CCNU in NSCLC Patients with Methylation of the MGMT Gene

肺癌是美国每年约1/3的癌症相关死亡的原因。 研究新的范例，包括新的治疗方法，已成为肿瘤学界的当务之急。 CpG岛异常甲基化已被确定为使关键调控基因失活的机制，并且也可能用于指导治疗。 肿瘤细胞在体外和体内对甲基化和单氯乙基化试剂的抗性与DNA修复蛋白O 6-甲基鸟嘌呤-DNA甲基转移酶（MGMT）的表达有关。 我们已经开发了甲基化特异性PCR检测（MS-PCR），该方法具有高度的特异性和敏感性，并且已经证明约1/3的非小细胞肺癌（NSCLC）具有异常甲基化的MGMT基因。 本提案的目的是验证MGMT甲基化异常的晚期NSCLC患者对亚硝基脲CCNU敏感的假设。 为了验证这一假设，我们将在IIIB和IV期疾病患者中进行CCNU的II期试验，这些患者的肿瘤已被发现具有MGMT基因的异常CpG岛甲基化。 该试验的具体目的是：（1）确定MGMT异常甲基化的晚期NSCLC患者对CCNU的缓解率;次要目的将评估至进展时间和总生存期。(2)将免疫组化（IHC）上的MGMT水平与临床结局相关联。(3)将MGMT蛋白的IHC染色与MS-PCR相关联。 这项资助可以确定一种新的治疗策略，该策略利用了负责保护细胞免受CCNU细胞毒性作用的MGMT基因在某些肿瘤中失活的事实。 如果疗效通过提高应答率来证明，这些研究将导致更大规模的多机构临床试验。 此外，这种方法可以促进未来的研究，其中患者接受更个性化的联合治疗方案，以利用灭活或重新激活诱导细胞周期停滞和凋亡所需的基因的途径。

Lung cancer is responsible for approximately 1/3 of all cancer related deaths in the US each year. Investigation of new paradigms, including novel therapeutic approaches, has become an urgent priority for the oncology community. Aberrant CpG island methylation has been identified as a mechanism of inactivating critical regulatory genes, and may also be useful for directing therapy. Resistance of tumor cells to methylating and monocloroethylating agents in vitro and in vivo has been linked to expression of the DNA repair protein, O6-methylguanine-DNA methyltransferase (MGMT). We have developed a methylation- specific PCR assay (MS-PCR) which has given us high specificity and sensitivity, and have demonstrated that about 1/3 of non- small cell lung cancers (NSCLC) have aberrantly methylated MGMT genes. The objective of this proposal is to test the hypothesis that patients with advanced NSCLC and aberrant MGMT methylation will be sensitive to the nitrosourea CCNU. To test this hypothesis, we will conduct a Phase II trial of CCNU in patients with Stage IIIB and IV disease whose tumors have been found to have aberrant CpG island methylation of the MGMT gene. The specific aims of the trial are to: (1) Determine the response rate of patients with advanced NSCLC with aberrant MGMT methylation to CCNU; secondary objectives will assess time to progression and overall survival. (2) Correlate MGMT levels on immunohistochemistry (IHC) with clinical outcome. (3) Correlate IHC staining of the MGMT protein and the MS-PCR. This grant could identify a novel treatment strategy that exploits the fact that the MGMT gene responsible for protecting cells from the cytotoxic effects of CCNU is inactivated in some tumors. If efficacy is demonstrated by enhanced response rates, these studies would lead to larger scale, multi-institutional clinical trials. Moreover, this approach could facilitate future studies in which patients receive more individualized combination treatment regimens to exploit pathways that are either inactivated or to reactivate genes needed to induce cell cycle arrest and apoptosis.