Novel, orally available ATM inhibitor for glioma conformal radiosensitization

用于神经胶质瘤适形放射增敏的新型口服 ATM 抑制剂

基本信息

批准号：
9184543
负责人：
KRISTOFFER Carl VALERIE
金额：
$ 16.58万
依托单位：
VIRGINIA COMMONWEALTH UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2015
资助国家：
美国
起止时间：
2015-12-01 至 2017-11-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9184543
关键词：
Adjuvant Adverse effects Animal Experimentation Animal Model Animals Blood - brain barrier anatomy Brain Brain Neoplasms Cannulas Cell Differentiation process Cells Central Nervous System Neoplasms Characteristics Clinic Clinical Clinical Treatment Convection DNA Damage Data Diagnosis Disease Dose DsRed Fluorescence Generations Glioblastoma Glioma Human Human Engineering Impairment In Vitro Inflammation Life Expectancy Malignant Glioma Malignant Neoplasms Malignant neoplasm of brain Modeling Molecular Monitor Mus Mutant Strains Mice Mutate Mutation Neurons Normal tissue morphology Nude Mice Oral PTEN gene Patients Pharmaceutical Preparations Preparation Process Proliferating Property Protein-Serine-Threonine Kinases Proteins Proto-Oncogene Proteins c-akt Publishing Radiation Radiation-Sensitizing Agents Radiosensitization Reagent Reporting Role Running Schedule Signal Transduction Site Stem cells System TP53 gene Testing Therapeutic Therapeutic Agents Therapeutic Intervention Time Toxic effect Xenograft Model Xenograft procedure ataxia telangiectasia mutated protein base bioluminescence imaging brain parenchyma cell motility clinical practice clinically relevant combat epidermal growth factor receptor VIII experimental study improved in vivo inhibitor/antagonist insight kinase inhibitor mutant nerve stem cell nestin protein neurogenesis novel novel strategies novel therapeutic intervention novel therapeutics outcome forecast patient population promoter public health relevance radioresistant relating to nervous system research clinical testing response standard care temozolomide therapeutic target treatment effect treatment strategy tumor tumor growth

项目摘要

DESCRIPTION (provided by applicant): Glioblastoma multiforme (GBM) is a devastating disease with a median survival of only about a year. Little progress has been made in the treatment of GBM during the last 30 years. Thus, novel approaches and therapeutic agents are urgently needed. We recently showed that the second-generation ATM inhibitor (ATMi), KU-60019, is a potent radiosensitizer in the first report published on this novel compound. Briefly, KU-60019 is a very specific ATM kinase inhibitor in vitro and impressively radiosensitizes human glioma cells irrespective of PTEN and p53 status but has much better effect in vivo with mutant p53 gliomas. In addition, our studies have shown that glioma cell migration and invasion in vitro were inhibited by KU-60019 perhaps by interfering with AKT and ERK signaling. Thus, the potential clinical benefit of an ATMi as a radiosensitizer for GBM is not limited to its abilit to block the DNA damage response (DDR) and potently radiosensitize glioma cells but also to inhibit invasion and spread of the cancer in between radiation fractions. However, one of the drawbacks with KU-60019 is that it does not cross the blood-brain-barrier (BBB) and requires direct intra-tumoral delivery to be effective. Thus, an ATMi able to cross the BBB would facilitate and improve treatment at every level. Herein, we will test a third-generation ATMi, AZ31, with enhanced properties for treating brain tumors. Our preliminary data shows that AZ31 radiosensitizes human and mouse glioma cells and blocks the DDR in vitro, and prolongs the survival of mice growing syngeneic orthotopic tumors with mutant p53. However, radiation scheduling and dosing using a representative panel of human xenografts, such as glioma stem cells, now needs to be performed in order to bring this compound closer to clinical testing. Thus, further testing of AZ31 in mouse glioma models using clinically relevant human GBM xenografts with different p53 status as well as other critical GBM characteristics is now warranted (Aim 1). Little is known about the molecular processes occurring in the brain in response to DNA damage resulting from an ATMi and radiation but, in general, it is believed that neurogenesis would be impaired due to DDR sequelae and inflammation. Except for stem cells and neural progenitors (NPs), the brain consists mostly of terminally differentiated cells that do not proliferate. Thus, aggressively growing glial brain tumors residing in the brain parenchyma would be very favorable for therapeutic intervention with AZ31, in particular if the tumor carries mutation in p53, which is the case at least 30% of the time. In this case one expects the therapeutic gain to be highly favorable. Nevertheless, it is very important to examine what effect this treatment might have on the neural compartment so that appropriate steps can be taken to spare normal tissue such as using conformal radiation (Aim 2). We expect that insights gained from the proposed animal studies will demonstrate proof-of-principle of a novel `synthetical lethal' drug and radiation combination strategy for the treatment of GBM that would be effective and safe.

描述（由申请人提供）：多形性胶质母细胞瘤（GBM）是一种毁灭性的疾病，其中位生存期仅为约一年。因此，在过去的 30 年中，GBM 的治疗几乎没有取得任何进展。我们最近在关于这种新型化合物的第一份报告中表明，第二代 ATM 抑制剂 (ATMi) KU-60019 是一种有效的放射增敏剂。 KU-60019 是一种非常特异的体外 ATM 激酶抑制剂，无论 PTEN 和 p53 状态如何，都能显着增强人神经胶质瘤细胞的放射敏感性，但在体内对突变 p53 神经胶质瘤具有更好的效果。此外，我们的研究表明，神经胶质瘤细胞的迁移和侵袭在体内具有明显的抑制作用。 KU-60019 可能通过干扰 AKT 和 ERK 信号传导来抑制体外细胞因子，因此，ATMi 作为一种药物具有潜在的临床益处。 GBM 放射增敏剂不仅能够阻断 DNA 损伤反应 (DDR) 和有效地使神经胶质瘤细胞放射增敏，而且还能抑制放射部分之间癌症的侵袭和扩散。然而，KU-60019 的缺点之一是。它不会穿过血脑屏障（BBB），需要直接肿瘤内递送才能有效，因此，能够穿过 BBB 的 ATMi 将有利于治疗。在此，我们将测试第三代 ATMi AZ31，它具有增强的治疗脑肿瘤的特性。我们的初步数据表明，AZ31 可以在体外增强人类和小鼠神经胶质瘤细胞的放射敏感性并阻断 DDR，并延长治疗时间。然而，使用具有代表性的人类异种移植物组（例如神经胶质瘤干细胞）的放射计划和剂量现在需要改变。因此，现在需要使用具有不同 p53 状态以及其他关键 GBM 特征的临床相关人类 GBM 异种移植物在小鼠神经胶质瘤模型中进一步测试 AZ31（目标 1）。人们已经了解大脑中因 ATMi 和辐射造成的 DNA 损伤而发生的分子过程，但一般认为，除干细胞和神经细胞外，神经发生会因 DDR 后遗症和炎症而受损。祖细胞（NP），大脑主要由不增殖的终末分化细胞组成，因此，位于脑实质中的积极生长的神经胶质脑肿瘤将非常有利于 AZ31 的治疗干预，特别是如果肿瘤携带 p53 突变。至少 30% 的情况是这样，在这种情况下，人们预计治疗效果会非常有利，但检查这种治疗对神经室可能产生的影响非常重要。这样就可以采取适当的措施来保护正常组织，例如使用适形辐射（目标2），我们期望从拟议的动物研究中获得的见解将证明新型“合成致死”药物和辐射组合策略的原理验证。治疗 GBM 是有效且安全的。