactions are being evaluated in vitro and in vivo for the ability to limit tumor growth. Development of noninvasive imaging approaches for staging prostate tumors and relating these results to more conventional molecular correlates of progression is also being pursued. Finally, novel immunotoxins are being developed to improve the treatment of various hematopoietic and solid tissue tumors. These studies involve the design of bivalent sFv antibodies coupled with diptheria toxin to target and kill neoplasms: Some of these agents are currently in phase I clinical trials and others are being developed for future clinical studies. The long term goal of the program is to identify and target key pathways used by malignant tumors for dysregulated growth, invasion and resistance to therapy.

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