Discovery of immunotherapeutic biologics against the RAS-driven extracellular proteome

发现针对 RAS 驱动的细胞外蛋白质组的免疫治疗生物制剂

基本信息

批准号：
9050439
负责人：
Peter Sung Keun Lee
金额：
$ 2.36万
依托单位：
UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
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：
2016-04-01 至 2016-08-26
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9050439
关键词：
Affinity Antibodies Antibody Affinity Antibody Specificity Antigens Bacteriophages Binding Breast Epithelial Cells Cancer cell line Cell Line Cell Surface Proteins Cell surface Cells Cellular Morphology Coupled Data Set Detergents Development Diagnostic Engineering Extracellular Protein Generations Genetic Transcription Goals Housing Human Immune system Immunofluorescence Immunologic Immunotherapeutic agent Interferometry Investigation KRAS2 gene Lead MCF10A cells Maintenance Malignant Neoplasms Malignant neoplasm of prostate Mass Spectrum Analysis Membrane Membrane Proteins Molecular Molecular Profiling Mutate Normal Cell Oncogenes Oncogenic Pathway interactions Patients Phage Display Production Property Proteins Proteome Proteomics Reagent Recombinant Antibody Recombinants Recruitment Activity Regulation Resolution Signal Transduction Surface Surface Antigens Technology Testing Therapeutic Tissues Tumor Tissue Validation Work base cancer cell cancer therapy cell transformation combat diagnostic biomarker differential expression extracellular insight malignant breast neoplasm malignant state mutant new technology novel potential biomarker protein protein interaction public health relevance ras Oncogene receptor function research study tumor

项目摘要

DESCRIPTION (provided by applicant): The goals of this proposal are to (i) understand how Ras oncogene transformation changes the cell surface proteome and to (ii) generate recombinant antibodies against the extracellular proteome of Ras-driven cancer cells to serve as diagnostic biomarkers and potential therapeutic reagents. Ras is the most common oncogene and is mutated in over 30% of cancers. Transformation of a normal cell to a malignant state is associated with many changes in the proteome including proteins at the cell surface, as well as changes in cell morphology, and result in aberrant signaling and proliferation. Identification of extracellular proteome changes at the surface of Ras-driven cancer cells will lead to a better understanding of the underlying mechanisms that cause these phenotypic alterations. The changes induced by K-Ras mutants will be investigated using several approaches: (i) determination of the differentially expressed protein targets on the extracellular surface of the Ras-induced cells in comparison to normal cells, (ii) antibody generation against the identified extracellular targets, and (iii) assessment of the therapeutic potential of the antibodies against patient-derived cancer cell lines and tissues. Thus, this proposal will be aimed at creating a general platform for understanding and interrogating oncogenic cellular surfaces with novel membrane proteomics and new immunotherapeutic technologies, which can ultimately be extended to many other cancers. The development of these data sets, technologies, and molecular toolkits will provide new insights into how oncogene transformed cells remodel their surfaces.

描述（由申请人提供）：本提案的目标是 (i) 了解 Ras 癌基因转化如何改变细胞表面蛋白质组，以及 (ii) 生成针对 Ras 驱动的癌细胞的细胞外蛋白质组的重组抗体，以用作诊断生物标志物Ras 是最常见的癌基因，在超过 30% 的癌症中发生突变，正常细胞向恶性状态的转变与细胞的许多变化有关。蛋白质组包括细胞表面的蛋白质，以及细胞形态的变化，并导致异常的信号传导和增殖。鉴定 Ras 驱动的癌细胞表面的细胞外蛋白质组变化将有助于更好地了解导致异常信号传导和增殖的潜在机制。将使用多种方法研究 K-Ras 突变体引起的这些表型改变：(i) 与正常细胞相比，确定 Ras 诱导细胞的细胞外表面差异表达的蛋白质靶标；(ii) 抗体。针对已确定的细胞外靶标的生成，以及（iii）评估针对患者来源的癌细胞系和组织的抗体的治疗潜力。因此，该提案旨在创建一个通用平台，用于理解和探究具有新颖性的致癌细胞表面。膜蛋白质组学和新的免疫治疗技术，最终可以扩展到许多其他癌症，这些数据集、技术和分子工具包的开发将为癌基因转化细胞如何重塑其表面提供新的见解。