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

描述(申请人提供)：许多常见人类癌症的基因组图谱已经被破译，许多导致癌症发生和发展的驱动基因突变已经被识别出来。现在要解决的一个重要问题是，这些驱动程序突变是在癌症进化过程中何时发生的，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尚无争议，但对它们发生的顺序以及任何给定顺序对肿瘤生理的影响的研究要少得多。对DIVE基因突变的时间发生的研究一直是我们理解治疗耐药和敏感性的分子机制的关键障碍。该项目建议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。在这个应用中，我们将使用我们建立的基底膜的基因工程小鼠模型，该模型基于最常见的驱动基因突变组：表皮生长因子受体的过度表达/激活和CDKN2a抑癌基因的缺失，以及pDGFR-α的过度表达/激活和p53的缺失。利用我们的EGFR；CDKN2a-/-小鼠进行的初步研究表明，PTEN丢失的时间在肿瘤的分子连接及其对EGFR抑制的反应中起着重要作用。我们建议揭示PTEN缺失的时机如何影响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连接(目标1)。这些研究的目标是揭示以前未被探索的治疗策略的分子脆弱性。我们还建议研究PTEN的暂时丢失如何影响治疗干预过程中分子重新连接的机制(目标2)。这里提出的研究是非常重要的，因为具有似乎相同的基因类型(例如，PTEN的突变)的GBM在接受治疗时可能本质上表现不同，这是由于驱动基因突变发生的顺序。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.