Targeting Pancreatic Cancer Using Peptide Chemistry: From Bench to Bedside

描述（由申请人提供）：胰腺癌（PCA）是一种几乎总是致命的疾病。此外，常规治疗通常失败，因为在将致癌的分子机制转化为可行的治疗方法方面存在显著差距。许多促有丝分裂生长因子及其受体的过表达，特别是IGF-1 R和EGFR的过表达，在晚期胰腺癌患者中已观察到高频率。已经完成了几项研究，试图了解导致IGF-1 R和EGFR介导的信号传导的途径，但受体过表达的分子机制仍不清楚。在我们发表的以及初步的研究中，我们已经确定了一个独特的机制，IGF-1 R和EGFR在PCA的过度表达。我们的数据还定义了GIPC的一种新的调节作用，GIPC是一种RGS/PDZ结合蛋白，通过两种不同的机制控制IGF-1 R和EGFR的表达。此外，我们还发现，表达GIPC的shRNA的胰腺癌细胞生长明显慢于亲本细胞，并且它们的转移能力受到限制。我们最近发表的结果也鼓励我们提出一种使用纳米技术改进药物递送方法的靶向治疗方法。综上所述，这些观察结果使我们假设GIPC功能的失活可以用于以靶向方式抑制IGF-1 R和EGFR过表达，这将在PCA中具有重要的临床意义。为了验证我们的假设，我们提出了四个目标。目的1探讨GIPC对前列腺癌细胞IGF-1 R和EGFR过表达调控的分子机制。目标2将开发化学发现平台，用于识别GIPC的新型肽基配体。在目标3中，我们将专注于基于肽的GIPC配体的生物化学表征和细胞探针的开发。目标4将侧重于基于纳米技术的靶向治疗的发展。我们将在体外合成和表征抗IGF-1 R抗体、附着在金纳米颗粒表面的GIPC肽（IGF-1 R和EGFR抑制剂）与或不与吉西他滨的不同组合。在这个目标的后半部分，我们将从先前的目标的知识和试剂外推到可以模拟人类疾病的正交性胰腺癌动物模型。我们将检查纳米金缀合药物的体内功效，以寻求了解多靶向组合药物在PCA进展和转移中的重要性。此外，我们将确定有效药物的药代动力学、药效学、生物分布和生物毒性，这将引导我们在不久的将来进行临床试验。总的来说，我们高度合作的拟议实验将确定胰腺癌治疗干预的具体目标，目前没有治疗方法。

DESCRIPTION (provided by applicant): Pancreatic adenocarcinoma (PCA) is an almost invariably fatal disease. Furthermore, conventional treatment generally fails because of a significant gap in translating the molecular mechanisms of carcinogenesis into feasible therapeutics. Overexpression of many mitogenic growth factors and their receptors, in particular the overexpression of IGF-1R and EGFR, has been observed with a high frequency in patients with advanced pancreatic cancer. Several studies have been completed in an attempt to understand the pathways that lead to IGF-1R and EGFR-mediated signaling, but the molecular mechanism of receptor overexpression remains unclear. In our published as well as preliminary studies, we have defined a unique mechanism of IGF-1R and EGFR overexpression in PCA. Our data also define a novel regulatory role of GIPC, a RGS/PDZ binding protein, which controls both IGF-1R and EGFR expression by two distinct mechanisms. Moreover, we have also shown that pancreatic cancer cells expressed shRNA of GIPC grow significantly slower than that of parental cells, and their metastasis capabilities are restricted. Our recent published results have also encouraged us to propose a targeted therapeutic approach using nanotechnology to improve drug delivery methods. Taken together, these observations have led us to hypothesize that inactivation of GIPC function can be exploited to inhibit IGF-1R and EGFR overexpression in a targeted manner that would have important clinical implications in PCA. To test our hypothesis, we have proposed four aims. Aim 1 will examine the molecular mechanism of the regulatory role of GIPC on IGF-1R and EGFR overexpression in PCA cells. Aim 2 will develop chemical discovery platforms for identifying novel peptide-based ligands for GIPC. In Aim 3, we will focus on biochemical characterization and cellular probe development of peptide-based ligands for GIPC. Aim 4 will focus on the development of nanotechnology-based targeted therapeutics. We will synthesize and characterize in vitro the different combinations of anti-IGF-1R antibody, GIPC peptides (IGF-1R and EGFR inhibitors) attached onto the surface of gold nanoparticles with or without gemcitabine. In the later part of this aim, we will extrapolate the knowledge and reagents from the previous aims to the animal model of orthotropic pancreatic cancer that can mimic human diseases. We will examine the in vivo efficacy of the nanogold conjugated drugs in vivo seeking to understand the importance of multi-targeted, combination drugs in PCA progression and metastasis. Furthermore, we will determine pharmacokinetics, pharmacodynamics, bio-distribution, and bio-toxicity of the effective drugs that will lead us toward clinical trials in the near future. Overall, our highly collaborative proposed experiments will identify specific targets for therapeutic interventions for pancreatic adenocarcinoma where no current therapy is available.