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Evolution of gliomas during treatment and resistance

神经胶质瘤在治疗和耐药过程中的演变

基本信息

批准号：
10656320
负责人：
RAMEEN BEROUKHIM
金额：
$ 68.37万
依托单位：
DANA-FARBER CANCER INST
依托单位国家：
美国
项目类别：
财政年份：
2015
资助国家：
美国
起止时间：
2015-04-01 至 2026-06-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10656320
关键词：
Ablation Address Adult Alkylating Agents Alkylation Amino Acids Biological Assay Biological Markers CHEK1 gene Carmustine Characteristics Clinical Trials Clonality Collection Combined Modality Therapy DNA Damage DNA Interstrand Crosslinking DNA Repair Data Defect Development Effectiveness Evaluation Evolution Generations Genes Genome Genomics Glioblastoma Glioma Grant Guanine Human Immune response Immunotherapy Induced Mutation Knowledge Lesion Light Lomustine MGMT gene Malignant - descriptor Malignant Glioma Malignant Neoplasms Mediating Methylation Mismatch Repair Mismatch Repair Deficiency Modeling Modernization Molecular Mutation New Agents Nitrosourea Compounds PD-1/PD-L1 PDL1 inhibitors Pathway interactions Patient Monitoring Patients Plasma Cells Primary Brain Neoplasms Proliferating Proteins Radiation Radiation Tolerance Radiation induced damage Research Resistance Role Shapes Source Technology Testing Therapeutic Tissues Toxic effect United States Work biobank biomarker driven cancer survival cell free DNA checkpoint inhibition checkpoint therapy chemotherapy clinical biomarkers clinical implementation clinical practice crosslink effective therapy experimental study functional genomics genome integrity improved improved outcome in vitro Model in vivo inhibitor innovation interest mouse model mutant neoantigens novel novel therapeutic intervention phase III trial predicting response prevent promoter radioresistant repaired resistance mechanism response targeted agent targeted treatment temozolomide therapeutic target treatment strategy tumor

项目摘要

Project Abstract Despite decades of research into targeted therapeutics, the most effective treatments in glioma remain DNA damaging agents: radiation and the alkylating agents temozolomide and nitrosureas like CCNU. In this project’s prior cycle, we found that mismatch repair deficiency (MMRd) is a common source of temozolomide resistance; and that unlike other cancers, gliomas that gain temozolomide resistance through MMRd tend not to respond to immune checkpoint inhibition. But they often do respond to CCNU. We hypothesize that a fuller understanding of the different resistance mechanisms to TMZ and CCNU will enable 1) improved knowledge of when and how to use these agents, including clinically useful biomarkers, and 2) optimization of combined strategies using targeted and immunotherapies developed over the last decade. Although extensive work has been done to understand how CCNU damages DNA and to detect genes and pathways involved in repairing this damage, the field lacks a unified understanding of how CCNU effects vary across gliomas with different DNA damage response (DDR) characteristics, how resistance arises, and how the effects of CCNU interact with other agents including DNA damaging agents such as temozolomide and radiation, as well as therapeutics targeting specific DDR functions and pathways. As a result, we lack biomarkers that can accurately guide clinicians to prescribe CCNU to patients who are likely to respond, do not know the optimal combined therapeutic approaches involving CCNU, and clinical practice varies widely. We propose to pursue a systematic evaluation of the genomic effects and potential therapeutic roles of CCNU. A major innovation in our proposal is our systematic approach to evaluating the effects of CCNU on cancer survival and proliferation and genome integrity: when used alone and in combination with temozolomide, RT, and agents targeting DNA damage response pathways; and across a wide variety of DNA damage response contexts. For this, we will leverage a living tissue biobank of over 250 gliomas in vivo and in vitro models and state-of-the-art technologies for functional genomics and genome characterization across treatment conditions and DDR backgrounds. Our Aims are: Aim 1: Test the hypothesis that MMRd based resistance to TMZ within a GBM indicates relative sensitivity to CCNU and RT and can be detected through plasma cell-free DNA. Aim 2: Test the hypothesis that defects in proteins involved in repair of CCNU-induced ICLs determine resistance to CCNU and strategies to overcome. Aim 3: Test the hypothesis that intentional manipulation of mutational profiles and clonal dynamics by coordinating TMZ, CCNU, RT, and DDR pathway inhibition can increase the effectiveness of immunotherapy. DNA damaging agents remain the most effective agents in glioma and all other cancers, the unified understanding of their effects in isolation and combination across the varied DDR contexts in this proposal will shape the use of these agents in clinical practice and guide the development of new biomarker-driven combinations with novel DDR targets.

项目摘要

项目成果

期刊论文数量（23）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

miRNA-194-3p represses NF-κB in gliomas to attenuate iPSC genes and proneural to mesenchymal transition.

DOI：
10.1016/j.isci.2023.108650
发表时间：
2024-01-19
期刊：
ISCIENCE
影响因子：
5.8
作者：
Jacob, John Ryan;Singh, Rajbir;Okamoto, Masa;Chakravarti, Arnab;Palanichamy, Kamalakannan
通讯作者：
Palanichamy, Kamalakannan

The genomic landscape and evolution of endometrial carcinoma progression and abdominopelvic metastasis.

DOI：
10.1038/ng.3602
发表时间：
2016-08
期刊：
Nature genetics
影响因子：
30.8
作者：
Gibson WJ;Hoivik EA;Halle MK;Taylor-Weiner A;Cherniack AD;Berg A;Holst F;Zack TI;Werner HM;Staby KM;Rosenberg M;Stefansson IM;Kusonmano K;Chevalier A;Mauland KK;Trovik J;Krakstad C;Giannakis M;Hodis E;Woie K;Bjorge L;Vintermyr OK;Wala JA;Lawrence MS;Getz G;Carter SL;Beroukhim R;Salvesen HB
通讯作者：
Salvesen HB

Cells isolated from residual intracranial tumors after treatment express iPSC genes and possess neural lineage differentiation plasticity.

DOI：
10.1016/j.ebiom.2018.09.019
发表时间：
2018-10
期刊：
EBioMedicine
影响因子：
11.1
作者：
Palanichamy K;Jacob JR;Litzenberg KT;Ray-Chaudhury A;Chakravarti A
通讯作者：
Chakravarti A

Oncogenic transgelin-2 is differentially regulated in isocitrate dehydrogenase wild-type vs. mutant gliomas.

DOI：
10.18632/oncotarget.26365
发表时间：
2018-12-14
期刊：
Oncotarget
影响因子：
0
作者：
Beyer, Sasha J;Bell, Erica H;Chakravarti, Arnab
通讯作者：
Chakravarti, Arnab

Patient-derived xenografts undergo mouse-specific tumor evolution.

DOI：
10.1038/ng.3967
发表时间：
2017-11
期刊：
Nature genetics
影响因子：
30.8
作者：
Ben-David U;Ha G;Tseng YY;Greenwald NF;Oh C;Shih J;McFarland JM;Wong B;Boehm JS;Beroukhim R;Golub TR
通讯作者：
Golub TR