MUC1-Targeted Nanotherapy for Pancreatic Cancer

针对胰腺癌的 MUC1 纳米疗法

• 批准号: 8582822
• 负责人: Jordan M Winter
• 金额: $ 21.97万
• 依托单位: THOMAS JEFFERSON UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-07-01 至 2015-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8582822
• 关键词: Address; Adenocarcinoma Cell; Adjuvant; Antimetabolite Chemotherapy; Biodistribution; Biological Markers; Biology; Cancer Death Rates; Candidate Disease Gene; Cell Line; Cells; Cessation of life; Clinical; Code; Collaborations; Complex; DNA; DNA Sequence; DNA analysis; DNA delivery; Data; Death Rate; Dendrimers; Development; Diphtheria Toxin; Dose; Drug resistance; Enzymes; Event; Excision; Female; Foundations; Genes; Genetic Enhancer Element; Gleevec; Histology; In Vitro; Injection of therapeutic agent; KRAS2 gene; Lead; Ligand Binding; Ligands; Luc Gene; Luciferases; MUC1 gene; Malignant Neoplasms; Malignant neoplasm of ovary; Malignant neoplasm of pancreas; Malignant neoplasm of prostate; Metabolic; Molecular; Molecular Target; Mucin-1 Staining Method; Mus; Normal Cell; Nude Mice; Oncogenes; Organ; Pancreatic Ductal Adenocarcinoma; Pathway interactions; Patients; Peptides; Pharmaceutical Preparations; Phase; Polymers; Prostate; Proteins; Reporter; Resistance; Safety; Sampling; Scientist; Signal Transduction; Specificity; Stromal Neoplasm; Suicide Gene Therapy; System; Testing; Therapeutic; Toxic effect; Toxin; Transfection; Transferrin Receptor; Translating; Transplantation; Treatment Efficacy; Tumor Biology; Viral; Viral Vector; Work; Xenograft procedure; base; biodegradable polymer; cancer cell; cell killing; chemotherapy; effective therapy; gain of function mutation; gene therapy; improved; innovation; mesothelin; mouse model; nanoparticle; nanotherapy; neoplastic cell; novel; novel strategies; optical imaging; overexpression; pancreatic cancer cells; pancreatic neoplasm; pancreatic tumorigenesis; pre-clinical; preclinical study; promoter; protein expression; public health relevance; research study; response; screening; skills; success; treatment response; treatment strategy; tumor; tumor growth; vector

DESCRIPTION (provided by applicant): Pancreatic ductal adenocarcinoma (PDA) remains one of the most aggressive cancers with a rising death rate. The treatment paradigm has not changed over the past three decades, with antimetabolite chemotherapy as the mainstay of treatment. Novel approaches to develop effective therapies are needed. Promoter-driven gene therapy exploits an overactive cancer- specific promoter to express a desired gene in a cancer cell. This exciting strategy has been studied extensively in PDA using viral vectors, but has stalled at the pre-clinical level due to limitations of viral therapy. In prior studies, we developd a non-viral nanotherapy in which a biodegradable polymer DNA vector is injected locally into tumors. Using this approach, delivery of diphtheria toxin A (DTA) placed under the control of a cancer-specific promoter resulted in tumor shrinkage in pre-clinical mouse models of ovarian and prostate cancer, as well as in vitro studies of PDA. We recently demonstrated effective systemic targeting of DNA in prostate cancer-bearing mice using a novel DNA dendrimer conjugated to a targeting peptide against the transferrin receptor (TFRC). TFRC is overexpressed in most tumors (including PDA), but not in normal cells. Complementary to these studies, we used a rigorous approach to identify 13 promising promoter candidates for gene therapy from over 2500 putative PDA biomarkers, and tested these proteins for expression in our patient samples. Based on this work, MUC1 was identified as the best candidate promoter for transcriptionally-driven nanotherapy, since it was tightly correlated with aggressive biology i these PDA samples, and previous gene therapy studies (all viral) established efficacy of the MUC1 promoter. In this proposal, we detail plans to develop a MUC1 promoter-driven construct and use a derivatized DNA dendrimer to target PDA cell lines in culture and systemically in pre-clinical PDA mouse models (xenografts and orthotopic tumors). We will use a MUC1 promoter-driven luciferase reporter to test specificity in cell lines and a promoter-driven DTA construct to test treatment efficacy, biodistribution, and non-specific toxicity in mice. We hypothesize that MUC1-expressing cells will be exquisitely sensitive to treatment in vitro, and MUC1 non-expressing cells will be resistant. Similarly, we expect stunted tumor growth in MUC1-expressing xenografts and improved survival in mice with MUC1-expressing orthotopic tumors. If effective, these studies will serve as a foundation for rapid testing of systemically administerd MUC1 promoter-driven nanoparticles in patients with PDA, followed by early phase-safety trials of DTA nanotherapy in patients.

描述（由申请人提供）：胰腺导管腺癌（PDA）仍然是最具侵袭性的癌症之一，死亡率不断上升。治疗模式在过去的三十年中没有改变，抗代谢物化疗是主要的治疗方法。需要新的方法来开发有效的治疗方法。启动子驱动基因治疗利用过度活跃的癌症特异性启动子在癌细胞中表达所需基因。这种令人兴奋的策略已经在使用病毒载体的PDA中进行了广泛的研究，但由于病毒治疗的局限性，在临床前水平停滞不前。在之前的研究中，我们开发了一种非病毒纳米疗法，将可生物降解的聚合物DNA载体局部注射到肿瘤中。使用这种方法，在癌症特异性启动子的控制下，白喉毒素A （DTA）的递送在卵巢癌和前列腺癌的临床前小鼠模型以及PDA的体外研究中导致肿瘤缩小。我们最近证明了一种新型的DNA树状大分子结合了一种针对转铁蛋白受体（TFRC）的靶向肽，可以在前列腺癌小鼠中有效地全身靶向DNA。TFRC在大多数肿瘤（包括PDA）中过表达，但在正常细胞中不表达。作为这些研究的补充，我们使用严格的方法从2500多个假定的PDA生物标志物中鉴定出13个有希望用于基因治疗的启动子候选物，并测试了这些蛋白质在我们的患者样本中的表达。基于这项工作，MUC1被确定为转录驱动纳米治疗的最佳候选启动子，因为它与这些PDA样本中的侵袭性生物学密切相关，并且先前的基因治疗研究（均为病毒）确定了MUC1启动子的功效。在本提案中，我们详细计划开发MUC1启动子驱动的构建体，并使用衍生的DNA树突状物在培养和临床前PDA小鼠模型（异种移植和原位肿瘤）中靶向PDA细胞系。我们将使用MUC1启动子驱动的荧光素酶报告子来测试细胞系的特异性，并使用启动子驱动的DTA构建来测试