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 尽管数十年来研究针对神经膜瘤的靶向治疗剂，但最成功的治疗方法 保持DNA损伤剂：辐射和烷基化剂替莫唑胺和Lomustine。 DNA损伤 产生特定的障碍，以快速分裂细胞；当细胞受到这种损害的过程中 细胞周期，它们可以发生遗传毒性或有丝分裂灾难。最近已经开发了多种化合物 这会干扰细胞周期调节，目的是在癌细胞中产生有丝分裂灾难。这些 包括针对G2/M检查点调节器的化合物，包括CHK1和CHK2； wee1;还有其他。 其中一些正在临床试验中应用于胶质瘤，包括WEE1抑制剂AZD1775在 胶质母细胞瘤的患者。但是，对哪些神经胶质瘤最有可能需要的详细了解 功能性G2/M检查点，在什么条件下，不可用。因此，尽管有这样的途径 与最成功的现有治疗剂高度相关，我们不知道何时或如何使用调节剂 神经胶质瘤患者的途径。该提议的目的是确定是否以及在什么情况下 G2/M检查点，尤其是CHK1/2的抑制剂可以改善神经胶质瘤的结果。我们 评估了400个生物活性小分子对78个神经胶质瘤细胞系的影响 基因组表征，包括常规和神经球线。最突出的结果之一 是TP53的灭活与几乎所有化合物的反应较差有关，但损失合并 TP53和CDKN2A/b的细胞对G2/M检查点抑制剂更敏感，尤其是抑制剂 CHK1/2（CHK1/2I）。我们假设TP53和其他G1/S细胞周期调节剂的综合损失导致 依赖CHK1/2控制的G2/M检查点，以避免在遗传毒性的背景下进行不受控制的细胞循环 或复制压力。通过了解G2/M抑制剂灵敏度的基础机制，我们将拥有 通过使用这些优化的治疗策略对治疗产生重大影响的潜力 已经正在开发的抑制剂可以立即纳入新的临床试验中 策略。我们将以以下特定目标来实现这一目标：目标1：测试合并损失的假设 TP53和G1/S检查点控制对G2/M检查点抑制剂产生灵敏度。目标2：测试 细胞分化状态确定对G2/M检查点抑制的敏感性的假设。目标3：测试 假设MDM2抑制剂可以在DNA损害的情况下增加CHK1/2I的治疗窗口 代理商。总而言之，所描述的提案应为患病者提供更好的诊断和治疗方法 通过神经胶质瘤，为患者研究中的临床试验设计和实施提供了新的途径。