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

• 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
• 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

 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）是一种破坏性疾病，中位生存期仅约一年。在过去的30年里，GBM的治疗进展甚微。因此，迫切需要新的方法和治疗剂。我们最近表明，第二代ATM抑制剂（ATMi），KU-60019，是一种有效的放射增敏剂，在第一份报告中发表了这种新的化合物。简而言之，KU-60019在体外是一种非常特异的ATM激酶抑制剂，并且令人印象深刻地使人神经胶质瘤细胞放射增敏，而与PTEN和p53状态无关，但在体内对突变型p53神经胶质瘤具有更好的效果。此外，我们的研究表明，KU-60019可能通过干扰AKT和ERK信号转导抑制胶质瘤细胞的体外迁移和侵袭。因此，ATMi作为GBM的放射增敏剂的潜在临床益处不限于其阻断DNA损伤反应（DDR）和有效地放射增敏神经胶质瘤细胞的能力，而且还在放射部分之间抑制癌症的侵袭和扩散。然而，KU-60019的缺点之一是它不能穿过血脑屏障（BBB），需要直接在肿瘤内递送才能有效。因此，能够穿过BBB的ATMi将促进 并改善各个层面的治疗。在此，我们将测试第三代ATMi AZ 31，其具有治疗脑肿瘤的增强特性。我们的初步数据显示，AZ 31在体外对人类和小鼠胶质瘤细胞具有放射增敏作用，并阻断了DDR，并抑制了生长有突变型p53的同基因原位肿瘤的小鼠的存活。然而，现在需要使用一组代表性的人类异种移植物（如神经胶质瘤干细胞）进行辐射调度和给药，以使这种化合物更接近临床测试。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GBM异种移植物在小鼠神经胶质瘤模型中进一步测试AZ 31（目的1）。关于在大脑中响应于由ATMi和辐射引起的DNA损伤而发生的分子过程知之甚少，但是一般认为，由于DDR后遗症和炎症，神经发生会受损。除了干细胞和神经祖细胞（NP），大脑主要由不增殖的终末分化细胞组成。因此，存在于脑实质中的侵袭性生长的神经胶质脑肿瘤将非常有利于用AZ 31进行治疗性干预，特别是如果肿瘤携带p53突变，至少30%的时间是这种情况。在这种情况下，预期治疗增益是非常有利的。然而，检查这种治疗可能对神经隔室产生的影响是非常重要的，以便采取适当的步骤来保护正常组织，例如使用适形放射（目标2）。我们希望从拟议的动物研究中获得的见解将证明一种新的“合成致死”药物和放射联合治疗GBM的策略是有效和安全的。