Mechanism of non-oncogene addiction

非癌基因成瘾机制

基本信息

批准号：
10091403
负责人：
Mohammad Azam
金额：
$ 36.37万
依托单位：
CINCINNATI CHILDRENS HOSP MED CTR
依托单位国家：
美国
项目类别：
财政年份：
2018
资助国家：
美国
起止时间：
2018-02-15 至 2023-01-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10091403
关键词：
Accelerated Phase Acute leukemia Affect Alleles Applications Grants Basic Science Binding Blast Phase Cells Chemicals Chromatin Chronic Chronic Myeloid Leukemia Chronic Phase Clinical Complex Data Development Diagnosis Disabled Persons Disease EVI1 gene Enhancers Epigenetic Process Evolution FOS gene Failure Genes Genetic Growth Factor HOXA9 gene Histone H3 Histones Indolent Internal Ribosome Entry Site Investigation Knowledge Link MAP Kinase Gene Maintenance Malignant Neoplasms Malignant neoplasm of lung Malignant neoplasm of prostate Mediating Mediator of activation protein Medicine Modality Modeling Molecular Mutation NUP98 gene Nature Oncogenic Oncoproteins Organ Patients Phase Protein Tyrosine Kinase Publishing RUNX1 gene Reporter Reporter Genes Research Residual Neoplasm Resistance Signal Transduction Solid Solid Neoplasm TP53 gene Testing Therapeutic Transcription Factor AP-1 Tyrosine Kinase Inhibitor Work bcr-abl Fusion Proteins cancer cell chronic myeloid leukemia cell cytokine insight kinase inhibitor leukemia leukemic transformation malignant breast neoplasm mortality mouse model novel therapeutics overexpression p38 Mitogen Activated Protein Kinase paracrine personalized medicine refractory cancer relapse patients response stem cells targeted treatment transcription factor tumor

项目摘要

Abstract With the advent of personalized cancer medicine, mutations in tumors can be paired with targeted therapies such as tyrosine kinase inhibitors (TKI). However, even the most potent TKI fail to eradicate all cancer cells. Subsequently, tumor-repopulating cells within minimal residual disease (MRD) contribute to patient relapse. The application of Abl-kinase inhibitors to the BCR/ABL oncoprotein in chronic myelogenous leukemia (CML) is a paradigm for personalized medicine. TKI therapy in CML leads to long lasting therapeutic benefit; however, MRD remains and can eventually evolve to blast crisis. Although the molecular mechanisms underlying the failure of TKI to eradicate CML MRD are not known, growth factor signals are suspected to replace the TKI- disabled oncoprotein survival signals. We have determined that c-Fos and Dusp1 are critical for growth-factor- mediated TKI resistance. Both genetic and chemical inhibition of Dusp1 and c-Fos render CML exquisitely sensitive to TKI, and cure a mouse model of CML. Overall, our published and preliminary data suggests that expression levels of c-Fos and Dusp1 determine the threshold of TKI efficacy during chronic CML disease. Extending this line of investigation, the proposed research will determine whether c-Fos and Dusp1 are necessary and sufficient for the evolution of CML to blast crisis, and whether c-Fos and Dusp1 levels determine response to TKI in blast crisis. Next, we hypothesize that Fos and Dusp1 signals converge upon oncogenically-activated enhancers. We propose that Fos-Jun AP-1 complexes facilitate oncogenically active enhancers, while in the absence of c-Fos and Dusp1 signals, Jun-JunD AP-1 complexes predominate but do not support tumor maintenance. Specifically, we will molecularly link c-Fos-Jun AP-1 and Dusp1 activity to global enhancer chromatin dynamics. Moreover, we will exploit chromatin-embedded target-gene-reporter alleles to provide a detailed analysis of functionally-relevant downstream genes at a single-cell level in primary CML cells. The proposed work is expected to delineate the necessity of c-Fos and Dusp1 in CML-blast-crisis TKI sensitivity, as well as to provide deep molecular insight into the mechanisms underlying blast crisis and cytokine-mediated TKI resistance. We expect that this information will be informative not only for CML and blast crisis, but also the broad group of tyrosine-kinase oncoprotein-driven tumors that are not cured by TKI.

抽象的随着个性化癌症医学的出现，肿瘤突变可以与靶向治疗相结合例如酪氨酸激酶抑制剂（TKI）。然而，即使是最有效的 TKI 也无法根除所有癌细胞。随后，微小残留病（MRD）内的肿瘤再生细胞导致患者复发。 Abl激酶抑制剂针对BCR/ABL癌蛋白在慢性粒细胞白血病（CML）中的应用个性化医疗的典范。 CML 的 TKI 治疗可带来持久的治疗效果；然而， MRD 仍然存在，并最终可能演变成爆炸性危机。尽管其背后的分子机制 TKI 未能根除 CML MRD 尚不清楚，生长因子信号被怀疑取代了 TKI- 禁用癌蛋白生存信号。我们已经确定 c-Fos 和 Dusp1 对于生长因子至关重要- 介导的 TKI 耐药。 Dusp1 和 c-Fos 的遗传和化学抑制使 CML 完美呈现对 TKI 敏感，并治愈 CML 小鼠模型。总体而言，我们发布的初步数据表明 c-Fos 和 Dusp1 的表达水平决定了慢性 CML 疾病期间 TKI 疗效的阈值。扩展这一研究方向，拟议的研究将确定 c-Fos 和 Dusp1 是否是 CML 爆发危机的必要和充分条件，以及 c-Fos 和 Dusp1 水平是否水平确定爆炸危机中对 TKI 的反应。接下来，我们假设 Fos 和 Dusp1 信号收敛于致癌激活增强剂。我们建议 Fos-Jun AP-1 复合物促进致癌活性增强子，而在没有 c-Fos 和 Dusp1 信号的情况下，Jun-JunD AP-1 复合物占主导地位，但确实不支持肿瘤维持。具体来说，我们将在分子上将 c-Fos-Jun AP-1 和 Dusp1 活性与全局增强子染色质动力学。此外，我们将利用染色质嵌入的目标基因报告基因等位基因，以在原代细胞中的单细胞水平上提供功能相关下游基因的详细分析慢性粒细胞白血病细胞。拟议的工作预计将描述 c-Fos 和 Dusp1 在 CML 急变危机中的必要性 TKI 敏感性，以及提供对爆炸危机和潜在机制的深入分子洞察细胞因子介导的 TKI 耐药。我们希望这些信息不仅能为 CML 提供信息，急变，还包括酪氨酸激酶癌蛋白驱动的、TKI 无法治愈的广泛肿瘤。