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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.

精准癌症医学的主流方法依赖于患者的基因图谱，鉴定恶性基因产物，并描述该蛋白质产物引起肿瘤的机制。疾病因此，精确肿瘤学的未来很大程度上是建立在定制治疗的希望之上的。基于获取复杂基因组和转录组数据的诊断技术的干预措施。尽管关注癌症遗传学，肿瘤发生过程中正常细胞获得的独特功能肿瘤细胞蛋白质组的异常激活不仅导致了基因突变，而且还来自表观遗传重编程、翻译后改变或信号通路的重新布线。不幸的是，将反映肿瘤细胞生物学的蛋白质生物化学的传统测量与肿瘤细胞的生物学特性相结合，肿瘤将对癌症患者的临床决策做出反应的治疗是具有挑战性的，每种蛋白质的独特性和现有技术的局限性。因此，我们的建议侧重于在化学和癌症生物学的界面上进行基于机制的癌症研究，评估蛋白质组动态变化的方法，以表征肿瘤的独特特征生物学与激励新的靶向治疗的长期目标。具体来说，我们的目标是建立一个创新的新开发和发现平台，称为肿瘤探针激活活动报告（PEAR）蛋白质组分析通过利用化学生物学方法来了解分子的复杂性，肿瘤细胞功能所必需的蛋白质组变化，以及细胞对癌症治疗的适应。的我们从床边到长凳再回来的方法的基础是基于这样的假设：新的化学物质探针反应组存在于癌细胞本身中，治疗将反映驱动癌细胞适应的蛋白质功能的改变，未来的新治疗模式。在相互关联和跨学科的发现和阐明模块，我们将利用最先进的患者来源的癌症模型来可视化和识别蛋白质在治疗前和治疗后的化学生物学探针的目标，假设差异反应组将指示蛋白质组责任、治疗反应和肿瘤细胞生物学的独特方面。的投资PEAR进行肿瘤蛋白质组分析以实现治疗开发的主要成果将是开发可视化反应性靶标的方法，识别治疗诱导的反应性靶标，建立它们的功能相关性，并基于一种新的肿瘤细胞生物学机制，分区反应目标法综上所述，我们的建议将建立和验证新的概念和方法，可以应用于广泛的实体瘤和作为一个扩展，具有提供肿瘤生物学基本见解和改变精确肿瘤学的潜力，提供一个平台来改进现有的药物发现范式。