Center for Cancer Systems Therapeutics (CaST)

癌症系统治疗中心 (CaST)

基本信息

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
项目类别：
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

项目摘要

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.

项目概要患有侵袭性癌症的患者通常不存在可药理学作用的突变，并且表现不佳或没有对免疫检查点阻断的敏感性，因此仅能适度改善无病生存率靶向治疗和免疫治疗通过促进重编程进一步增加了复杂性，耐药细胞的适应、选择和最终扩增，以及耐药细胞的出现免疫抑制肿瘤微环境（TME），两者都是导致患者复发的最终原因应对这些挑战，即确定更普遍、基于机制的目标。药物干预并评估其在高度异质性肿瘤中的潜在价值至关重要取决于准确、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），它是癌细胞及其细胞自主行为的基础拟议的癌症系统治疗（CaST）中心将与其他 TME 亚群相互作用。继续在 U54 癌症系统生物学中心 (CSBC) 网络内进行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以及新颖的实验技术，包括使用 3D 结构和基于多组学的证据。支持将癌症研究为共同进化的亚群的完全集成系统，包括两者分子上不同的、共存的恶性细胞状态以及招募到肿瘤的非恶性细胞状态微环境并可能被重新编程以实现促恶性、免疫抑制的环境。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针对个体的作用机制亚群驱动联合治疗或挽救耐药肿瘤的免疫治疗。