A PHASE I/II STUDY OF NELFINAVIR IN LIPOSARCOMA

这个子项目是许多研究子项目中的一个 由NIH/NCRR资助的中心赠款提供的资源。子项目和 研究者（PI）可能从另一个NIH来源获得了主要资金， 因此可以在其他CRISP条目中表示。所列机构为 研究中心，而研究中心不一定是研究者所在的机构。 脂肪肉瘤是第二常见的软组织肉瘤，据估计，2000年美国有1,550例新发病例。 近18，000例的总体患病率符合指定为孤儿疾病的标准。HIV蛋白酶诱导的脂肪营养不良综合征的临床综合征与HIV蛋白酶抑制剂（PI）的使用有关。受影响的个体发展与胰岛素抵抗和高脂血症相关的外周脂肪消耗和中心脂肪积聚。临床前研究表明，PI抑制前脂肪细胞分化，并促进终末分化的脂肪细胞凋亡。 综上所述，这些临床和临床前发现使我们研究了PI在脂肪肉瘤治疗中的应用。我们的实验室已经证明，PI，奈非那韦，选择性诱导脂肪肉瘤细胞凋亡。这与固醇调节元件结合蛋白-1（SREBP-1）转录因子的激活和表达有关，该转录因子与诱导凋亡基因表达有关。基于这些临床前研究结果，本提案中评价的总体假设是奈非那韦是一种新型的靶向脂肪肉瘤的细胞毒性药物。 具体目的：（1）在初步的、脂肪肉瘤特异性的、I期研究中确定奈非那韦的最大耐受剂量和药代动力学。(2)在随后的II期研究中评估接受奈非那韦治疗的患者的缓解率和无进展生存期。(3)评价奈非那韦对肿瘤和替代正常脂肪组织中SREBP-1和SREBP-1靶基因表达的影响。

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.