P-4: Therapeutic Targeting of Telomerase and Lung Cancer

端粒酶在几乎所有的癌细胞中都有表达，包括肺癌，但在肺癌细胞中不表达。 大多数正常细胞，除了一小部分干细胞。需要端粒酶活性来维持 线性染色体的末端，作为肿瘤前进展的一部分而变短。 端粒缩短和高端粒酶活性几乎总是与癌症的严重程度相关， 肺。我们以前的研究结果已经证明，端粒酶的小分子抑制剂， GRN163L在实验性异种移植小鼠模型中可以有效地预防肺癌转移。 我们假设可能存在一个治疗机会窗口，以消除残余肺 在患者体内的癌细胞，而不会不利地损害正常干细胞功能。我们的长期 目的是确定联合收割机标准化疗与端粒酶结合的最有效方法 抑制剂，以预防或延长复发或进展的患者的时间， 晚期肺癌以及预防早期非小细胞肺癌术后复发 标准手术切除为实现这一目标，我们的具体目标如下： 目的1）完成I期序贯队列、剂量递增试验以确定安全性， 耐受性和每周施用的GRN163L与 紫杉醇和卡铂治疗晚期或转移性非小细胞肺癌的疗效。我们将 包括对循环肿瘤细胞（CTC）的相关研究，以确定端粒酶是否被抑制， 如果CTC的绝对数量减少。 目的2）确定端粒酶抑制剂与化疗药物联合应用是否 药物在临床前模型中产生抗肺癌作用。 目的3）确定端粒酶抑制剂GRN163L是否靶向干细胞 肺癌细胞的亚群。

Telomerase is expressed in almost all cancer cells, including lung cancer, but it is not expressed in most normal cells, except in a small fraction of stem cells. Telomerase activity is needed to maintain the ends of linear chromosomes that become shortened as part of pre-neoplastic progression. Shortened telomeres and high telomerase activity almost always correlate with cancer severity in the lung. Our previous results have documented that a small molecule inhibitor of telomerase, GRN163L, can effectively prevent lung cancer metastasis in experimental xenograft mouse models. We hypothesize that there may be a window of therapeutic opportunity to eliminate residual lung cancer cells in patients without adversely compromising normal stem cell function. Our long-term goal is to determine the most effective way to combine standard chemotherapy with telomerase inhibitors clinically so as to prevent or prolong the time to relapse or progression of patients with advanced lung cancer as well as prevent recurrences in early stage non-small cell lung cancer after standard surgical resection. To accomplish this goal our specific aims are as follows: Aim 1) To complete a Phase I sequential cohort, dose escalation trial to determine the safety, tolerability, and maximum tolerated dosage of weekly administered GRN163L in combination with paclitaxel and carboplatin in patients with advanced or metastatic non-small cell lung cancer. We will include correlative studies on circulating tumor cells (CTC) to determine if telomerase is inhibited and if the absolute number of CTCs decreases. Aim 2) To determine if the combination of telomerase inhibitors with additional chemotherapeutic agents results in anti-lung cancer effects in preclinical models. Aim 3) To determine if the telomerase inhibitor, GRN163L, targets the putative stem cell subpopulation of lung cancer cells.