ANTICANCER RESEARCH 31: 3921-3926 (2011) ADH-1 in the Treatment of Metastatic Adrenocortical Carcinoma - Case Report NIRIT YAROM1, DAVID STEWART3, LEONARD AVRUCH1, RAJESH MALIK2, JULIE WELLS1 and DEREK J. JONKER1 1The Ottawa Hospital Cancer Centre, Ottawa, ON, Canada; 2Agennix Incorporated, Houston, TX, U.S.A.; 3MD Anderson Cancer Centre, Houston, TX, U.S.A. Abstract. Adrenocortical Carcinoma (ACC) is rare with an AdrenoCortical Carcinoma (ACC) is a rare disease, with a annual incidence of 0.5-2 cases per million worldwide. Some worldwide annual incidence of 0.5-2 cases per million. It ACC tumors over express N-cadherin, which correlates with accounts for 0.04-0.2% of all cancer deaths(1). For advanced metastatic potential. ADH-1 (Exherin™) is a competitive unresectable disease, treatment improvements have been inhibitor of N-cadherin, resulting in rapid onset of tumor limited, and prognosis remains poor. In an attempt to vascular angiolysis and apoptosis in preclinical models. establish a treatment standard, there is currently an ongoing Targeting N-cadherin may cause direct anti-tumor and anti- international randomized phase III trial (FIRM-ACT) vascular effects. We report a case of ACC with benefit from comparing etoposide, doxorubicin, cisplatin plus mitotane vs. ADH-1 therapy. A 24 year old woman with an N-cadherin streptozotocin plus mitotane (2). In addition, recently expressing metastatic ACC was treated on a phase I trial and published case reports have described beneficial effects of treated with ADH-1 subsequently received additional doses biological agents in individuals with this disease (3). through a special access program. The patient presented with In view of the poor response to conventional chemotherapy cushingoid features from cortisol over-secretion and was there is a need for novel therapeutic agents. Cadherins diagnosed with metastatic ACC in January 2003. Tumor represent a novel target in cancer therapy. Many carcinomas progression followed treatment with a combination of overexpress N-cadherin, with concomitant down-regulation of doxorubicin, cisplatin and mitotane. In October 2003, as a E-cadherin (the cadherin switch). This phenomenon correlates part of a phase I clinical trial she was treated with as a single with a phenotypic change termed the epithelial mesanchymal dose of ADH-1 at 150 mg/m2. This resulted in transient transition (EMT) and with acquired tumor invasiveness and normalization of cortisol, tumor necrosis on CT imaging, and metastatic potential. The cadherin switch has been observed reduction in tumor perfusion on DCE-MRI. Following in various types of cancers, including adrenal tumors (4, 5). It progression on several additional lines of chemotherapy, she is also thought that N-cadherin prevents ligand-induced was again treated with ADH-1 under a Special Access receptor internalization and down-regulation, resulting in Program (SAP). After 33 weekly doses (22 with 150 mg/m2 sustained (MAPK) signaling, thus promoting proliferation (6). and 11 with 300 mg/m2) radiographic tumor progression was With both tumor overexpression and association with tumor demonstrated and treatment discontinued. She survived 40 aggressiveness, cadherins represent an attractive novel target months with metastatic disease, dying 12 months after her for cancer therapy. last dose of ADH-1. This observation merits consideration for ADH-1 is a cyclic pentapeptide which contains the prospectively evaluating the efficacy of ADH-1 in patients cadherin cell adhesion recognition sequence His-Ala-Val and with cortisol secreting ACC that over express N-cadherin. competitively inhibits N-cadherin function, resulting in rapid onset of tumor vascular angiolysis and apoptosis in preclinical models. Targeting N-cadherin may cause direct anti-tumor and anti-vascular effects. Correspondence to: Nirit Yarom, 60 Ha’amakim, Ganey-Tikva, Previous reports showed that peptides containing this Israel 55900. Tel: +973 545619418, Fax: +972 89779714, e-mail: sequence disrupt cell adhesion, induce apoptosis, and alter [email protected]; [email protected] the intracellular distribution of h-catenin and actin in Key Words: Adrenocortical carcinoma, ADH-1, Dynamic contrast endothelial cells (6). enhancing magnetic resonance imaging (DCE-MRI), phase-I, N- Injection of ADH-1 into tumor-bearing mice has been cadherin. shown to induce angiolysis. ADH-1 damages tumor blood 0250-7005/2011 $2.00+.40 3921 ANTICANCER RESEARCH 31: 3921-3926 (2011) vessels, but not normal, mature blood vessels, and herewith Table I. Mean Ktrans (1/min) in the region of interest. Post treatment inhibits growth of breast, ovarian, colon and lung carcinomas there is an increase in the mean ktrans, suggesting increased vascular (7). ADH-1 results in a tumor specific local increase in blood permeability due to vascular disruption. vessel permeability that leads to highly synergistic effects Pre-treatment Post-treatment with conventional cytotoxic drugs such as melphalan (5). Even at very high doses, ADH-1 does not affect mature Right tumor 0.211 0.376 blood vessels, as shown in a preclinical rat toxicity model. Left tumor 0.273 0.356 ADH-1 is being studied in phase II trials in a variety of cancers, including esophageal, non-small cell lung, renal cell, and hepatocellular carcinomas (5). In murine melanoma xenografts, ADH-1 in combination measuring 12.5×10.0 cm with extensive necrosis, 8 mitoses with melphalan significantly reduced tumor growth up to 30- per 10 high power fields, invasion of the inferior vena cava fold over melphalan alone. ADH-1 enhancement of response (IVC), negative nodes, and a positive microscopic margin at to melphalan was associated with increased formation of the IVC. By the McFarlane system, disease was stage 3 (13). DNA adducts, increased apoptosis, and intracellular No adjuvant therapy was prescribed, and she was well signaling changes (8). until February 2003 when she experienced two weeks of dry In sixteen human patients with metastatic melanoma, cough without fever and mild left flank pain. CT scan including six patients who had not responded to melphalan confirmed recurrence in the abdomen and metastases in both alone, treatment with ADH-1 plus melphalan was associated lungs. Her cortisol levels were within normal limits. with promising activity. Within three months of treatment, She received 4 months treatment with combination eight patients had complete responses, two had partial epirubicin, cisplatin, mitotane, and ketoconazole with responses, two had stable disease, and four had progressive radiological clinical progression associated with increased disease (9). cushingoid features. The patient consented to a phase I clinical Results from two Phase I studies with ADH-1 have been trial with ADH-1, and her tumor was found to be positive for reported (10, 11). In both, ADH-1 was generally well N-cadherin expression. She received intravenous ADH-1 at a tolerated and the maximal tolerated dose (MTD) was not dose of 150 mg/m2. She developed transient normalization of reached. The most common adverse events at the doses used steroid hormones (Figure 1), increased disruption of blood were nausea, fatigue, dysgeusia and hot flashes. Some vessels seen by increased permeability (k trans) on dynamic cardiovascular effects were seen but were thought to be contrast enhanced – magnetic resonance imaging (DCE-MRI) related, at least in part, to prior cardiac history and injection 90 min post ADH-1 (Table I and Figures 2 and 3) and rate. No responses or changes in blood flow were reported evidence of tumor necrosis on her six-week MRI scan. in patients with N-cadherin-negative tumors. Four patients However, according to the protocol she was withdrawned from with N-cadherin-positive tumors showed some evidence of the trial, since only patients responding by the World Health antitumor activity, including a PR in esophageal cancer. In Organiztion criteria were permitted to receive additional addition, phase I studies where ADH-1 is being evaluated in therapy. For the next year she was treated with various three separate combinations with docetaxel, carboplatin or chemotherapies (temozolomide, gemcitabine, docetaxel, 5- capecitabine are ongoing (12). fluorouracil, cisplatin, and doxorubicin) and modifiers of We report here for the first time the results of a young steroidogenesis (ketoconazole, aminoglutethemide and patient with metastatic ACC who was treated with ADH-1 mitotane) none of which yielded a sustained reduction of both as part of a clinical trial and subsequently through an cortisol levels. unrelated special access program (SAP). She subsequently was permitted to receive ADH-1 under an approved SAP and was treated with an additional 33 Case Report weekly doses (22 with 150 mg/m2 and 11 with 300 mg/m2). She tolerated the treatment well, with reported grade 1 In January 2002, a 22-year-old woman previously healthy nausea and diarrhea. In addition, an episode of facial flashing presented with increasing abdominal pressure and occurred immediately after infusion of ADH-1. The patient discomfort. An ultrasound identified a mass in the left was hemodynamically stable and there were no associated adrenal gland measuring 10 cm which was displacing the symptoms. On another occasion she experienced chest spleen, pancreas and left kidney. There were no metastases discomfort occurring a few days after administration of seen. This was confirmed by MRI. A CT scan of her thorax ADH-1, thought to be possibly related. This was not and head showed