Apical-basal polarity signaling in glioblastoma

描述（由申请人提供）：在美国，每年有超过44，500人被诊断患有脑或脊柱原发性肿瘤。在这一组中，约有20，500人被诊断患有原发性恶性脑肿瘤。脑肿瘤也是儿童期第二常见的癌症，占所有儿科癌症的约25%。它是儿童实体瘤癌症死亡的主要原因。脑肿瘤的死亡率极高，中位生存期约为12个月。值得注意的是，死亡率在过去二十年中保持不变，因为恶性神经胶质瘤继续对当前手术、放疗或化疗方案的成功临床治疗提出重大问题。恶性胶质瘤的高度侵袭性-胶质母细胞瘤细胞迅速侵入周围的脑实质-源于控制细胞运动的基因缺陷。手术切除后残留的侵袭性肿瘤细胞混淆了临床管理，并显著导致这种疾病的致死性。此外，胶质瘤细胞的化疗和放疗抗性亚群保留干细胞样性质以重新接种肿瘤。这导致复发，预后更差。神经胶质瘤干细胞群体可能在控制自我更新、增殖和分化的基因中存在缺陷。有效靶向这些侵袭性细胞和干细胞群体对于改善恶性胶质瘤的管理和积极的临床结果至关重要。这个建议的目的是确定是否顶端-基底极性信号传导是胶质瘤侵袭性病理和复发的重要分子因素。我们已经观察到，改变的顶-基底极性信号导致发育中的鸡中枢神经系统中携带胚胎神经干细胞标记的未分化细胞的快速增殖和异常迁移。基于上述研究，我们推测顶-基底极性信号通路的异常功能可能在胶质母细胞瘤的侵袭性进展和生长中起重要作用。该提案的具体目的是：（i）验证我们对升高的顶部-基底极性信号通路成分与临床胶质母细胞瘤之间正相关性的初步观察，并研究该通路在胶质瘤病理学中的功能。本研究有望阐明顶-基底极性信号通路在胶质瘤侵袭、生长和进展中的分子功能，并为靶向该通路作为胶质母细胞瘤治疗的新策略提供概念验证。我们的长期目标是在神经胶质瘤的改进治疗模式中合理靶向该通路。 公共卫生相关性：胶质瘤治疗方案的更好疗效的前景取决于控制胶质瘤肿瘤的异常侵袭和复发的分子途径的成功解开。我们的实验旨在确定一种新的分子元件，有助于胶质瘤的侵袭和生长，并了解其功能的分子基础。这项研究的成功完成将为一种新型、易处理的药物发现靶标的合理治疗靶向建立概念验证，以特异性对抗胶质瘤肿瘤扩散和生长。

DESCRIPTION (provided by applicant): Over 44,500 people in the United States are diagnosed with a primary tumor in the brain or spine each year. Of this group, approximately 20,500 are diagnosed with primary malignant brain tumors. Brain tumors are also the second most common cancer of childhood comprising approximately 25% of all pediatric cancers. It is the leading cause of solid tumor cancer death in children. Mortality rates from brain tumors are extremely high, with a median survival of approximately 12 months. Notably, mortality rates have remained unchanged over the last two decades as malignant gliomas continue to present significant problems for successful clinical treatment with the current regimen of surgery, radiotherapy or chemotherapy. The highly aggressive nature of malignant gliomas- glioblastoma cells rapidly invade the surrounding brain parenchyma - stems from defects in genes that control cell motility. Invasive tumor cells remaining after surgical resection confound clinical management and significantly contribute to the lethality of this disease. Additionally, a chemotherapy and radiotherapy resistant subpopulation of glioma cells retain stem cell-like properties to re-seed the tumor. This leads to recurrence with even poorer prognosis. The glioma stem cell population may harbor defects in genes that control self-renewal, proliferation and differentiation. Effective targeting of these invasive cells and the stem cell population is critical for the improved management and positive clinical outcome in malignant gliomas. The objective of this proposal is to determine if apical-basal polarity signaling is an important molecular element in the invasive pathology and recurrence of gliomas. We have observed that altered apical- basal polarity signaling causes the rapid proliferation and abnormal migration of undifferentiated cells bearing markers of embryonic neural stem cells in the developing chick central nervous system. Based on this previous study, we hypothesize that aberrant function of apical-basal polarity signaling pathway may play a central role in the invasive progression and growth of glioblastoma. The specific aims of this proposal are: (i) to validate our preliminary observation of a positive association between elevated apical-basal polarity signaling pathway components and clinical glioblastoma, and to investigate the function of this pathway in glioma pathology. This study is likely to elucidate the molecular function of apical-basal polarity signaling pathway in glioma invasion, growth and progression, and provide the proof-of-concept for targeting this pathway as a novel strategy for glioblastoma therapy. Our long-term goal is the rational targeting of this pathway in an improved therapeutic paradigm for gliomas. PUBLIC HEALTH RELEVANCE: Prospects for better efficacy of glioma treatment protocols hinge on the successful unraveling of molecular pathways that control the aberrant invasion and recurrence of glioma tumors. Our experiments are designed to identity a novel molecular element that aids glioma invasion and growth, and understand the molecular basis of its function. Successful completion of this study will establish the proof-of-concept for rational therapeutic targeting of a novel, pharmacologically tractable, drug discovery target to specifically counter glioma tumor spread and growth.