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。最后，甲状腺癌是最常见的内分泌恶性肿瘤，占内分泌癌死亡的大多数。在美国，每年大约有14000例新的甲状腺癌病例被诊断出来，1200名患者死于这种疾病。常规治疗包括手术切除和放射性碘（131I）治疗。然而，对于不浓缩碘的低分化甲状腺癌（PDTCs）和间变性癌，131I治疗无效。在这些患者中，治疗选择很少，而且大多无效。在肾上腺皮质癌方面，我们正在寻求有希望导致靶向治疗的策略。我们一直对对正常肾上腺有毒性的新型化疗药物感兴趣，并一直在努力确定正常肾上腺中可能负责激活化合物的步骤，否则这些化合物可能没有细胞毒性。作为类固醇生物合成途径一部分的独特酶的表达可能是候选的，我们已经确定在肾上腺癌中，有很高比例的酶表达水平与正常肾上腺中的酶表达水平相当。基于这些信息，我们正在寻找一种对正常肾上腺有毒性的化合物。我们也在寻找调节这些基因在肾上腺癌中的表达的策略，目标是上调关键酶的表达，从而使肾上腺癌对这些化合物易感。最后，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多样化的生物学。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。在甲状腺癌方面，我们正在扩大我们的努力，以基础/转化/临床项目，旨在帮助了解新型药物的作用机制，以及它们在甲状腺恶性肿瘤中的靶点。我们已经开始了这项研究，旨在确定评估酪氨酸激酶抑制剂治疗甲状腺髓样癌（MTC）中RET抑制程度的最佳方法。正在进行的研究旨在确定实现这一目标的最佳方式，并将得到正在进行的转化研究的支持。其他甲状腺组织学的进一步研究将很快开始，所有的研究都有翻译成分。此外，我们正在寻找新的/替代方法来调节RET表达/功能，而不是使用TK抑制剂。

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. Finally, thyroid carcinoma is the most common endocrine malignancy, accounting for the majority of deaths from endocrine cancers. Each year in the US, approximately 14,000 new cases of thyroid carcinoma are diagnosed and 1200 patients die from this disease. Conventional therapy consists of surgical resection and radioiodine (131I) therapy. However, for poorly differentiated thyroid carcinomas (PDTCs) and anaplastic carcinomas that do not concentrate iodine, 131I therapy is ineffective. In these patients, therapeutic options are few and largely ineffective. In adrenocortical cancer we are pursuing strategies that will hopefully lead to targeted therapies. We have been interested in novel chemotherapeutic agents that are toxic to the normal adrenal gland and have been working to identify the steps in the normal adrenal that might be responsible for activating compounds that might otherwise not be cytotoxic. The expression of unique enzymes as part of the steroid biosynthetic pathway are likely candidates, and we have identified in adrenal cancers, a high percentage that express levels of the enzymes that are comparable to those in the normal adrenal. We are pursuing a compound that is toxic to the normal adrenal based on this information. We are also seeking to identify strategies to modulate the expression of these genes in adrenal cancers, with the goal of up-regulating the expression of crucial enzymes so as to render the adrenal cancers vulnerable to these compounds. Finally we are pursuing genetic and expression analyses to better understand these unique cancers and their diverse biology.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 inderstanindg of how our therapie work and preclinical and laboratory studies to better understand the biology of cancers driven by mutations in the SDHB gene.In thyroid cancer we are expanding our effort to a basic/translational/clinical program that aims to help understand the mechanism of action of novel agents, and their targets in thyroid malignancies. We have begun this effort with translational studies aimed at identifying the best way in which to assess the extent of RET inhibition in medullary thyroid carcinomas (MTC) treated with tyrosine kinase inhibitors. Ongoing studies are designed to identify the best way in which to accomplish this are ongoing, and will be supported by the ongoing translational studies. Additional studies will be staring soon in other thyroid histologies, all with translational components. Additionally we are looking at novel/alternate ways to modulate RET expression/function other than the use of TK inhibitors.