PRE-CLINICAL COMBINATION CHEMO/RADIOANTIBODY THERAPY

临床前联合化疗/放射抗体治疗

• 批准号: 6376968
• 负责人: ROSALYN D BLUMENTHAL
• 金额: $ 94.87万
• 依托单位: CTR FOR MOLECULAR MEDICINE/IMMUNOLOGY
• 依托单位国家: 美国
• 财政年份: 2002
• 资助国家: 美国
• 起止时间: 2002-05-06 至 2006-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6376968
• 关键词: apoptosis; athymic mouse; breast neoplasms; carboplatin; clinical research; combination cancer therapy; doxorubicin; drug resistance; gene expression; human subject; immunomagnetic separation; neoplasm /cancer chemotherapy; neoplasm /cancer radioimmunotherapy; ovary neoplasms; paclitaxel; polymerase chain reaction; technology /technique development; topotecan; transfection; tumor antigens

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？描述）多模式治疗方法是 需要绕过肿瘤保护机制，防止最大的反应， 细胞毒疗法已经发表了几篇关于 放免联合化疗（赖特） 模型药物选择的依据、剂量安排 （同时或顺序）和模式之间的间隔， 顺序时间表尚未解决。每一位患者？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 治疗所有患者。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，它可能是有可能的，以定制的组合方式的基础上， 分子特征，从而增强肿瘤反应。 我们建议将重点放在化疗和放疗的主要调节剂上， 根据目前的知识。主要特征是 考虑与增殖相关的那些（S期百分比，Ki-67 表达），药物抗性（MDR 1，MRP，cerbB 2/neu），p53表达（无效， wt、mut-p53）和凋亡途径（bcl-2、BAX、FAS）。分析 这些标志物的表达将在SKOV-3卵巢癌模型中进行 和MCF-7乳腺癌模型。未来5年，我们将致力于 主要有三个目的：1）确定放射性抗体或化疗的效果 在裸鼠体内生长的肿瘤的分子图谱上。母体肿瘤， 亲本的稳定转染子（MDR+、MRP+、p53 mut、cerb 2/neu+或BAX+） 肿瘤和药理学产生的肿瘤变体（高Fas或低bcl-2） 将被评估。我们假设：（1）肿瘤的分子特征 可以通过细胞毒性治疗改变， 用第二种方式治疗;和（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)评价多模式治疗的疗效 放射性抗体和4种标准药物治疗。几种矩阵设计将 联合化疗的最佳组合和给药方案 将针对每种肿瘤变体确定放射性抗体疗法。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方案。3)评价 化疗前和化疗后患者中耐药和凋亡标志物的表达 在赖特+/-化疗后数天内。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， 从患者血液样品免疫磁性分离肿瘤细胞，和 采用RT-PCR检测耐药基因和凋亡标志物的表达 在赖特+/-化疗前和化疗后数天内。 假设：1）某些分子表型将比 其他人提出的临床方案。 2)治疗后标记物表达的治疗诱导的变化可以在临床上在循环肿瘤细胞的小样品中鉴定。