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Unlocking the Chemical Space of Cancer-Associated Perturbations

解锁癌症相关扰动的化学空间

基本信息

批准号：
10478520
负责人：
Donita C Brady
金额：
$ 43.18万
依托单位：
UNIVERSITY OF PENNSYLVANIA
依托单位国家：
美国
项目类别：
财政年份：
2022
资助国家：
美国
起止时间：
2022-09-14 至 2027-08-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10478520
关键词：
Aftercare Award Back Basic Science Biochemical Biological Assay Biological Models Biology Biomedical Research Bypass Cancer Biology Cancer Model Cancer Patient Cell Line Cell physiology Chemicals Chemistry Clinical Clustered Regularly Interspaced Short Palindromic Repeats Complex Coupled Coupling Data Development Diagnostic Discipline Disease Elements Engineering Epigenetic Process Foundations Future Gene Mutation Generations Genetic Genomic approach Genomics Goals Individual Label Link Malignant - descriptor Malignant Neoplasms Maps Measurement Methodology Methods Modality Molecular Monitor Normal Cell Oncogene Activation Oncogenic Outcome Patient-Focused Outcomes Patients Plant Roots Post-Translational Protein Processing Prediction of Response to Therapy Primary carcinoma of the liver cells Protein Biochemistry Proteins Proteome Proteomics Reagent Reporting Research Research Personnel Resources Sampling Signal Pathway Solid Neoplasm Technology Therapeutic Therapeutic Intervention Tissue Banks Tissue Sample Translations Tumor Biology Tumor Cell Biology Visualization anticancer research base behavioral response bench to bedside cancer cell cancer genetics cancer genomics cancer initiation cancer therapy cancer type chemoproteomics clinical decision-making design diagnostic technologies driver mutation drug development drug discovery empowered gene product genetic approach genetic predictors genetic profiling imaging approach imaging probe improved innovation insight neoplastic cell new technology new therapeutic target novel novel therapeutics patient subsets precision medicine precision oncology protein degradation protein function response targeted treatment therapeutic development therapeutic target tool transcriptomics treatment response treatment strategy tumor

项目摘要

The prevailing approach to precision cancer medicine relies on genetic profiling of patients, followed by identification of the malignant gene product, and delineation of the mechanisms of that protein product in causing disease. As a result, much of the future of precision oncology is built on the hope of tailoring therapeutic interventions based on diagnostic technologies that acquire complex genomic and transcriptomic data. Despite the focus on cancer genetics, the unique functional capabilities acquired by normal cells during tumor development are driven by the aberrantly activated tumor cell proteome that arises not only from gene mutations but also from epigenetic reprogramming, post-translational alterations, or rewiring of signaling pathways. Unfortunately, integrating traditional measurements of protein biochemistry that reflect tumor cell biology and the therapeutics to which a tumor would respond into clinical decision-making for cancer patients is challenging due to the uniqueness of each protein and limitations in existing technologies. Thus, our proposal focuses on mechanism-based cancer research at the interface of chemistry and cancer biology to develop quantitative approaches that evaluate dynamic changes in the proteome in order to characterize unique features of tumor biology with the long-term goal of motivating novel targeted therapies. Specifically, we aim to establish an innovative new development and discovery platform termed Probe Enabled Activity Reporting (PEAR) for tumor proteome profiling by leveraging chemical biology approaches to understand the molecular complexity of proteomic changes necessary for tumor cell function, as well as cellular adaptations to cancer therapy. The foundation of our bedside-to-bench and back again approach is rooted in the hypothesis that novel chemical probe reactomes exist in cancer cells themselves and changes in the reactome profile in response to cancer therapeutics will reflect alterations in protein function that drive cancer cell adaptations and thus, would be ideal for new treatment modalities in the future. In interconnected and interdisciplinary discovery and elucidation modules, we will utilize state-of-the-art patient derived cancer models to both visualize and identify the protein targets of chemical biology probes in pre- and post-treatment with the hypothesis that the differential reactomes will be indicative of proteomic liabilities, therapeutic response, and unique aspects of tumor cell biology. The major outcomes from investing in PEAR for tumor proteome profiling to enable therapeutic development will be development of methodology to visualize reactive targets, identification of treatment induced reactive targets and establishing their functional relevance, and unraveling unique tumor cell biology based on a novel compartmentalized reactive target method. Taken together, our proposal will establish and validate novel concepts and methodologies that can be applied across the broad spectrum of solid tumors and as an extension, holds the potential to provide fundamental insights into tumor biology and transform precision oncology by providing a platform to improve existing paradigms for drug discovery.

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