Abstract 1554: Corticorelin acetate, a synthetic corticotropin releasing factor, demonstrates antiangiogenic and antitumor activity alone and enhances bevacizumab activity in human tumor models
Authors: Maria I. Gamez, Robert P. Ryan, LaKesha D. Reid, Sheri M. Routt, Beth A. Hollister
Journal: Cancer Research (2010)

Abstract Corticorelin acetate (CrA) is a synthetic form of corticotropin-releasing factor undergoing clinical trials in the treatment of peritumoral brain edema (PBE). A corneal micropocket angiogenesis assay (CMA) was performed to assess the activity of CrA relative to bevacizumab (BEV). We also investigated the in vivo anti-tumor efficacy of CrA as a single agent and in combination with BEV, in two preclinical human tumor models, the MX-1 breast and Colo-205 colon carcinomas. These models were selected based on their sensitivity to BEV. In the CMA, six groups of female mice were implanted with pellets containing VEGF or no VEGF, and treated for 7 days. The vehicle control group received phosphate buffered saline, sc, bid. The positive reference group received BEV, ip, qd, at 5 mg/kg/inj. The two remaining groups received CrA sc, bid, at 0.1 mg/kg/inj or 0.2 mg/kg/inj. Treatment outcome was determined from semi-quantitative characterization of neovascularization. CrA produced a substantial (&amp;gt;70%) inhibition of neovascularization (p&amp;lt;0.01) in the CMA. In the xenograft studies, mice were implanted sc in the flank with approximately 1 mm3 tumor fragments obtained from donor passage mice (MX-1), or with 1 × 106 tissue culture-derived Colo-205 cells implanted in 50% matrigel. When tumors were generally between 80-240 mg (mm3), mice were distributed to control and treatment sets. CrA was administered at two dose levels, 0.1 and 0.2 mg/kg/injection, sc, twice daily (bid). BEV was administered at a dose of 5 mg/kg/inj, ip, twice weekly. All treatments were continued until each group achieved its tumor target size, 1 gm in the Colo-205 experiment, and 1.5 gm in the MX-1 experiment. A log cell kill (LCK) of ≥1.0, equivalent to a delay in tumor growth of ≥ 3.32 x tumor volume doubling time, accompanied by statistical significance (p&amp;lt;0.05) was considered indicative of activity. CrA was active as a single agent in the MX-1 breast carcinoma (1.0 LCK; p&amp;lt;0.02), but inactive in the Colo-205 colon carcinoma. BEV was active (1.1 LCK; p&amp;lt;0.002) or near active (0.9 LCK; p&amp;lt;0.001) in both the MX-1 and Colo-205 models, respectively. When BEV was administered concomitantly with CrA, therapeutic outcomes were observed that were significantly better (3.3 LCK in MX-1, p&amp;lt;0.03; 1.9 LCK in Colo-205, p&amp;lt;0.01) than those obtained using either monotherapy. These therapeutic potentiations using CrA plus BEV were obtained in the absence of any observable increase in toxicities. Conclusion: CrA has demonstrated anti-angiogenic activity in vivo, which may be one possible mechanism to explain its observed preclinical antitumor activity. Importantly it enhances the antitumour activity of BEV in both MX-1 and Colo-205 models. Given the good safety profile of CrA and its lack of hypertensive side effects in clinical trials, CrA should be evaluated clinically in combination with BEV. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 1554.