(PQB5)Molecular Wiring and Therapeutic Targeting of EGFR and PDGFR Signaling Netw

(PQB5)EGFR 和 PDGFR 信号网络的分子布线和治疗靶向

基本信息

批准号：
9122358
负责人：
Alain Charest
金额：
$ 88.24万
依托单位：
BETH ISRAEL DEACONESS MEDICAL CENTER
依托单位国家：
美国
项目类别：
财政年份：
2014
资助国家：
美国
起止时间：
2014-09-01 至 2018-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9122358
关键词：
Address Affect Aftercare Bioinformatics CDKN2A gene Cancer Model Catalogs Clinical Code Data Databases EGFR inhibition Epidermal Growth Factor Receptor Evolution Gene Mutation Genes Genetically Engineered Mouse Genomics Genotype Glioblastoma Goals Growth Human Knowledge Lead Malignant - descriptor Malignant Neoplasms Malignant neoplasm of brain Malignant neoplasm of central nervous system Methods Molecular Molecular Profiling Mus Mutation PDGFRB gene PTEN gene Pathway Analysis Pathway interactions Phenotype Physiology Platelet-Derived Growth Factor alpha Receptor Play Process Proteome Proteomics Radiation therapy Recurrence Research Role Sampling Signal Pathway Signal Transduction Signaling Protein Suppressor Genes System Systems Biology TP53 gene Technology Therapeutic Therapeutic Intervention Time Tumor Suppressor Genes Validation actionable mutation base cancer cell cancer initiation chemotherapy clinically relevant comparative in vivo inhibitor/antagonist mathematical model mouse model mutant neoplastic cell overexpression patient biomarkers patient stratification phosphoproteomics public health relevance response standard of care temozolomide therapeutic development therapeutic target therapy resistant transcriptome treatment response treatment strategy tumor tumor progression tumorigenesis

项目摘要

DESCRIPTION (provided by applicant): The genomic landscapes of many common human cancers have been deciphered and many of the driver gene mutations that are responsible for cancer initiation and progression have been identified. An important question to address now is when do these driver mutations occur during the evolution of cancers and does the order in which they appear matters? Although the identity of the driver mutations and their role in various cancers including primary malignant brain cancer is not debated, the order in which they occur and the consequences of any given order on tumor physiology are much less studied. Studies on the temporal occurrence of driver gene mutations have been a critical barrier to our understanding of molecular mechanisms of therapeutic resistance and sensitivity. This project proposes to directly study the consequences of sequential driver gene mutations on therapeutic treatment sensitivity using glioblastoma multiforme (GBM) as a cancer model. In this application, we will use genetically engineered mouse models of GBM that we developed based on the most common groups of driver gene mutations; overexpression/activation of EGFR together with loss of the Cdkn2a tumor suppressor gene with and without loss of PTEN and overexpression/activation of PDGFR-α together with loss of p53 with and without loss of PTEN. Preliminary studies using our EGFR; Cdkn2a-/- mice indicate that the timing of PTEN loss plays a significant role in the molecular wiring of the tumors and their responses to EGFR inhibition. We propose to reveal how the timing of PTEN loss influences the utilization of downstream pathways within the EGFR and PDGFR-α signaling networks and dictate the molecular wiring of the resulting tumor cells (Aim 1). The goal of these studies is to reveal previously unexplored molecular vulnerabilities for therapeutic strategies. We also propose to study how the temporal loss of PTEN affects mechanisms of molecular re-wiring during therapeutic intervention (Aim 2). The research presented here is very important because GBM with seemingly identical genotypes (e.g. mutant for PTEN) may intrinsically behave differently when exposed to therapeutics due to the order with which driver gene mutations arose. A molecular understanding of this process will directly lead to better stratification of patients and choice of suitable treatments.

描述（由适用提供）：已经确定了许多人类癌症的基因组景观，并且已经确定了导致癌症启动和进展的许多驱动基因突变。现在要解决的一个重要问题是，这些驱动因素突变何时发生在癌症的演变过程中，并且它们看起来重要的顺序是否重要？尽管尚未辩论驱动突变突变的身份及其在包括原发性恶性脑癌在内的各种癌症中的作用，但研究的顺序以及任何给定秩序对肿瘤生理学的后果的研究较少。关于驱动基因突变的暂时发生的研究一直是我们对热阻力和敏感性分子机制的理解的关键障碍。该项目的建议是直接研究使用胶质母细胞瘤多形（GBM）作为癌症模型的顺序驱动基因突变对治疗敏感性的后果。在此应用程序中，我们将使用我们基于最常见的驱动基因突变组开发的一般设计的GBM的小鼠模型。 EGFR的过表达/激活以及CDKN2A肿瘤抑制基因的丧失，而PTEN和PTEN损失和PDGFR-α的过表达/激活以及p53的损失，而p53损失有或没有PTEN的损失。使用我们的EGFR进行初步研究； CDKN2A - / - 小鼠表明，PTEN损失的时机发挥作用A，我们建议揭示PTEN损耗的时机如何影响EGFR和PDGFR-α信号网络内下游途径的利用，并决定所得肿瘤细胞的分子布线（AIM 1）。这些研究的目的是揭示以前意外的分子脆弱性治疗策略。我们还建议研究PTEN的暂时性损失如何影响治疗干预期间分子重播的机制（AIM 2）。此处介绍的研究非常重要，因为具有看似相同基因型的GBM（例如PTEN突变体）可能在接受治疗时本质上的行为可能会有所不同。对这一过程的分子理解将直接导致更好的患者分层和选择合适的治疗方法。