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，每年发病率为每百万人1至1.6例。高达 40% 的病例出现转移性疾病。 对于晚期或复发性疾病，治疗选择有限，使用米托坦、顺铂和阿霉素等药物治疗的肿瘤反应率低于 30%。嗜铬细胞瘤已成为一种内分泌恶性肿瘤，选择很少，但具有有希望的靶点和非常有趣的遗传学，并且正在研究这些。最后，甲状腺癌是最常见的内分泌恶性肿瘤，占内分泌癌症死亡的大部分。在美国，每年大约诊断出 14,000 例甲状腺癌新病例，并有 1200 名患者死于该病。常规治疗包括手术切除和放射性碘（131I）治疗。然而，对于低分化甲状腺癌（PDTC）和不浓缩碘的未分化癌，131I治疗无效。对于这些患者，治疗选择很少，而且基本上无效。在肾上腺皮质癌中，我们正在寻求有望带来靶向治疗的策略。我们一直对对正常肾上腺有毒的新型化疗药物感兴趣，并一直致力于确定正常肾上腺中可能负责激活可能不具有细胞毒性的化合物的步骤。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者，我们已经在肾上腺癌中发现了很高比例的酶表达水平与正常肾上腺中的酶水平相当。根据这些信息，我们正在寻找一种对正常肾上腺有毒的化合物。我们还在寻求确定调节肾上腺癌中这些基因表达的策略，目的是上调关键酶的表达，从而使肾上腺癌容易受到这些化合物的影响。最后，我们正在进行遗传和表达分析，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，并且具有日益复杂和令人费解的遗传学。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的生物学。在甲状腺癌方面，我们正在将我们的努力扩大到基础/转化/临床计划，旨在帮助了解新型药物的作用机制及其在甲状腺恶性肿瘤中的靶点。我们已经开始这项工作，进行转化研究，旨在确定评估酪氨酸激酶抑制剂治疗的甲状腺髓样癌 (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法，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研究很快就会开始，所有研究都具有转化成分。此外，我们正在寻找除使用 TK 抑制剂之外的新的/替代的方法来调节 RET 表达/功能。