Developing Combination Therapies for Medullary Thyroid Cancer

开发甲状腺髓样癌的联合疗法

• 批准号: 8588547
• 负责人: Matthew D Ringel
• 金额: $ 28.39万
• 依托单位: OHIO STATE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-09-25 至 2018-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8588547
• 关键词: BAY 54-9085; Behavior; CDK6-associated protein p18; Cancer Center; Cell Line; Clinical Pathology; Clinical Trials; Combined Modality Therapy; Correlation Studies; Correlative Study; Cyclin-Dependent Kinase Inhibitor; Cyclin-Dependent Kinases; DNA; Data; Disease; Functional Imaging; Gene Abnormality; Genomics; Human; In Vitro; In complete remission; Inherited; Instruction; MEKs; Malignant Neoplasms; Malignant neoplasm of thyroid; Mus; Mutation; Neoplasm Metastasis; Nuclear; Ohio; Pathway interactions; Patients; Phase II Clinical Trials; Phosphorylation; Phosphotransferases; Progression-Free Survivals; Proteomics; Publishing; Research; Resistance; Retinoblastoma; Sampling; Signal Transduction; Somatic Mutation; TNFRSF5 gene; Techniques; Testing; Time; Tissues; Universities; University of Texas M D Anderson Cancer Center; Vascular Endothelial Growth Factor Receptor-2; cancer cell; cancer therapy; combinatorial; in vivo; inhibitor/antagonist; kinase inhibitor; knock-down; medullary thyroid carcinoma; neoplastic cell; novel; outcome forecast; preclinical study; raf Kinases; response; response marker; therapeutic target; treatment strategy; tumor

Patients with metastatic medullary thyroid cancer (MTC) have a poor prognosis. Recently, vandetanib, a multikinase inhibitor, was approved for treating patients with progressive metastatic MTC creating a new first-line therapy. However, in several studies using vandetanib and other multikinase inhibitors in MTC, complete responses did not occur and acquired resistance was common. Thus, there is a crucial need to develop effective second line treatments. While all of the compounds that have an effect on progression free survival in MTC inhibit a variety of kinases, all include Ret and VEGFR2 in their targets suggesting similar mechanisms of action. However, of the studied kinase inhibitors, only sorafenib also inhibits Raf kinases suggesting potentially unique synergies. In preliminary data it is shown that, as predicted by cell signaling data the combination of sorafenib with a Mek inhibitor is synergistic. These data, along with previously published in vivo data from other groups in other cancers establishing tolerability, suggest this combination might be a reasonable alternative to explore in vandetanib-resistant MTC. It is also recognized that other pathways may be responsible for vandetanib resistance that remain to be identified. Ret is a common target of the compounds studied in MTC. While activating RET mutations in the germline cause of inherited MTC, somatic mutations are found in only ~40% of sporadic tumors, suggesting other pathways may also cause MTC. Activation of cyclin dependent kinases (CDK) through knock down of CDK inhibitors or inactivation of retinoblastoma (Rb) cause MTC in mice. In addition, it is shown in preliminary data that CDK pathway activation and gene abnormalities are common in human MTC. Taken together, these results suggest CDKs are a rational therapeutic target for MTC. Thus, in Project 3 we propose to test the following hypotheses: 1) Combination therapy using sorafenib/MEK inhibitor is effective in patients with metastatic vandetanib- resistant MTC and novel pathways of vandetanib resistance can be identified that predict synergy and 2) CDK inhibitors are active as phmary;Single therapy or in combination as a therapy for metastatic progressive MTC and CDK pathway activation predicts metastases. RELEVANCE (See instructions): Metastatic progressive MTC is currently an incurable disease. Despite recent advances in therapy with multikinase inhibitors, even patients that initially respond acquire resistance and progress over time. Project 3 focuses on this critical need to develop new second-line strategies for patients with MTC and to identify novel targets for combinatorial and single treatment strategies making it highly relevant for cancer therapy.

转移性甲状腺髓样癌(MTC)预后不良。最近，Vandetanib，一个 多激酶抑制剂，被批准用于治疗进展性转移性MTC患者，创造了一种新的 一线治疗。然而，在几项在MTC中使用Vandetanib和其他多激酶抑制剂的研究中， 没有出现完全应答，获得性耐药性很常见。因此，迫切需要 开发有效的二线治疗方法。而所有对进程自由起作用的化合物 MTC的存活抑制了多种激酶，它们的靶点都包括Ret和VEGFR2，这表明类似的 行动机制。然而，在所研究的激酶抑制剂中，只有索拉非尼也抑制Raf激酶 潜在的独一无二的协同效应。初步数据表明，正如细胞信号所预测的那样 数据显示，索拉非尼与MEK抑制剂的联合是协同作用的。这些数据以及之前 来自其他癌症组的体内发表的数据证实了耐受性，表明这种组合 可能是在对凡地坦尼耐药的MTC进行研究的合理替代方案。人们还认识到，其他 这些通路可能是导致Vandetanib耐药的原因，目前尚不清楚。RET是一个常见的目标 在MTC研究的化合物中。在激活遗传性MTC胚系原因中的RET突变时， 仅在40%的散发性肿瘤中发现了体细胞突变，这表明其他途径也可能导致 MTC。细胞周期蛋白依赖性激酶(CDK)抑制物被击倒或失活后激活 视网膜母细胞瘤(RB)可引起小鼠的MTC。此外，初步数据表明，CDK途径 在人类MTC中，激活和基因异常是常见的。综上所述，这些结果表明CDK 是治疗MTC的合理靶点。因此，在项目3中，我们建议检验以下假设：1) 索拉非尼/MEK抑制剂联合治疗转移性血管内皮细胞癌有效 耐药的MTC和新的Vandetanib耐药途径可以预测协同作用和2) CDK抑制剂是一种有效的药物；单独治疗或联合治疗转移的进展性 MTC和CDK通路激活可预测转移。 相关性(请参阅说明)： 转移性进展性MTC目前是一种不治之症。尽管最近在治疗方面取得了进展，但 多激酶抑制剂，即使是最初有反应的患者，也会随着时间的推移而产生耐药性并取得进展。项目 3侧重于这一迫切需要，为MTC患者开发新的二线策略，并确定 组合和单一治疗策略的新靶点使其与癌症治疗高度相关。