Towards rational design of combination therapeutic targets

合理设计联合治疗靶点

基本信息

批准号：
9978415
负责人：
SARAH KATHLEEN TASIAN
金额：
$ 51.14万
依托单位：
CHILDREN'S HOSP OF PHILADELPHIA
依托单位国家：
美国
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-06-01 至 2025-05-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/9978415
关键词：
ATAC-seq Acute Lymphocytic Leukemia Algorithm Design Algorithms B-Cell Acute Lymphoblastic Leukemia B-Lymphocytes Cell Line Cell Proliferation Cell Survival ChIP-seq Chemicals Child Clinical Clustered Regularly Interspaced Short Palindromic Repeats Combined Modality Therapy Complex Cytokine Receptors Data Development Disease Drug Targeting Drug resistance Engineering Gene Proteins Gene Targeting Genes Genetic Genetic Medicine Genetic Transcription Genomics Goals Histones Human In Vitro Institution Knock-out Malignant Neoplasms Methods Multiomic Data Mutation Oncogene Deregulation Oncogenes Oncogenic Outcome Pathway interactions Patients Performance Pharmaceutical Preparations Philadelphia Phosphotransferases Prevalence Proteome Proteomics Regulator Genes Regulatory Pathway Research Research Personnel Resistance development Sampling Signal Pathway Signal Transduction Systems Biology Testing Therapeutic Intervention Time Toxic effect Translational Research Xenograft Model Xenograft procedure base cancer cell case control cohort combat design disease heterogeneity experimental study follow-up high risk in vivo kinase inhibitor novel strategies novel therapeutic intervention phosphoproteomics protein expression research clinical testing resistance mutation side effect small molecule small molecule inhibitor synergism therapeutic target therapy development transcriptome sequencing young adult

项目摘要

Project Summary Given the prevalence of crosstalk among oncogenic pathways and disease heterogeneity, it has become increasingly apparent that combination therapies are required to achieve long-term cure and to minimize development of resistance mutations and escape pathways. The majority of existing combination therapies are developed in an ad hoc fashion, namely one agent at a time, without systematic consideration of potential complex interactions among the gene targets by leveraging disease-specific omics data. Moreover, the existing combination therapies are based on targets of existing drugs, which only represent a small portion of the human proteome. To this end, we hypothesize that systematic identification of synergistic key regulators represents a promising approach for nominating targets of combination therapy. Towards this goal, we will forward engineer a platform for identifying synergistic regulatory nodes in a cancer gene regulatory network as the targets for combination therapy. We will generate disease-specific multi-omics data to construct an integrative gene regulatory network, a pre-requisite for understanding the deregulated gene network in the cancer cells and for developing effective and lasting therapy. We will focus our study on Philadelphia-like acute lymphoblastic leukemia as a proof-of-principle. Our team proposes a novel approach to this problem by leveraging the unique strengths of the investigators in systems biology, genomics, proteomics, and translational research, as well as the large cohort of patient samples available at our institutions. If successful, the proposed framework would be a tremendous advance and paradigm shift to understand genetic interactions among oncogenic pathways for eventual therapeutic intervention.

项目摘要鉴于致癌途径和疾病之间的串扰率异质性，越来越明显的是组合疗法是需要实现长期治愈并最大程度地减少抗性突变的发展并逃脱路径。大多数现有组合疗法都是在临时时尚，一次是一个代理人，没有系统的考虑通过利用特异性疾病的基因靶标之间的潜在复杂相互作用 OMICS数据。此外，现有的组合疗法基于现有药物，仅代表人类蛋白质组的一小部分。为此，我们假设对协同关键调节器的系统识别代表提名联合疗法目标的有前途的方法。针对这个目标，我们将转发一个平台，用于识别一个在癌症基因调节网络作为联合疗法的靶标。我们将生成疾病特异性的多摩学数据构建综合基因调节网络，一个理解癌细胞中失调的基因网络的先决条件发展有效和持久的疗法。我们将把研究重点放在像费城一样急性淋巴细胞白血病作为原则证明。我们的团队提出了一本小说通过利用调查人员的独特优势来解决这个问题系统生物学，基因组学，蛋白质组学和转化研究以及大型我们机构提供的患者样本队列。如果成功，提议框架将是一个巨大的进步和范式转移，以了解遗传最终治疗干预的致癌途径之间的相互作用。