PRE-CLINICAL COMBINATION CHEMO- AND RADIOANTIBODY THERAP

临床前化疗和放射抗体联合治疗

• 批准号: 6620132
• 负责人: ROSALYN D BLUMENTHAL
• 金额: $ 92.24万
• 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/6620132
• 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：(申请者？S描述)多模式治疗方法有 需要绕过肿瘤保护机制，以防止对 细胞毒疗法。已经发表了几篇关于沙门氏菌的疗效的论文 放射免疫联合化疗在实验动物中的应用 模特们。选择药物的基本原理，剂量安排 (同时的或顺序的)和一个 尚未解决顺序调度问题。自从每一个病人？S癌症？ 呈现一种特定的分子表型，我们假设它不会 只能使用药物和放射抗体的一种组合方法 为所有患者提供治疗。通过了解肿瘤细胞的基因图谱 治疗前和肿瘤细胞对各种治疗方式的分子反应 治疗，有可能量身定做的组合模式方法基于 分子图谱，从而增强肿瘤的反应。 我们建议把重点放在化疗和辐射的主要调节因素上。 根据目前的知识，抵抗。主要特征是 考虑的是与增殖相关的细胞(S期百分比，Ki-67 表达)、耐药性(mdr1、mrp、cerbB2/neu)、p53表达(空， WT、MUT-P53)和细胞凋亡途径(BCL-2、Bax、Fas)。分析 这些标志物的表达将在SKOV-3卵巢癌模型中完成 和MCF-7乳腺癌模型。在未来5年，我们将解决 以下三个目标：1)确定放射抗体或化疗的效果 在裸鼠体内生长的肿瘤的分子图谱。亲代肿瘤， 亲本的稳定转染体(mdr+、mrp+、p53mut、cerb2/neu+或bax+) 肿瘤和药物产生的肿瘤变异体(高Fas或低bcl2) 将会被评估。我们假设：(1)肿瘤的分子图谱 可以通过细胞毒疗法改变，从而为 用第二种方式治疗；和(2)初始分子表型 将决定一种特定形式的治疗对表达 不同的肿瘤标志物。2)评价多模式的治疗效果 使用放射抗体和4种标准药物进行治疗。几种矩阵设计将 应考虑联合用药的最佳组合和给药方案 放射抗体治疗将针对每种肿瘤变异体进行确定。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 耐药和细胞凋亡标记物在治疗前和治疗前的表达 在RAIT+/-化疗后的几天内。这项工作将是第一次 尝试应用从临床前模型中获得的知识 免疫磁性分离患者血液样本中的肿瘤细胞，以及 用RT-PCR检测耐药细胞和细胞凋亡标记物的表达 在RAIT+/-化疗之前和之后的几天内。 假设：1)某些分子表型会比 其他人则向临床方案提出。2)治疗后标志物表达的改变可以在临床上在小样本循环肿瘤细胞中确定。