PRE-CLINICAL COMBINATION CHEMO- AND RADIOANTIBODY THERAP

临床前化疗和放射抗体联合治疗

基本信息

批准号：
6868172
负责人：
RHONA N STEIN
金额：
$ 100.65万
依托单位：
CTR FOR MOLECULAR MEDICINE/IMMUNOLOGY
依托单位国家：
美国
项目类别：
财政年份：
2002
资助国家：
美国
起止时间：
2002-05-06 至 2007-03-31
项目状态：
已结题

项目摘要

DESCRIPTION: (Applicant?s Description) Multimodal therapy approaches are needed to bypass tumor protective mechanisms that prevent maximal responses to cytotoxic therapy. Several papers have been published on the efficacy of combined radioimmunotherapy (RAIT) and chemotherapy in experimental animal models. The rationale for the choice of drug, the dose scheduling (simultaneous or sequential) and the spacing between modalities in a sequential schedule has not been addressed. Since each patient?s cancer presents with a specific molecular phenotype, we hypothesize that it will not be possible to use only one combination approach with drug and radioantibody therapy for all patients. By understanding the genetic profile of tumor cells pre therapy and the molecular response of tumor cells to each modality of therapy, it may be possible to tailor combined modality approaches based on the molecular profile and, thus, enhance tumor responses. We propose to focus on the dominant regulators of chemo- and radiation resistance according to current knowledge. The primary traits to be considered are those associated with proliferation (percent S-phase, Ki-67 expression), drug resistance (MDR1, MRP, cerbB2/neu), p53 expression (null, wt, mut-p53), and apoptotic pathways (bcl-2, BAX, FAS). Analysis of expression of these markers will be done in the SKOV-3 ovarian cancer model and the MCF-7 breast cancer model. Over the next 5 years we will address the following three aims: 1) Determine the effect of radioantibody or chemotherapy on the molecular profile of tumors grown in nude mice. Parental tumors, stable transfectants (MDR+, MRP+, p53mut, cerb2/neu+, or BAX+) of the parental tumor, and pharmacologically-generated tumor variants (high Fas, or low bcl-2) will be evaluated. We hypothesize that: (1)The molecular profile of the tumor can be altered by cytotoxic therapy, allowing a window of opportunity for treatment with a second modality; and (2), the initial molecular phenotype will determine the effect that a specific form of therapy has on expression of different tumor markers. 2) Evaluate the therapeutic efficacy of multimodal therapy using radioantibody and 4 standard drugs. Several matrix designs will be considered and the optimal combination and dose-schedule of combined chemoand radioantibody therapy will be determined for each tumor variant. We hypothesize that the molecular phenotype of the tumor will determine the optimal dose-schedule of the two therapeutic modalities. 3) Evaluate expression of drug resistant and apoptotic markers in patients before and within days after RAIT +/- chemotherapy. This work will serve as a first attempt to apply the knowledge gained from the preclinical models by immuno-magnetically isolating tumor cells from patient blood samples, and using RT-PCR, to evaluate expression of drug resistance, and apoptotic markers before and within days after RAIT +/- chemotherapy. Hypothesis: 1) Certain molecular phenotypes will be more responsive than others to the clinical protocols proposed. 2) Therapy-induced changes in marker expression post therapy can be identified clinically in small samples of circulating tumor cells.

描述：（申请人的描述）多模式疗法方法是需要绕过肿瘤保护机制，以防止对细胞毒性疗法。已经发表了几篇论文实验动物中的放射免疫疗法（RAIT）和化学疗法型号。选择药物的基本原理，剂量调度（同时或顺序）以及在A中的模态之间的间距顺序时间表尚未解决。既然每个患者的癌症呈现特定的分子表型，我们假设它不会可以仅使用一种组合方法和放射疗法所有患者的治疗。通过了解肿瘤细胞的遗传特征肿瘤细胞对每种方式的治疗和分子反应治疗，可能可以根据分子谱，因此增强了肿瘤反应。我们建议专注于化学和辐射的主要调节剂根据当前知识的抵抗。主要特征是考虑的是与增殖相关的（S阶段百分比，KI-67）表达），耐药性（MDR1，MRP，CERBB2/neu），p53表达（无效， WT，MUT-P53）和凋亡途径（Bcl-2，Bax，FAS）。分析这些标记的表达将在SKOV-3卵巢癌模型中进行和MCF-7乳腺癌模型。在接下来的5年中，我们将解决以下三个目的：1）确定射线抗体或化学疗法的作用在裸鼠中生长的肿瘤的分子谱。父母肿瘤，父母肿瘤和药理学生成的肿瘤变体（高FAS或低Bcl-2）将进行评估。我们假设：（1）肿瘤的分子谱可以通过细胞毒性疗法改变第二种方式治疗；（2），初始分子表型将确定特定形式的治疗对表达的影响不同的肿瘤标记。 2）评估多模式的治疗功效使用Radio抗体和4种标准药物的治疗。几个矩阵设计将被考虑以及合并化学和剂量的最佳组合和剂量 - 安排将针对每种肿瘤变体确定射线抗体疗法。我们假设肿瘤的分子表型将决定两种治疗方式的最佳剂量划分。 3）评估前后患者中耐药性和凋亡标志物的表达在Rait +/-化学疗法后的几天内。这项工作将作为第一个尝试通过从临床前模型中获得的知识免疫磁性从患者血液样本中分离肿瘤细胞，然后使用RT-PCR，评估耐药性的表达和凋亡标记 Rait +/-化学疗法后的几天前和几天内。假设：1）某些分子表型比其他人提出了临床方案。 2）在循环肿瘤细胞的小样本中，可以在临床上鉴定治疗诱导的标记表达变化。