权益分类	功能权益	普通用户	{{item.name}}会员
{{category.name}}	{{benefitItem.name}}

Molecular mechanism and preclinical development of BETi and PARPi combination therapy

BETi和PARPi联合疗法的分子机制和临床前开发

基本信息

批准号：
10082442
负责人：
Lin Zhang
金额：
$ 36.83万
依托单位：
UNIVERSITY OF PENNSYLVANIA
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：
2019-02-01 至 2024-01-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10082442
关键词：
Adult Animal Model BRCA1 gene Biological Assay Biology Breast Breast Cancer Model Breast Cancer Treatment Bromodomain CD8-Positive T-Lymphocytes Cancer Model Cell Line Cells Chemicals Clinical Clinical Trials Clustered Regularly Interspaced Short Palindromic Repeats Combined Modality Therapy DNA Damage DNA Repair DNA Sequence Alteration Development Dose Drug Combinations Drug Targeting Enhancers Epigenetic Process Essential Genes FDA approved Gene Expression Gene Fusion Genes Genetic Genetic Transcription Immune response Immunocompetent Immunology Impairment Interferon Type II Lead Malignant Neoplasms Malignant neoplasm of ovary Methods Modeling Molecular Nonhomologous DNA End Joining Oncology Ovarian PARP inhibition Patients Pharmaceutical Preparations Pharmacodynamics Poly(ADP-ribose) Polymerases Pre-Clinical Model Proteins Reporter Research Personnel Resistance Resources Role Schedule Side Solid T-Cell Depletion Testing Therapeutic Toxic effect Transcription Elongation Translational Research Woman Xenograft Model cancer care cancer cell cancer therapy chromosome conformation capture clinical application cytokine design drug development early phase clinical trial epigenetic drug experimental study genome editing homologous recombination in vivo inhibitor/antagonist malignant breast neoplasm novel patient derived xenograft model pre-clinical preclinical development preclinical study response targeted treatment transcriptome sequencing translational medicine tumor tumor microenvironment

项目摘要

PROJECT SUMMARY Although poly (ADP-ribose) polymerase inhibitor (PARPi) has emerged as a promising drug for patients with cancer, primary and acquired resistance is a major clinical problem for PARPi in cancer treatment. Several drug combination strategies have been designed and evaluated in preclinical and early clinical trials to overcome this challenge. Therefore, strategies to enhance response to PARPi in primary and acquired homologous recombination (HR)-proficient tumors would represent a significant advance in cancer care. Bromodomains and extra-terminal domain inhibitor (BETi) has been rapidly advanced into early clinical trials and has shown impressive anti-tumor activity. Given that clinical activity of BETi alone may be insufficient to manage patients according to recent clinical trials, the combination of BETi with other treatment methods need to be designed and evaluated. Using a drug synergistic screen that combined a PARPi with 20 well-characterized epigenetic drugs, we identified BETi as a drug that acted synergistically with PARPi in HR-proficient cancer cells. Functional assays demonstrated that repressed BET activity reduces HR and subsequently enhances PARPi-induced DNA damage in cancer cells. Chemical inhibition or genetic depletion of BET proteins impairs transcription of several essential genes in HR. Moreover, BETi treatment sensitized tumors to PARP inhibition in preclinical animal models of HR-proficient breast and ovarian cancers. Finally, we showed that the BRD4 gene was significantly and focally amplified across common adult cancers, although its gene fusion was a rare genomic alteration. Thus, we hypothesize that BETi may suppress HR and enhance NHEJ, thereby sensitizing HR-proficient cancer cells to PARP inhibition. Aim 1. Characterize the molecular mechanisms by which BETi synergistically acts with PARPi. Aim 2. Evaluate the combination therapy of BET and PARP inhibitors in preclinical models. Aim 3. Define immune responses to BETi and PARPi treatment in the tumor microenvironment. Our proposed studies may provide strong rationale for clinical application of PARPi in the setting of combination with BETi to treat both cancers with de novo resistance to PARPi therapy and cancers with acquired resistance. Therefore, combination with BETi could greatly expand the utility of PARP inhibition to patients with HR-proficient cancer.

项目总结