Development Therapy for Metastatic Colorectal Cancer

转移性结直肠癌的开发治疗

• 批准号: 6929464
• 负责人: JANET A. HOUGHTON
• 金额: $ 29.63万
• 依托单位: ST. JUDE CHILDREN'S RESEARCH HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2005
• 资助国家: 美国
• 起止时间: 2005-05-01 至 2008-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6929464
• 关键词: antineoplastics; biomarker; clinical research; colorectal neoplasms; combination chemotherapy; fluorouracil; human subject; interferon gamma; metastasis; microarray technology; neoplasm /cancer chemotherapy; neoplasm /cancer genetics; neoplastic process; patient oriented research; pharmacogenetics; prognosis

DESCRIPTION (provided by applicant): The interaction between FUra/LV and recombinant human IFN-gamma is synergistic in human colon carcinoma cells, dependent on Fura/LV-induced DNA damage, the Fas signaling pathway, and independent of p53. Preliminary studies also demonstrate sites of interaction in addition to Fas that involve caspases, the IAP protein survivin, and p21Cip1. A Phase I trial of FUra/LV combined with IFN-gamma has demonstrated responses in heavily pretreated and untreated patients. A Phase II trial will now be conducted in patients with previously untreated or previously treated metastatic colorectal cancer, with the overall goal to elucidate the prognostic significance of expression of genes that influence FUra/LV, Fas and IFN-gamma signaling and the synergistic interaction between these pathways in the induction of apoptosis, cellular cytotoxicity and response. We will elucidate, by tissue microarray (protein) or Real Time PCR (mRNA), the prognostic significance of genes known to determine sensitivity to FUra/LV (TS,DPD, TP, Cox-2) or influence the Fas or IFN-gamma signaling pathways (Bcl-2, Bax, p53, p21Cip1, Fas, caspases -1, -3, -8, survivin, STAT1) in colon carcinoma cells. Gene expression will be determined in metastases both before (sample 2) and at 4 days after (sample 3) FUra/LV/IFN-gamma treatment, and in primary tumors (sample 1) from the same patients. The significance of changes in gene expression in metastases in predicting time to disease progression, response, and how changes in Fas expression correlate with elevated expression in CD15+ and CD56+ cells, as well as toxicity and IFN-gamma pharmacokinetics, will be determined. Using oligonucleotide microarray analyses (Affymetrix), the hypothesis is that we will elucidate additional genes that are independent molecular determinants for predicting time to disease progression, response at 8 weeks, overall response, intrinsic drug resistance or acquired drug resistance following FUra/LV/IFN-gamma therapy. It is anticipated that the proposed studies will identify critical targets that 1) are convergent between death receptor, FUra/LV and IFN-gamma signaling pathways, 2) determine synergistic interactions between FUra/LV and IFN-gamma in metastatic colorectal carcinoma, 3) predict for response, intrinsic drug resistance or acquired drug resistance in FUra/LV/IFN-gamma therapy, and 4) will further our knowledge in the identification of new targets for therapeutic intervention, and in the development of highly effective therapeutic approaches in the treatment of this disease, based upon rational preclinical design.

描述（由申请人提供）：FUra/LV 和重组人 IFN-γ 之间的相互作用在人结肠癌细胞中具有协同作用，依赖于 Fura/LV 诱导的 DNA 损伤、Fas 信号通路，并且独立于 p53。初步研究还表明，除了 Fas 之外，还存在涉及 caspase、IAP 蛋白 survivin 和 p21Cip1 的相互作用位点。 FUra/LV 联合 IFN-γ 的 I 期试验已证明对经过大量预处理和未经治疗的患者有反应。现在将在既往未经治疗或既往治疗过的转移性结直肠癌患者中进行一项 II 期试验，总体目标是阐明影响 FUra/LV、Fas 和 IFN-gamma 信号传导的基因表达的预后意义，以及这些途径在诱导细胞凋亡、细胞毒性和反应中的协同相互作用。 我们将通过组织微阵列（蛋白质）或实时 PCR (mRNA) 阐明已知确定对 FUra/LV 敏感性（TS、DPD、TP、Cox-2）或影响 Fas 或 IFN-gamma 信号通路（Bcl-2、Bax、p53、p21Cip1、Fas、caspases -1、-3、-8、survivin、 STAT1）在结肠癌细胞中。将在 FUra/LV/IFN-gamma 治疗前（样品 2）和治疗后 4 天（样品 3）转移瘤中以及来自同一患者的原发性肿瘤（样品 1）中测定基因表达。将确定转移灶中基因表达变化在预测疾病进展时间、反应中的重要性，以及 Fas 表达变化如何与 CD15+ 和 CD56+ 细胞表达升高相关，以及毒性和 IFN-γ 药代动力学。 使用寡核苷酸微阵列分析 (Affymetrix)，假设我们将阐明作为独立分子决定因素的其他基因，用于预测疾病进展时间、8 周时的反应、总体反应、内在耐药性或 FUra/LV/IFN-gamma 治疗后获得性耐药性。 预计拟议的研究将确定以下关键靶点：1）死亡受体、FUra/LV 和 IFN-γ 信号通路之间的趋同；2）确定转移性结直肠癌中 FUra/LV 和 IFN-γ 之间的协同相互作用；3）预测 FUra/LV/IFN-γ 治疗中的反应、内在耐药性或获得性耐药性；4）将进一步加深我们在识别方面的知识。 基于合理的临床前设计，确定治疗干预的新目标，并开发治疗该疾病的高效治疗方法。