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）多模式治疗方法是需要绕过阻止最大反应的肿瘤保护机制细胞毒疗法。已发表多篇关于其功效的论文实验动物的放射免疫治疗（RAIT）和化疗联合治疗模型。选择药物的基本原理、剂量安排（同时或顺序）以及模式之间的间隔顺序时间表尚未解决。由于每个患者的癌症呈现出特定的分子表型，我们假设它不会可以仅使用药物和放射性抗体的一种组合方法对所有患者进行治疗。通过了解肿瘤细胞的遗传特征治疗前和肿瘤细胞对每种治疗方式的分子反应治疗，也许可以根据情况定制组合治疗方法分子谱，从而增强肿瘤反应。我们建议重点关注化学和放射的主要调节因子根据目前的知识，阻力。主要特征是考虑的是与增殖相关的那些（S 期百分比、Ki-67 表达）、耐药性（MDR1、MRP、cerbB2/neu）、p53 表达（null、 wt、mut-p53）和凋亡途径（bcl-2、BAX、FAS）。分析这些标记物的表达将在 SKOV-3 卵巢癌模型中进行和MCF-7乳腺癌模型。未来5年我们将解决以下三个目的：1）确定放射抗体或化疗的效果裸鼠肿瘤生长的分子谱。亲代肿瘤，亲本的稳定转染子（MDR+、MRP+、p53mut、cerb2/neu+ 或 BAX+）肿瘤和药理学产生的肿瘤变异体（高 Fas 或低 bcl-2）将被评估。我们假设：（1）肿瘤的分子谱可以通过细胞毒疗法改变，从而提供机会之窗采用第二种方式治疗； (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志物。 2）评估多模式治疗效果使用放射性抗体和 4 种标准药物进行治疗。几种矩阵设计将需要考虑联合化疗的最佳组合和剂量方案放射抗体治疗将针对每种肿瘤变异而确定。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方案。 3）评估治疗前后患者耐药及凋亡标志物的表达情况 RAIT +/- 化疗后几天内。这项工作将作为第一个尝试应用从临床前模型中获得的知识从患者血液样本中免疫磁性分离肿瘤细胞，以及使用 RT-PCR 评估耐药性和细胞凋亡标记物的表达 RAIT +/- 化疗之前和之后几天内。假设：1）某些分子表型比其他人建议的临床方案。 2) 治疗后标志物表达的治疗诱导变化可以在临床上通过循环肿瘤细胞的小样本进行鉴定。