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Diapause-like adaptation of triple-negative breast cancer cells during chemotherapy treatment

三阴性乳腺癌细胞在化疗期间的滞育样适应

基本信息

批准号：
10616703
负责人：
Eugen Dhimolea
金额：
$ 19.13万
依托单位：
ALBERT EINSTEIN COLLEGE OF MEDICINE
依托单位国家：
美国
项目类别：
财政年份：
2022
资助国家：
美国
起止时间：
2022-05-02 至 2025-04-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10616703
关键词：
3-Dimensional Adopted Aftercare Anabolism Antineoplastic Agents Apoptotic Attenuated Biological Biological Assay Breast Cancer Cell Breast Cancer Patient Breast Cancer Treatment Bromodomains and extra-terminal domain inhibitor Cancer Model Clinical Clinical Management Cytotoxic Chemotherapy Cytotoxic agent Data Dependence Development Diapause Disease Disease model Disease remission Drug Modelings Embryo Evaluation Genes Genetic Transcription Genomics Goals Growth Investigational Drugs Lesion Maintenance Malignant Neoplasms Maps Mediating Mediator Methods Minor Modeling Molecular Molecular Analysis Molecular Profiling Organoids Outcome Oxidation-Reduction Paper Pathologic Patients Pharmaceutical Preparations Phenotype Pre-Clinical Model Principal Investigator Recurrent disease Relapse Research Residual Cancers Residual Neoplasm Residual state Role Stress System Techniques Therapeutic Time Validation Writing cancer cell cancer subtypes chemotherapy clinically relevant gain of function high risk in vitro Model in vivo loss of function malignant breast neoplasm neoplastic cell personalized medicine pharmacologic pre-clinical programs relapse patients relapse risk response simulation therapeutic target therapy development triple-negative invasive breast carcinoma tumor tumor eradication two-dimensional

项目摘要

PROJECT SUMMARY Treatment with cytotoxic drugs often fail to completely eradicate breast cancers (BrCa) due to viable tumor cells that persist (“residual tumors”) and represent a reservoir for eventual relapse. In triple-negative breast cancer (TNBC), a highly lethal BrCa subtype, the presence of post-treatment residual cancer cells is strongly associated with aggressive disease relapse. Eradicating the drug-persistent TNBC foci could lead to cures, but their therapeutic vulnerabilities remain elusive, mainly because bona fide preclinical models of this cancer cell state amenable to genomic and pharmacological interrogation had been lacking. In our recent studies we demonstrated that treatment-persistent residual tumor cells adopt a distinct and reversible transcriptional program resembling that of embryonic diapause, a dormant stage of suspended development triggered by stress and associated with suppressed Myc activity and overall biosynthesis. Importantly, we developed 3-dimensional (3D) organoid based in vitro models (treatment-persistent organoids, TP-organoids) that faithfully recapitulate the phenotype and molecular profile of the residual tumors in PDX and in BrCa patients. To our knowledge, this is a first in vitro model of post-chemotherapy residual dormant cancer lesions. Our molecular and functional analyses strongly suggest that chemo-persistent dormant tumor cells possess distinct genomic and pharmacological vulnerabilities that are not reflected by historical cancer models (e.g. 2D cultures or conventional 3D/organoid cultures). The novelty and relevance of our models warrant the evaluation of putative mediators of the drug-persistent cancer cell state, which could reveal new, previously unappreciated, therapeutic targets for this clinically critical setting. In this exploratory project, we will combine our TNBC TP-organoid models of drug-persistent dormancy with genomic and pharmacological methods to i) identify the key mediators controlling TNBC cell exit from the dormancy state; and ii) develop therapeutic approaches that specifically kill dormant drug-persistent TNBC tumors. We will apply controllable loss-of-function (LOF) and gain-of-function (GOF) techniques to determine whether reactivation of Myc and/or other genes is necessary or sufficient for BrCa cells to exit dormancy. Similarly, we will use LOF approaches targeting genes commonly upregulated in our preclinical models of residual disease to assess their role on the viability of diapause-like persistent TNBC cells. In parallel, we will leverage the high-throughput capacity of our TP-organoid systems to map the landscape of pharmacological vulnerabilities of the chemo-persistent TNBC cells. The therapeutic value of candidate targets that enable the viability of persistent TNBC cells, or their exit from the dormant state, will be validated in appropriate in vivo residual disease models. This exploratory project will outline a first preclinical framework of therapeutic approaches to specifically target diapause-like drug-persistent TNBC tumors. Specifically targeting the candidate mediators that enable the viability during, or the exit from, treatment-induced protective dormancy of persistent residual cancer cells could lead to durable responses or even tumor eradication.

项目总结