Targeting Pancreatic Cancer Using Peptide Chemistry: From Bench to Bedside

使用肽化学靶向胰腺癌：从实验室到临床

• 批准号: 8212469
• 负责人: DEBABRATA MUKHOPADHYAY
• 金额: $ 57.27万
• 依托单位: MAYO CLINIC ROCHESTER
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-04-07 至 2015-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8212469
• 关键词: Adenocarcinoma Cell; Affinity; Animal Model; Antibodies; Bacteriophage T7; Bacteriophages; Binding; Binding Proteins; Biochemical; Biological; Biological Assay; Biotin; Calorimetry; Cancer Etiology; Carcinogenesis Mechanism; Cell Line; Cells; Cellular biology; Cessation of life; Chemicals; Chemistry; Clinic; Clinical; Clinical Trials; Data; Development; Diagnosis; Disease; Disease Progression; Drug Combinations; Drug Delivery Systems; Drug Kinetics; Enzyme-Linked Immunosorbent Assay; Epidermal Growth Factor Receptor; Epidermal Growth Factor Receptor Tyrosine Kinase Inhibitor; Exhibits; Experimental Designs; Family; Fluorescence; Frequencies; Future; Gold; Growth; Growth Factor; In Vitro; Individual; Integrins; Investigation; Knowledge; Laboratories; Lead; Libraries; Ligand Binding; Ligands; Link; Lipids; Malignant Neoplasms; Malignant neoplasm of pancreas; Mediating; Methods; Microarray Analysis; Modification; Molecular; Molecular Profiling; Nanotechnology; Neoplasm Metastasis; Pancreatic Adenocarcinoma; Pathway interactions; Patients; Pattern; Peptide Hydrolases; Peptide Library; Peptides; Phage Display; Pharmaceutical Preparations; Pharmacodynamics; Preclinical Testing; Preparation; Prevention; Principal Investigator; Property; Protein Binding Domain; Protein Family; Proteins; Publishing; Reagent; Relative (related person); Role; Screening procedure; Signal Transduction; Site-Directed Mutagenesis; Staging; Surface; Techniques; Testing; Therapeutic; Therapeutic Intervention; Tissue Microarray; Titrations; Toxic effect; Translating; United States; Work; Xenograft Model; base; bench to bedside; conventional therapy; design; drug development; effective therapy; gemcitabine; human disease; improved; in vivo; inhibitor/antagonist; mouse model; nano; nanoGold; nanoparticle; nanoprobe; novel; novel strategies; overexpression; pancreatic cancer cells; peptidomimetics; pre-clinical; preclinical study; protein transport; public health relevance; receptor; research study; small hairpin RNA; small molecule libraries; therapeutic target; translational approach; tumor; tumor growth

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. PUBLIC HEALTH RELEVANCE: Pancreatic adenocarcinoma (PaCA) is, almost invariably, a fatal disease. This work will focus on the prevention and therapeutic aspects of this cancer. Overall, our proposed experiments will define the regulatory role of GIPC and their downstream molecules that can influence the tumor growth and metastasis. The proposed study might define the mechanism of pancreatic cancer growth and progression and identify specific targets for therapeutic interventions for pancreatic adenocarcinoma where no current therapy is available.

描述（由申请人提供）：胰腺腺癌（PCA）是一种几乎总是致命的疾病。此外，由于在将致癌分子机制转化为可行的治疗方法方面存在显着差距，传统治疗通常会失败。在晚期胰腺癌患者中观察到许多促有丝分裂生长因子及其受体的过度表达，特别是 IGF-1R 和 EGFR 的过度表达。已经完成了几项研究，试图了解导致 IGF-1R 和 EGFR 介导的信号传导的途径，但受体过度表达的分子机制仍不清楚。在我们已发表的研究和初步研究中，我们定义了 PCA 中 IGF-1R 和 EGFR 过表达的独特机制。我们的数据还定义了 GIPC（一种 RGS/PDZ 结合蛋白）的新调节作用，它通过两种不同的机制控制 IGF-1R 和 EGFR 表达。此外，我们还发现表达GIPC shRNA的胰腺癌细胞生长速度明显慢于亲本细胞，并且其转移能力受到限制。我们最近发表的结果也鼓励我们提出一种利用纳米技术来改进药物输送方法的靶向治疗方法。综上所述，这些观察结果使我们推测，GIPC 功能失活可用于有针对性地抑制 IGF-1R 和 EGFR 过度表达，这对 PCA 具有重要的临床意义。为了检验我们的假设，我们提出了四个目标。目标1将研究GIPC对PCA细胞中IGF-1R和EGFR过表达的调节作用的分子机制。目标 2 将开发化学发现平台，用于识别 GIPC 的新型肽配体。在目标 3 中，我们将重点关注 GIPC 肽配体的生化表征和细胞探针开发。目标 4 将专注于开发基于纳米技术的靶向疗法。我们将在体外合成并表征附着在金纳米颗粒表面（有或没有吉西他滨）的抗 IGF-1R 抗体、GIPC 肽（IGF-1R 和 EGFR 抑制剂）的不同组合。在该目标的后半部分，我们将把先前目标的知识和试剂外推到可以模拟人类疾病的正交胰腺癌动物模型中。我们将检查纳米金缀合药物的体内功效，以了解多靶点组合药物在 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目前尚无治疗方法的胰腺腺癌治疗干预的具体目标。 公共卫生相关性：胰腺腺癌 (PaCA) 几乎总是一种致命疾病。这项工作将重点关注这种癌症的预防和治疗方面。总的来说，我们提出的实验将确定 GIPC 及其下游分子对肿瘤生长和转移的调节作用。拟议的研究可能会定义胰腺癌生长和进展的机制，并确定目前尚无治疗方法的胰腺癌治疗干预的具体目标。