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

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已被鉴定。现在需要解决的一个重要问题是，这些驱动突变在癌症演变过程中何时发生，以及它们出现的顺序是否重要？虽然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研究得少得多。对驱动基因突变的时间发生的研究一直是我们理解治疗抗性和敏感性的分子机制的关键障碍。该项目提出使用多形性胶质母细胞瘤（GBM）作为癌症模型直接研究顺序驱动基因突变对治疗敏感性的影响。在本申请中，我们将使用我们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过表达/激活以及Cdkn 2a肿瘤抑制基因缺失，伴和不伴PTEN缺失，以及PDGFR-α过表达/激活以及p53缺失，伴和不伴PTEN缺失。使用我们的EGFR; Cdkn 2a-/-小鼠的初步研究表明，PTEN丢失的时间在肿瘤的分子布线及其对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-α信号网络中下游通路的利用，并决定所产生的肿瘤细胞的分子布线（Aim 1）。这些研究的目的是揭示以前未探索的分子脆弱性的治疗策略。我们还建议研究PTEN的暂时丢失如何影响治疗干预期间分子重新布线的机制（目的2）。这里提出的研究是非常重要的，因为GBM与看似相同的基因型（例如突变的PTEN）可能本质上表现不同，当暴露于治疗，由于驱动基因突变出现的顺序。对这一过程的分子理解将直接导致更好的患者分层和药物选择。 适当的治疗。

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.