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Targeting cell cycle dysregulation in GIST

针对 GIST 中的细胞周期失调

基本信息

批准号：
10826776
负责人：
Inga-Marie Schaefer
金额：
$ 7.56万
依托单位：
BRIGHAM AND WOMEN'S HOSPITAL
依托单位国家：
美国
项目类别：
财政年份：
2019
资助国家：
美国
起止时间：
2019-07-10 至 2024-10-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10826776
关键词：
14q Address Advisory Committees Behavior Benign Biological Biology CDK4 gene CRISPR screen Cancer Model Cell Cycle Cell Survival Chromosome Deletion Clinical Clinical Trials Collaborations Combined Modality Therapy DNA Dependence Development Diagnosis Discipline Disease Disease Progression Disease Resistance Down-Regulation Drug resistance Environment Evaluation Event FDA approved FRAP1 gene Fostering Frequencies Future Gastrointestinal Stromal Tumors Gene Fusion Genes Genetic Genetic Transcription Genomics Goals Home Hospital Departments Hospitals Human Image In Vitro International K-Series Research Career Programs Knowledge Leadership Malignant - descriptor Malignant Neoplasms Mediating Medical Mentors Mentorship Mesenchymal Cell Neoplasm Microscopic Modeling Mutation Neoplasm Metastasis Oncogenic PDGFRA gene Pathology Pathway interactions Patients Pharmaceutical Preparations Physicians Positioning Attribute Proteomics RB1 gene Recurrence Research Research Project Summaries Resistance Resolution Role Scientist Surgical Oncology Testing Therapeutic Time Training Translational Research Tumor Cell Line Tumor Suppressor Genes Tumor Suppressor Proteins Tyrosine Kinase Inhibitor Unresectable Validation Woman advanced disease career career development cell growth clinical practice gain of function mutation gene repression genome-wide improved in vivo in vivo Model inhibitor inhibitor therapy innovation insight neoplastic cell novel novel therapeutics patient derived xenograft model pre-clinical preclinical evaluation preclinical study programs research study resistance mutation response sarcoma tenure track treatment response tumor tumor diagnostic tumor initiation tumor progression virtual

项目摘要

PROJECT SUMMARY Research: Gastrointestinal stromal tumors (GISTs) are among the most common mesenchymal neoplasms. Most GISTs are initiated by KIT or PDGFRA gain-of-function mutations which are therefore already found in microscopic forms of GISTs. During progression to aggressive disease, early GISTs acquire a canonical sequence of chromosomal deletions including 14q deletions that inactivate MAX, fostering cell cycle dysregulation through p16 transcriptional repression. Genomic mutations that directly inactivate p16 and other cell cycle regulators occur at subsequent stages in progression. While tyrosine kinase inhibitor (TKI) therapies for advanced GISTs result in dramatic clinical responses, secondary TKI resistance often leads to fatal disease progression, highlighting the need for novel targets defined by biologic vulnerabilities, particularly aberrations present across the entire metastatic burden in a given patient. The objective of this mentored research career development proposal is to characterize the events in GIST genomic progression that lead to incremental cell cycle dysregulation, particularly aberrations impacting p16/CDK4/RB1, with the goal of developing novel therapies for patients with advanced GIST. Leveraging GIST as a unique model amongst sarcomas to study genomic progression, my Aim 1 studies address the hypothesis that cell cycle perturbations, including targetable aberrations of the p16/CDK4/RB1 pathway, are virtually universal events in advanced GIST. The Aim 2 studies are motivated by my hypothesis that GIST responses to CDK4/6-inhibition will be maximized by combination approaches. These studies use genome-wide CRISPR screens to identify synthetic lethals with CDK4/6-inhibition in GIST. The Aim 3 studies are preclinical in vitro and in vivo validations of combination therapies that might increase GIST response to CDK4/6 inhibition. Candidate Career Goals: To expedite these translational research studies, I will foster international collaborations with experts in sarcoma genomics, biology, pathology, medical/surgical oncology, and scientific innovation. The studies encompassed by this career development award will be critical to obtain the training, knowledge, and expertise needed to successfully establish an independent translational sarcoma research program and apply for a tenure-track physician-scientist position in academic pathology. The proposed research will be performed under the mentorship of Dr. Jonathan A. Fletcher, leader of two international GIST research consortia, with guidance from an interdisciplinary Scientific Advisory Committee composed of leading experts in the sarcoma field. Environment: Brigham and Women’s Hospital (BWH) houses internationally recognized research programs in scientific discovery training physician-scientists for leadership roles in translational research. The BWH Department of Pathology is home to global leaders in sarcoma/GIST diagnostics, biology, and genetics, who collaborate effectively with clinical disciplines to leverage scientific discoveries into clinical practice for improved diagnosis and treatment.

项目总结

项目成果

期刊论文数量（15）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Diagnosis and management of tropomyosin receptor kinase (TRK) fusion sarcomas: expert recommendations from the World Sarcoma Network.

DOI：
10.1016/j.annonc.2020.08.2232
发表时间：
2020-11
期刊：
Annals of oncology : official journal of the European Society for Medical Oncology
影响因子：
0
作者：
Demetri GD;Antonescu CR;Bjerkehagen B;Bovée JVMG;Boye K;Chacón M;Dei Tos AP;Desai J;Fletcher JA;Gelderblom H;George S;Gronchi A;Haas RL;Hindi N;Hohenberger P;Joensuu H;Jones RL;Judson I;Kang YK;Kawai A;Lazar AJ;Le Cesne A;Maestro R;Maki RG;Martín J;Patel S;Penault-Llorca F;Premanand Raut C;Rutkowski P;Safwat A;Sbaraglia M;Schaefer IM;Shen L;Serrano C;Schöffski P;Stacchiotti S;Sundby Hall K;Tap WD;Thomas DM;Trent J;Valverde C;van der Graaf WTA;von Mehren M;Wagner A;Wardelmann E;Naito Y;Zalcberg J;Blay JY
通讯作者：
Blay JY

SWI/SNF complex-deficient soft tissue neoplasms: An update.

DOI：
10.1053/j.semdp.2020.05.005
发表时间：
2021-05
期刊：
Seminars in diagnostic pathology
影响因子：
2.3
作者：
Schaefer IM;Hornick JL
通讯作者：
Hornick JL

Hypertensive Heartbreak.

高血压心碎。

DOI：
10.1056/nejmimc2031595
发表时间：
2021
期刊：
The New England journal of medicine
影响因子：
0
作者：
Lau,EmilyS;Vaidya,Anand;Schaefer,Inga-Marie;Scirica,BenjaminM
通讯作者：
Scirica,BenjaminM

Clinicopathologic characterization of malignant chondroblastoma: a neoplasm with locally aggressive behavior and metastatic potential that closely mimics chondroblastoma-like osteosarcoma.

DOI：
10.1038/s41379-020-0604-2
发表时间：
2020-11
期刊：
Modern pathology : an official journal of the United States and Canadian Academy of Pathology, Inc
影响因子：
0
作者：
Papke DJ;Hung YP;Schaefer IM;Bredella MA;Charville GW;Reith JD;Fletcher CDM;Nielsen GP;Hornick JL
通讯作者：
Hornick JL

The GIST of Advances in Treatment of Advanced Gastrointestinal Stromal Tumor.