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: 10443386
• 负责人: RAMEEN BEROUKHIM
• 金额: $ 66.89万
• 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/10443386
• 关键词: Adult; Alkylating Agents; Apoptosis; 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; Lead; Lomustine; MDM2 gene; Malignant Neoplasms; Mediating; Mediator of activation protein; Mesenchymal; Methods; Mitotic; Neurosphere; Normal Cell; Null Lymphocytes; Optics; Outcome; Pathway interactions; Patients; Pharmaceutical Preparations; Population; RB1 gene; Radiation; Research; Resistance; Sampling; 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; 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.

总结