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Gamez I.,Celtic Pharmaceutical Development Services America Inc. | Ryan R.P.,Celtic Pharmaceutical Development Services America Inc. | Reid L.D.,Piedmont Research Center | Routt S.M.,Piedmont Research Center | Hollister B.A.,Piedmont Research Center
Cancer Chemotherapy and Pharmacology | Year: 2011

Purpose: Corticorelin acetate (CrA) is a synthetic form of corticotropin-releasing factor undergoing clinical trials in the treatment of peritumoral brain edema (PBE). We sought to investigate preclinically its potential as an antitumor agent against human solid tumors and to assess its ability to enhance the therapeutic activity of bevacizumab (BEV) in these same models. Methods: The in vivo efficacy of CrA as a single agent and in combination with the antiangiogenic agent, BEV, was examined in two preclinical human tumor models, the MX-1 breast and Colo-205 colon carcinomas. These models were selected based on their known sensitivity to BEV and were tumor types in which BEV has been approved for clinical use. The corneal micropocket assay was also performed to assess the antiangiogenic activity of CrA relative to BEV. The exposure level of CrA in the mouse using a typical preclinical regimen was measured so as to compare it to reported clinical exposure levels. Results: CrA was active as a single agent in the MX-1 breast carcinoma, but did not exhibit statistically significant activity as a single agent in the Colo-205 colon carcinoma under the doses and schedules used in the study. When BEV, which was active or near active in both the MX-1 and Colo-205 models, was administered concomitantly with CrA, therapeutic outcomes were observed that were significantly better than those obtained using either monotherapy. These therapeutic potentiations using CrA plus BEV were obtained in the absence of any observable increase in toxicities. CrA was active in the corneal micropocket assay, producing a substantial (>70%) inhibition of neovascularization. A representative CrA regimen in mice produced an exposure within eightfold of human exposure determined at one-half the current clinical dose. Conclusions: The application of CrA for the treatment of PBE likely involves its activity as an antiangiogenic agent, which may be one possible mechanism to explain its observed preclinical antitumor activity. That activity, as well as its ability to provide an enhanced therapeutic outcome when given in conjunction with BEV in the absence of increased toxicity, supports the use of CrA clinically as other than a replacement therapy for dexamethasone in PBE. © 2010 Springer-Verlag. Source


Moroz M.A.,Sloan Kettering Cancer Center | Huang R.,Sloan Kettering Cancer Center | Kochetkov T.,Sloan Kettering Cancer Center | Shi W.,Sloan Kettering Cancer Center | And 5 more authors.
Clinical Cancer Research | Year: 2011

Purpose/Experimental Design: Treatment of cerebral tumors and peritumoral brain edema remains a clinical challenge and is associated with highmorbidity andmortality. Dexamethasone is an effective drug for treating brain edema, but it is associated with well-documented side effects. Corticorelin acetate (Xerecept) or human corticotrophin-releasing factor (hCRF) is a comparatively new drug and has been evaluated in two orthotopic glioma models (U87 and C6), by a direct comparison with dexamethasone and temozolomide. Results: In vitro combination therapy and monotherapy showed a variable response in 6 different glioma cell lines. In vivo studies showed a dose-dependent effect of hCRF (0.03 and 0.1 mg/kg q12h) on survival of U87 intracranial xenograft-bearing animals [median survival: control - 41 days (95% CI 25-61); "low-hCRF" 74.5 days (95% CI 41-88); "high-hCRF" >130 days (95% CI not reached)]. Dexamethasone treatment had no effect on survival, but significant toxicity was observed. A survival benefit was observed with temozolomide and temozolomide + hCRF-treated animals but with significant temozolomide toxicity. C6-bearing animals showed no survival benefit, but there were similar treatment toxicities. The difference in hCRF treatment response between U87 and C6 intracranial gliomas can be explained by a difference in receptor expression. RT-PCR identified CRF2r mRNA in U87 xenografts; no CRF receptors were identified in C6 xenografts. Conclusions: hCRF was more effective than either dexamethasone or temozolomide in the treatment of U87 xenografts, and results included improved prognosis with long-term survivors and only mild toxicity. The therapeutic efficacy of hCRF seems to be dependent on tumor hCRF receptor (CRFr) expression. These results support further clinical assessment of the therapeutic efficacy of hCRF and levels of CRFr expression in different human gliomas. ©2011 AACR. Source


Gamez I.,Celtic Pharmaceutical Development Services America Inc. | Ryan R.P.,Celtic Pharmaceutical Development Services America Inc. | Keir S.T.,Duke University
Anticancer Research | Year: 2010

Background: Corticorelin acetate (CrA) is a synthetic form of corticotropin-releasing factor that is currently undergoing clinical trials in the treatment of peritumoral brain edema (PBE). This study preclinically investigated its potential as an antitumor agent against human brain tumor xenografts. Materials and Methods: The in vivo efficacy of CrA as a single agent and in combination with the antiangiogenic agent, bevacizumab, was examined in three different patient-derived human brain tumor xenografts implanted orthotopically (intracranially) or subcutaneously in athymic mice. Results: CrA significantly increased the lifespan of mice implanted orthotopically with two different pediatric brain tumor xenograft models. In one of these tumor models, the combination of CrA with bevacizumab produced a therapeutic outcome superior to that found using either of the two agents alone. Conclusion: The application of CrA for the treatment of PBE likely involves its activity as an anti-angiogenic agent, which may be one possible mechanism to explain its observed preclinical antitumor activity against orthotopic human brain tumor models. Additional studies to investigate other possible mechanisms of action are underway. Source

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