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

描述（由申请人提供）：许多常见的人类癌症的基因组景观已经被破译，许多负责癌症起始和进展的驱动基因突变已经被确定。现在要解决的一个重要问题是，在癌症的进化过程中，这些驱动突变是什么时候发生的，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却很少被研究。对驱动基因突变时间发生的研究是我们理解治疗耐药和敏感性分子机制的关键障碍。本项目拟以多形性胶质母细胞瘤（GBM）为肿瘤模型，直接研究序列驱动基因突变对治疗敏感性的影响。在本应用中，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过表达/激活并缺失Cdkn2a肿瘤抑制基因，PTEN缺失和不PTEN缺失；PDGFR-α过表达/激活并p53缺失，PTEN缺失和不PTEN缺失。使用我们的EGFR进行初步研究；Cdkn2a-/-小鼠表明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。我们打算揭示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，并决定由此产生的肿瘤细胞的分子连接（目的1）。这些研究的目的是揭示以前未探索的治疗策略的分子脆弱性。我们还建议研究PTEN的时间缺失如何影响治疗干预期间分子重新布线的机制（目的2）。这里提出的研究非常重要，因为表面上具有相同基因型的GBM（例如PTEN突变）在暴露于治疗药物时，由于驱动基因突变发生的顺序，可能本质上表现不同。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

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.