Developing Combination Therapies for Medullary Thyroid Cancer

转移性甲状腺髓样癌（MTC）患者预后不良。最近，凡德他尼， 多激酶抑制剂，被批准用于治疗进行性转移性MTC患者， 一线治疗然而，在几项使用凡德他尼和其他多激酶抑制剂治疗MTC的研究中， 没有出现完全反应，获得性耐药很常见。因此，迫切需要 制定有效的二线治疗方案。虽然所有的化合物，有一个无进展的影响， MTC中存活抑制多种激酶，所有激酶在其靶点中都包括Ret和VEGFR 2，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， 这表明潜在的独特协同作用。初步数据显示，正如细胞信号传导所预测的那样， 数据显示索拉非尼与Mek抑制剂的组合是协同的。这些数据，沿着先前 来自其他癌症中其他组的已发表的体内数据表明了这种组合的耐受性， 可能是一个合理的替代，以探索在耐凡德他尼MTC。人们还认识到， 途径可能是导致凡德他尼耐药性的原因，但仍有待鉴定。Ret是一个常见的目标 在MTC中研究的化合物。当激活生殖系中的RET突变导致遗传性MTC时， 体细胞突变仅见于约40%的散发性肿瘤，这表明其他途径也可能导致 MTC。通过敲低细胞周期蛋白依赖性激酶（CDK）抑制剂或灭活细胞周期蛋白依赖性激酶（CDK）， 视网膜母细胞瘤（Rb）引起小鼠MTC。此外，初步数据显示，CDK途径 活化和基因异常在人MTC中是常见的。综上所述，这些结果表明CDK 是MTC的合理治疗靶点。因此，在项目3中，我们建议测试以下假设：1） 使用索拉非尼/MEK抑制剂的联合治疗对转移性凡德他尼患者有效- 可以鉴定耐药MTC和预测协同作用的凡德他尼耐药的新途径，以及2） CDK抑制剂作为药物是有活性的;作为转移性进展性肿瘤的治疗， MTC和CDK通路活化预测转移。 相关性（参见说明）： 转移性进展性MTC是目前无法治愈的疾病。尽管最近在治疗方面取得了进展， 多激酶抑制剂，即使最初有反应的患者也会获得耐药性并随着时间的推移而进展。项目 3重点关注这一关键需求，为MTC患者制定新的二线策略，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。

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.