Surgical Studies of Signaling Pathways in GI Cancers

描述(由申请人提供)： 在美国，结直肠癌是与癌症相关的死亡的第三大原因，每年新增确诊病例13万例，2003年估计约有5.7万人死于这种疾病。尽管在手术切除和综合治疗方面有所改进，但大约50%的结直肠癌患者将死于他们的疾病。更好地了解促进结直肠癌增殖和转移的信号通路将为新的治疗药物和药物输送方法提供靶点，并进一步提高患者的生存率。我们的实验室专注于促进胃肠道(GI)癌和正常粘膜增殖的信号通路。最近，我们发现抑制磷脂酰肌醇-3激酶(PI3K)促进了肠道细胞的分化，并刺激了下游靶基因的表达，这些基因对分化和细胞凋亡至关重要。此外，我们还表明，抑制PI3K可以增强丁酸钠(NABT)诱导的细胞凋亡，并降低体外和体内人结肠癌的存活率和生长。因此，这一建议的中心假设是，PI3K活性的增加促进了结肠癌的生长和肿瘤的进展；抑制PI3K可以抑制肿瘤的生长，而且可以使结直肠癌对化疗药物敏感。这项提议的长期目标是确定治疗结直肠癌的特定分子靶点。为了验证我们的假设和解决长期目标，我们设计了以下特定目标的实验：1)进一步确定PI3K及其下游效应蛋白在结肠癌和周围间质中的表达模式。在这些研究中，我们将进一步分析PI3K/Akt及其下游效应蛋白在结直肠癌及其周围间质中的表达模式。此外，我们将确定PI3K活性何时增加与癌症的发展有关，最后，我们将评估结直肠癌及其周围间质组织的蛋白质组学特征。2)探讨肿瘤间质细胞在结肠癌PI3K/Akt信号转导中的作用。我们将确定周围间质组织对PI3K/Akt信号在结肠癌中的作用，并具体评估与PI3K信号有关的肿瘤相关成纤维细胞。3)评价PI3K/Akt抑制体内肿瘤生长和转移的新策略。利用结直肠癌转移模型，我们将确定PI3K/Akt抑制肿瘤生长的有效性。最后，我们将利用新的药物输送技术来确定增强的PI3K/Akt抑制剂的输送是否可以进一步增强对肿瘤的抑制作用，并提供一种更具选择性的治疗结直肠癌的方法。最终，从这些研究中获得的累积信息将导致更好的结直肠癌靶向治疗和治疗范例。

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.