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: 10055648
• 负责人: Eneda Toska
• 金额: $ 18.78万
• 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/10055648
• 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/antagonist; 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.

项目总结/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。 驱动人类疾病的发病机制。我寻求获得一个终身职位，让我建立一个 一项研究计划，研究驱动乳腺癌的表观遗传机制和基本基因的翻译。 研究成果转化为潜在的新疗法。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） 提高我的领导能力，指导技能和专业发展，3）在我的职业生涯中获得支持 罗斯·莱文博士的过渡以及我的合作者毛里齐奥博士的研究指导和职业支持 斯卡特里蒂、萨拉特·钱德拉帕蒂、罗敏奎、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）过渡到终身制研究的独立职位。 环境：拟定研究将在MSKCC进行，该研究因其特殊患者而得到认可 护理，最先进的设施和创新的研究。我是人类肿瘤学和发病机制的一部分， 该计划（HOPP）汇集了对基于机制的实验室和翻译感兴趣的科学家 research.在Charles Sawyers博士的领导下，HOPP创造了一个高度协作的环境， 将极大地促进我的转化研究工作。 研究：PI 3 K通路的改变发生在40-60%的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PI 3 K信号通路 在肿瘤依赖性肿瘤的发生中起重要作用。重要的双向 乳腺癌和前列腺癌中PI 3 K和ER或AR信号传导之间的调节串扰，导致 当任何一条通路被抑制时，肿瘤都能适应并存活下来。我最近 证明PI 3 K抑制激活ER功能以驱动ER+/PIK 3CA突变体中的肿瘤生长， 表观遗传调节因子KMT 2D。我们假设KMT 2D可能是控制的一般机制 核激素受体功能和调节AR-PI 3 K串扰在前列腺的细胞特异性增强子 细胞初步数据显示，KMT 2D是PI 3 K抑制后雄激素反应所需的。我们现在的目标是 利用前列腺癌细胞研究KMT 2D调节AR-PI 3 K相互作用的分子机制 细胞系和人前列腺类器官（AIM 1和2）。此外，在寻找表观遗传调节因子和 他们参与ER+乳腺癌的治疗反应，我们还进行了CRISPR敲除 筛选，确定了表观遗传调节因子ARID 1A作为最佳候选者，其损失介导对 通过谱系转换进行抗ER治疗。为此，我们的目标是解剖体内功能和染色质- 基于ARID 1A作为内分泌治疗应答的关键介质的调节（AIM 3）。总之，这 了解这些对于设计新的和改进的用于肿瘤依赖性肿瘤的疗法至关重要。