PEGYLATED PEPTIDES LIGANDS TARGETING RADIATION-INDUCIBLE RECEPTORS ON CANCER

 描述(由申请人提供)：拟议的研究是对癌症治疗和癌症药物开发的新范式的研究。这一平台技术将显着增加癌症特异性表面受体和抗原的数量，这些受体和抗原可以通过多肽配体靶向药物输送。这项新技术的一般原理是，癌细胞通过应激反应对电离辐射做出反应，应激反应涉及膜运输和应激蛋白在细胞表面的呈现。这些蛋白质通常被隔离在癌细胞内，但由于电离辐射引起的氧化应激和DNA链断裂，这些蛋白质被运输到表面。我们通过开发与辐射诱导的应激蛋白高度亲和力和特异性结合的多肽配体来利用这种生理反应。自1998年以来，Hallahan实验室已经通过使用平台技术鉴定了40多种辐射诱导的细胞表面蛋白。为了确定这些表面蛋白的候选配体，一个代表超过20亿个多肽的噬菌体展示文库被注入到携带辐射癌症的小鼠的循环中。将与照射肿瘤结合的噬菌体进行扩增，并在照射后注射到另一只荷瘤小鼠体内。经过5次辐射后，多肽与辐射后的肿瘤特异性结合。用蛋白质组学和基因组学方法鉴定了这些多肽的细胞表面受体。由此产生的多肽配体-受体对根据癌症特异性、延长的结合时间和与多种癌症亚型的结合而优先考虑。达到所有这些标准的铅辐射诱导受体包括TIP-1和GRP-78。为了开发针对辐射肿瘤的药物传递系统，我们将利用多肽配体来引导受体 我们已经确定了。多肽与治疗剂的偶联可以将细胞毒剂特异性地输送到人类癌症的小鼠模型中。通过这种方法，我们改善了肿瘤控制、药物动力学和抗癌药物的生物利用度。我们建议进行研究，以检验癌症上可诱导的细胞表面蛋白可以被用来实现患者癌症特异性药物递送的假设。我们将把先导肽与聚乙二醇和螯合剂结合起来，在计划的临床试验中用于成像多肽的空间和时间分布。

 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.