This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. Liposarcomas are the second most common soft-tissue sarcomas, with an estimated U.S. incidence of 1,550 new cases in 2000. The overall prevalence of nearly 18,000 satisfies criteria for designation as an orphan disease. The clinical syndrome of HIV protease-induced lipodystrophy syndrome is associated with use of HIV protease inhibitors (PIs). Affected individuals develop peripheral fat wasting and central fat accumulation in association with insulin resistance and hyperlipidemia. Preclinical studies have demonstrated that PIs inhibit preadipocyte differentiation, and promote apoptosis of terminally differentiated adipocytes. Taken together, these clinical and preclinical findings led us to investigate the use of PIs for liposarcoma therapy. Our laboratory has demonstrated that a PI, nelfinavir, selectively induces apoptosis in liposarcomas. This was associated with the activation and expression of the sterol regulatory element binding protein-1 (SREBP-1) transcription factor, which has been linked to induction of apoptotic gene expression. Based upon these preclinical findings, the overall hypothesis to be evaluated in this proposal is that nelfinavir is a novel, cytotoxic agent targeting liposarcomas.
Specific Aims : (1) Establish the maximal tolerated dose and pharmacokinetics of nelfinavir in the preliminary, liposarcoma-specific, phase I study. (2) Assess response rate and progression-free survival in patients treated with nelfinavir in the ensuing, phase II study. (3) Evaluate nelfinavir effect on expression of SREBP-1 and SREBP-1 target genes in tumor and surrogate normal adipose tissue.
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