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: 10622626
• 负责人: Eneda Toska
• 金额: $ 14.86万
• 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/10622626
• 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; 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; PIK3CG gene; Pathogenesis; Pathway interactions; Patient Care; Patients; 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; 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; pharmacologic; 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.

项目概要/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 驱动人类疾病的发病机制。我寻求获得终身教职，使我能够建立一个 研究驱动乳腺癌的表观遗传机制和基础基因转化的研究项目 潜在新疗法的研究结果。为了实现我的目标，我制定了职业发展计划 有四个关键要素：1）扩展和加强我的实验技能和科学知识，2） 增强我的领导力、指导技能和专业发展，3) 获得职业支持 Ross Levine 博士的过渡以及我的合作者 Drs. 的研究指导和职业支持。毛里齐奥 Scaltriti、Sarat Chanderlapaty、Mikui Luo、Charles Sawyers、Ari Melnick 和我的顾问 Drs.拉里·诺顿 和沉荣来 4) 过渡到终身教授独立研究职位。 环境：拟议的研究将在 MSKCC 进行，该中心以其杰出的患者而闻名 护理、最先进的设施和创新研究。我是人类肿瘤学和发病机制的一部分 计划（HOPP）汇集了对基于机制的实验室和转化感兴趣的科学家 研究。在 Charles Sawyers 博士的领导下，HOPP 创建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：40-60% 的 ER+ 乳腺癌或 AR+ 乳腺癌中发生 PI3K 通路的改变， 代表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中起重要作用。有重要的双向 乳腺癌和前列腺癌中 PI3K 与 ER 或 AR 信号传导之间的调控串扰分别导致 当任一单一途径受到药理学抑制时，肿瘤能够适应并存活。我最近有 证明 PI3K 抑制可激活 ER 功能，从而驱动 ER+/PIK3CA 突变体中的肿瘤生长，通过 表观遗传调节因子 KMT2D。我们假设 KMT2D 可能是控制的通用机制 核激素受体功能并调节前列腺细胞特异性增强子的 AR-PI3K 串扰 细胞。初步数据表明，KMT2D 是 PI3K 抑制后雄激素反应所必需的。我们现在的目标 利用前列腺癌细胞研究KMT2D调节AR-PI3K串扰的分子机制 细胞系和人类前列腺类器官（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 筛选确定表观遗传调节因子 ARID1A 是最佳候选者，其丢失介导耐药性 通过谱系转换进行抗 ER 治疗。为此，我们的目标是剖析体内功能和染色质 ARID1A 的基础调节作为内分泌治疗反应的关键介质 (AIM 3)。总而言之，这 了解对于设计新的和改进的激素依赖性肿瘤疗法至关重要。

项目成果

The Oncogenic PI3K-Induced Transcriptomic Landscape Reveals Key Functions in Splicing and Gene Expression Regulation.

致癌 PI3K 诱导的转录组景观揭示了剪接和基因表达调控的关键功能。

• 发表时间: 2022-06-15
• 影响因子: 11.2
• 作者: Ladewig, Erik;Michelini, Flavia;Jhaveri, Komal;Castel, Pau;Carmona, Javier;Fairchild, Lauren;Zuniga, Adler G;Arruabarrena;Cocco, Emiliano;Blawski, Ryan;Kittane, Srushti;Zhang, Yuhan;Sallaku, Mirna;Baldino, Laura;Hristidis
• 通讯作者: Hristidis