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: 9153617
• 负责人: Antonio Fojo
• 金额: $ 55.8万
• 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/9153617
• 关键词: Accounting; Adrenal Gland Cancer; Adrenocortical carcinoma; Adriamycin PFS; Anaplastic Carcinomas; Biological; Biology; Cancer Biology; Cessation of life; Cisplatin; Clinical; Complex; Cyclophosphamide; Dacarbazine; Data; Disease; Doctor of Philosophy; Endocrine; Etiology; Excision; Genes; Genetic; Goals; Hereditary Disease; I131 isotope; IGF2 gene; Incidence; Iodine; Laboratory Study; Lead; Malignant Neoplasms; Malignant Pheochromocytoma; Malignant neoplasm of adrenal cortex; Malignant neoplasm of thyroid; Mediating; Modeling; Mutation; National Institute of Child Health and Human Development; Neoplasm Metastasis; Operative Surgical Procedures; Outcome; P-Glycoprotein; Papillary; Paraganglioma; Patients; Pheochromocytoma; Pre-Clinical Model; Property; Publishing; Radioactive Iodine; Rare Diseases; Recurrent disease; Refractory; Regimen; Reporting; Resistance; Therapeutic; Thyroid carcinoma; Vascular Endothelial Growth Factors; Vincristine; Work; advanced disease; chemotherapy; conventional therapy; effective therapy; follow-up; improved; inhibitor/antagonist; insight; interest; malignant endocrine gland neoplasm; medullary thyroid carcinoma; novel strategies; novel therapeutics; preclinical study; radioiodine therapy; response; targeted treatment; therapeutic target; 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. 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.

肾上腺皮质癌（ACC）是一种高度恶性的肿瘤，其发病率为每年百万分之1 ~ 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，治疗选择是有限的，并且使用诸如米托坦、顺铂和阿霉素的药剂的疗法产生小于30%的肿瘤响应率。嗜铬细胞瘤已成为一种内分泌恶性肿瘤，选择很少，但有前途的目标和非常有趣的遗传学，这些正在进行中。在肾上腺皮质癌中，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的生物学。附带说明一下，在ACC中进行的多项“靶向药物”试验，最值得注意的是三项靶向IGF 2的试验，许多人认为IGF 2是ACC中最有希望的靶点，尚未发表。我的计划就是在这种背景下提出的。我认为最有希望的方法是新的治疗模式，要么利用我们最有效的治疗方法-手术切除-要么确定不涉及“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，并且具有日益复杂和令人困惑的遗传学。我们正在寻求临床策略，希望能带来更好的疗法，更好地了解我们的疗法如何工作，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，MD，PhD在嗜铬细胞瘤患者的管理方面进行了广泛的合作。帕卡克博士看到了大量的转诊，并对那些有遗传原因的人感兴趣。患有恶性嗜铬细胞瘤/副神经节瘤的患者被转介到我们进行管理，我们与Pacak博士一起，目前跟踪了几十名患者，包括许多正在接受治疗的患者。我们的主要治疗方案是环磷酰胺、长春新碱和达卡巴嗪（CVD）的联合治疗。我们发表了对接受该方案治疗的患者的长期随访，但现在能够确定那些具有遗传原因（通常是SDHB突变）的患者。我们以前注意到，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。我们目前还在SDHB突变患者中进行VEGF抑制剂阿西替尼的试验，因为在这种情况下报告了HIF-1水平升高。我们的最终目标是改善CVD方案。

项目成果

Pulmonary resection for metastatic adrenocortical carcinoma: the National Cancer Institute experience.

• DOI: 10.1016/j.athoracsur.2011.05.013
• 发表时间: 2011-10
• 期刊: The Annals of thoracic surgery
• 作者: Kemp CD;Ripley RT;Mathur A;Steinberg SM;Nguyen DM;Fojo T;Schrump DS
• 通讯作者: Schrump DS

MicroRNA profiling of adrenocortical tumors reveals miR-483 as a marker of malignancy.

• DOI: 10.1002/cncr.25724
• 发表时间: 2011-04-15
• 期刊: CANCER
• 影响因子: 6.2
• 作者: Patterson, Erin E;Holloway, Alisha K;Weng, Julie;Fojo, Tito;Kebebew, Electron
• 通讯作者: Kebebew, Electron

Operative management for recurrent and metastatic adrenocortical carcinoma.

• DOI: 10.1002/jso.23015
• 发表时间: 2012-06-01
• 期刊: JOURNAL OF SURGICAL ONCOLOGY
• 影响因子: 2.5
• 作者: Datrice, Nicole M.;Langan, Russell C.;Ripley, R. Taylor;Kemp, Clinton D.;Steinberg, Seth M.;Wood, Bradford J.;Libutti, Steven K.;Fojo, Tito;Schrump, David S.;Avital, Itzhak
• 通讯作者: Avital, Itzhak