Targeting metabolic vulnerabilities in Astrocytoma, IDH-mutant, Grade 4

针对星形细胞瘤、IDH 突变、4 级的代谢脆弱性

• 批准号: 10491830
• 负责人: Tracy T Batchelor
• 金额: $ 17.03万
• 依托单位: BRIGHAM AND WOMEN'S HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-09-21 至 2026-08-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10491830
• 关键词: Address; Adolescent; Adult; Adult Glioma; Agar; Anabolism; Apoptosis; Astrocytoma; Basic Science; Biological Markers; Biology; Brain; Branched-Chain Amino Acids; Catabolism; Cells; Central Nervous System Neoplasms; Classification; Clinic; Clinical; Clinical Trials; Collection; Combined Modality Therapy; DHODH gene; DNA Damage; Defect; Dependence; Diffuse; Dihydroorotate dehydrogenase; Disease; Drug Targeting; Enrollment; Enzymes; Excision; FDA approved; Foundations; Future; Genes; Genomics; Glioblastoma; Glioma; Gliomagenesis; Glutamates; Glutaminase; Glutathione; Goals; Human; Image; Immunohistochemistry; In Vitro; Isocitrate Dehydrogenase; Knowledge; Lead; Magnetic Resonance Spectroscopy; Malignant - descriptor; Malignant Glioma; Malignant Neoplasms; Medical; Metabolic; Methods; Modeling; Molecular; Monitor; Mutation; Newly Diagnosed; Nucleotide Biosynthesis; Oncogenes; Oncoproteins; Operative Surgical Procedures; Pathway interactions; Patients; Pharmaceutical Preparations; Pharmacodynamics; Pharmacology; Pharmacotherapy; Phase; Process; Property; Pyrimidine; Pyrimidine Nucleotides; Radiation; Recurrence; Research; Research Personnel; Resected; Resistance; Safety; Spectrometry, Mass, Matrix-Assisted Laser Desorption-Ionization; Technology; Testing; Tissue Sample; Translating; Tumor-Derived; United States; Work; World Health Organization; base; clinical material; clinical translation; cohort; effective therapy; gain of function; human subject; inhibitor; liquid chromatography mass spectrometry; mass spectrometric imaging; mutant; new therapeutic target; novel; novel therapeutics; nucleotide metabolism; patient population; pharmacokinetics and pharmacodynamics; phase 2 study; pre-clinical; programs; rational design; response; screening; single-cell RNA sequencing; standard care; stem-like cell; targeted treatment; treatment strategy; tumor

PROJECT SUMMARY Gliomas represent 80% of the 26,000 newly diagnosed cases of malignant brain and central nervous system tumors in the United States each year and are among the most lethal and treatment-resistant human cancers. Although there is a dire need for effective therapies for this disease, the standard treatment for gliomas has not changed since 2005 and no new medical therapies have been approved for adult gliomas in the last decade. In response to this challenge, we have devised a new way to treat gliomas that have a mutation in either of the IDH1 or IDH2 genes. Collectively, IDH mutations are present in ~20% of adult diffuse gliomas, indicating that any treatment advance in this patient population would have broad impact. Based on our knowledge that IDH mutations cause profound metabolic reprogramming in glioma cells, we used a novel pharmacological screening platform to systematically identify vulnerabilities that result from this process. We discovered that a class of drugs targeting nucleotide metabolism preferentially kill glioma cells with IDH mutations, thereby revealing an avenue for tumor-selective, biomarker-guided therapy that is poised for rapid clinical translation. To build on this discovery and translate exploitation of this vulnerability to the clinic, we propose to conduct a phase 0 surgical window clinical trial of a brain-penetrant nucleotide metabolism inhibitor in IDH-mutant grade 4 glioma patients. We will characterize response to this agent by addressing three Specific Aims. Specific Aim #1 is to use matrix-assisted laser desorption ionization mass spectrometry imaging (MALDI-MSI), conventional liquid chromatography-mass spectrometry, and magnetic resonance spectroscopy to comprehensively characterize the pharmacokinetic and pharmacodynamic properties of this targeted therapeutic in glioma patients. Specific Aim #2 is to investigate how this inhibitor alters the biology of IDH-mutant grade 4 gliomas at the molecular and cellular levels by analyzing resected primary tissue samples via single-cell RNA sequencing and immunohistochemistry. Finally, Specific Aim #3 is to evaluate the safety and tolerability of this drug in a focused cohort of IDH-mutant grade 4 glioma patients. Taken together, our work will outline and test a new treatment strategy for glioma patients that could be expanded to a larger multi-center phase II study if our trial is successful. Furthermore, our efforts to elucidate key components of the mechanism of action of this nucleotide metabolism inhibitor are expected to inform the rational design of combination therapies centered on this agent that can be explored in future studies.

项目总结