Synthetic lethalities to cell cycle disruption in glioma

神经胶质瘤细胞周期破坏的综合致死率

• 批准号: 10621824
• 负责人: RAMEEN BEROUKHIM
• 金额: $ 66万
• 依托单位: DANA-FARBER CANCER INST
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-05-13 至 2027-04-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10621824
• 关键词: Adult; Alkylating Agents; Bar Codes; Biological Markers; Brain Neoplasms; CDKN2A gene; CHEK1 gene; CHEK2 gene; Cell Cycle; Cell Cycle Regulation; Cell Differentiation process; Cells; Chemotherapy and/or radiation; Child; Clinical Trials; Clinical Trials Design; Clonal Evolution; Clustered Regularly Interspaced Short Palindromic Repeats; Combined Modality Therapy; DNA Damage; Development; Diagnostic; Disease; Epigenetic Process; Genes; Genomics; Genotoxic Stress; Glioblastoma; Glioma; Growth; Heterogeneity; Immune checkpoint inhibitor; Induction of Apoptosis; Lomustine; MDM2 gene; Malignant Neoplasms; Mediating; Mediator; Mesenchymal; Methods; Mitotic; Neurosphere; Normal Cell; Null Lymphocytes; Optics; Outcome; Pathway interactions; Patients; Pharmaceutical Preparations; Population; RB1 gene; Radiation; Research; Resistance; Sampling; Stress; TP53 gene; Testing; Therapeutic; Toxic effect; cancer cell; cancer type; checkpoint inhibition; chemotherapy; gene discovery; genome-wide; genotoxicity; glioma cell line; improved; improved outcome; inhibitor; innovation; new therapeutic target; novel; patient subsets; replication stress; resistance mechanism; response; response biomarker; single-cell RNA sequencing; small molecule; synthetic lethal interaction; targeted treatment; temozolomide; therapy resistant; transcription factor

Summary Despite decades of research into targeted therapeutics against gliomas, the most successful treatments remain DNA damaging agents: radiation and the alkylating agents temozolomide and lomustine. DNA damage generates particular obstacles for rapidly dividing cells; as cells undergoing such damage progress through the cell cycle, they can undergo genotoxic or mitotic catastrophe. Multiple compounds have recently been developed that interfere with cell cycle regulation, with the aim of generating mitotic catastrophe in cancer cells. These include compounds targeting regulators of the G2/M checkpoint, including CHK1 and CHK2; WEE1; and others. Some of these are being applied to gliomas in clinical trials, including a trial of the WEE1 inhibitor AZD1775 in patients with glioblastoma. However, a detailed understanding of which gliomas are most likely to require a functional G2/M checkpoint, and under what conditions, is not available. Therefore, despite this pathway being highly relevant to the most successful existing therapeutics, we do not know when or how to use modulators of the pathway in patients with glioma. The objective of this proposal is to determine whether and in what instances inhibitors of the G2/M checkpoint, and particularly CHK1/2, can lead to improved outcomes in gliomas. We evaluated the effects of 400 biologically active small molecules on 78 glioma cell lines with comprehensive genomic characterization, including conventional and neurosphere lines. One of the most prominent outcomes was that inactivation of TP53 was associated with worse response to almost all compounds, but combined loss of TP53 and CDKN2A/B rendered cells more sensitive to G2/M checkpoint inhibitors, especially inhibitors of CHK1/2 (CHK1/2i). We hypothesize that combined loss of TP53 and other G1/S cell cycle regulators leads to a reliance on the CHK1/2-controlled G2/M checkpoint to avoid uncontrolled cell cycling in the context of genotoxic or replicative stress. By understanding the mechanisms underlying G2/M inhibitor sensitivity, we will have potential for a major near-term impact on treatment through optimized therapeutic strategies using these inhibitors, which are already under development, that can lead to immediate incorporation into new clinical trials strategies. We will achieve this with the following specific aims: Aim 1: Test the hypothesis that combined loss of TP53 and G1/S checkpoint control generates sensitivity to G2/M checkpoint inhibitors. Aim 2: Test the hypothesis that cell differentiation state determines sensitivity to G2/M checkpoint inhibition. Aim 3: Test the hypothesis that MDM2 inhibitors can increase the therapeutic window of CHK1/2i in the context of DNA damaging agents. In summary, the proposal described should lead to better diagnostics and treatments for those afflicted by gliomas and offer new avenues for clinical trial design and implementation in patient studies.

概括 尽管对神经胶质瘤的靶向治疗进行了数十年的研究，但最成功的治疗方法 仍然是DNA损伤剂：辐射和烷化剂替莫唑胺和洛莫司汀。 DNA损伤 对快速分裂的细胞产生特殊的障碍；当经历这种损伤的细胞通过 在细胞周期中，它们可能会经历基因毒性或有丝分裂灾难。最近开发了多种化合物 干扰细胞周期调节，目的是在癌细胞中产生有丝分裂灾难。这些 包括针对 G2/M 检查点调节因子的化合物，包括 CHK1 和 CHK2； WE1；和其他人。 其中一些正在临床试验中应用于神经胶质瘤，包括 WEE1 抑制剂 AZD1775 在 胶质母细胞瘤患者。然而，详细了解哪些神经胶质瘤最有可能需要 功能性 G2/M 检查点以及在什么条件下不可用。因此，尽管这条途径 与最成功的现有疗法高度相关，我们不知道何时或如何使用调节剂 神经胶质瘤患者的通路。该提案的目的是确定是否以及在什么情况下 G2/M 检查点抑制剂，特别是 CHK1/2，可以改善神经胶质瘤的治疗效果。我们 综合评估了 400 种生物活性小分子对 78 种神经胶质瘤细胞系的影响 基因组表征，包括常规和神经球系。最突出的成果之一 TP53 失活与对几乎所有化合物的较差反应相关，但综合损失 TP53 和 CDKN2A/B 的表达使细胞对 G2/M 检查点抑制剂更加敏感，尤其是 CHK1/2 (CHK1/2i)。我们假设 TP53 和其他 G1/S 细胞周期调节因子的联合缺失导致 依赖 CHK1/2 控制的 G2/M 检查点来避免基因毒性背景下不受控制的细胞周期 或复制压力。通过了解 G2/M 抑制剂敏感性的机制，我们将 通过使用这些优化的治疗策略，可能对治疗产生重大的近期影响 已经在开发的抑制剂可以立即纳入新的临床试验 策略。我们将通过以下具体目标来实现这一目标： 目标 1：检验组合损失的假设 TP53 和 G1/S 检查点控制的缺失会产生对 G2/M 检查点抑制剂的敏感性。目标 2：测试 假设细胞分化状态决定对 G2/M 检查点抑制的敏感性。目标 3：测试 假设 MDM2 抑制剂可以在 DNA 损伤的情况下增加 CHK1/2i 的治疗窗口 代理。总而言之，所描述的提案应该能够为患者带来更好的诊断和治疗 神经胶质瘤，并为患者研究中的临床试验设计和实施提供新途径。