Development of a plectin-1 targeted payload delivery system for treating pancreat

开发用于治疗胰腺的 plectin-1 靶向有效负载递送系统

• 批准号: 8313566
• 负责人: Greg Brian Fralish
• 金额: $ 30.13万
• 依托单位: ITI HEALTH, INC.
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-08-13 至 2014-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8313566
• 关键词: Adjuvant Chemotherapy; Adverse effects; Adverse event; Affinity; Animals; Binding; Biological Markers; Cancer Etiology; Cancer Patient; Cell Line; Cell surface; Cells; Cessation of life; Clinic; Clinical; Combination Drug Therapy; Cytoplasm; Cytoplasmic Protein; Data; Dependovirus; Development; Disease; Dose; Drug Delivery Systems; Drug Formulations; Dyes; Epidermal Growth Factor Receptor; Esophageal; Excision; FDA approved; Goals; Health; Human; Image; In Vitro; Lead; Lesion; Liposomes; Lung; Malignant Neoplasms; Malignant neoplasm of pancreas; Metastatic Lesion; Metastatic Neoplasm to Lymph Nodes; Microfilaments; Modality; Modeling; Molecular Genetics; Mus; Muscle; Neoplasm Metastasis; Outcome; Outcome Study; Ovarian; Pancreas; Pancreatic Ductal Adenocarcinoma; Pathway interactions; Patients; Peptides; Peritoneum; Permeability; Phage Display; Pharmaceutical Preparations; Phase; Premalignant; Primary Neoplasm; Protein Binding; Publications; Qualifying; Quality of life; Reagent; Refractory; Research; Site; Skin; Small Business Innovation Research Grant; Specificity; Staging; Surface; Survival Rate; System; Testing; Therapeutic; Therapeutic Clinical Trial; Therapeutic Intervention; Toxic effect; Toxicology; Treatment Efficacy; Validation; Work; advanced disease; angiogenesis; base; cancer cell; cell growth; cell killing; chemotherapy; design; flexibility; gemcitabine; improved; in vivo; innovation; mouse model; nanoparticle; novel; novel therapeutics; pancreatic cancer cells; pancreatic neoplasm; particle; plectin; pre-clinical; programs; research study; response; single photon emission computed tomography; small molecule; subcutaneous; success; targeted delivery; tumor; tumorigenesis; tumorigenic

DESCRIPTION (provided by applicant): While only the 31st most common cause of cancer, pancreatic cancer is the fourth most common cause of cancer-related death in the US. Patients typically present with advanced disease that is notoriously refractory to chemotherapy. Indeed, the 5 year survival rate is below 5%. Radical resection with adjuvant chemotherapy is potentially curative, but less than 15% of patients qualify for resection (local disease). Despite decades of research, meaningful advancements in the therapeutic intervention of PDAC have been largely absent. In other oncologic indications, there have been several recent clinical successes in targeted tumor delivery of therapeutic payloads, and the first clinical product will likely be approved in the US in 2011. Therefore, the overall goal of this proposal is to develop a molecularly targeted nanoparticle based platform capable of being loaded with and targeting efficacious chemotherapies directly to pancreatic tumors. Recently, in a screen of cell surface markers of pancreatic cancer, we have identified a highly specific and novel cell surface biomarker, Plectin-1. Plectin-1 is normally a cytoplasmic protein predominantly expressed in the muscle and skin. But it is aberrantly surface expressed in in early, precancerous lesions as well as in 100% of human pancreatic tumors and metastatic lesions tested to date (N>100). Plectin-1 is up-regulated in a number of additional cancers including lung, ovarian and esophageal. A novel high-affinity and specific plectin-1 targeting peptide (PTP) that internalizes upon binding has been identified and thoroughly characterized. The proposed work has the long-term objective to develop a flexible therapeutic payload delivery platform capable of targeting to cells expressing the biomarker plectin-1, such as pancreatic tumors. Outcomes from these studies will provide feasibility data on the ability to target cell- killing agents to various pancreatic cncer cell lines in vitro and in vivo. A lead product will be identified for advancing this work to a phae II effort focusing on product optimization, preclinical enabling toxicology and IND filing. PUBLIC HEALTH RELEVANCE: The overall goal of this proposal is to develop a new drug delivery system that targets to a novel cancer tag for use in treating pancreatic cancer and other cancers. We will do this by making small particles that are capable of holding drugs and are targeted to the cancer through the use of tags that identify the cancer. The developed targeted drug delivery system will ultimately be used for delivery of numerous cell-killing agents specifically to cancer cells, potentially extending and improving cancer patient's lives.

描述（由申请人提供）：虽然胰腺癌仅为第31位最常见的癌症原因，但它是美国癌症相关死亡的第四位最常见原因。患者通常表现为晚期疾病，这是众所周知的化疗难治性。实际上，5年生存率低于5%。根治性切除术联合辅助化疗具有潜在的治愈性，但只有不到15%的患者符合切除（局部疾病）的条件。尽管进行了数十年的研究，但在PDAC的治疗干预方面基本上没有取得有意义的进展。在其他肿瘤适应症中，最近在靶向肿瘤递送治疗有效载荷方面取得了几项临床成功，第一个临床产品可能于2011年在美国获得批准。因此，本提案的总体目标是开发一种基于分子靶向纳米颗粒的平台，该平台能够装载有效的化疗药物并将其直接靶向胰腺肿瘤。最近，在胰腺癌细胞表面标志物的筛选中，我们已经鉴定出一种高度特异性和新型的细胞表面生物标志物，Plectin-1。凝集素-1通常是主要在肌肉和皮肤中表达的细胞质蛋白。但它在早期癌前病变以及迄今为止检测的100%的人胰腺肿瘤和转移性病变中异常表达（N>100）。Plectin-1在许多其他癌症中上调，包括肺癌、卵巢癌和食管癌。一种新型的高亲和力和特异性的plectin-1靶向肽（PTP），内化后结合已被确定和彻底的特点。拟议的工作的长期目标是开发一种能够靶向细胞的灵活的治疗有效载荷递送平台 表达生物标志物plectin-1的肿瘤，如胰腺肿瘤。这些研究的结果将提供关于体外和体内将细胞杀伤剂靶向各种胰腺癌细胞系的能力的可行性数据。将确定一种主导产品，以将这项工作推进到II期，重点是产品优化、临床前毒理学和IND申报。 公共卫生相关性：该提案的总体目标是开发一种新的药物递送系统，其靶向用于治疗胰腺癌和其他癌症的新型癌症标签。我们将通过制造能够容纳药物的小颗粒来做到这一点，并通过使用识别癌症的标签来靶向癌症。开发的靶向药物递送系统最终将用于递送多种细胞杀伤剂，特别是癌细胞，可能延长和改善癌症患者的生命。