PEGYLATED PEPTIDES LIGANDS TARGETING RADIATION-INDUCIBLE RECEPTORS ON CANCER

靶向癌症辐射诱导受体的聚乙二醇化肽配体

基本信息

批准号：
9038604
负责人：
Sriram Devanathan
金额：
$ 22.5万
依托单位：
MEDICAL GUIDANCE SYSTEMS, LLC
依托单位国家：
美国
项目类别：
财政年份：
2016
资助国家：
美国
起止时间：
2016-03-01 至 2018-02-28
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9038604
关键词：
Acidosis Address Affinity Agreement Antigen Receptors Antigens Antineoplastic Agents Award Bacteriophages Binding Biodistribution Biological Availability Biotechnology Blood Circulation Budgets Cancer Patient Cancer Prognosis Cell Surface Proteins Cell Surface Receptors Cell surface Chelating Agents Clinical Clinical Trials Cytotoxic agent DNA strand break Data Development Disease Drug Delivery Systems Drug Kinetics Epidermal Growth Factor Receptor Feasibility Studies Funding Future GRP gene Genomics Glucose Goals Grant Heat shock proteins Human Hypoglycemia Hypoxia Image Intellectual Property Intravenous infusion procedures Investigational New Drug Application Ionizing radiation Irradiated tumor Laboratories Lead Libraries Licensing Ligand Binding Ligands Liposomes Malignant Neoplasms Malignant neoplasm of lung Marketing Mediation Medical Membrane Proteins Methods Mus Normal tissue morphology Oxidative Stress Patients Pentetic Acid Peptide antibodies Peptides Phage Display Pharmaceutical Preparations Pharmacologic Substance Phase Physiological Polyethylene Glycols Pre-Clinical Model Proteins Proteomics Radiation Radiation therapy Radiolabeled Radiopharmaceuticals Recruitment Activity Research Research Contracts Research Proposals Scientist Small Business Technology Transfer Research Specificity Stress Surface System Technology Testing Therapeutic Agents Therapeutic Effect Toxicology Transmembrane Transport Universities Washington animal imaging base biological adaptation to stress cancer cell cancer subtypes cancer therapy chemotherapeutic agent commercial application commercialization cost dosimetry drug development genetic regulatory protein human cancer mouse model humanized antibody improved irradiation molecular targeted therapies mouse model nanoparticle new technology oncology overexpression pre-clinical preclinical efficacy preclinical safety public health relevance radiotracer receptor response safety testing stress protein technological innovation tumor tumor growth

项目摘要

DESCRIPTION (provided by applicant): The proposed research is the study of new paradigms in both the treatment of cancer and cancer drug development. This platform technology will markedly expand the number of cancer specific surface receptors and antigens that can be targeted for drug delivery using peptide ligands. The general principle of this new technology is that cancer cells respond to ionizing radiation through a stress response that involves membrane transport and presentation of stress proteins on the cell surface. These proteins are normally sequestered within the cancer cell but are transported to the surface in response to oxidative stress and DNA strand breaks caused by ionizing radiation. We exploit this physiologic response by developing peptide ligands that bind to radiation-inducible stress proteins with high affinity and specificity. Since 1998, the Hallahan lab has identified over 4 dozen radiation-inducible cell surface proteins through the use of platform technologies. To identify candidate ligands for these surface proteins, a phage display library representing over 2 billion peptides was injected into the circulation of mice bearing irradiated cancers. Phage that bound to the irradiated tumor were amplified and injected into another tumor-bearing mouse after irradiation. After 5 passages through irradiated tumors, peptides bind specifically to irradiated cancers. The cell surface receptors for these peptides were identified by proteomic and genomic methods. The resulting peptide ligand-receptor pairs have been prioritized by cancer specificity, prolonged binding and binding to multiple cancer subtypes. The lead radiation inducible receptors that achieve all of these criteria include TIP-1, and GRP-78. To develop drug delivery systems targeting irradiated tumors, we will utilize peptide ligands to the lead receptors we have identified. Conjugation of peptides to therapeutic agents can specifically deliver cytotoxic agents to mouse models of human cancer. With this approach, we have improved tumor control, pharmacokinetics and bioavailability of cancer drugs. We propose research to test the hypothesis that inducible cell-surface proteins on cancer can be exploited to achieve cancer specific drug delivery in patients. We will conjugate the lead peptide to PEG and chelators that will serve to image the spatial and temporal distribution of peptides in planned clinical trials.

描述（由应用提供）：拟议的研究是对癌症和癌症药物发展治疗的新范式的研究。该平台技术将明显扩大癌症特异性表面受体和抗原的数量，这些受体和抗原可用于使用肽配体进行药物递送。这项新技术的一般原则是，癌细胞通过涉及膜运输和呈现压力蛋白在细胞表面的应激反应来响应电离辐射。这些蛋白通常在癌细胞内隔离，但由于电离辐射引起的氧化应激和DNA链断裂而被转运到表面。我们通过开发与具有高亲和力和特异性的辐射诱导应激蛋白结合的肽配体来利用这种生理反应。自1998年以来，Hallahan Lab通过使用平台技术确定了超过4二个辐射诱导的细胞表面蛋白。为了鉴定这些表面蛋白的候选配体，将代表超过20亿倍底的噬菌体展示文库注入了带有辐照癌症的小鼠的循环中。辐照后，将与辐照肿瘤结合的噬菌体扩增并注入另一只肿瘤小鼠。 5通过辐照肿瘤后，辣椒专门与辐照癌症结合。通过蛋白质组学和基因组方法鉴定出这些宠物的细胞表面受体。由癌症特异性，长时间结合并与多种癌症亚型结合，优先考虑了所得的肽配体对受体对。达到所有这些标准的铅辐射诱导的受体包括TIP-1和GRP-78。为了开发针对辐照肿瘤的药物输送系统，我们将利用肽配体来铅受体我们已经确定了。将Petides与治疗剂结合可以特异性地将细胞毒性剂传递到人类癌症的小鼠模型中。通过这种方法，我们改善了癌症药物的肿瘤控制，药代动力学和生物利用度。我们提出研究以检验以下假设：可以利用可诱导的细胞表面蛋白在癌症上实现患者的特定药物递送。我们将将铅肽与PEG和螯合剂结合在一起，以对计划的临床试验中的空间和临时分布进行图像。