Center for Cancer Systems Therapeutics (CaST)

癌症系统治疗中心 (CaST)

• 批准号: 10729383
• 负责人: ANDREA CALIFANO
• 金额: $ 175.41万
• 依托单位: COLUMBIA UNIVERSITY HEALTH SCIENCES
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-09-19 至 2028-08-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10729383
• 关键词: Acceleration; Address; Advanced Malignant Neoplasm; Behavior; Binding; Biological; Biological Markers; Buffers; Cancer Center; Cells; Clinical; Collaborations; Combined Modality Therapy; Dependence; Development; Disease-Free Survival; Dissection; Drug resistance; Education; Endocrine; Epigenetic Process; Event; Fostering; Genetic; Genetic Transcription; Goals; Immunotherapy; Individual; Intervention; Intervention Trial; Ligands; Maintenance; Malignant - descriptor; Malignant Neoplasms; Mediating; Metastatic malignant neoplasm to brain; Methodology; Molecular; Mutation; Network-based; Non-Malignant; Non-Small-Cell Lung Carcinoma; Outcome; Patients; Pharmaceutical Preparations; Pharmacology; Phenotype; Printing; Productivity; Prognosis; Proteome; Proteomics; Publications; Research; Research Personnel; Reverse engineering; Science; Scientist; Signal Transduction; Structure; System; Systems Biology; Systems Integration; Technology; Therapeutic; Therapy trial; Tissues; Validation; actionable mutation; cancer cell; cancer therapy; cell type; clinical translation; clinically relevant; design; drug mechanism; evidence base; forging; immune checkpoint blockade; improved; innovation; interest; melanoma; multiple data sources; multiple omics; next generation; novel; outreach; paracrine; patient responsibilities; pharmacologic; programs; receptor; receptor-mediated signaling; recruit; relapse patients; single cell technology; targeted treatment; three dimensional structure; tumor; tumor heterogeneity; tumor initiation; tumor microenvironment; tumor progression; tumor-immune system interactions; virtual

PROJECT SUMMARY Patients with aggressive cancers often present with no pharmacologically actionable mutations and poor or no sensitivity to immune checkpoint blockade, thus deriving only modest improvement in disease-free survival from targeted therapy and immunotherapy. Tumor heterogeneity adds further complexity by fostering reprogramming, adaptation, selection, and ultimately expansion of drug-resistant cells, as well as emergence of an immunosuppressive tumor microenvironment (TME), both of which are ultimately responsible for patient relapse and poor outcome. Addressing these challenges—i.e., identifying more universal, mechanism-based targets for pharmacological intervention and assessing their potential value in highly heterogeneous tumors—is critically dependent on the availability of accurate, comprehensive, and cell type-specific molecular interaction networks (cellular networks, hereafter), which underlie both the cell-autonomous behavior of cancer cells and their interaction with other TME subpopulations. The proposed Cancer Systems Therapeutics (CaST) Center, will continue its highly productive collaboration within the U54 Cancer Systems Biology Center (CSBC) network by extending its successful network-based methodologies—which integrate cutting edge computational advances and novel experimental technologies, including use of 3D structure and multi-omics-based evidence. This will support studying cancer as a fully integrated system of co-evolving, interacting subpopulations, comprising both molecularly distinct, coexisting malignant cell states as well as non-malignant cell states recruited to the tumor microenvironment and potentially reprogrammed to implement a pro-malignant, immunosuppressive milieu. The ultimate goal of this proposal is to leverage recent advances by CaST center investigators to elucidate the Mechanism of Action of clinically relevant drugs and late-stage experimental compounds to target individual subpopulation to either drive combination therapy or to rescue immunotherapy in drug resistant tumors.

项目摘要 患有侵袭性癌症的患者通常不存在可消除的突变， 对免疫检查点阻断的敏感性，因此仅从 靶向治疗和免疫治疗。肿瘤异质性通过促进重编程而增加了进一步的复杂性， 适应，选择，并最终扩大耐药细胞，以及出现一个 免疫抑制性肿瘤微环境（TME），这两者最终导致患者复发 结果不佳。应对这些挑战，即，确定更普遍的、基于机制的目标， 药物干预和评估其在高度异质性肿瘤中的潜在价值是至关重要的 依赖于准确、全面和细胞类型特异性分子相互作用网络的可用性 （细胞网络，下文），这是癌细胞的细胞自主行为及其 与其他TME亚群的相互作用。拟议中的癌症系统治疗中心（CAST）将 继续其在U 54癌症系统生物学中心（CSBC）网络内的高效合作， 扩展其成功的基于网络的方法-集成了尖端的计算进步 和新的实验技术，包括使用3D结构和多组学证据。这将 支持将癌症作为共同进化、相互作用的亚群的完全集成系统进行研究， 分子上不同的、共存的恶性细胞状态以及募集到肿瘤中的非恶性细胞状态 微环境，并可能重新编程以实现促恶性的免疫抑制环境。的 该提案的最终目标是利用CAST中心研究人员的最新进展来阐明 临床相关药物和后期实验化合物对靶向个体的作用机制 在耐药肿瘤中，可以将免疫治疗用于驱动联合治疗或挽救免疫治疗。