Unlocking the Chemical Space of Cancer-Associated Perturbations

解锁癌症相关扰动的化学空间

• 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
• 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

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.

精准癌症医学的流行方法依赖于患者的基因图谱，其次是 恶性基因产物的鉴定及该蛋白产物致癌机制的研究 疾病。因此，精确肿瘤学的未来在很大程度上建立在对治疗方法进行量身定制的希望之上 以获取复杂基因组和转录组数据的诊断技术为基础的干预。尽管 关注癌症遗传学，即正常细胞在肿瘤过程中获得的独特功能 发育是由异常激活的肿瘤细胞蛋白质组驱动的，而这种蛋白质组不仅仅是由基因突变引起的 但也来自表观遗传的重新编程、翻译后的改变或信号通路的重新布线。 不幸的是，结合反映肿瘤细胞生物学的传统蛋白质生物化学测量和 肿瘤将对癌症患者的临床决策产生反应的治疗方法具有挑战性 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交界处开展基于机制的癌症研究 评估蛋白质组动态变化以确定肿瘤独特特征的方法 生物学，其长期目标是激励新的靶向治疗。具体来说，我们的目标是建立一个 创新的肿瘤新开发和发现平台，称为探针使能活动报告(PEAR) 利用化学生物学方法进行蛋白质组谱分析以了解其分子复杂性 肿瘤细胞功能所必需的蛋白质组学变化，以及细胞对癌症治疗的适应。这个 我们的床边到长凳再回来的方法的基础是一种假设，即新的化学物质 探针反应存在于癌细胞本身以及反应组谱的变化对癌症的反应 治疗学将反映驱动癌细胞适应的蛋白质功能的变化，因此，将是理想的 用于未来新的治疗方式。在相互关联和跨学科的发现和解释中 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 差异反应假说下治疗前后化学生物学探针的靶点 将指示蛋白质组的责任、治疗反应和肿瘤细胞生物学的独特方面。这个 投资PEAR用于肿瘤蛋白质组分析以实现治疗开发的主要结果将是 开发可视化反应目标的方法，识别治疗引起的反应目标和 建立它们的功能相关性，并基于一种新的 分区反应性靶标法。综上所述，我们的提案将建立和验证小说 可以广泛应用于实体肿瘤的概念和方法，作为延伸， 具有提供对肿瘤生物学的基本见解并通过以下方式转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例。