ADH-1 in the Treatment of Metastatic Adrenocortical Carcinoma - Case Report
NIRIT YAROM1, DAVID STEWART3, LEONARD AVRUCH1, RAJESH MALIK2, JULIE WELLS1 and DEREK J. JONKER 1
1The Ottawa Hospital Cancer Centre, Ottawa, ON, Canada;
2 Agennix Incorporated, Houston, TX, U.S.A .;
3MD Anderson Cancer Centre, Houston, TX, U.S.A.
Abstract. Adrenocortical Carcinoma (ACC) is rare with an annual incidence of 0.5-2 cases per million worldwide. Some ACC tumors over express N-cadherin, which correlates with metastatic potential. ADH-1 (Exherin™M ) is a competitive inhibitor of N-cadherin, 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. We report a case of ACC with benefit from ADH-1 therapy. A 24 year old woman with an N-cadherin expressing metastatic ACC was treated on a phase I trial and treated with ADH-1 subsequently received additional doses through a special access program. The patient presented with cushingoid features from cortisol over-secretion and was diagnosed with metastatic ACC in January 2003. Tumor progression followed treatment with a combination of doxorubicin, cisplatin and mitotane. In October 2003, as a part of a phase I clinical trial she was treated with as a single dose of ADH-1 at 150 mg/m2. This resulted in transient normalization of cortisol, tumor necrosis on CT imaging, and reduction in tumor perfusion on DCE-MRI. Following progression on several additional lines of chemotherapy, she was again treated with ADH-1 under a Special Access Program (SAP). After 33 weekly doses (22 with 150 mg/m2 and 11 with 300 mg/m2) radiographic tumor progression was demonstrated and treatment discontinued. She survived 40 months with metastatic disease, dying 12 months after her last dose of ADH-1. This observation merits consideration for prospectively evaluating the efficacy of ADH-1 in patients with cortisol secreting ACC that over express N-cadherin.
Correspondence to: Nirit Yarom, 60 Ha’amakim, Ganey-Tikva, Israel 55900. Tel: +973 545619418, Fax: +972 89779714, e-mail: Nirit.yarom@gmail.com; yaromn@asaf.health.gov.il
Key Words: Adrenocortical carcinoma, ADH-1, Dynamic contrast enhancing magnetic resonance imaging (DCE-MRI), phase-I, N- cadherin.
AdrenoCortical Carcinoma (ACC) is a rare disease, with a worldwide annual incidence of 0.5-2 cases per million. It accounts for 0.04-0.2% of all cancer deaths(1). For advanced unresectable disease, treatment improvements have been limited, and prognosis remains poor. In an attempt to establish a treatment standard, there is currently an ongoing international randomized phase III trial (FIRM-ACT) comparing etoposide, doxorubicin, cisplatin plus mitotane vs. streptozotocin plus mitotane (2). In addition, recently published case reports have described beneficial effects of biological agents in individuals with this disease (3).
In view of the poor response to conventional chemotherapy there is a need for novel therapeutic agents. Cadherins represent a novel target in cancer therapy. Many carcinomas overexpress N-cadherin, with concomitant down-regulation of E-cadherin (the cadherin switch). This phenomenon correlates with a phenotypic change termed the epithelial mesanchymal transition (EMT) and with acquired tumor invasiveness and metastatic potential. The cadherin switch has been observed in various types of cancers, including adrenal tumors (4, 5). It is also thought that N-cadherin prevents ligand-induced receptor internalization and down-regulation, resulting in sustained (MAPK) signaling, thus promoting proliferation (6). With both tumor overexpression and association with tumor aggressiveness, cadherins represent an attractive novel target for cancer therapy.
ADH-1 is a cyclic pentapeptide which contains the cadherin cell adhesion recognition sequence His-Ala-Val and 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.
Previous reports showed that peptides containing this sequence disrupt cell adhesion, induce apoptosis, and alter the intracellular distribution of h-catenin and actin in endothelial cells (6).
Injection of ADH-1 into tumor-bearing mice has been shown to induce angiolysis. ADH-1 damages tumor blood
vessels, but not normal, mature blood vessels, and herewith inhibits growth of breast, ovarian, colon and lung carcinomas (7). ADH-1 results in a tumor specific local increase in blood vessel permeability that leads to highly synergistic effects with conventional cytotoxic drugs such as melphalan (5). Even at very high doses, ADH-1 does not affect mature blood vessels, as shown in a preclinical rat toxicity model. 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 with melphalan significantly reduced tumor growth up to 30- fold over melphalan alone. ADH-1 enhancement of response to melphalan was associated with increased formation of DNA adducts, increased apoptosis, and intracellular signaling changes (8).
In sixteen human patients with metastatic melanoma, including six patients who had not responded to melphalan alone, treatment with ADH-1 plus melphalan was associated with promising activity. Within three months of treatment, eight patients had complete responses, two had partial responses, two had stable disease, and four had progressive disease (9).
Results from two Phase I studies with ADH-1 have been reported (10, 11). In both, ADH-1 was generally well tolerated and the maximal tolerated dose (MTD) was not reached. The most common adverse events at the doses used were nausea, fatigue, dysgeusia and hot flashes. Some cardiovascular effects were seen but were thought to be related, at least in part, to prior cardiac history and injection rate. No responses or changes in blood flow were reported in patients with N-cadherin-negative tumors. Four patients with N-cadherin-positive tumors showed some evidence of antitumor activity, including a PR in esophageal cancer. In addition, phase I studies where ADH-1 is being evaluated in three separate combinations with docetaxel, carboplatin or capecitabine are ongoing (12).
We report here for the first time the results of a young patient with metastatic ACC who was treated with ADH-1 both as part of a clinical trial and subsequently through an unrelated special access program (SAP).
Case Report
In January 2002, a 22-year-old woman previously healthy presented with increasing abdominal pressure and discomfort. An ultrasound identified a mass in the left adrenal gland measuring 10 cm which was displacing the spleen, pancreas and left kidney. There were no metastases seen. This was confirmed by MRI. A CT scan of her thorax and head showed no evidence of metastatic disease. She underwent an adrenalectomy. Histologic examination of the resected mass revealed an adrenal cortical carcinoma (ACC)
| Pre-treatment | Post-treatment | |
|---|---|---|
| Right tumor | 0.211 | 0.376 |
| Left tumor | 0.273 | 0.356 |
measuring 12.5×10.0 cm with extensive necrosis, 8 mitoses per 10 high power fields, invasion of the inferior vena cava (IVC), negative nodes, and a positive microscopic margin at the IVC. By the McFarlane system, disease was stage 3 (13).
No adjuvant therapy was prescribed, and she was well until February 2003 when she experienced two weeks of dry cough without fever and mild left flank pain. CT scan confirmed recurrence in the abdomen and metastases in both lungs. Her cortisol levels were within normal limits.
She received 4 months treatment with combination epirubicin, cisplatin, mitotane, and ketoconazole with radiological clinical progression associated with increased cushingoid features. The patient consented to a phase I clinical trial with ADH-1, and her tumor was found to be positive for N-cadherin expression. She received intravenous ADH-1 at a dose of 150 mg/m2. She developed transient normalization of steroid hormones (Figure 1), increased disruption of blood vessels seen by increased permeability (k trans) on dynamic contrast enhanced - magnetic resonance imaging (DCE-MRI) 90 min post ADH-1 (Table I and Figures 2 and 3) and evidence of tumor necrosis on her six-week MRI scan. However, according to the protocol she was withdrawned from the trial, since only patients responding by the World Health Organiztion criteria were permitted to receive additional therapy. For the next year she was treated with various chemotherapies (temozolomide, gemcitabine, docetaxel, 5- fluorouracil, cisplatin, and doxorubicin) and modifiers of steroidogenesis (ketoconazole, aminoglutethemide and mitotane) none of which yielded a sustained reduction of cortisol levels.
She subsequently was permitted to receive ADH-1 under an approved SAP and was treated with an additional 33 weekly doses (22 with 150 mg/m2 and 11 with 300 mg/m2). She tolerated the treatment well, with reported grade 1 nausea and diarrhea. In addition, an episode of facial flashing occurred immediately after infusion of ADH-1. The patient was hemodynamically stable and there were no associated symptoms. On another occasion she experienced chest discomfort occurring a few days after administration of ADH-1, thought to be possibly related. This was not associated with dyspnea nor electrocardiogram (ECG) changes, with the discomfort resolving spontaneously without intervention.
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While receiving the treatment the patient benefited from prolonged improvement of cortisol hypersecretion (Figure 1), and resolution of cushingoid features. By chest X-ray in December 2004 there was a minor response in the lung metastases. Throughout her ADH-1 SAP treatment the patient continued to take aminoglutethemide and took mitotane during the first 5 months of treatment until February 22, 2005. After 8 months of treatment the CT scan showed progression and the treatment was stopped.
After progressing on ADH-1 she received oral etoposide and cyclophosphamide. She progressed on both treatments.
The patient lived for 40 months from the diagnosis of metastatic disease and for 12 months after treatment with ADH-1 was stopped. This is compared (with the caveat of comparing to historical data) to a reported median survival in stage IV ACC of 6-12 months only (14).
Discussion
Adrenocortical carcinoma (ACC) is an extremely rare and aggressive disease. Data on the efficacy of systemic anti- neoplastic treatments (mitotane and cytotoxic therapy) in the treatment of advanced disease is limited. Currently an ongoing randomized international trial aims to define the best chemotherapy regimen to combine with mitotane. Genetic and biological studies have identified molecular targets, and suggest
a role for evaluation of agents such as IGF receptor inhibitors and antiangiogenetic drugs (15). N-cadherin is involved in the development of malignant tumors of both the adrenal medulla and the adrenal cortex. Information regarding expression of N- cadherin in ACC is very limited. In one study, 40% of adult ACC had expression of N-cadherin (4). In contrast to the patient in this report, two reports show that N-cadherin is down-regulated in adrenal cortical tumors (4, 16). The authors postulated that N-cadherin may be a tumor suppressor, which
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when down-regulated leads to more aggressive behaviour of the adrenocortical tumor. However, in other tumor types, N- cadherin expression is increased - often de novo expression - with the concomitant down-regulation of E-cadherin (the cadherin switch). This phenomenon is correlated with acquired invasiveness and metastatic potential of cancer cells. Cadherin switching has been observed in various malignancies, including melanoma, breast and prostate cancer (5, 17). These findings support N-cadherin as a therapeutic target. ADH-1 is a competitive inhibitor of N-cadherin function (6). In patients where N-cadherin is expressed there are some reports of response to ADH-1 (7, 8). In patients with locally advanced
melanoma, with the combination of melphalan and ADH-1, half the patients achieved complete response (9). Our patient had an aggressive and resistant tumor which was controlled metabolically and symptomatically only when the patient was treated with ADH-1. Unfortunately her subjective and metabolic response did not translate into an objective tumor response. This raises the question of whether an alternate method of response evaluation is required for biological agents, especially vascular-disrupting agents, one which evaluates the functional changes and not merely anatomical changes (18, 19). Tumor blood flow change by DCE-MRI is a potentially independent predictor of outcome when patients are treated
with antiangiogenic agents (20). DCE-MRI is a non-invasive technique that records tissue perfusion, arterial input function (i.e. the concentration time course of contrast agent in the artery supplying the vascular bed), capillary surface area, capillary permeability (K-trans) and the volume of the extracellular extravascular leakage space. DCE-MRI analysis generates parameters that can be used to measure abnormalities in tumor vessel flow, blood volume, permeability, tortuosity and interstitial pressure (21). While receiving ADH-1 on the SAP, this patient received concurrent ‘conventional’ steroidogenensis-modifying therapy with mitotane and aminogluthetemide, making it difficult to decipher whether the ADH-1 alone or its combination with the other agents were responsible for the cortisol control over 8 months. Mitotane and aminogluthetemide were administered before and after the period when she received ADH-1 without disease control suggesting attribution of the benefit to ADH-1 is appropriate.
ADH-1 might potentiate the efficacy of mitotane and aminogluthetemide. This coincides with other reports in the literature that show that ADH-1 may potentiate and reverse resistance to conventional treatments (8, 9).
ADH-1 toxicity was minimal, and is reported so even at doses higher than used in this patient (10).
The patient presented in this report comprises a few unique characteristics; she had a rare disease with even a rarer expression of N-cadherin and at least subjectively responded to a new N-cadherin antagonist. Although a rare condition, ADH-1 should be considered for further evaluation in patients with advanced ACC who progressed on conventional therapy if their tumors express N-cadherin.
References
1 Kirschner LS: Emerging treatment strategies for adrenocortical carcinoma: a new hope. J Clin Endocrinol Metab 91(1): 14-21, 2006.
2 Fassnacht M and Allolio B: Clinical management of adrenocortical carcinoma. Best Practice & Research Clinical Endocrinology & Metabolism 23(2): 273-289, 2009.
3 Rini BI, Garcia JA, Cooney MM, Elson P, Tyler A, Beatty K, Bokar J, Mekhail T, Bukowski RM, Budd GT, Triozzi P, Borden E, Ivy P, Chen HX, Dolwati A and Dreicer R: A phase I study of sunitinib plus bevacizumab in advanced solid tumors. Clin Cancer Res 15(19): 6277-6283, 2009.
4 Khorram-Manesh A, Ahlman H, Jansson S and Nilsson O: N- cadherin expression in adrenal tumors: up-regulation in malignant pheochromocytoma and down-regulation in adrenocortical carcinoma. Endocr Pathol 13(2): 99-110, 2002.
5 Mariotti A, Perotti A, Sessa C and Ruegg C: N-cadherin as a therapeutic target in cancer. Expert Opin Investig Drugs 16(4): 451-465, 2007.
6 Schmidmaier R and Baumann P: Anti-Adhesion evolves to a promising therapeutic concept in oncology. Curr Med Chem 15(10): 978-990, 2008.
7 Lepekhin E JX, Michaud S, Tonary A, Yu W, Symonds JM and Blaschuk OW: Adherex Technologies Inc, editor. Early and long-
term effects of exherin on tumor vasculature. 2003 ASCO Annual Meeting, 2003.
8 Augustine CK, Yoshimoto Y, Gupta M, Zipfel PA, Selim MA, Febbo P et al: Targeting N-cadherin enhances antitumor activity of cytotoxic therapies in melanoma treatment. Cancer Res 68(10): 3777-3784, 2008 .
9 Tyler D. Regional therapeutic strategies in melanoma: not just local disease control, but an opportunity to develop novel therapeutic strategies with potential implications for systemic therapy. Ann Surg Oncol 15(11): 2987-2990, 2008.
10 Perotti A, Sessa C, Mancuso A, Noberasco C, Cresta S, Locatelli A et al: Clinical and pharmacological phase I evaluation of Exherin (ADH-1), a selective anti-N-cadherin peptide in patients with N-cadherin-expressing solid tumors. Ann Oncol 20(4): 741- 745, 2009.
11 Stewart DJ, Jonker DJ, Goel R, Maroun JA, Cripps CM, Wells J, Wargin W, Mallik RK and Peters WP: Final clinical and pharmacokinetic (PK) results from a phase 1 study of the novel N- cadherin (N-cad) antagonist, Exherin (ADH-1), in patients with refractory solid tumors stratified according to N-cad expression. 2006 ASCO Annual Meeting, 2006.
12 Siemann DW and Chaplin DJ: An update on the clinical development of drugs to disable tumor vasculature. Exp Opin Drug Discov 2(10): 1357-1367, 2007.
13 Macfarlane DA: Cancer of the adrenal cortex; the natural history, prognosis and treatment in a study of fifty-five cases. Ann R Coll Surg Engl 23(3): 155-186, 1958.
14 Icard P CY, Andreassian B, Bernard A and Proye C: Adrenocortical carcinoma in surgically treated patients: a retrospective study on 156 cases by the French Association of Endocrine Surgery. Surgery 112(6): 972-980, 1992.
15 Berruti A, Ferrero A, Sperone P, Daffara F, Reimondo G, Papotti M, Dogliotti L, Angeli A and Terzolo M: Emerging drugs for adrenocortical carcinoma. Expert Opin Emerg Drugs 13(3): 497- 509, 2008.
16 Velazquez-Fernandez D, Laurell C, Geli J, Hoog A, Odeberg J, Kjellman M, Lundeberg J, Hamberger B, Nilsson P and Backdahl M: Expression profiling of adrenocortical neoplasms suggests a molecular signature of malignancy. Surgery 138(6): 1087-1094, 2005.
17 Hazan RB, Qiao R, Keren R, Badano I and Suyama K: Cadherin switch in tumor progression. Ann NY Acad Sci 1014: 155-163, 2004.
18 Gaya AM and Rustin GJ: Vascular disrupting agents: a new class of drug in cancer therapy. Clin Oncol (R Coll Radiol) 17(4): 277-290, 2005.
19 Kapse N and Goh V: Functional imaging of colorectal cancer: positron emission tomography, magnetic resonance imaging, and computed tomography. Clin Colorectal Cancer 8(2): 77-87, 2009.
20 Flaherty KT, Rosen MA, Heitjan DF, Gallagher ML, Schwartz B, Schnall MD and O’Dwyer PJ: Pilot study of DCE-MRI to predict progression-free survival with sorafenib therapy in renal cell carcinoma. Cancer Biol Ther 7(4): 496-501, 2008.
21 O’Connor JP, Jackson A, Parker GJ and Jayson GC: DCE-MRI biomarkers in the clinical evaluation of antiangiogenic and vascular disrupting agents. Br J Cancer 96(2): 189-195, 2007.