Phase I Ovarian cancer is the fifth leading cause of cancer death among U.S. women and has the highest mortality rate of all gynecologic cancers, with 23,400 new cases and 13,900 deaths projected in 2001. Screening markers and therapies remain limited, and 5-year survival rates for the 60% of women diagnosed with Stage III or IV disease are less than 20%. Improved therapies for advanced disease, and, in particular, for recurrent disease that has failed initial therapy, are urgently needed. FASgen, Inc. is developing a novel set of antineoplastic agents, inhibitors of the enzyme fatty acid synthase (FAS), which is overproduced in 50-80% of ovarian cancers. In Phase I of this FAST TRACK application to the NCI FLAIR program, a lead compound will have been selected which at <90% of the MTD in normal mice increases the median survival time of athymic nude mice bearing the OVCAR-3 tumor in their peritoneal cavities by at least 25% with <10% weight loss. Phase II work over the proposed 4-year period will produce GMP material, complete animal safety trials in rats and dogs, result in the filing of an IND, complete an initial safety evaluation (Phase I/IItrial) in 25-30 women, and culminate in a Phase II proof-of-efficacy trial in 25-30 women with FAS+ advanced ovarian cancers. Both clinical trials will enroll women with recurrent disease that have failed initial therapy and overexpresses FAS, as detected by the serum FAS assay. Serum CA-125 and serum FAS will be added to the usual disease monitors and measures of progression. The clinical trials will be carried out at the Oncology Center of the Johns Hopkins University under the direction of Dr. Deborah Armstrong. Success will be demonstrated if a response rate of >25% is observed in the Phase II clinical trial. Completion of this work should produce a data package sufficient to interest a corporate partner in further development of the FASgen lead compound. Phase II Ovarian cancer is the fifth leading cause of cancer death among U.S. women and has the highest mortality rate of all gynecologic cancers, with 23,400 new cases and 13,900 deaths projected in 2001. Screening markers and therapies remain limited, and 5-year survival rates for the 60% of women diagnosed with Stage III or IV disease are less than 20%. Improved therapies for advanced disease, and in particular for recurrent disease that has failed initial therapy, are urgently needed. FASgen, Inc. is developing a novel set of antineoplastic agents based on inhibition of the enzyme fatty acid synthase (FAS), which is overproduced in 50-80% of ovarian cancers. The work proposed in SBIR Phase I of this FAST TRACK application to the NCI FLAIR program is designed to improve on a first generation inhibitor (C75) that had significant activity but also dose limiting anorexigenic effects in the OVCAR-3 model. Six candidate compounds have been identified that represent two different chemical families, have been shown to maintain anti-FAS potency, and cause minimal weight loss.
Specific aims i nclude: 1) a modest scale-up and resupply of the 6 candidate molecules and C75; 2) in vitro testing against the multidrug resistant ovarian cancer-derived cell line OVCAR-3; 3) a determination of the maximum tolerated dose (MTD) and dose limiting toxicity (DLT) in BALB/C mice on low and high fat diets; and, 4) efficacy studies using OVCAR-3 xenografts grown in athymic BALB/C mice. In addition, an assay will be developed to measure the blood concentration of the lead compound and used to evaluate plasma samples taken during the MTD determinations. Efficacy in the animal model will be assessed using improved survival time, alteration in the distribution of the tumor intraperitoneally, and changes in the serum levels of CA-125 and FAS. Success will be demonstrated if at least one compound is identified which at <90% of the MTD in normal mice increases the median survival time of athymic nude mice bearing the OVCAR-3 tumor in their peritoneal cavities by at least 25% with <10% weight loss. SBIR Phase II goals will be to address any formulation or scale-up issues identified in the SBIR Phase I work, complete pre-clinical pharmacology and safety studies using GMP material, and conduct a Phase I/II safety trial and a Phase II efficacy trial for the lead compound identified in SBIR Phase I.
| Zhou, Weibo; Han, Wan Fang; Landree, Leslie E et al. (2007) Fatty acid synthase inhibition activates AMP-activated protein kinase in SKOV3 human ovarian cancer cells. Cancer Res 67:2964-71 |
| Alli, Patricia M; Pinn, Michael L; Jaffee, Elizabeth M et al. (2005) Fatty acid synthase inhibitors are chemopreventive for mammary cancer in neu-N transgenic mice. Oncogene 24:39-46 |
| McFadden, Jill M; Medghalchi, Susan M; Thupari, Jagan N et al. (2005) Application of a flexible synthesis of (5R)-thiolactomycin to develop new inhibitors of type I fatty acid synthase. J Med Chem 48:946-61 |
