Liposarcomas are the second most common soft-tissue sarcomas, with an estimated United States 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 the investigators to study the use of PIs for liposarcoma therapy. The investigators' 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 that selectively targets liposarcomas.
The Specific Aims are: (1) to establish the maximal tolerated dose (MTD) of nelfinavir in the preliminary, liposarcoma-specific, Phase 1 study; (2) to assess response rate, progression-free survival, and nelfinavir pharmacokinetics in patients treated at the MTD in the ensuing, Phase 2 study; and (3) to evaluate nelfinavir effect on expression of SREBP-1 and SREBP-1 target genes in tumor and surrogate normal adipose tissue. This Phase 1/2 clinical trial and the associated correlative studies are expected to validate nelfinavir as a novel therapy for recurrent liposarcoma, and provide valuable insight into its mechanism(s) of action in vivo.
