Development Therapy for Metastatic Colorectal Cancer

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信号传导途径，不依赖于p53。初步研究还表明，除了涉及半胱天冬酶，IAP蛋白生存素和p21 Cip 1的Fas的相互作用的网站。FUra/LV联合IFN-γ的I期试验已证明在重度预治疗和未治疗患者中的反应。现在将在既往未接受治疗或既往接受过治疗的转移性结直肠癌患者中进行II期试验，总体目标是阐明影响FUra/LV、Fas和IFN-γ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）或真实的时间PCR（mRNA）阐明已知决定结肠癌细胞对FUra/LV敏感性（TS、DPD、TP、考克斯-2）或影响Fas或IFN-γ信号通路（Bcl-2、Bax、p53、p21 Cip 1、Fas、半胱天冬酶-1、-3、-8、生存素、STAT 1）的基因的预后意义。将在FUra/LV/IFN-γ治疗前（样品2）和治疗后4天（样品3）以及同一患者的原发性肿瘤（样品1）中测定转移瘤的基因表达。将确定转移瘤中基因表达变化在预测疾病进展时间、缓解、Fas表达变化与CD 15+和CD 56+细胞表达升高的相关性以及毒性和IFN-γ药代动力学方面的意义。 使用寡核苷酸微阵列分析（Affyximab），假设我们将阐明作为预测疾病进展时间、8周缓解、总体缓解、内在耐药或FUra/LV/IFN-γ治疗后获得性耐药的独立分子决定因素的其他基因。 预期所提出的研究将鉴定以下关键靶标：1）死亡受体、FUra/LV和IFN-γ信号传导途径之间的会聚，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治疗中的应答、内在耐药性或获得性耐药性，和4）将进一步加深我们在鉴定治疗干预的新靶点和基于合理的临床前设计开发治疗这种疾病的高效治疗方法方面的知识。

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.