Adrenocortical Cancer and Thyroid Carcinomas: Models with Unique Properties

肾上腺皮质癌(ACC)是一种高度恶性的肿瘤，每年发病率为1-1.6例/百万。高达40%的病例表现为转移性疾病。在晚期或复发的疾病中，治疗选择有限，使用米托坦、顺铂和阿霉素等药物的治疗对肿瘤应答率的影响不到30%。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部分。在美国，每年大约有14,000例新的甲状腺癌被诊断出来，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，而且很大程度上无效。最后，嗜铬细胞瘤已经成为一种内分泌恶性肿瘤，几乎没有选择，但有希望的靶点，这些正在被追寻。对于肾上腺皮质癌，我们正在寻求有望导致靶向治疗的策略。我们一直对对正常肾上腺有毒的新型化疗药物感兴趣，并一直在努力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的一部分，独特的酶的表达可能是候选的，我们已经在肾上腺癌中发现，表达与正常肾上腺相当的酶水平的比例很高。根据这一信息，我们正在寻找一种对正常肾上腺有毒性的化合物。我们还在寻求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，从而使肾上腺癌更容易受到这些化合物的影响。我们的研究表明，去脂肽可以提高腺病毒在肿瘤细胞、造血细胞和人脐静脉内皮细胞(HUVEC)中的转基因表达效率，并可能用于癌症的基因治疗。用最小细胞毒性剂量的去脂肽治疗，可优先增加癌细胞中的car和av整合素rna。我们还在研究这种类型或相关类型的绅士可能能够调节可能被认为是差异基因的表达的可能性。在甲状腺癌方面，我们正在将我们的努力扩展到一个基础/转译/临床计划，旨在帮助了解新药物的作用机制，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工作，翻译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式。临床上，我们在难治性MTC患者中开展了一项由蛋白酶体抑制剂Bortezomib和VEGF、EGF、RET激酶抑制剂Vandetanib组成的联合治疗试验。这项研究的目标是在I期部分建立MTD，然后在单用凡得坦尼和万得坦尼与波替佐米联合使用之间进行随机对照研究。旨在评估RET抑制程度的翻译研究正在进行中，以确定这是否确实是Vandetanib治疗这种癌症的靶点，并将得到正在进行的翻译研究的支持。其他甲状腺组织学的更多研究也将很快展开，这些研究都含有翻译成分。最后，令人惊讶的是，添加HDAC抑制剂后的变化，我们检查了脱脂肽调节甲状腺特异基因表达的能力。用亚细胞毒性浓度的去脂肽(1 ng/ml)处理两个滤泡性甲状腺癌细胞系(FTC 132和FTC 136)和两个间变性甲状腺癌细胞系(SW1736和KAT-4)。3天后，甘油三酯和Na+/I-转运体(NIS)的mRNA水平接近正常甲状腺。~(125)I的蓄积表明诱导了功能性的NIS。这些体外实验结果表明，脱脂肽或另一种HDAC抑制剂可能用于临床上不捕集碘的甲状腺癌，作为放射性碘治疗的辅助手段目前正在临床上进行研究最终对于低分化甲状腺癌和间变性甲状腺癌，治疗选择有限，基本上不成功。他们不能捕获碘被认为是失去Na+/I-转运体(NIS)表达的结果。我们的结果表明，HDAC抑制剂上调NIS转录。我们对去脂肽的临床经验发现，它的耐受性很好，达到的水平远远超过了调节甲状腺基因表达的水平。检验这一观察结果的第一阶段试验正在进行中。

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.