Exploiting Mutant IDH1/2-induced Homologous Recombination Defects in Cancer

只有少数几种疗法可用于治疗胶质瘤的一线：放射治疗， 替莫唑胺和PCV(丙卡巴肼、环胞嘧啶和长春新碱)。这些疗法在三年多的时间里没有改变 几十年，在大多数情况下，它们不是治愈的，也不是针对潜在的突变驱动的 这些肿瘤。2-羟基戊二酸(2HG)以两种对映体R-2HG和S-2HG的形式存在，并且都是 通过抑制依赖于α-酮戊二酸(α-KG)的双加氧酶而参与肿瘤进展。 前者是一种由异柠檬酸引起的新形性代谢产物。 脱氢酶-1和-2(IDH1/2)突变，而后者是在以下病理过程中产生的 缺氧。我们实验室最近发现IDH1/2突变导致同源重组(HR) 使肿瘤细胞对聚(ADP-核糖)聚合酶(PARP)抑制剂高度敏感的缺陷。 值得注意的是，这种“BRCAness”表型可以被小分子突变体IDH1完全逆转 抑制剂，它可以通过在完整的细胞中用2HG对映体处理而完全重现 IDH1/2。我们在一系列临床相关模型中证明了IDH1依赖的PARP抑制剂的敏感性。 包括体外原代患者来源的胶质瘤细胞和体内基因匹配的肿瘤异种移植。这些 这一发现直接挑战了目前通过直接抑制来阻断IDH1/2突变功能的治疗策略， 相反，他们提供了一种用DNA修复抑制剂治疗这些肿瘤的新方法。此外，我们的 结果揭示了肿瘤代谢、DNA修复和遗传不稳定之间意想不到的联系。 基于上面提出的初步数据，我们的中心假设是IDH1/2突变的肿瘤 港口固有的双链断裂(DSB)修复缺陷，这可以被利用来获得治疗收益。这个 本应用程序的总体目标是(1)了解R-2HG和相关的肿瘤代谢物是如何 由IDH1/2突变和其他过程诱导，抑制DSB修复，(2)DSB修复的特异性 受这些肿瘤代谢产物的影响，以及(3)利用DNA修复来利用这种缺陷的最有效方法 以抑制剂为基础的治疗方案。在本应用程序的目标1中，我们将测试特定αKG- 依赖的双加氧酶介导了观察到的肿瘤代谢物诱导的DSB修复抑制的表型。 在目标2中，我们将对DNA损伤反应网络中的关键节点进行全面评估 以定位抑制双链断裂修复的确切作用机制(S)。最后，在目标3中，我们将 验证这样一种假设，即通过组合可以靶向由肿瘤素诱导的DSB修复缺陷 使用DNA修复抑制剂和DNA损伤剂进行治疗。这项研究的长期目标是 将我们的新发现转化为临床试验，在临床试验中，我们将测试联合疗法的疗效 在这份提案中确定的。这项试验将是组织不可知和生物标记物驱动的，重点是肿瘤 这会产生高水平的肿瘤代谢物，可以通过基于DNA修复抑制剂的疗法来利用。

Only a handful of therapies are available for treatment in the front-line for glioma: radiotherapy, temozolomide, and PCV (procarbazine, CCNU, and vincristine). These therapies have not changed in over 3 decades, and in most cases they are not curative, nor are they targeted to the underlying mutations driving these tumors. 2-Hydroxyglutarate (2HG) exists as two enantiomers, R-2HG and S-2HG, and both are implicated in tumor progression via their inhibitory effects on α-ketoglutarate (αKG)-dependent dioxygenases. The former is an oncometabolite that is induced by the neomorphic activity conferred by isocitrate dehydrogenase-1 and -2 (IDH1/2) mutations, while the latter is produced under pathologic process such as hypoxia. Our laboratory recently discovered that IDH1/2 mutations induce a homologous recombination (HR) defect which renders tumor cells exquisitely sensitive to Poly (ADP-Ribose) polymerase (PARP) inhibitors. Remarkably, this “BRCAness” phenotype can be completely reversed by small molecule mutant IDH1 inhibitors, and it can be entirely recapitulated by treatment with either 2HG enantiomer in cells with intact IDH1/2. We demonstrated IDH1-dependent PARP inhibitor sensitivity in a range of clinically relevant models, including primary patient-derived glioma cells in vitro and genetically-matched tumor xenografts in vivo. These findings directly challenge the current therapeutic strategy to block IDH1/2 mutant function by direct inhibition, and they instead provide a novel approach to treat these tumors with DNA repair inhibitors. Furthermore, our results uncover an unexpected link between oncometabolites, DNA repair and genetic instability. Based on the preliminary data presented above, our central hypothesis is that IDH1/2-mutant tumors harbor intrinsic double-strand break (DSB) repair defects, which can be exploited for a therapeutic gain. The overall goals of this application are (1) to understand how R-2HG and related oncometabolites, which are induced by IDH1/2 mutations and other processes, suppress DSB repair, (2) how DSB repair specifically is affected by these oncometabolites, and (3) the most effective way to exploit this defect using DNA repair inhibitor-based treatment regimens. In Aim 1 of this application, we will test the hypothesis that specific αKG- dependent dioxygenases mediate the observed phenotype of oncometabolite-induced DSB repair suppression. In Aim 2, we will perform a comprehensive evaluation of key nodes in the DNA damage response network, in order to localize the exact mechanism(s) of action by which DSB repair is suppressed. Finally, in Aim 3, we will test the hypothesis that the oncometabolite-induced DSB repair defect can be targeted by combination treatment with DNA repair inhibitors and DNA damaging agents. The long term goal of this study is to translate our novel findings into a clinical trial, in which we will test the efficacy of the combination therapies that are identified in this proposal. This trial would be tissue-agnostic and biomarker-driven, focusing on tumors that produce high levels of oncometabolites, which can be exploited with DNA repair inhibitor-based regimens.