Developing Nanotechnology to Target HMGA1 in Pancreatic Cancer

开发纳米技术靶向胰腺癌中的 HMGA1

• 批准号: 8883440
• 负责人: Linda M S Resar
• 金额: $ 8.1万
• 依托单位: JOHNS HOPKINS UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-07-01 至 2017-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8883440
• 关键词: 3-Dimensional; Accounting; Adenocarcinoma Cell; Applications Grants; Caliber; Cancer Biology; Cancer cell line; Cells; Cessation of life; Chromatin; Chromatin Structure; Cultured Cells; Cytotoxic Chemotherapy; Disease; Disease Progression; Ensure; Epithelial; Event; Experimental Models; Future; Gene Expression; Goals; Grant; HMGA1 gene; HMGA1b Protein; Health; Human; In Vitro; International; Laboratories; Lead; Lesion; Lipids; Malignant Neoplasms; Malignant neoplasm of pancreas; Mesenchymal; MicroRNAs; Modeling; Molecular; Mus; Nanotechnology; Neoplasm Metastasis; Oncogenes; Oncogenic; Oncologist; Outcome; Pancreas; Pancreatic Ductal Adenocarcinoma; Paper; Pathogenesis; Pathologist; Pathway interactions; Patients; Phenotype; Plasmids; Pre-Clinical Model; Principal Investigator; Property; Proteins; Publishing; Reagent; Research; Research Personnel; Resected; Resources; Shapes; Somatic Cell; Specimen; Staphylococcal Protein A; Stem cells; System; Technology; Testing; Therapeutic; Transgenic Mice; Transgenic Model; Transgenic Organisms; Work; Xenograft procedure; anticancer research; base; biophysical properties; cancer cell; cancer stem cell; cell growth; chromatin remodeling; cytotoxicity; design; effective therapy; experience; gemcitabine; improved; in vivo; induced pluripotent stem cell; innovation; knock-down; migration; mouse model; multidisciplinary; nanomedicine; nanoparticle; new technology; novel; novel strategies; overexpression; pancreas xenograft; pancreatic neoplasm; plasmid DNA; preclinical study; response; small hairpin RNA; stem; success; tumor; tumor growth; tumor progression; tumor xenograft

DESCRIPTION (provided by applicant): The primary goal of this proposal is to develop and test innovative "nanoparticles" to systemically deliver novel therapy (short hairpin or shRNA) in preclinical models for pancreatic cancer. Pancreatic ductal adenocarcinomas (PDACs) are highly lethal tumors accounting for >150,000 deaths worldwide each year. Most patients present with inoperable, metastatic disease for which there are no effective therapies. Thus, research is urgently needed to determine how to block metastatic progression in PDACs. We are studying the molecular pathways that lead to tumor progression in PDAC. Our focus is the HMGA1 oncogene, which encodes the HMGA1a and HMGA1b chromatin remodeling proteins. HMGA1 proteins regulate gene expression by altering chromatin structure. My laboratory was the first to discover that HMGA1 functions as a potent oncogene in cultured cells and transgenic mice. We also found that inhibiting HMGA1 expression blocks oncogenic and cancer stem cell properties. Recently published studies from our group and others demonstrate that HMGA1 is overexpressed in >90% of primary, human PDACs, with highest levels in invasive, metastatic tumors, but no expression in precursor lesions or normal pancreas. Moreover, we found that HMGA1 protein levels are positively correlated with poor differentiation status and decreased survival. Knock-down of HMGA1 blocks multiple oncogenic and stem cell properties, including anchorage-independent cell growth, migration, invasion, 3-dimensional sphere formation in vitro and metastatic progression in murine models of PDAC. These findings indicate that HMGA1 promotes tumor progression in PDAC. Strikingly, our recent studies show that knock-down of HMGA1 with shRNA reprograms cancer cell lines from highly invasive, mesenchymal-like cells to noninvasive, epithelial-like cells by down-regulating transcriptional networks important in stem cells and tumor progression. Knock-down of HMGA1 also enhances sensitivity to cytotoxic therapy. Our co-investigators, Drs. Hanes and Maitra, have recently pioneered novel approaches to systemically deliver plasmid nanoparticles (NPs) with effective and sustained changes in gene expression in preclinical models. Based on these exciting results, we hypothesize that: 1.) HMGA1 drives tumor progression in PDAC and could serve as a target in therapy, and, 2.) shRNA NPs will block HMGA1 expression and reprogram PDAC cells into less aggressive cells that respond to therapy. Here, we propose to test these hypotheses using our unique resources and expertise with the following Specific Aims: 1.) To determine if inducible shRNA to HMGA1 reprograms PDAC cells into noninvasive, therapy-responsive cells in our preclinical models, and, 2.) To develop NP technology to deliver HMGA1 shRNA in preclinical models of PDAC. We will test shRNA delivery using our NPs that have been optimized for delivery and efficiency by altering diameter, shape, lipid content, and other biophysical properties. If successful, our studies should provide a new paradigm for the treatment of PDAC and improve outcomes for patients.

描述（由申请人提供）：该提案的主要目标是开发和测试创新的“纳米颗粒”，以在胰腺癌的临床前模型中系统地提供新的治疗（短发夹或shRNA）。胰腺导管腺癌（PDAC）是高致死性肿瘤，每年在全世界造成> 150，000例死亡。大多数患者患有无法手术的转移性疾病，对此没有有效的治疗方法。因此，迫切需要研究以确定如何阻断PDAC的转移进展。我们正在研究导致PDAC肿瘤进展的分子途径。我们的重点是HMGA1癌基因，它编码HMGA1a和HMGA1b染色质重塑蛋白。HMGA1蛋白通过改变染色质结构来调节基因表达。我的实验室是第一个发现HMGA1在培养细胞和转基因小鼠中作为一种有效的致癌基因发挥作用的实验室。我们还发现，抑制HMGA1表达阻断致癌和癌症干细胞特性。我们小组和其他人最近发表的研究表明，HMGA1在>90%的原发性人类PDAC中过表达，在侵袭性转移性肿瘤中水平最高，但在前体病变或正常胰腺中不表达。此外，我们发现HMGA1蛋白水平与分化状态差和生存率降低呈正相关。HMGA1的敲低阻断多种致癌和干细胞特性，包括锚定非依赖性细胞生长、迁移、侵袭、体外三维球体形成和PDAC小鼠模型中的转移进展。这些发现表明HMGA1促进PDAC中的肿瘤进展。引人注目的是，我们最近的研究表明，用shRNA敲低HMGA1通过下调在干细胞分化中重要的转录网络，将癌细胞系从高度侵袭性的间充质样细胞重编程为非侵袭性的上皮样细胞。 细胞和肿瘤进展。HMGA1的敲低也增强了对细胞毒性疗法的敏感性。我们的合作研究者Hanes和Maitra博士最近开创了一种新的方法，可以在临床前模型中系统性地递送质粒纳米颗粒（NP），并有效和持续地改变基因表达。基于这些令人兴奋的结果，我们假设：1。HMGA1驱动PDAC中的肿瘤进展，并且可以用作治疗中的靶点，以及，2.）shRNA NP将阻断HMGA1表达，并将PDAC细胞重编程为对治疗有反应的侵袭性较低的细胞。在这里，我们建议使用我们独特的资源和专业知识来测试这些假设，具体目标如下：1.为了确定在我们的临床前模型中，针对HMGA1的可诱导的shRNA是否将PDAC细胞重编程为非侵入性的治疗响应性细胞，以及，2.）开发NP技术在PDAC临床前模型中递送HMGA1 shRNA。我们将使用我们的NP测试shRNA递送，这些NP已经通过改变直径、形状、脂质含量和其他生物物理特性来优化递送和效率。如果成功，我们的研究将为PDAC的治疗提供一个新的范例，并改善患者的预后。