Targeting invasion and DNA DSB repair in glioma with a multi-pronged approach.

多管齐下，针对神经胶质瘤的侵袭和 DNA DSB 修复。

基本信息

批准号：
8206662
负责人：
KRISTOFFER Carl VALERIE
金额：
$ 19.51万
依托单位：
VIRGINIA COMMONWEALTH UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2010
资助国家：
美国
起止时间：
2010-12-15 至 2013-11-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8206662
关键词：
Adjuvant Animal Model Animals Ataxia-Telangiectasia-Mutated protein kinase BRCA1 gene BRCA2 gene Bioluminescence Brain Brain Neoplasms Brain Stem Cannulas Cell Cycle Cell Death Cells Chemosensitization Clinical Trials Coculture Techniques Convection DNA Double Strand Break DNA Repair DNA biosynthesis Data Development Diagnosis Disease Double Strand Break Repair Drug Combinations Funding Future Glioblastoma Glioma Goals Human Human Engineering In Vitro Inflammation Late Effects Lead Letters Life Expectancy Low Dose Radiation Malignant Neoplasms Malignant neoplasm of brain Modeling Molecular Mus Mutation Normal Cell PTEN gene Pathway interactions Patients Pharmaceutical Preparations Pharmacologic Substance Phase Poly(ADP-ribose) Polymerases Population Preclinical Testing Procedures Process Proliferating Proteins Proto-Oncogene Proteins c-akt Publishing Pump Radiation Radiation therapy Radiation-Sensitizing Agents Radio Radiosensitization Reagent Reporting Role S Phase Safety Signal Transduction Site Specificity Staging Stem cells Technology Testing Therapeutic Therapeutic Effect Therapeutic Intervention Toxic effect Transgenic Mice Translating Treatment Efficacy Xenograft Model Xenograft procedure animal efficacy base cell injury cell motility clinical practice combat fluorescence imaging glioma cell line homologous recombination improved in vivo inhibitor/antagonist insight killings kinase inhibitor migration neoplastic cell nerve stem cell nestin protein neurogenesis novel novel therapeutic intervention outcome forecast pre-clinical progenitor promoter public health relevance recombinational repair repaired research clinical testing response standard care treatment strategy tumor tumor growth

项目摘要

DESCRIPTION (provided by applicant): We recently showed that the ATM inhibitor (ATMi), KU-60019, is a potent radiosensitizer, the first report published on this novel compound. Briefly, KU-60019 is a very specific ATM kinase inhibitor and superior over its predecessor KU-55933 and shows at least 10-fold better efficacy in vitro for radio sensitizing human glioma cells. In addition, pro-survival signaling through the AKT and ERK pathways is also inhibited by KU-60019. The ATMi does so irrespective of PTEN and p53 status. Our studies also showed that glioma cells migration and invasion in vitro were inhibited to a large extent perhaps by interfering with AKT and ERK signaling in the presence of ATMi. Thus, the potential benefit of KU-60019 as a radiosensitizer for GBM is not limited to its ability to block the DDR and potently radiosensitize glioma cells but also having the ability to inhibit invasion and spread of the cancer. Preclinical testing of KU-60019 as a radiosensitizer for glioma is ongoing. We would now like to determine whether the PARP inhibitor (PARPi) AZD2281/KU-59436 alone, in combination with KU-60019 and/or radiation would show improved therapeutic efficacy in a preclinical glioma model. AZD2281 targets and kills tumor cells with mutations in BRCA1/BRCA2, or cells that are defective in homologous recombination repair (HRR) failing to repair DNA double-strand breaks (DSBs) during replication. Thus, synergistic killing should occur in glioma cells treated with AZD2281 and KU-60019 during DNA synthesis even in the absence of radiation. Low dose radiation (d 2 Gy) is expected to enhance the toxicity to AZD2281 and KU-60019 and further increase killing and promote radiosensitization of cells in S-phase, the most radioresistant cell cycle phase. In fact, our preliminary data show that this multi-pronged approach kills human glioma cells with little to no toxicity to normal cells in co-cultures. Thus, proof-of-principle testing of this strategy in an animal glioma model is warranted. 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 AZD2281 in combination with the ATMi with radiation perhaps providing further potentiation. However, it is very important to examine what impact this treatment might have on the NPs so that appropriate steps can be taken to spare normal brain. Little is known about the molecular processes occurring in normal brain in response to radiation but in general it is believed that radiation of neural stem cell compartments results in impaired neurogenesis due to radiation late effects and inflammation. We hope that insights gained from the proposed animal studies will demonstrate proof-of-principle of a novel drug combination strategy for the treatment of GBM that would be effective and safe and with the full support of KuDOS Pharmaceuticals/AstraZeneca can relatively quickly be translated into a clinical trial. PUBLIC HEALTH RELEVANCE: At best, standard treatment of glioblastoma multiforme (GBM) prolongs patient survival by a little more than a year. Thus, there is great need for developing and testing novel therapeutic approaches to combat this dreadful disease. We have developed a multi-pronged strategy targeting invasion, pro-survival signaling as well as DNA repair for treating GBM and now propose to test this approach for proof-of-principle in an animal model.

描述（由申请人提供）：我们最近证明 ATM 抑制剂 (ATMi) KU-60019 是一种有效的放射增敏剂，这是关于这种新型化合物的第一份报告。简而言之，KU-60019 是一种非常特异性的 ATM 激酶抑制剂，优于其前身 KU-55933，并且在体外对放射增敏的人神经胶质瘤细胞的疗效至少高出 10 倍。此外，KU-60019 还抑制通过 AKT 和 ERK 途径的促生存信号传导。无论 PTEN 和 p53 状态如何，ATMi 都会这样做。我们的研究还表明，在 ATMi 存在的情况下，神经胶质瘤细胞的体外迁移和侵袭在很大程度上可能是通过干扰 AKT 和 ERK 信号传导而受到抑制的。因此，KU-60019 作为 GBM 放射增敏剂的潜在益处不仅限于其阻断 DDR 和有效放射增敏神经胶质瘤细胞的能力，而且还具有抑制癌症侵袭和扩散的能力。 KU-60019 作为神经胶质瘤放射增敏剂的临床前测试正在进行中。我们现在想确定单独使用 PARP 抑制剂 (PARPi) AZD2281/KU-59436 与 KU-60019 和/或放射组合是否会在临床前神经胶质瘤模型中显示出更好的治疗效果。 AZD2281 靶向并杀死具有 BRCA1/BRCA2 突变的肿瘤细胞，或同源重组修复 (HRR) 有缺陷、无法修复复制过程中 DNA 双链断裂 (DSB) 的细胞。因此，即使在没有辐射的情况下，在 DNA 合成过程中，用 AZD2281 和 KU-60019 处理的神经胶质瘤细胞也会发生协同杀伤。低剂量辐射（d 2 Gy）预计会增强对 AZD2281 和 KU-60019 的毒性，并进一步增加杀伤力并促进 S 期（最抗辐射的细胞周期阶段）细胞的放射增敏。事实上，我们的初步数据表明，这种多管齐下的方法可以杀死人类神经胶质瘤细胞，而对共培养中的正常细胞几乎没有毒性。因此，有必要在动物神经胶质瘤模型中对该策略进行原理验证测试。除了干细胞和神经祖细胞（NP）之外，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 AZD2281 与 ATMi 组合的治疗干预，放射可能会提供进一步的增强作用。然而，检查这种治疗可能对 NP 产生什么影响非常重要，以便采取适当的措施来保护正常大脑。人们对正常大脑响应辐射而发生的分子过程知之甚少，但一般认为，神经干细胞区室的辐射由于辐射迟发效应和炎症而导致神经发生受损。我们希望从拟议的动物研究中获得的见解将证明治疗 GBM 的新型药物组合策略的原理证明，该策略将是有效和安全的，并且在 KuDOS Pharmaceuticals/阿斯利康的全力支持下可以相对较快地转化为临床试验。公共卫生相关性：多形性胶质母细胞瘤 (GBM) 的标准治疗充其量只能将患者的生存期延长一年多一点。因此，非常需要开发和测试新的治疗方法来对抗这种可怕的疾病。我们开发了一种多管齐下的策略，针对 GBM 的治疗，针对侵袭、促生存信号传导以及 DNA 修复，现在建议在动物模型中测试这种方法以进行原理验证。