Novel, orally available ATM inhibitor for glioma conformal radiosensitization

 描述(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，对基底膜的治疗几乎没有取得什么进展。因此，迫切需要新的方法和治疗剂。我们最近在关于这种新化合物的第一篇报道中证明了第二代atm抑制剂KU-60019是一种有效的放射增敏剂。简而言之，KU-60019在体外是一种非常特异的ATM激酶抑制剂，对人胶质瘤细胞具有令人印象深刻的放射增敏作用，与PTEN和P53状态无关，但在体内对突变的P53胶质瘤有更好的效果。此外，我们的研究表明，KU-60019可能通过干扰AKT和ERK信号通路来抑制胶质瘤细胞的体外迁移和侵袭。因此，ATMI作为GBM放射增敏剂的潜在临床益处不仅限于其阻断DNA损伤反应(DDR)和有效地使胶质瘤细胞放射增敏的能力，而且还抑制了放射部分之间的癌症的侵袭和扩散。然而，KU-60019的一个缺点是它不能穿过血脑屏障，需要直接在肿瘤内注射才能有效。因此，能够穿越BBB的ATMI将有助于 并在各个层面上提高治疗水平。在这里，我们将测试第三代ATMI，AZ31，具有增强的治疗脑瘤的性能。我们的初步数据显示，AZ31对人和小鼠胶质瘤细胞具有放射增敏作用，并在体外阻断了DDR，并延长了带有突变型p53的同种原位肿瘤小鼠的生存时间。然而，为了使这种化合物更接近临床测试，现在需要进行使用具有代表性的人类异种移植细胞(如胶质瘤干细胞)的放射计划和剂量。因此，现在有必要使用具有不同P53状态和其他关键的GBM特征的临床相关的人GBM异种移植，在小鼠胶质瘤模型中进一步测试AZ31(目标1)。对ATMI和辐射引起的DNA损伤在大脑中发生的分子过程知之甚少，但通常认为，由于DDR后遗症和炎症，神经发生将受到损害。除了干细胞和神经前体细胞(NPs)外，大脑主要由不会增殖的终末分化细胞组成。因此，位于脑实质的侵袭性生长的胶质脑瘤将非常有利于AZ31的治疗干预，特别是如果肿瘤携带P53突变，这种情况至少有30%是这样的。在这种情况下，人们预计治疗收益将是非常有利的。然而，非常重要的是要检查这种治疗可能对神经室有什么影响，以便采取适当的步骤来保留正常组织，如使用适形放射(目标2)。我们预计，从拟议的动物研究中获得的见解将证明一种新的“合成致命”药物和辐射组合策略用于治疗GBM将是有效和安全的。

 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.