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Systematic Targeting of Oncogene Interacting Proteins to Reveal New Therapeutic Strategies

系统靶向癌基因相互作用蛋白以揭示新的治疗策略

基本信息

批准号：
9756188
负责人：
Mehdi Bouhaddou
金额：
$ 6.09万
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：
2019
资助国家：
美国
起止时间：
2019-06-01 至 2022-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9756188
关键词：
Adaptor Signaling Protein Aerobic Affinity Chromatography Binding Biochemical Biological Process CRISPR/Cas technology Cancer cell line Cell Proliferation Cell physiology Cells Cessation of life Clustered Regularly Interspaced Short Palindromic Repeats Complementary DNA Complex Computing Methodologies Data Development Differential Equation Disease Enzyme-Linked Immunosorbent Assay FRAP1 gene GAB1 gene Genes Genetic Glucose Transporter Goals Growth Head and Neck Cancer Human Hyperglycemia Interruption Knock-out Knowledge Link Lipids Malignant - descriptor Malignant Neoplasms Mass Spectrum Analysis Measurement Mediating Mediator of activation protein Metabolic Metabolism Mission Modeling Mutate Oncogenes Oncogenic Outcome PIK3CA gene Pathway interactions Pharmacology Phenotype Phosphatidylinositol 4,5-Diphosphate Phosphatidylinositols Phosphotransferases Problem Solving Proteins Proteomics Proto-Oncogene Proteins c-akt Public Health Regulation Research Research Proposals Role Signal Pathway Signal Transduction Specificity Techniques Technology Testing Therapeutic Toxic effect United States National Institutes of Health Work base blood glucose regulation cancer initiation cancer therapy cell growth cell growth regulation cell motility clinical development computer framework design experimental study fighting fitness insight kinase inhibitor knockout gene live cell microscopy mathematical model mutant network models new therapeutic target novel novel therapeutic intervention novel therapeutics overexpression phosphatidylinositol 3,4,5-triphosphate phosphoproteomics programs protein protein interaction recruit side effect systemic toxicity therapeutic target tumor progression

项目摘要

PROJECT SUMMARY/ABSTRACT Cancer is an intimate part of us, recruiting a complex array of endogenous cellular processes to drive its fitness. Cancer initiation and progression is frequently the result of coordinated dysregulation of multiple signaling pathways by key oncogenes that strategically coopt the cancer signaling network. These oncogenes rarely work in isolation but instead form intricate higher-order complexes and participate in multifaceted networks of protein- protein interactions. One of the most commonly mutated proteins across all of human cancers is the phosphoinositide 3-kinase (PI3K) oncogene, a lipid kinase that can exploit diverse cellular programs to drive disease, including increased proliferation, survival, motility, cell growth and metabolic activity. Broad inhibition of PI3K is known to generate systemic toxicities, especially metabolic, which limit its clinical development. However, targeting PI3K interacting proteins may enable a safer alternative, by interrupting PI3K oncogenic activity while minimizing metabolic dysregulation. The long-term goal of this proposal is to deepen and refine our understanding of oncogene regulation of cancer signaling networks using systematic genetic, proteomic, and mathematical modeling approaches. The overall objective of this proposal is to identify the role of PI3K interacting proteins in modulating PI3K activity and recruitment of downstream cellular processes and to use this understanding to identify alternative therapeutic targets. This objective will be reached by testing the central hypothesis that PI3K interacting proteins, or downstream signaling pathways, can be modulated to tune PI3K activity and specificity, with the potential to simultaneously reduce malignancy and systemic toxicity. To test this hypothesis, the following three aims will be pursued. (Aim 1) Reveal Regulation of PI3K Activity and Cancer Phenotypes by PIK3CA Interacting Proteins. This aim will use CRISPR/Cas9 gene knockout technology to systematically delete and overexpress genes corresponding to PIK3CA interacting proteins and use live cell microscopy, combined with biochemical measurements, to assess the resulting impact on cell proliferation, survival, growth, motility, and metabolism. (Aim 2) Elucidate Proteomic Exploitation by PI3K as Mediated by PIK3CA Interacting Proteins. Here, PIK3CA interactors that preferentially bind the common H1047R mutant, as well as hits identified from Aim 1, will be subject to global proteomics and phosphoproteomics profiling to identify signaling pathways and biological processes regulated by each PIK3CA interacting protein. (Aim 3) Delineate Mechanisms of PI3K-mediated Manipulation of Pro-Cancer Signaling. Here, a novel computational framework will be developed by uniting data-driven network propagation techniques with mechanistic ordinary differential equation (ODE) modeling to delineate mechanistic pathways linking each PIK3CA interacting protein to its downstream effect. Successful completion of the proposed research will greatly enhance our mechanistic understanding of oncogene regulation in cancer. This will be a significant contribution as it will reveal novel therapeutic strategies to fight cancer while minimizing systemic toxicities.

项目总结/文摘