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

基本信息

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
项目类别：
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

项目摘要

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专注于表观遗传机制的主要研究者推动人类疾病的发病机理。我试图获得终身制职位，使我能够建立一个研究驱动乳腺癌的表观遗传机制和基本的翻译的研究计划对潜在的新疗法的研究结果。为了实现我的目标，我制定了职业发展计划具有四个关键要素：1）扩展和增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从罗斯·莱文（Ross Levine）博士和我的合作者DRS的研究指导和职业支持过渡。毛里齐奥 Scaltriti，Sarat Chanderlapaty，Minkui Luo和Charles Sawyers，Ari Melnick和我的顾问Drs。拉里·诺顿（Larry Norton） Ronglai Shen 4）过渡到终身研究独立的职位。环境：拟议的研究将在MSKCC进行，以其杰出患者而公认护理，最先进的设施和创新研究。我是人类肿瘤学和发病机理的一部分计划（HOPP）将科学家汇集在一起，对基于机制的实验室和翻译感兴趣研究。在查尔斯·索耶（Charles Sawyers）博士的领导下，霍普（Hopp）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途径的改变发生在40-60％的ER+乳腺癌或AR+乳腺癌中，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肿瘤发生中起重要作用。有重要的双向乳腺和前列腺癌中PI3K和ER或AR信号之间的调节串扰，导致当两种途径在药理上抑制时，适应和生存的肿瘤。我最近有证明PI3K抑制激活ER功能以通过ER+/PIK3CA突变体中的肿瘤生长，表观遗传调节器KMT2D。我们假设KMT2D可能是控制的一般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，在PI3K抑制后，雄激素反应需要KMT2D。我们现在瞄准研究使用前列腺癌细胞调节AR-PI3K串扰的KMT2D的分子机制线条和人类前列腺器官（AIM 1和2）。此外，在寻找表观遗传调节器和他们参与了ER+乳腺癌的治疗反应，我们还进行了CRIS敲除屏幕鉴定表观遗传调节剂ARID1A是最高候选者，其损失介导了抵抗力通过谱系切换进行抗AR治疗。为此，我们旨在剖析体内功能和染色质 - 基于ARID1A作为对内分泌治疗反应的关键介体（AIM 3）。总共，这个理解对于设计新的和改进的激素依赖性肿瘤疗法至关重要。