Overexpression of Interleukin-13 Receptor-α2 in Neuroendocrine Malignant Pheochromocytoma: A Novel Target for Receptor Directed Anti-Cancer Therapy

Context: Pheochromocytomas and paragangliomas are rare catecholamine-secreting neuroendocrine tumors arising from the adrenal medulla and sympathetic tissues. When complete surgical resection is not an option, the treatment of pheochromocytoma is limited. Objective: The objective of the study was to identify and characterize overexpression of IL-13 receptor-alpha 2 (IL-13R alpha 2) gene expression in human and murine tumors and verify xenograft mouse pheochromocytoma cell (MPC)-derived tumor's response to a selective cytotoxin. Design/Setting/Patients: Expression of IL-13R alpha 2 was evaluated in a panel of 25 human pheochromocytoma clinical samples by RT-PCR and eight MPC tumors by indirect immunofluorescence assay and RT-PCR. Intervention: The function of IL-13R alpha 2 in these tumor cells was examined by evaluating tumor sensitivity to a recombinant IL-13-Pseudomonas exotoxin (IL-13PE). Subcutaneous small and large MPC tumors in athymic nude mice (n = 10) were treated intratumorally with IL-13PE (100 mu g/kg). Main Outcome Measures: IC50 and tumor size were measured. Results: IL-13PE immunotoxin was highly cytotoxic to IL-13R alpha 2-overexpressing MPC cells (IC50 < 2.5 ng/ml) in vitro. Furthermore, IL-13PE was highly cytotoxic to sc tumors. Our results showed a statistically significant decrease in tumor size as early as 3 d after initial treatment and further suppressed growth of MPC tumors. All tumors displayed a histological evidence of necrosis in response to IL-13 immunotoxin without any adverse effects in host at this dose. Conclusions: Human and murine neuroendocrine pheochromocytoma overexpress the IL-13R alpha 2 chain, and an IL-13PE-based receptor-directed anticancer approach may prove useful in treatment for metastatic pheochromocytoma patients. (J Clin Endocrinol Metab 94: 2952-2957, 2009)