(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：
8687251
负责人：
Alain Charest
金额：
$ 84.56万
依托单位：
TUFTS 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/8687251
关键词：
Address Affect Aftercare Bioinformatics Biological Markers CDKN2A gene Cancer Model Cataloging Catalogs Code Data Databases EGFR inhibition Epidermal Growth Factor Receptor Evolution Gene Expression Gene Expression Profile 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 Patients Physiology Play Process Proteome Proteomics Radiation therapy Recurrence Research Resistance Role Sampling Signal Pathway Signal Transduction Signaling Pathway Gene Stratification System Systems Biology Technology Therapeutic Therapeutic Intervention Time Tumor Suppressor Genes Validation base cancer cell cancer initiation chemotherapy clinically relevant comparative in vivo inhibitor/antagonist mathematical model mouse model mutant neoplastic cell overexpression public health relevance response standard of care temozolomide therapeutic development therapeutic target 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-? 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-? 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（由申请人提供）：许多常见人类癌症的基因组图谱已被破译，许多导致癌症发生和进展的驱动基因突变也已被识别。现在需要解决的一个重要问题是，这些驱动突变在癌症进化过程中何时发生，它们出现的顺序重要吗？尽管驱动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没有争议，但它们发生的顺序以及任何给定顺序对肿瘤生理学的影响的研究却少得多。对驱动基因突变的时间发生的研究一直是我们理解治疗耐药性和敏感性分子机制的关键障碍。该项目拟使用多形性胶质母细胞瘤（GBM）作为癌症模型，直接研究连续驱动基因突变对治疗敏感性的影响。在此应用中，我们将使用基于最常见的驱动基因突变组开发的 GBM 基因工程小鼠模型； EGFR 的过表达/激活以及 Cdkn2a 肿瘤抑制基因的缺失，伴或不伴 PTEN 的缺失以及 PDGFR-α 的过表达/激活以及 p53 的缺失（伴或不伴 PTEN 的缺失）。使用我们的 EGFR 进行的初步研究； Cdkn2a-/- 小鼠表明 PTEN 丢失的时间在肿瘤的分子线路及其对 EGFR 抑制的反应中起着重要作用。我们建议揭示 PTEN 丢失的时间如何影响 EGFR 和 PDGFR-？信号网络并决定所产生的肿瘤细胞的分子线路（目标 1）。这些研究的目的是揭示以前未探索的治疗策略的分子弱点。我们还建议研究 PTEN 的暂时缺失如何影响治疗干预期间分子重新布线的机制（目标 2）。这里提出的研究非常重要，因为具有看似相同基因型（例如 PTEN 突变体）的 GBM 在接受治疗时可能由于驱动基因突变发生的顺序而本质上表现不同。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。