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。

• 批准号: 8059203
• 负责人: KRISTOFFER Carl VALERIE
• 金额: $ 16.26万
• 依托单位: VIRGINIA COMMONWEALTH UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-12-15 至 2012-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8059203
• 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; recombinational repair; repaired; research clinical testing; response; standard care; treatment strategy; tumor; tumor growth

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）：我们最近发现ATM抑制剂（ATMi） KU-60019是一种有效的放射增敏剂，这是关于这种新化合物的第一篇报道。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，并且在体外对人类胶质瘤细胞的放射增敏效果至少提高10倍。此外，通过AKT和ERK通路的促生存信号也被KU-60019抑制。无论PTEN和p53的状态如何，ATMi都会这样做。我们的研究还表明，在ATMi存在的情况下，可能通过干扰AKT和ERK信号，在很大程度上抑制胶质瘤细胞在体外的迁移和侵袭。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试验正在进行中。我们现在想确定PARP抑制剂（PARPi） AZD2281/KU-59436单独使用，与KU-60019联合使用和/或放疗是否会在临床前胶质瘤模型中显示出更好的治疗效果。AZD2281靶向并杀死BRCA1/BRCA2突变的肿瘤细胞，或同源重组修复（HRR）中不能修复DNA双链断裂（DSBs）的细胞。因此，即使在没有辐射的情况下，AZD2281和KU-60019处理的胶质瘤细胞在DNA合成过程中也会发生协同杀伤。低剂量辐射（d 2 Gy）有望增强AZD2281和KU-60019的毒性，并进一步增加细胞在s期（最耐辐射的细胞周期）的杀伤和促进辐射敏化。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胶质瘤细胞，而对共同培养的正常细胞几乎没有毒性。因此，该策略在动物胶质瘤模型中的原理验证测试是必要的。除了干细胞和神经祖细胞（NPs）外，大脑主要由不增殖的终末分化细胞组成。因此，AZD2281与ATMi联合使用，可能会进一步增强AZD2281在脑实质中侵袭性生长的神经胶质性脑肿瘤的治疗干预效果。然而，检查这种治疗对NPs的影响是非常重要的，这样就可以采取适当的措施来保护正常的大脑。对正常大脑中发生的辐射反应的分子过程知之甚少，但一般认为，由于辐射的晚期效应和炎症，神经干细胞室的辐射导致神经发生受损。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，该策略将有效且安全，并且在KuDOS制药/阿斯利康的全力支持下，可以相对较快地转化为临床试验。