Inhibition of CDK5 as a Treatment for Pancreatic Cancer

我们实验室和其他实验室最近的研究表明，CDK5基因或其辅助激活因子被扩增 在大多数人胰腺癌中，CDK5在所有测试的胰腺癌细胞系中都有表达 由于突变的k-ras的作用，活性增加，进而增强胰腺癌。 细胞生长、侵袭和转移。我们提出的证据表明，3，5-CDK5的抑制作用 二取代吡唑显著减少肿瘤大小、转移和胰腺肿瘤的血管形成 在裸鼠体内作为异种移植生长。我们建议研究CDK5抑制对胰腺的影响。 两种不同的小鼠模型中腺癌的进展情况，这两种模型概括了人类疾病 进展从胰腺炎到Panin病变，从Panin形成到转移。这项研究将 专注于在疾病发展的早期单独抑制CDK5，并评估其治疗能力 在以后的疾病进展中抑制CDK5，使用该抑制剂和吉西他滨-阿布拉沙尼。一秒钟 抑制CDK5的好处是，鉴于它在伤害性信号转导中的作用，它可以减轻疼痛。因此，我们将 也进行临床前研究，以确定抑制CDK5是否能阻止与胰腺炎相关的疼痛 和肿瘤的生长。我们还将进行一项第一阶段的人体临床试验，以评估 在其他治疗方案失败的晚期胰腺癌患者中抑制CDK5。在更长的时间里 这些研究可能使治疗胰腺炎和胰腺癌的第二阶段临床试验成为可能。我们会 还进行平行的药物设计研究，以开发下一代分子，提高靶向性 CDK5在胰腺癌患者中的表达

Recent studies in our laboratory and others demonstrate that the CDK5 gene or its coactivators is amplified in a majority of human pancreatic cancers, expressed in all pancreatic cancer cell lines tested and that CDK5 activity increases as a consequence of the action of mutant k-Ras, which in turn enhaces pancreatic cancer cell growth, invasion and metastasis. We present evidence that the inhibition of CDK5 with a 3, 5- disubstituted pyrazole significantly reduces tumor size, metastasis, and vascularization of pancreatic tumors growing as xenografts in nude mice. We propose to study the effects of CDK5 inhibition on pancreatic adenocarcinoma progression in two distinct mouse models that recapitulate the human disease as it progresses from pancreatitis to PanIN lesions and from PanIN formation through metastasis. This study will focus on inhibiting CDK5 alone during early disease development and evaluate the therapeutic capacity of inhibiting CDK5 in later disease progression, using the inhibitor and Gemcitabine-Abraxane. A second benefit of inhibiting CDK5 is that it reduces pain, given its role in nociceptive signaling. Consequently, we will also undertake preclinical studies to determine if CDK5 inhibition blocks pain associated with pancreatitis and tumor growth. We will also undertake a Phase I human clinical trials that evaluate the clinical utility of inhibiting CDK5 in advanced pancreatic cancer patients that have failed other therapy options. In the longer term these studies may enable Phase II clinical trials for treateing pancreatitis and pancreatic cancer. We will also undertake parallel drug design studies to develop next-generation molecules that improve targeting of CDK5 in pancreatic cancer patients.