Adrenocortical carcinoma (ACC) is a highly malignant tumor with an incidence of 1 to 1.6 cases per million per year. It presents with metastatic disease in up to 40% of cases. In advanced or recurrent disease treatment options are limited, and therapies using agents such as mitotane, cisplatin and adriamycin effect a tumor response rate of less than 30%. Pheochromocytomas have emerged as an endocrine malignancy with few options but with promising targets and very interesting genetics and these are being pursued. In adrenocortical cancer we are pursuing genetic and expression analyses to better understand these unique cancers and their diverse biology. Parenthetically here I would note that multiple trials that have been conducted in ACC with targeted agents most notably three trials targeting IGF2, believed by many the most promising target in ACC, have yet to be published. It is on this background that my plans will be presented. I see as the most promising way forward new therapeutic paradigms that either leverage our most effective therapy - surgical resection - or identify novel strategies that do not involve targeted therapies. Pheochromocytomas present a very rare disease with very unique biological and clinical properties and with increasingly complex and puzzling genetics. We are pursuing clinical strategies that will hopefully lead to better therapies and better understanding of how our therapies work and preclinical and laboratory studies to better understand the biology of cancers driven by mutations in the SDHB gene. We cooperate extensively with Karel Pacak, MD, PhD of the NICHD in the management of patients with pheochromocytoma. Dr. Pacak sees a large number of referrals, and has an interest in those with a genetic cause for their disease. Patients who have malignant pheochromocytoma/paraganglioma are referred to us for management and together with Dr. Pacak we currently follow several dozen patients including many who are receiving therapy. Our primary regimen has been a combination of cyclophosphamide, vincristine and dacarbazine (CVD). We published a long-term follow up of patients treated with this regimen but are now able to identify those with a genetic cause (usually a mutation in SDHB). We had previously noted that patients with SDHB mutations appeared to respond well to CVD chemotherapy and have now accumulated data that supports this. We are also currently conducting a trial with the VEGF inhibitor, axitinib, in patients with SDHB mutations since elevated HIF-1 levels have been reported in this setting. Our ultimate goal is to improve on the CVD regimen.
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