Surgical Studies of Signaling Pathways in GI Cancers

胃肠道癌症信号通路的外科研究

• 批准号: 6925405
• 负责人: Bernard Mark Evers
• 金额: $ 30.96万
• 依托单位: UNIVERSITY OF TEXAS MED BR GALVESTON
• 依托单位国家: 美国
• 财政年份: 2004
• 资助国家: 美国
• 起止时间: 2004-08-01 至 2009-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6925405
• 关键词: adult human (21+); athymic mouse; biological signal transduction; cell differentiation; cell growth regulation; cell line; clinical research; colorectal neoplasms; connective tissue stroma; gastric mucosa; immunoprecipitation; kinase inhibitor; metastasis; neoplastic growth; northern blottings; phosphatidylinositol 3 kinase; protein structure function; stromal cells; thin layer chromatography; tissue /cell culture; western blottings

DESCRIPTION (provided by applicant): Colorectal cancer is the third leading cause of cancer-related deaths in the United States with 130,000 new cases diagnosed per year and approximately 57,000 deaths estimated in 2003 secondary to this disease. Despite improvements in surgical resection and multimodality therapy, approximately 50% of patients with colorectal cancer will succumb to their disease. A better understanding of the signaling pathways contributing to colorectal cancer proliferation and metastasis will provide targets for novel therapeutic agents and drug delivery methods and further enhance patient survival. Our laboratory is specifically focused on the signaling pathways contributing to gastrointestinal (GI) cancer as well as normal mucosal proliferation. Recently, we have shown that inhibition of phosphatidylinositol-3 kinase (PI3K) enhances intestinal cell differentiation and stimulates expression of downstream target genes that are important for differentiation and apoptosis. Furthermore, we have shown that inhibition of PI3K enhances sodium butyrate (NaBT)-mediated apoptosis and decreases viability and growth of human colon cancers both in vitro and in vivo. Therefore, the central hypothesis of this proposal is that colon cancer growth and tumor progression are augmented by increased PI3K activity; the inhibition of PI3K can inhibit tumor growth, and, moreover, can sensitize colorectal cancers to chemotherapeutic agents. The long-term goal of this proposal is to identify specific molecular targets for the treatment of colorectal cancer. To examine our hypothesis and address the long-term goal, we have designed experiments with the following Specific Aims: 1) To further define the localization of expression patterns of PI3K and downstream effector proteins in colon cancers and surrounding stroma. For these studies, we will further analyze expression patterns of PI3K/Akt and downstream effector proteins in colorectal cancers as well as surrounding stroma. In addition, we will determine when PI3K activity is increased in relation to cancer development, and finally, we will assess the proteomic profile of colorectal cancers and surrounding stromal tissue. 2) To determine the contribution of tumor stromal cells on PI3K/Akt signaling in colon cancers. We will determine the contribution of surrounding stromal tissue on PI3K/Akt signaling to colon cancers and specifically assess tumor-associated fibroblasts with respect to PI3K signaling. 3) To assess novel strategies of PI3K/Akt inhibition on in vivo tumor growth and metastasis. Using models of colorectal cancer metastasis, we will determine the effectiveness of PI3K/Akt inhibition on tumor growth. Finally, we will utilize novel techniques of drug delivery to determine whether enhanced delivery of the PI3K/Akt inhibitors can further augment tumor inhibition and provide a more selective method of treating colorectal cancers. Ultimately, the cumulative information derived from these studies will lead to better targeted therapies and treatment paradigms for colorectal cancer.

描述（由申请人提供）： 结直肠癌是美国与癌症相关死亡的第三大主要原因，每年诊断为130,000例新病例，2003年估计约有57,000例死亡。尽管手术切除和多模式疗法有所改善，但大约50％的结直肠癌患者会屈服于他们的疾病。更好地理解有助于结直肠癌的增殖和转移的信号传导途径将为新型治疗剂和药物递送方法提供目标，并进一步增强患者的生存。我们的实验室专门集中于导致胃肠道（GI）癌以及正常粘膜增殖的信号传导途径。最近，我们已经表明，抑制磷脂酰肌醇-3激酶（PI3K）可以增强肠细胞分化，并刺激对分化和凋亡至关重要的下游靶基因的表达。此外，我们已经表明，PI3K的抑制可以增强丁酸钠（NABT）介导的凋亡，并降低体外和体内人类结肠癌的生存力和生长。因此，该提议的中心假设是结肠癌的生长和肿瘤进展通过PI3K活性增加而增加。 PI3K的抑制作用可以抑制肿瘤的生长，此外，可以使结直肠癌对化学治疗剂敏感。该提案的长期目标是确定用于治疗结直肠癌的特定分子靶标。为了检验我们的假设并解决了长期目标，我们设计了以下特定目的的实验：1）进一步定义PI3K和下游效应蛋白在结肠癌和周围基质中的表达模式的定位。对于这些研究，我们将进一步分析结直肠癌和周围基质中PI3K/AKT和下游效应蛋白的表达模式。此外，我们将确定何时与癌症发展有关PI3K活性何时增加，最后，我们将评估结直肠癌和周围基质组织的蛋白质组学特征。 2）确定肿瘤基质细胞对结肠癌中PI3K/AKT信号传导的贡献。我们将确定周围基质组织对PI3K/AKT信号传导对结肠癌的贡献，并专门评估与PI3K信号传导相关的肿瘤相关的成纤维细胞。 3）评估PI3K/AKT抑制体内肿瘤生长和转移的新型策略。使用结直肠癌转移的模型，我们将确定PI3K/AKT抑制对肿瘤生长的有效性。最后，我们将利用新颖的药物输送技术来确定PI3K/AKT抑制剂的递送是否可以进一步增强肿瘤抑制作用，并提供一种更具选择性的方法来治疗结直肠癌。最终，从这些研究中得出的累积信息将导致靶向疗法和治疗结肠癌的治疗范例。