Microenvironmental Regulation of Glioblastoma Angiogenesis via CHD7

 描述（由申请人提供）：多形性胶质母细胞瘤（GBM）是成人中最常见的原发性恶性脑肿瘤，也是最致命的癌症之一，部分原因是治疗耐药性和肿瘤复发。一个令人信服的原因是GBM的异质性，治疗开发已被证明具有挑战性。这些恶性肿瘤含有称为脑肿瘤起始细胞（BTIC）的肿瘤细胞亚群，其由于能够促进肿瘤血管生成而具有高度致瘤性，并且具有非肿瘤性神经干细胞的一些特性。BTIC具有在以血管或坏死/缺氧小生境为特征的独特肿瘤微环境中存活的独特能力。坏死/缺氧小生境含有大于生理标准的酸度水平，并且低细胞外pH有助于肿瘤生长并富集BTIC表型。这些微环境压力的表观遗传机制尚未阐明。在这项研究中，已被确定为染色质重塑分子的目标将进行调查，以确定其在调节血管生成的作用。我们还将靶向酸性肿瘤微环境，以确定肿瘤内pH的调节是否对治疗策略有益。通过这项研究，我们希望更好地了解酸性微环境对表观遗传变化的贡献，并开发一种新的治疗策略，以靶向患者治疗中的血管生成。

 DESCRIPTION (provided by applicant): Glioblastoma multiform (GBM) is the most common primary malignant brain tumor in adults and among the deadliest cancers due, in part, to therapeutic resistance and tumor recurrence. One compelling reason therapy development has proven challenging is the heterogeneous nature of GBMs. These malignancies contain a subset of tumor cells known as brain tumor initiating cells (BTICs) that are highly tumorigenic due to an ability to promote tumor angiogenesis and have some properties of non-neoplastic neural stem cells. BTICs have a unique ability to survive in a distinct tumor microenvironments characterized as either vascular or necrotic/hypoxic niches. The necrotic/hypoxic niches contain levels of acidity greater than physiologic norms, and low extracellular pH contributes to tumor growth and enriches for BTIC phenotypes. Epigenetic mechanisms contributing to these microenvironmental pressures have not been elucidated. In this study, a molecular target that has been identified as a chromatin remodeler will be investigated to determine its role in regulating angiogenesis. We will also target the acidic tumor microenvironment to determine if the modulation of intratumoral pH can be a benefit to therapeutic strategies. Through this study we hope to achieve a greater understanding of the contribution of acidic microenvironments to epigenetic changes and develop a novel treatment strategy to target angiogenesis in patient therapies.