Understanding druggable drivers of meningioma tumorigenesis

了解脑膜瘤肿瘤发生的药物驱动因素

• 批准号: 10663243
• 负责人: David R Raleigh
• 金额: $ 55.26万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-08-01 至 2026-07-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10663243
• 关键词: Address; African American; Automobile Driving; Binding; Biochemical; Biochemistry; Biology; Brain Neoplasms; CDK4 gene; CRISPR interference; CRISPR screen; California; Cell Cycle; Cell Cycle Inhibition; Cell Line; Cell Proliferation; Cells; Central Nervous System; Cerebrum; ChIP-seq; Clinical; Clinical Research; Clinical Trials; Coculture Techniques; Collaborations; Copy Number Polymorphism; Cyclin-Dependent Kinase Inhibitor 2A; DNA Methylation; DNA Probes; DNA methylation profiling; Data; Developmental Therapeutics Program; Diagnosis; Drug Kinetics; Elderly; Enhancers; Epigenetic Process; Foundations; Future; Genetic; Goals; Growth; Hand; Histologic; Histology; Homeostasis; Hong Kong; Human; In Vitro; Intracranial Neoplasms; Investigation; Malignant Intracranial Neoplasm; Malignant Neoplasms; Meningeal; Meningeal Neoplasms; Modeling; Molecular; Molecular Profiling; Morbidity - disease rate; Mus; Neurologic; Normal tissue morphology; Oncogenic; Organoids; Outcome; Pathway interactions; Patients; Pharmacodynamics; Pharmacological Treatment; Pharmacology; Pre-Clinical Model; Predisposition; Process; Reagent; Recurrence; Research; Resistance; Sampling; San Francisco; Signal Transduction; Study models; Subgroup; TP53 gene; Testing; Therapeutic; Tissues; Tumor Tissue; USF1 gene; Universities; Woman; Work; Xenograft procedure; cohort; experience; follow-up; genome-wide; improved; inhibitor; innovation; insight; meningioma; mortality; mouse model; neuron development; new therapeutic target; novel; novel therapeutics; patient derived xenograft model; pharmacokinetics and pharmacodynamics; pre-clinical; preclinical study; predict clinical outcome; prevent; promoter; resistance mechanism; response biomarker; success; targeted treatment; transcription factor; transcriptome sequencing; treatment and outcome; tumor; tumor growth; tumorigenesis

Project summary The meningeal lining of the central nervous system is critical for neuronal development and homeostasis. However, meningeal tumors account for the majority of primary intracranial cancers. Meningiomas are overwhelmingly diagnosed in older adults, women, and African American patients, all of which are underrepresented in clinical trials. Thus, there are no effective pharmacologic treatments for meningioma patients. New therapies have been further encumbered by limited understanding of meningioma biology and a lack of tractable models for preclinical meningioma investigation. To address these problems, we performed multiplatform molecular profiling on 565 human meningiomas from patients with comprehensive follow-up data to discover that meningioma is comprised of 3 epigenetic subgroups with distinct clinical outcomes. Moreover, we recently developed novel cerebral organoid and patient derived xenograft models for each subgroup of meningiomas. Our preliminary data presented in this application reveal convergent genetic mechanisms misactivating the cell cycle at the level of CDK6 in the subgroup of meningiomas with the worst clinical outcomes. Our central hypothesis is that CDK6 is required for meningioma growth, and that clinical CDK4/6 inhibitors will show activity in preclinical meningioma models. To test this hypothesis, we will define the efficacy and biomarkers of response to CDK4/6 inhibitors in meningioma, define the molecular mechanisms underlying CDK6 misactivation in meningiomas, and identify pathways mitigating resistance to CDK4/6 blockade in meningioma. Our proposal will integrate human samples, organoid models of meningioma tumorigenesis, and understudied patient derived xenografts with CRISPR interference and pharmacology. This approach is based on the premise that improving treatments for meningioma patients depends on our ability to identify and target key molecular mechanisms driving meningioma cell proliferation. We know surprisingly little about how meningiomas develop, and almost nothing about how to block the molecular mechanisms underlying meningioma growth. Though the short-term objective of this proposal is to broadly improve our understanding of meningioma cell proliferation, a long-term goal of this research is to understand this process well enough to develop targeted therapeutic strategies that will improve treatments and outcomes for meningioma patients. Thus, this work will not only explain how meningiomas grow, but will also elucidate druggable mechanisms and establish preclinical foundation to support new clinical trials for meningioma patients.

项目总结

项目成果

Supervised machine learning algorithms demonstrate proliferation index correlates with long-term recurrence after complete resection of WHO grade I meningioma.

• DOI: 10.3171/2022.4.jns212516
• 发表时间: 2023-01-01
• 期刊: JOURNAL OF NEUROSURGERY
• 影响因子: 4.1
• 作者: Nguyen, Minh P.;Morshed, Ramin A.;Ore, Cecilia L. Dalle;Cummins, Daniel D.;Saggi, Satvir;Chen, William C.;Choudhury, Abrar;Ravi, Akshay;Raleigh, David R.;Magill, Stephen T.;McDermott, Michael W.;Theodosopoulos, Philip, V
• 通讯作者: Theodosopoulos, Philip, V

Canine meningiomas are comprised of 3 DNA methylation groups that resemble the molecular characteristics of human meningiomas.

犬脑膜瘤由 3 个 DNA 甲基化基团组成，类似于人类脑膜瘤的分子特征。

• DOI: 10.1007/s00401-024-02693-2
• 发表时间: 2024
• 期刊: Acta neuropathologica
• 影响因子: 12.7
• 作者: Zakimi,Naomi;Mazcko,ChristinaN;Toedebusch,Christine;Tawa,Gregory;Woolard,Kevin;LeBlanc,AmyK;Dickinson,PeterJ;Raleigh,DavidR
• 通讯作者: Raleigh,DavidR

Gene expression analysis during progression of malignant meningioma compared to benign meningioma.

• DOI: 10.3171/2022.7.jns22585
• 发表时间: 2023-05-01
• 期刊: JOURNAL OF NEUROSURGERY
• 影响因子: 4.1
• 作者: Maier, Andrea D.;Meddis, Alessandra;Mirian, Christian;Haslund-Vinding, Jeppe;Bartek Jr, Jiri;Krog, Sebastian M.;Nguyen, Thi Uyen Phuong;Areskeviciute, Ausrine;Melchior, Linea C.;Heegaard, Steffen;Kristensen, Bjarne W.;Munch, Tina N.;Fugleholm, Kare;Ziebell, Morten;Raleigh, David R.;Poulsen, Frantz R.;Gerds, Thomas A.;Litman, Thomas;Scheie, David;Mathiesen, Tiit
• 通讯作者: Mathiesen, Tiit

A molecularly integrated grade for meningioma.

用于脑膜瘤的分子整合等级。

• DOI: 10.1093/neuonc/noab213
• 发表时间: 2022-05-04
• 期刊: Neuro-oncology
• 影响因子: 15.9

Increased mRNA expression of CDKN2A is a transcriptomic marker of clinically aggressive meningiomas.

• DOI: 10.1007/s00401-023-02571-3
• 发表时间: 2023-07
• 期刊: ACTA NEUROPATHOLOGICA
• 影响因子: 12.7
• 作者: Wang, Justin;Patil, Vikas;Liu, Jeff;Dogan, Helin;Tabatabai, Ghazaleh S.;Yefet, Leeor;Behling, Felix;Hoffman, Elgin;Bunda, Severa;Yakubov, Rebecca;Kaloti, Ramneet;Brandner, Sebastian;Gao, Andrew;Cohen-Gadol, Aaron;Barnholtz-Sloan, Jill;Skardelly, Marco;Tatagiba, Marcos R.;Raleigh, David;Sahm, Felix C.;Boutros, Paul;Aldape, Kenneth;Nassiri, Farshad;Zadeh, Gelareh
• 通讯作者: Zadeh, Gelareh