Clinical Trials of FTI Radiosensitization

描述(申请人提供)：在体外和体内，RAS信号通路的激活与辐射敏感性的改变有关。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法尼化可导致放射敏感性增强。R115777是一种特异性的法尼基转移酶抑制剂，在临床上得到了广泛的研究。R115777是一种体内外放射增敏剂，可抑制RAS信号通路。该项目的长期目标是开发R115777与放射治疗相结合，作为非小细胞肺癌(NSCLC)患者的靶向治疗。这笔赠款的具体目的是1)进行FTI的第一阶段和第二阶段临床试验，R115777结合放射治疗不可切除的非小细胞肺癌(NSCLC)患者，以及2)将非小细胞肺癌肿瘤中分子标志物的状态与R115777和放射治疗的临床疗效联系起来。在第一阶段临床研究中，将确定R115777与标准放射治疗相结合的最大耐受剂量(MTD)和推荐第二阶段剂量(RPTD)。在第二阶段研究中，将确定R115777和标准放射治疗对局部晚期非小细胞肺癌患者的疗效。将在NSCLC肿瘤活检标本中检测与RAS信号通路激活相关的特定分子标志物，并将与临床疗效相关 R115777和放射治疗。

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.