Overcome the lineage plasticity conferred targeted therapy resistance in advanced prostate cancer

克服谱系可塑性赋予晚期前列腺癌靶向治疗耐药性

• 批准号: 9893832
• 负责人: Ping Mu
• 金额: $ 24.9万
• 依托单位: UT SOUTHWESTERN MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-04-15 至 2021-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9893832
• 关键词: Androgen Antagonists; Antiandrogen Therapy; Award; Basal Cell; Bioinformatics; Biology; Bypass; Canes; Career Mobility; Cell Lineage; Cells; ChIP-seq; Chromatin; Clinical; Clustered Regularly Interspaced Short Palindromic Repeats; DNA; DNA Sequence Alteration; Data; Deaminase; Drug Targeting; Drug resistance; Epigenetic Process; Epithelial Cells; Fibroblasts; Generations; Genes; Goals; Grant; Interruption; Intervention; Job Application; Libraries; Malignant Neoplasms; Malignant neoplasm of prostate; Manuscripts; Mediating; Methylation; Modification; Molecular; Mutation; Organoids; Outcome; Pathway interactions; Patients; Pharmacology; Phenotype; Play; Prostate; RB1 gene; RNA Editing; Regulation; Reporting; Research; Research Personnel; Resistance; Resistance development; Role; Signal Transduction; Somatic Cell; Survival Rate; TP53 gene; Testing; Therapeutic; Time; Training; Transcriptional Activation; Tumor Escape; Tumor Suppressor Genes; Up-Regulation; Work; Writing; advanced prostate cancer; anti-cancer; anticancer research; base; cancer heterogeneity; career; career development; cell type; demethylation; epigenetic regulation; epigenome; epigenomics; epitranscriptomics; in vivo; insight; knock-down; neoplastic cell; novel; novel strategies; novel therapeutic intervention; pluripotency; prevent; progenitor; resistance mechanism; screening; small hairpin RNA; targeted cancer therapy; targeted treatment; therapeutic target; transcriptome sequencing; transdifferentiation; tumor

PROJECT SUMMARY: Despite the intensive effort and huge progress in cancer research, survival rate of many cancers remains low and one of the biggest challenges is resistance to anti-cancer targeted therapies. Recently, a novel mechanism of resistance has been recognized: by switching lineages from a cell type that is dependent on the drug target to a different cell type that is not. My previous and ongoing work revealed that advanced prostate cancer might escape antiandrogen therapy by increasing cellular lineage plasticity and transdifferentiate into a progenitor-like transition state which no longer responds to treatment. I have further demonstrated that this lineage plasticity is enabled by reactivation of SOX2, and can be reversed by inhibiting SOX2 expression. Although direct therapeutic inhibition of SOX2 is currently infeasible, clinical interruption of SOX2 upregulation and its downstream signaling is very promising, upon a clear elucidation of the mechanism of SOX2-driven plasticity. Furthermore, my preliminary observation shows that epigenetic modification may contribute to this SOX2-driven plasticity and resistance, which suggests novel therapeutic approaches targeting the epigenetic modifying machinery. Building on these findings, the proposed studies in Aim 1 and 2 focus on elucidating the exact mechanism of increasing plasticity and resistance driven by SOX2 in prostate cancer, possibly through epigenetic modification, and developing novel strategies to prevent it. In an effort to identify additional genomic alterations responsible for resistance, I successfully identified a novel tumor suppressor gene, SYNCRIP, that confer resistance to antiandrogen therapy via in vivo library screening. Because of the known interaction between SYNCRIP and deaminase Apobec-1, I will also test the hypothesis that loss of SYNCRIP in prostate cancer may confer resistance by releasing the inhibition of Apobec-1-driven methylation/demethylation, thus leading to increased epigenetic reprogramming and cell plasticity in Aim 3. The potential outcome of proposed studies will provide novel insight into the connection between epigenetic modification and resistance to targeted therapy in advanced prostate cancer, as well as novel approaches for clinical intervention of resistance. The support of the K99/R00 award for these proposed studies will provide me the protected time and required training in the fields of cancer epigenetics, chromatin biology and bioinformatics, as well as serve as a platform for me to obtain career development trainings such as grant writing, job application, manuscript writing and lab management. I believe all these supports and trainings are critical for achieving my career goal to become an independent investigator studying targeted therapy resistance.

项目概要： 尽管在癌症研究方面付出了大量努力并取得了巨大进展，但许多癌症的存活率仍然很低 最大的挑战之一是对抗癌靶向治疗的耐药性。最近，一种新的机制 已经认识到耐药性的存在：通过将依赖于药物靶点的细胞类型转换为 一种不同的细胞类型，而不是。我以前和正在进行的工作表明，晚期前列腺癌可能 通过增加细胞谱系可塑性和转分化成祖细胞样细胞来逃避抗雄激素治疗 过渡状态，不再对治疗有反应。我进一步证明了这种谱系可塑性是 通过SOX 2的再激活而实现，并且可以通过抑制SOX 2表达而逆转。虽然直接 治疗性抑制SOX 2目前是不可行的，临床中断SOX 2上调及其 下游信号是非常有前途的，在一个清晰的阐明机制的SOX 2驱动的可塑性。 此外，我的初步观察表明，表观遗传修饰可能有助于这种SOX 2驱动的 可塑性和抗性，这表明新的治疗方法，针对表观遗传修饰 机械.在这些发现的基础上，目标1和目标2中拟议的研究重点是阐明 前列腺癌中SOX 2驱动的增加可塑性和抵抗力的机制，可能通过 表观遗传修饰，并开发新的战略，以防止它。在努力确定其他基因组 我成功地发现了一种新的肿瘤抑制基因，SYNCRIP， 通过体内文库筛选赋予对抗雄激素治疗的抗性。由于已知的相互作用， SYNCRIP和脱氨酶Apobec-1，我还将检验前列腺癌中SYNCRIP缺失的假设， 可能通过释放Apobec-1驱动的甲基化/去甲基化的抑制来赋予抗性，从而导致 Aim 3中增加的表观遗传重编程和细胞可塑性。拟议研究的潜在成果将 为表观遗传修饰与靶向治疗耐药性之间的联系提供了新的见解， 晚期前列腺癌，以及临床干预耐药性的新方法。的支持 K99/R 00奖励这些拟议的研究将为我提供受保护的时间和所需的培训领域 癌症表观遗传学，染色质生物学和生物信息学，以及作为一个平台，我获得 职业发展培训，如基金写作，工作申请，手稿写作和实验室管理。我 我相信所有这些支持和培训对于实现我的职业目标，成为一个独立的人至关重要 研究靶向治疗耐药性的研究员。