Surgical Studies of Signaling Pathways in GI Cancers

描述（由申请人提供）： 结直肠癌是美国癌症相关死亡的第三大原因，每年诊断出130，000例新病例，2003年估计约57，000例继发于该疾病的死亡。尽管手术切除和多模式治疗有所改进，但约50%的结直肠癌患者仍会死于疾病。更好地了解有助于结直肠癌增殖和转移的信号通路将为新型治疗剂和药物递送方法提供靶点，并进一步提高患者生存率。我们的实验室特别关注导致胃肠道（GI）癌症以及正常粘膜增殖的信号通路。最近，我们已经表明，磷脂酰肌醇-3激酶（PI 3 K）的抑制增强肠细胞分化，并刺激下游的靶基因的表达是重要的分化和凋亡。此外，我们已经表明，抑制PI 3 K增强丁酸钠（NaBT）介导的细胞凋亡，并在体外和体内降低人结肠癌的生存力和生长。因此，该提议的中心假设是结肠癌生长和肿瘤进展通过增加的PI 3 K活性而增强; PI 3 K的抑制可以抑制肿瘤生长，并且，此外，可以使结肠直肠癌对化疗剂敏感。该提案的长期目标是确定治疗结直肠癌的特定分子靶点。为了检验我们的假设并解决长期目标，我们设计了具有以下特定目的的实验：1）进一步确定PI 3 K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PI 3 K/Akt和下游效应蛋白在结直肠癌以及周围间质中的表达模式。此外，我们将确定PI 3 K活性何时增加与癌症发展有关，最后，我们将评估结直肠癌和周围间质组织的蛋白质组学特征。2)探讨肿瘤基质细胞对结肠癌PI 3 K/Akt信号通路的影响。我们将确定周围基质组织对结肠癌PI 3 K/Akt信号传导的贡献，并具体评估肿瘤相关成纤维细胞对PI 3 K信号传导的影响。3)评估PI 3 K/Akt抑制对体内肿瘤生长和转移的新策略。使用结直肠癌转移模型，我们将确定PI 3 K/Akt抑制对肿瘤生长的有效性。最后，我们将利用新的药物递送技术来确定PI 3 K/Akt抑制剂的增强递送是否可以进一步增强肿瘤抑制并提供治疗结直肠癌的更具选择性的方法。最终，从这些研究中获得的累积信息将为结直肠癌提供更好的靶向治疗和治疗模式。

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.