Clinical Trials of FTI Radiosensitization

描述（由申请人提供）：Ras信号通路的激活与体外和体内辐射敏感性的改变相关。在Ras信号通路被激活的人肿瘤细胞中，用法尼基转移酶抑制剂（FTI）抑制Ras法尼基化导致放射敏感性增强。R115777是法尼基转移酶的特异性抑制剂，已在临床上进行了广泛的研究。R115777是一种体外和体内放射增敏剂，可抑制Ras信号通路。本项目的长期目标是开发R115777联合放疗作为非小细胞肺癌（NSCLC）患者的靶向治疗。该基金的具体目的是：1）在不可切除的非小细胞肺癌（NSCLC）患者中开展FTI、R115777联合放疗的I期和II期临床试验; 2）将NSCLC肿瘤中的分子标志物状态与R115777和放疗的临床疗效联系起来。在I期临床研究中，将确定R115777联合标准放疗的最大耐受剂量（MTD）和推荐II期剂量（RPTD）。在II期研究中，将在局部晚期NSCLC患者中确定R115777和标准放疗的疗效。将在NSCLC肿瘤活检标本中测量与Ras信号传导途径活化相关的特异性分子标志物，并将其与化疗的临床疗效相关。 R115777和放疗。

DESCRIPTION (provided by applicant): Activation of the Ras signaling pathway has been associated with altered radiation sensitivity in vitro and in vivo. In human tumor cells in which the Ras signaling pathway is activated, inhibition of Ras farnesylation with farnesyltransferase inhibitors (FTI) leads to enhanced radiosensitivity. R115777 is a specific inhibitor of farnesyltransferase that has been studied extensively in the clinic. R115777 is an in vitro and in vivo radiosensitizer and inhibits the Ras signaling pathway. The long-term objective of this project is to develop R115777 in combination with radiotherapy as a targeted therapy for patients with non-small cell lung cancer (NSCLC). The specific aims of this grant are 1) to perform Phase I and Phase II clinical trials of the FTI, R115777 in combination with radiotherapy in patients with unresectable non-small cell lung cancer (NSCLC) and 2) to relate the status of molecular markers in NSCLC tumors to clinical efficacy of R115777 and radiotherapy. In the Phase I clinical study, the maximally tolerated dose (MTD) and recommended Phase II dose (RPTD) of R115777 in combination with standard radiotherapy will be determined. In the Phase II study, the efficacy of R115777 and standard radiotherapy will be determined in patients with locally advanced NSCLC. Specific molecular markers that are associated with activation of the Ras signaling pathway will be measured in NSCLC tumor biopsy specimens and will be related to the clinical efficacy of R115777 and radiotherapy.