Targeting early events in prostate cancer lineage plasticity

针对前列腺癌谱系可塑性的早期事件

基本信息

批准号：
10587265
负责人：
Scott M. Dehm
金额：
$ 48.68万
依托单位：
UNIVERSITY OF MINNESOTA
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：
2022-12-01 至 2027-11-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10587265
关键词：
Affinity Anchorage-Independent Growth Androgen Receptor Androgens Automobile Driving Basal Cell Benign Biology Biopsy Castration Cell Line Cell Lineage Cells Cessation of life ChIP-seq Chromatin Classification Clinical Clinical Trials Data Data Set Development Disease ERBB2 gene Endocrine Epithelial Cells Epithelium Event Gene Expression Regulation Genes Genetic Transcription Genomic approach Genomics Growth In Vitro Knockout Mice Ligands Malignant Neoplasms Malignant neoplasm of prostate Modeling Neurosecretory Systems Oncogenes Oncogenic Organoids Outcome Pathway interactions Patients Pharmaceutical Preparations Phenotype Prevention Process Prostate Prostate Cancer therapy Prostatic Neoplasms Recurrence Resistance Resistance development Role Specific qualifier value Stains Stanolone Stress Testing Testosterone Therapeutic Tissues Tumor Biology Tumor Suppressor Proteins United States Up-Regulation War abiraterone addiction advanced disease advanced prostate cancer androgen deprivation therapy androgen sensitive antagonist castration resistant prostate cancer cell type clinical development drug sensitivity effective therapy efficacy testing enzalutamide genome-wide hormone therapy in vivo inhibitor knock-down male migration novel therapeutic intervention patient derived xenograft model pharmacologic pressure prevent programs prostate cancer cell spatiotemporal standard of care stem cells synergism targeted treatment therapeutic evaluation therapeutic target therapeutically effective therapy resistant transcription factor transcriptome sequencing treatment strategy tumor

项目摘要

PROJECT SUMMARY/ABSTRACT Prostate cancer is the most common non-cutaneous cancer in males. Prostate cancer cells are dependent on a transcription factor called the androgen receptor (AR), which is activated by the androgens testosterone and dihydrotestosterone. Accordingly, an effective treatment for patients with advanced prostate cancer is androgen deprivation therapy, which blocks the effects of androgens, inhibits the AR, and halts the growth of prostate cancer cells. Although this form of treatment is very effective for advanced prostate cancer, the stress of this therapy will eventually lead to the prostate cancer cells developing resistance. In approximately 25-30% of cases, the stress of prostate cancer therapy will cause the prostate cancer cells to transform into cellular states where they no longer resemble the original disease. These prostate cancer cells take on features of alternative cell types through a process called lineage plasticity. These lineage plastic prostate cancers are very difficult to treat because they do not contain AR and there are no effective therapeutics available. Additionally, the processes by which standard prostate cancer therapies can cause prostate cancer lineage plasticity is poorly understood. This proposal seeks to understand the biology of prostate cancer lineage plasticity and develop new therapeutic strategies to treat, prevent, or reverse this disease stage. Our preliminary data demonstrates the stem cell transcription factor KLF5 is up-regulated by standard prostate cancer therapies that inhibit the AR. Up-regulation of KLF5 enhances androgen-independent growth of prostate cancer cells, as well as migration and colony formation phenotypes. Functionally, the transcriptional program initiated by up-regulated KLF5 clashes with the transcriptional program activated by the AR. Because the AR transcriptional program controls prostate cancer cell identity, KLF5 up-regulation breaks down this identity and promotes very early steps in lineage plasticity of prostate cancer cells. We hypothesize that targeting this early step in therapy-induced prostate cancer lineage plasticity will block later events that lead to very aggressive, treatment-resistant manifestations of the disease. We have identified ERBB2 as a focal point of this tug-of-war between AR and KLF5, and shown that ERBB2 inhibitors can block the oncogenic effects of KLF5. To advance these findings and identify additional therapeutic vulnerabilities in this pathway, we propose 2 Specific Aims. In Aim 1, we will study induction of KLF5 and lineage plasticity phenotypes in CRPC. In Aim 2, we will test therapeutic potential of blocking early steps in CRPC lineage plasticity. A successful outcome can lead to rapid development of clinical trials testing these therapeutic strategies for treatment or prevention of lineage plastic prostate cancer.

项目摘要/摘要前列腺癌是雄性最常见的非乳腺癌。前列腺癌细胞取决于一种称为雄激素受体（AR）的转录因子，该转录因子被雄激素睾丸激素和二氢睾丸激素。因此，对晚期前列腺癌患者的有效治疗是雄激素剥夺疗法阻止了雄激素的作用，抑制AR并停止生长前列腺癌细胞。尽管这种治疗形式对于晚期前列腺癌非常有效，但应力这种疗法最终将导致前列腺癌细胞发展耐药。大约25-30％在病例中，前列腺癌疗法的压力将导致前列腺癌细胞转化为细胞声明它们不再类似于原始疾病。这些前列腺癌细胞具有通过称为谱系可塑性的过程替代细胞类型。这些血统塑料前列腺癌是很难治疗，因为它们不含AR，也没有有效的治疗剂。此外，标准前列腺癌疗法可以引起前列腺癌谱系的过程可塑性知之甚少。该建议旨在了解前列腺癌血统的生物学可塑性并制定新的治疗策略来治疗，预防或扭转这种疾病阶段。我们的初步数据表明，干细胞转录因子KLF5被标准前列腺上调抑制AR的癌症疗法。 KLF5的上调增强了与雄激素无关的生长前列腺癌细胞，迁移和菌落形成表型。在功能上，转录由上调的KLF5与AR激活的转录程序启动的程序。因为 AR转录程序控制前列腺癌细胞的身份，KLF5上调破坏了这一点身份并促进了前列腺癌细胞谱系可塑性的很早的步骤。我们假设这一点针对治疗引起的前列腺癌谱系可塑性的早期一步将阻止后来的事件非常激进的疾病表现。我们已经将ERBB2确定为焦点在AR和KLF5之间的这场拖船中，ERBB2抑制剂可以阻止 KLF5。为了推进这些发现并确定该途径中的其他治疗漏洞，我们建议 2个具体目标。在AIM 1中，我们将研究CRPC中KLF5和谱系可塑性表型的诱导。在AIM 2中，我们将测试在CRPC谱系可塑性中阻止早期步骤的治疗潜力。成功的结果可以导致快速开发临床试验测试这些治疗或预防的治疗策略谱系塑料前列腺癌。