Targeting early events in prostate cancer lineage plasticity

针对前列腺癌谱系可塑性的早期事件

• 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
• 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

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.

项目概要/摘要 前列腺癌是男性最常见的非皮肤癌。前列腺癌细胞依赖于 一种称为雄激素受体 (AR) 的转录因子，由雄激素睾酮和 二氢睾酮。因此，对于晚期前列腺癌患者来说，有效的治疗方法是 雄激素剥夺疗法可阻断雄激素的作用，抑制 AR，并阻止雄激素的生长 前列腺癌细胞。虽然这种治疗方式对于晚期前列腺癌非常有效，但压力 这种疗法最终会导致前列腺癌细胞产生耐药性。大约25-30% 在大多数情况下，前列腺癌治疗的压力会导致前列腺癌细胞转化为细胞 它们不再类似于原始疾病的状态。这些前列腺癌细胞具有以下特征 通过称为谱系可塑性的过程替代细胞类型。这些谱系塑料前列腺癌是 治疗非常困难，因为它们不含 AR 并且没有有效的治疗方法。 此外，标准前列腺癌疗法导致前列腺癌谱系的过程 人们对可塑性知之甚少。该提案旨在了解前列腺癌谱系的生物学 可塑性并开发新的治疗策略来治疗、预防或逆转这一疾病阶段。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 的上调可增强雄激素非依赖性生长 前列腺癌细胞，以及迁移和集落形成表型。从功能上来说，转录 由上调的 KLF5 启动的程序与 AR 激活的转录程序发生冲突。因为 AR 转录程序控制前列腺癌细胞身份，KLF5 上调打破了这一点 身份并促进前列腺癌细胞谱系可塑性的早期步骤。我们假设 针对治疗诱导的前列腺癌谱系可塑性的这一早期步骤将阻止导致 该疾病具有非常侵袭性、难以治疗的表现。我们已将 ERBB2 确定为焦点 AR 和 KLF5 之间的这场拉锯战，并表明 ERBB2 抑制剂可以阻断 AR 和 KLF5 之间的致癌作用 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 具体目标。在目标 1 中，我们将研究 CRPC 中 KLF5 的诱导和谱系可塑性表型。在目标 2 中， 我们将测试阻断 CRPC 谱系可塑性早期步骤的治疗潜力。成功的结果可以 导致临床试验的快速发展，测试这些治疗或预防的治疗策略 谱系塑料前列腺癌。