Targeting Tumorigenic Pathways in Glioblastoma with Oncolytic HSV

描述（由申请人提供）：胶质母细胞瘤是最恶性的原发性脑肿瘤，在很大程度上对所有形式的治疗都是难治的，并且几乎是一致致命的， 中位生存期约为15个月。最近分离的胶质母细胞瘤干细胞（GSC）被认为是肿瘤逃避治疗的重要能力。此外，我们发现它们产生的脑肿瘤保留了患者肿瘤的许多特征，因此它们为测试新疗法提供了一个代表性的肿瘤模型，这是已建立的细胞系所没有的。我们和其他人已经开发出溶瘤单纯疱疹病毒（oHSV）载体，可以选择性地在癌细胞中复制并杀死癌细胞，而不会伤害周围的正常组织或引起疾病。oHSV治疗的安全性已在胶质母细胞瘤的临床试验中得到证实;然而，疗效仍然是轶事，需要改进。 用于胶质母细胞瘤临床试验的oHSV载体含有缺失的？34.5基因，这使得它们在GSC中不允许。因此，我们开发了一种新的oHSV，MG 18 L，删除了Us 3，这是这些研究的重点。Us 3基因是一种丝氨酸-苏氨酸激酶，可抑制细胞凋亡并磷酸化诱导翻译的TSC 2。我们假设MG 18 L在癌细胞中选择性复制，因为它不能促进正常细胞中的翻译或抑制病毒诱导的细胞凋亡，但GSC中的失调途径使它们具有许可性。为了降低病毒在大脑中的致病性，MG 18 L还在病毒核糖核苷酸还原酶基因中发生突变，该基因将病毒复制靶向分裂的癌细胞。Us 3缺失的HSV的另一个特征是PI 3 K/Akt通路的激活，其在大多数胶质母细胞瘤中发生遗传改变。因此，我们假设MG 18 L将与PI 3 K/Akt通路的小分子抑制剂协同作用，其中许多目前正在临床试验中，并杀死GSC和肿瘤。我们最近发现oHSV感染GSC靶向ATM途径并抑制同源重组（HR）DNA修复。HR缺陷的癌细胞在聚（ADP-核糖）聚合酶（PARP）抑制剂的作用下是合成致死的。因此，我们假设用MG 18 L处理GSC将使它们对PARP抑制剂敏感，从而诱导合成致死样效应。这两种联合策略应该大大改善胶质母细胞瘤的治疗并克服耐药性。我们预计，在拟议的研究中证明的疗法将可转化为临床。我们的长期目标是开发安全有效的oHSV载体用于临床，并阐明将提高疗效的组合策略。

DESCRIPTION (provided by applicant): Glioblastoma, the most malignant primary brain tumor, has remained largely refractory to all forms of therapy, and is almost uniformly lethal with a median survival of approximately 15 months. Recently isolated glioblastoma stem cells (GSCs) are thought to be important in the tumor's ability to evade therapy. In addition, we found that the brain tumors they generate retain many of the features of the patient tumors, so they provide a representative tumor model for testing new therapies, something that established cell lines do not. We, and others have developed oncolytic herpes simplex virus (oHSV) vectors that selectively replicate in and kill cancer cells, without harming the surrounding normal tissue or causing disease. The safety of oHSV therapy has been demonstrated in clinical trials for glioblastoma; however efficacy remains anecdotal and needs improvement. The oHSV vectors in clinical trial for glioblastoma contain deletions of the ?34.5 gene, which renders them non-permissive in GSCs. Therefore, we developed a new oHSV, MG18L, deleted for Us3 that is the focus of these studies. The Us3 gene is a serine-threonine kinase that inhibits apoptosis and phosphorylates TSC2 inducing translation. We hypothesize that MG18L selectively replicates in cancer cells because it is unable to promote translation or inhibit virus-induced apoptosis in normal cells, but dysregulated pathways in GSCs makes them permisive. To reduce virus pathogenicity in the brain, MG18L also is mutated in the viral ribonucleotide reductase gene, which targets virus replication to dividing cancer cells. Another feature of Us3-deleted HSV is activation of the PI3K/Akt pathway, genetically altered in the majority of glioblastomas. Therefore, we hypothesize that MG18L will synergize with small molecule inhibitors of the PI3K/Akt pathway, many of which are currently in clinical trial, and kill GSCs and tumors. We recently found that oHSV infection of GSCs targets the ATM pathway and inhibits homologous recombination (HR) DNA repair. Cancer cells deficient in HR are synthetic lethal with poly(ADP-ribose) polymerase (PARP) inhibitors. Thus, we hypothesize that treating GSCs with MG18L will sensitize them to PARP inhibitors inducing a synthetic lethal-like effect. Both of these combination strategies should greatly improve the treatment of glioblastoma and overcome drug resistance. We anticipate that therapies demonstrated in the proposed studies will be translatable to the clinic. Our long-term goal is to develop oHSV vectors that are safe and effective for clinical use and to elucidate combination strategies that will enhance efficacy.