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ANTICANCER RESEARCH 30: 5037-5042 (2010) Corticorelin Acetate, a Synthetic Corticotropin-releasing Factor with Preclinical Antitumor Activity, alone and with Bevacizumab, against Human Brain Tumor Models IDOIA GAMEZ1, ROBERT P. RYAN1 and STEPHEN T. KEIR2 1Celtic Pharmaceutical Development Services America, Inc., New York, NY 10022, U.S.A.; 2The Preston Robert Tisch Brain Tumor Center, Duke University, Durham, NC 27710, U.S.A. Abstract. Background: Corticorelin acetate (CrA) is a brain tumors. The cause of PBE is believed to result in part synthetic form of corticotropin-releasing factor that is from the leakage of edematous brain tumor fluid from currently undergoing clinical trials in the treatment of abnormal tumor vasculature into the surrounding tissue (1, peritumoral brain edema (PBE). This study preclinically 2). The mechanism(s) of action by which CrA exerts its investigated its potential as an antitumor agent against beneficial effect in the therapy of PBE has not been human brain tumor xenografts. Materials and Methods: The elucidated, but two factors appear to be relevant: decreased in vivo efficacy of CrA as a single agent and in combination vascular leakage and preserved integrity of the endothelial with the antiangiogenic agent, bevacizumab, was examined cells, which ultimately helps to maintain the blood-brain in three different patient-derived human brain tumor barrier (3, 4). xenografts implanted orthotopically (intracranially) or CrA appears to mediate its activity through two subtypes subcutaneously in athymic mice. Results: CrA significantly of G-protein coupled receptors: CRF receptor-1 (CRFR1) increased the lifespan of mice implanted orthotopically with and CRF receptor-2 (CRFR2) (5). These CRFRs are widely two different pediatric brain tumor xenograft models. In one distributed in the central nervous system, peripheral tissues, of these tumor models, the combination of CrA with and some types of human tumors (6, 7). It is known that bevacizumab produced a therapeutic outcome superior to CRFR2 plays a critical role in the tonic inhibition of adult that found using either of the two agents alone. Conclusion: neovascularization (8). Moreover, it has been found that The application of CrA for the treatment of PBE likely CRFR2 agonism inhibited the growth of hepatocellular involves its activity as an anti-angiogenic agent, which may carcinoma and reduced tumor microvessel density in nude be one possible mechanism to explain its observed mice (9). Hepatoma cells do not express CRFRs, whereas preclinical antitumor activity against orthotopic human brain associated blood vessels do, mainly CRFR2 (9). tumor models. Additional studies to investigate other Additionally, it was recently described that CrA has activity possible mechanisms of action are underway. as an antiangiogenic in the corneal micropocket assay (15). CrA is a well-tolerated drug based on data from ongoing Corticoreline acetate (Xerecept®, CrA) is a synthetic peptide clinical trials involving nearly 200 patients who have formulation of the endogenous neurohormone, corticotropin- received it subcutaneously (s.c.), often for extended periods releasing factor (CRF). The 41-amino acid sequence of CrA (10-12). The evolving clinical efficacy and safety data is identical to that of the human hormone and it is being indicate that CrA might provide a dexamethasone-sparing developed as an alternative to dexamethasone in the treatment (if not an alternative to dexamethasone) for the treatment of peritumoral brain edema (PBE). Patients are management of symptomatic PBE (13). typically debilitated by the effects of PBE associated with A preclinical study involving the use of CrA in the treatment of mice bearing an orthotopically implanted human brain tumor yielded encouraging positive data (14). Recently, the activity of CrA in the treatment of human solid tumor Correspondence to: Idoia Gamez, Celtic Pharma Development xenografts, particularly when combined with bevacizumab Services, 663 Fifth Ave, 7th Floor, NY, NY 10022, U.S.A. Tel: +1 (Avastin®, BEV; Genentech, South San Francisco, CA, 2126164084, Fax: +1 2126164099, e-mail: idoia.gamez@ dev.celticpharma.com USA), was described (15). The objective of the present study was to investigate further, preclinically, the potential of CrA Key Words: Xerecept®, bevacizumab, Avastin®, corticorelin acetate, as an antitumor agent in the treatment of brain tumors. brain tumor model. Additionally, this study evaluated the ability of CrA to 0250-7005/2010 $2.00+.40 5037 ANTICANCER RESEARCH 30: 5037-5042 (2010) provide an enhanced therapeutic benefit when given with In all experiments, control mice were treated with drug vehicle. BEV and so the tumor models selected were those known to Mice were weighed twice weekly, individually, and drugs were be sensitive to BEV therapy. administered on a mg/kg basis according to the last weight recorded for each mouse. Injection volumes were delivered in 0.01 ml/g of Materials and Methods body weight. Toxicity assessment Animals. Female athymic mice (nu/nu genotype, Balb/c background, Body weight. The average body weight of mice from each six weeks or older) were used for all antitumor studies. Animals treatment group and appropriate relative untreated control set was were maintained in filter top cages in Thoren units. The guidelines determined just prior to treatment initiation. The average body of the Institutional Animal Care and Use Committee of Duke weights of the same sets of mice were determined after (typically University (where all in vivo studies were performed) were utilized one day) completion of treatment. The difference in average body along with the National Institutes of Health guidelines. weights was used to estimate treatment related toxicity. A loss of average body weight greater than 20% was considered excessively Compounds. CrA was supplied in its clinical vials (1.2 mg/vial) by toxic. None of the treatments in any of the experiments was judged Celtic Pharma Development Services America (New York, NY, to have been excessively toxic by this criterion. In addition, no USA). Clinical vials of BEV (25 mg/ml) were purchased treatment-related deaths occurred in any of the experiments commercially (Genentech). performed. Tumor xenografts and implantation. The following patient-derived Efficacy assessment human tumor xenografts maintained by Duke University were used for Survival. Therapeutic results are presented in terms of: (i) increases experimentation: intracranially (i.c.) -implanted D-341 MED pediatric in lifespan reflected by the relative median survival time (MST) of medulloblastoma and D-456 MG pediatric multiforme glioblastoma, treated (T) mice versus control (C) mice (i.e., % T/C); and (ii) long- and s.c.-implanted D-245 MG adult multiforme glioblastoma. term survivors (LTS). A T/C of 125% was used as the threshold of For intracranial tumor transplantation, tumors were excised, activity when accompanied by a statistical test indicating minced, and cells separated with a cytosieve into Zinc Option significance (p<0.05) (17). Mice surviving to the end of an solution (Biowhitter Inc, Walkersville, MD, USA). After experiment are referred to as LTS. Statistical evaluation of survival centrifugation, supernatant was removed, and cells were mixed 1:1 time was performed using a log-rank test (18). with methylcellulose. Total homogenate (10 μl) was then injected Tumor growth delay. Therapeutic results are presented in terms with a Hamilton syringe (Hamilton, Co., Reno, NV, USA) as of: (i) tumor growth delay reflected by the relative median time for previously described (16). Subcutaneous tumor transplantation into T (treated) mice versus C (control) mice to achieve tumor target size the right flank of the animals with an inoculation volume of 50 μl (i.e., T-C in days); or (ii) percent tumor growth inhibition (%TGI). was carried out using a brei prepared from xenografts as previously Estimates of the median time for a group to achieve five times the described (16). original tumor size were calculated using a proprietary and customized Duke SAS statistical software program. The relative Tumor measurements. All tumors were measured twice weekly with times for treated and control mice to achieve tumor target size (five hand-held vernier calipers (Scientific Products, McGraw, IL, USA). times the initial) was subjected to a Wilcoxon statistical test for Tumor volume was calculated in cubic millimeters, according to the significance (19). following formula: V=[(width)2×(length)]/2. Efficacy was expressed in terms of percent tumor growth inhibition (% TGI), calculated using the formula: Antitumor drug therapy. For the i.c. tumor studies, groups of ten mice were randomized three days after i.c. tumor implantation, at which time all treatments were begun. CrA was administered at [1–(Tt/To × Co/Ct)] 0.1 and/or 0.2 mg/kg/injection, s.c., twice daily (bid). BEV was %TGI = ×100 administered at a dose of 1, 2.5 or 5 mg/kg/inj, intraperitoneally 1 – Co/Ct (i.p.), twice weekly, depending upon the experiment. Treatments were continued until a median day of death was reached per where Ct is the median control tumor size at the end of a group. selected observation period of no less a duration than one tumor For the s.c. D-245 MG tumor study, groups of ten mice were volume doubling time (which was 7.9 days in the D-245 MG distributed per control and treatment sets based on tumor experiment), Co is the median control tumor size at the volume, such that each set’s median tumor size was within 10% initiation of the selected observation period, Tt is median tumor of the overall median tumor size of all mice included in the size of a treated group at the end of the selected observation experiment. This distribution occurred when all the tumored mice period and To is median tumor size of a treated group at the had tumors within the range of 62 to 107 mm3 and treatments initiation of the selected observation period. The selected were initiated on that day, which was day ten post-tumor implant.

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