Mechanisms of epigenetic regulation of estrogen receptor function in breast cancer

乳腺癌雌激素受体功能的表观遗传调控机制

• 批准号: 10431771
• 负责人: Eneda Toska
• 金额: $ 19.09万
• 依托单位: JOHNS HOPKINS UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-06-16 至 2024-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10431771
• 关键词: 3-Dimensional; AKT1 gene; ARID1A gene; Affect; Androgen Receptor; Androgens; Architecture; Automobile Driving; Basic Science; Binding; Biochemical; Breast; Cancer Etiology; Career Mobility; Cells; Cessation of life; Chromatin; Clinic; Clinical; Clustered Regularly Interspaced Short Palindromic Repeats; Combined Modality Therapy; DNA Sequence Alteration; Data; Development; Development Plans; Drug resistance; Elements; Enhancers; Epigenetic Process; Estrogen Receptors; Estrogen receptor positive; Genetic; Genetic Transcription; Goals; Growth; Hormones; Human; In Vitro; Knock-out; Knowledge; Laboratory Research; Leadership; Lysine; Maintenance; Malignant Neoplasms; Malignant neoplasm of prostate; Mammary Neoplasms; Mediating; Mediator of activation protein; Memorial Sloan-Kettering Cancer Center; Mentors; Metastatic breast cancer; Methylation; Methyltransferase; Molecular; Morphogenesis; Mutation; Nature; Nuclear Hormone Receptors; Nuclear Receptors; Oncogenic; Oncology; Organoids; PI3K/AKT; PIK3CA gene; Pathogenesis; Pathway interactions; Patient Care; Patients; Pharmacology; Phosphorylation; Play; Positioning Attribute; Post-Translational Protein Processing; Principal Investigator; Progression-Free Survivals; Prostate; Prostatic Neoplasms; Regulation; Reporting; Research; Resistance; Resistance development; Role; Science; Scientist; Serine; Signal Pathway; Signal Transduction; Therapeutic; Translational Research; Translations; Treatment outcome; United States; Woman; Work; advanced prostate cancer; base; breast tumorigenesis; cancer diagnosis; career; career development; collaborative environment; design; epigenetic regulation; epigenomics; genome-wide; histone methyltransferase; hormone therapy; human disease; improved; in vivo; in vivo Model; inhibitor; innovation; interest; malignant breast neoplasm; mammary gland development; men; mouse model; multimodality; mutant; novel therapeutics; phase 3 study; pre-clinical; programs; prostate cancer cell; prostate cancer cell line; prostate cancer model; receptor function; research clinical testing; response; skills; tenure track; therapy outcome; treatment response; tumor; tumor growth; tumorigenesis

PROJECT SUMMARY/ ABSTRACT CANDIDATE: My ultimate goal is to become a principal investigator focused on the epigenetic mechanisms driving the pathogenesis of human diseases. I seek to attain a tenure-track position allowing me to establish a research program that studies the epigenetic mechanisms driving breast cancer and the translation of basic research findings into potential new therapies. To achieve my goal, I have developed a career development plan with four key elements: 1) To expand and strengthen my experimental skills and scientific knowledge, 2) To enhance my leadership, mentoring skills, and professional development, 3) To receive support on my career transition from Dr. Ross Levine and research guidance and career support from my collaborators Drs. Maurizio Scaltriti, Sarat Chanderlapaty, Minkui Luo, and Charles Sawyers, Ari Melnick and my advisers Drs. Larry Norton and Ronglai Shen 4) To transition into a tenure-track research independent position. ENVIRONMENT: The proposed study will be conducted at MSKCC, acknowledged for its exceptional patient care, state-of-the-art facilities, and innovative research. I am part of the Human Oncology and Pathogenesis Program (HOPP) that brings together scientists with an interest in mechanism-based laboratory and translational research. Under the leadership of Dr. Charles Sawyers, HOPP creates a highly collaborative environment that will greatly facilitate my translational research efforts. RESEARCH: Alterations in the PI3K pathway occur in 40-60% of ER+ breast cancer or AR+ breast cancer, representing the most common genomic alteration in such tumors, and indicating that the PI3K signaling pathway plays an important role in the tumorigenesis of hormone-dependent tumors. There is important bidirectional regulatory crosstalk between PI3K and ER or AR signaling in breast and prostate cancers respectively, leading to tumors that adapt and survive when either single pathway is pharmacologically inhibited. I have recently demonstrated that PI3K inhibition activates ER function to drive tumor growth in ER+/PIK3CA mutants, through the epigenetic regulator KMT2D. We hypothesized that KMT2D could be a general mechanism in controlling nuclear hormone receptor function and regulate the AR-PI3K crosstalk at cell-specific enhancers of prostate cells. Preliminary data show that KMT2D is required for androgen response upon PI3K inhibition. We now aim to study the molecular mechanisms of KMT2D in the regulation of AR-PI3K crosstalk using prostate cancer cell lines and human prostate organoids (AIM 1 and 2). Furthermore, while searching for epigenetic regulators and their involvement in therapeutic response in ER+ breast cancer, we have also conducted a CRISPR knockout screen that identified the epigenetic regulator ARID1A as the top candidate whose loss mediates resistance to anti-ER therapy through lineage switching. To this end, we aim to dissect the in vivo function and the chromatin- based regulation of ARID1A as a key mediator of response to endocrine therapy (AIM 3). Altogether, this understanding is critical to design new and improved therapies for hormone-dependent tumors.

项目摘要/摘要 候选人：我的最终目标是成为一名专注于表观遗传机制的首席研究员 推动人类疾病的发病机制。我希望获得一个终身教职的职位，这样我就可以建立一个 研究乳腺癌的表观遗传机制和BASIC翻译的研究项目 潜在新疗法的研究成果。为了实现我的目标，我制定了一个职业发展计划 有四个关键要素：1)扩大和加强我的实验技能和科学知识，2) 增强我的领导力、指导技能和职业发展，3)在我的职业生涯中获得支持 从罗斯·莱文博士过渡到我的合作者莫里齐奥博士的研究指导和职业支持 斯卡特里蒂、萨拉特·昌德拉帕蒂、罗明奎、查尔斯·索耶斯、阿里·梅尔尼克和我的顾问拉里·诺顿博士 和沈荣来4)过渡到终身教职研究独立职位。 环境：拟议的研究将在MSKCC进行，该中心因其特殊的患者而受到认可 护理、最先进的设施和创新的研究。我是人类肿瘤学和病因学的一部分 计划(Hopp)，将对基于机械的实验室和翻译感兴趣的科学家聚集在一起 研究。在查尔斯·索耶斯博士的领导下，霍普创造了一个高度协作的环境 将极大地促进我的翻译研究工作。 研究：PI3K通路改变发生在40-60%ER+乳腺癌或AR+乳腺癌中， 代表了此类肿瘤中最常见的基因组改变，并表明PI3K信号通路 在激素依赖性肿瘤的发生发展中起重要作用。有重要的双向 在乳腺癌和前列腺癌中，PI3K和ER或AR信号之间的调节串扰分别领先 当任何一种单一途径在药物上被抑制时，肿瘤就会适应并存活。我最近有过 证明PI3K抑制激活ER功能以驱动ER+/PIK3CA突变体中的肿瘤生长 表观遗传调控因子KMT2D。我们假设KMT2D可能是一种控制 核激素受体在前列腺细胞特异性增强子上的作用及其对AR-PI3K串扰的调节 细胞。初步数据显示，在PI3K抑制时，雄激素反应需要KMT2D。我们现在的目标是 KMT2D调节前列腺癌细胞AR-PI3K串扰的分子机制研究 LINES和人前列腺类器官(AIM 1和2)。此外，在寻找表观遗传调控因子和 他们参与ER+乳腺癌的治疗反应，我们还进行了CRISPR基因敲除 筛选确定表观遗传调节因子ARID1A为其丧失介导抗性的首选候选 通过血统转换进行抗ER治疗。为此，我们的目标是剖析体内功能和染色质- 基于ARID1A作为内分泌治疗反应的关键介质的调节(AIM 3)。总而言之，这 了解这一点对于设计新的和改进的激素依赖型肿瘤治疗方法至关重要。