Cancers with Unique Properties: Pheochromocytoma, Adrenal and Thyroid Cancer

具有独特性质的癌症：嗜铬细胞瘤、肾上腺癌和甲状腺癌

• 批准号: 8552755
• 负责人: Antonio Fojo
• 金额: $ 46.23万
• 依托单位: DIVISION OF BASIC SCIENCES - NCI
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/8552755
• 关键词: Accounting; Adrenal Gland Cancer; Adrenal Glands; Adrenocortical carcinoma; Adriamycin PFS; Anaplastic Carcinomas; Biological; Biology; Cancer Biology; Cessation of life; Cisplatin; Clinical; Complex; Diagnosis; Disease; Endocrine; Enzymes; Excision; Gene Expression; Genes; Genetic; Goals; Histology; Incidence; Iodine; Laboratory Study; Lead; Malignant Neoplasms; Malignant Pheochromocytoma; Malignant neoplasm of adrenal cortex; Malignant neoplasm of thyroid; Mediating; Modeling; Mutation; Neoplasm Metastasis; Operative Surgical Procedures; P-Glycoprotein; Papillary; Paraganglioma; Pathway interactions; Patients; Pheochromocytoma; Property; RET inhibition; Rare Diseases; Recurrent disease; Refractory; Research Design; Resistance; Steroids; Therapeutic; Thyroid Gland; Thyroid carcinoma; Tyrosine Kinase Inhibitor; Work; advanced disease; base; chemotherapeutic agent; chemotherapy; conventional therapy; cytotoxic; insight; interest; malignant endocrine gland neoplasm; medullary thyroid carcinoma; novel; preclinical study; programs; response; therapeutic target; translational study; tumor

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.

肾上腺皮质癌（ACC）是一种高度恶性肿瘤，每年每百万例1至1.6例。它在多达40％的病例中表现出转移性疾病。 在晚期或复发性疾病治疗方案中，有限的疗法使用米曲（Mitotane），顺铂和阿霉素（Adrimycin）作用肿瘤反应率小于30％。嗜铬细胞瘤已经成为一种内分泌恶性肿瘤，几乎没有选择，但有希望的靶标和非常有趣的遗传学，并且正在追求这些遗传学。最后，甲状腺癌是最常见的内分泌恶性肿瘤，这是内分泌癌的大部分死亡。每年在美国，大约有14,000例甲状腺癌的新病例被诊断出来，1200例患者死于这种疾病。常规治疗包括手术切除和放射性碘（131i）疗法。然而，对于不浓缩碘的甲状腺癌（PDTC）和那种肿瘤癌的分化差，131i治疗无效。在这些患者中，治疗选择很少，并且在很大程度上无效。在肾上腺皮质癌中，我们正在采取希望导致有针对性疗法的策略。我们一直对对正常肾上腺有毒的新型化学治疗剂感兴趣，并一直在努力识别正常肾上腺中的步骤，这些步骤可能导致激活否则可能不会具有细胞毒素的化合物。独特的酶作为类固醇生物合成途径的一部分的表达可能是候选者，我们在肾上腺癌中鉴定出来，这是表达与正常肾上腺中的酶相当的高百分比。我们正在根据这些信息追求一种对正常肾上腺有毒的化合物。我们还试图确定在肾上腺癌中调节这些基因表达的策略，目的是上调关键酶的表达，以使肾上腺癌易受这些化合物的影响。最后，我们正在追求遗传和表达分析，以更好地了解这些独特的癌症及其多样的生物学。磷光细胞瘤呈现出一种非常罕见的疾病，具有非常独特的生物学和临床特性，并且具有越来越复杂和令人困惑的遗传学。我们正在采取临床策略，希望我们的治疗中的治疗方法和临床前和实验室研究如何更好地理解由SDHB Gene.in甲状腺癌中的突变所驱动的癌症的生物学，我们正在努力将我们的努力扩展到基本/转化的目标，以帮助Maligrigrigrigrient and Ongimigrigrient of Socigright and and of Angorigy of Angimigy and and and cancer的生物学。我们已经通过转化研究开始了这项努力，旨在确定评估用酪氨酸激酶抑制剂治疗的甲状腺癌（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此目的的最佳方法，并将得到正在进行的翻译研究的支持。其他研究将很快在其他甲状腺组织学中凝视，所有研究都具有翻译成分。此外，我们正在研究除使用TK抑制剂以外的新型/替代方法来调节RET表达/功能。