Corticorelin acetate, a synthetic corticotropin-releasing factor with preclinical antitumor activity, alone and with bevacizumab, against human solid tumor models.
OBJECTIVE
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.
Gamez
Idoia
I
Celtic Pharmaceutical Development Services America, Inc, 663 Fifth Ave, 7th Floor, New York, 10022 NY, USA. idoia.gamez@dev.celticpharma.com
Ryan
Robert P
RP
Reid
Lakesha D
LD
Routt
Sheri M
SM
Hollister
Beth A
BA
D020533:Angiogenesis Inhibitors / Q000008:administration & dosage / Q000627:therapeutic use; D000818:Animals; D000911:Antibodies, Monoclonal / Q000008:administration & dosage / Q000627:therapeutic use*; D061067:Antibodies, Monoclonal, Humanized; D000970:Antineoplastic Agents / Q000493:pharmacokinetics / Q000627:therapeutic use*; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use; D000068258:Bevacizumab; D001943:Breast Neoplasms / Q000188:drug therapy*; D003110:Colonic Neoplasms / Q000188:drug therapy*; D003346:Corticotropin-Releasing Hormone / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000627:therapeutic use*; D005260:Female; D006801:Humans; D051379:Mice; D008819:Mice, Nude; D009368:Neoplasm Transplantation; D014183:Transplantation, Heterologous
D020533:Angiogenesis Inhibitors; D000911:Antibodies, Monoclonal; D061067:Antibodies, Monoclonal, Humanized; D000970:Antineoplastic Agents; D000068258:Bevacizumab; D003346:Corticotropin-Releasing Hormone