Adrenocortical Cancer and Thyroid Carcinomas: Models with Unique Properties

肾上腺皮质癌和甲状腺癌：具有独特特性的模型

• 批准号: 8157372
• 负责人: Antonio Fojo
• 金额: $ 44.65万
• 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/8157372
• 关键词: Adrenal Glands; Adrenocortical carcinoma; Adriamycin PFS; Anaplastic Carcinomas; Bortezomib; Cessation of life; Clinical; Diagnosis; Differentiated Gene; Disease; Dose; EGF gene; Endothelial Cells; Enzymes; Gene Expression; Genes; Goals; Hematopoietic; Histology; Histone Deacetylase Inhibitor; Human; In Vitro; Incidence; Integrins; Iodine; Lead; Malignant Epithelial Cell; Malignant neoplasm of adrenal cortex; Modeling; Oncogenes; P-Glycoprotein; Pathway interactions; Patients; Phase; Pheochromocytoma; Property; Proteasome Inhibitor; Randomized; Recurrent disease; Refractory; Therapeutic; Thyroid carcinoma; Tyrosine Kinase Inhibitor; Vascular Endothelial Growth Factors; base; cancer cell; cytotoxic; gene therapy; kinase inhibitor; malignant endocrine gland neoplasm; medullary thyroid carcinoma

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%. 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. finally pheochromocytomas have emerged as an endocrine malignancy with few options but with promising targets and these are being pursued. 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. Our studies have demonstrated that depsipeptide increases the efficiency of adenoviral transgene expression in vitro in cancer cells, in hematopoietic cells and in human umbilical vein endothelial cells (HUVEC) and may be useful in cancer gene therapy. Treatment with minimally cytotoxic doses of depsipeptide increases CAR and av integrin RNA preferentially in cancer cells. We are also investigating the possibility that gents of this class or of a related class might be able to modulate the expression of what might be considered differentiated genes. 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. Clinically we have launched a combination therapy trial in MTC comprised of the proteasome inhibitor bortezomib and the VEGF, EGF, RET kinase inhibitor vandetanib in patients with refractory MTC. The goal of this study is to establi9sh the MTD in a phase I portion and then to conduct a randomized sturdy between vandetanib alone ands the combination of vandetanib with bortezomib. Translational studies designed to evaluate the extent of RET inhibition so as to ascertain whether this is indeed the target of vandetanib in this cancer 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. Finally, surprised by the change following the addition of HDAC inhibitors, we examined the ability of depsipeptide to modulate expression of thyroid specific genes. Two follicular (FTC 132 and FTC 136) and two anaplastic thyroid carcinoma cell lines (SW 1736 and KAT-4) were treated with a sub-cytotoxic concentration of depsipeptide (1 ng/ml). After three days, Tg and Na+/I- symporter (NIS) mRNA levels approached those of a normal thyroid. 125I accumulations indicated a functional NIS was induced. These in vitro results suggest depsipeptide or another HDAC inhibitor might be used clinically in thyroid carcinomas that do not to trap iodine, as an adjunct to radioiodine therapy a strategy currently under investigation in the clinic Finally with both poorly differentiated thyroid carcinomas and anaplastic thyroid carcinomas, therapeutic options are limited and largely unsuccessful. Their inability to trap iodine is thought to be a consequence of a loss of expression of the Na+/I- symporter (NIS). Our results suggest HDAC inhibitors up-regulate NIS transcription. Our clinical experience with depsipeptide has found it to be well tolerated, and the levels achieved greatly exceed those that modulated expression of the thyroid genes. A phase one trial to test this observation is ongoing.

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%。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。最终，嗜铬细胞瘤已成为一种内分泌恶性肿瘤，选择很少，但有希望的靶点，并且正在研究这些靶点。 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。 我们的研究表明，缩酚肽可提高癌细胞、造血细胞和人脐静脉内皮细胞 (HUVEC) 中腺病毒转基因表达的效率，并可能用于癌症基因治疗。使用最低细胞毒性剂量的缩酚肽治疗会优先增加癌细胞中的 CAR 和 av 整合素 RNA。我们还在研究此类或相关类别的男性可能能够调节可能被视为分化基因的表达的可能性。在甲状腺癌方面，我们正在将努力扩展到基础/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。临床上，我们针对难治性MTC患者启动了一项针对MTC的联合治疗试验，该试验由蛋白酶体抑制剂硼替佐米和VEGF、EGF、RET激酶抑制剂凡德他尼组成。本研究的目的是建立 I 期部分的 MTD，然后在凡德他尼单独用药和凡德他尼与硼替佐米联合用药之间进行随机对照。旨在评估 RET 抑制程度的转化研究正在进行中，以确定这是否确实是凡德他尼在这种癌症中的靶点，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。 最后，我们对添加 HDAC 抑制剂后的变化感到惊讶，检查了缩酚肽调节甲状腺特异性基因表达的能力。用亚细胞毒性浓度的缩酚肽 (1 ng/ml) 处理两个滤泡细胞（FTC 132 和 FTC 136）和两个未分化甲状腺癌细胞系（SW 1736 和 KAT-4）。三天后，Tg 和 Na+/I- 同向转运体 (NIS) mRNA 水平接近正常甲状腺的水平。 125I 积累表明功能性 NIS 被诱导。这些体外结果表明，缩酚肽或另一种 HDAC 抑制剂可能在临床上用于不捕获碘的甲状腺癌，作为放射性碘治疗的辅助手段，目前临床上正在研究这一策略。最后，对于低分化甲状腺癌和未分化甲状腺癌，治疗选择有限且大多不成功。它们无法捕获碘被认为是 Na+/I- 同向转运体 (NIS) 表达缺失的结果。我们的结果表明 HDAC 抑制剂上调 NIS 转录。我们对缩酚肽的临床经验发现它具有良好的耐受性，并且达到的水平大大超过了调节甲状腺基因表达的水平。测试这一观察结果的第一阶段试验正在进行中。