Cancers with Unique Properties: Pheochromocytoma, Adrenal and Thyroid Cancer

肾上腺皮质癌（ACC）是一种高度恶性肿瘤，发病率为每年百万分之1至1.6例。它在高达40%的病例中表现为转移性疾病。在晚期或复发性疾病中，治疗选择有限，使用米托坦、顺铂和阿霉素等药物的治疗效果的肿瘤缓解率低于30%。嗜铬细胞瘤是一种内分泌恶性肿瘤，选择很少，但有希望的目标和非常有趣的遗传学，这些正在研究中。在肾上腺皮质癌中，我们正在进行基因和表达分析，以更好地了解这些独特的癌症及其不同的生物学。顺便说一句，我要指出，在ACC中使用“靶向药物”进行的多项试验，最值得注意的是针对IGF2的三项试验，许多人认为IGF2是ACC中最有希望的靶标，但尚未发表。我的计划就是在这样的背景下提出的。我认为最有希望的新治疗模式要么是利用我们最有效的治疗方法——手术切除，要么是确定不涉及“靶向治疗”的新策略。嗜铬细胞瘤是一种非常罕见的疾病，具有非常独特的生物学和临床特性，其遗传学也越来越复杂和令人困惑。我们正在寻求临床策略，希望能带来更好的治疗方法，更好地了解我们的治疗方法是如何起作用的，以及临床前和实验室研究，以更好地了解由SDHB基因突变驱动的癌症生物学。我们与NICHD的Karel Pacak医学博士在嗜铬细胞瘤患者的治疗方面进行了广泛的合作。帕克医生接诊了大量的转诊病人，并对那些因遗传原因而患病的人很感兴趣。患有恶性嗜铬细胞瘤/副神经节瘤的患者被转介到我们这里进行治疗，目前我们与Pacak博士一起跟踪了几十名患者，其中许多患者正在接受治疗。我们的主要方案是环磷酰胺、长春新碱和达卡巴嗪（CVD）的联合治疗。我们发表了一项长期随访的患者治疗方案，但现在能够确定那些有遗传原因（通常是突变的SDHB）。我们之前注意到SDHB突变的患者似乎对CVD化疗反应良好，现在已经积累了支持这一点的数据。我们目前也在SDHB突变患者中进行一项使用VEGF抑制剂阿西替尼的试验，因为在这种情况下有HIF-1水平升高的报道。我们的最终目标是改善心血管疾病治疗方案。

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.