Mechanisms by which histone methyltransferases regulate nuclear receptor activity and response to therapy in hormone-driven tumors.

组蛋白甲基转移酶调节核受体活性和激素驱动肿瘤治疗反应的机制。

• 批准号: 10563751
• 负责人: Eneda Toska
• 金额: $ 37.46万
• 依托单位: JOHNS HOPKINS UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-03-16 至 2028-02-29
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10563751
• 关键词: AKT inhibition; AKT1 gene; Ablation; Affect; Androgen Antagonists; Androgen Receptor; Androgens; Antiestrogen Therapy; Breast; Breast Cancer Model; Breast Cancer cell line; Cancer Etiology; Cancer Patient; Cell Differentiation process; Cells; Cessation of life; Chromatin; Clinical; Combined Modality Therapy; Computational Biology; DNA Sequence Alteration; Data; Diagnosis; Drug resistance; Enhancers; Environment; Epigenetic Process; Estrogen Nuclear Receptor; Estrogen Receptors; Estrogens; Genes; Genetic Transcription; Goals; Growth; Hormone Receptor; Hormones; Lysine; Malignant Neoplasms; Malignant neoplasm of prostate; Mammary Neoplasms; Mediating; Methylation; Methyltransferase; Modeling; Molecular; Mutation; Nuclear Hormone Receptors; Nuclear Receptors; Organoids; PI3K/AKT; PIK3CA gene; PIK3CG gene; Pathway interactions; Patients; Phosphorylation; Play; Prostate; Prostatic Neoplasms; Protein Methylation; Publishing; Reagent; Receptor Signaling; Regulation; Reporting; Resistance; Resources; Role; Science; Serine; Signal Pathway; Site; Therapeutic; Therapeutic Studies; Treatment outcome; United States; Woman; advanced prostate cancer; anticancer research; cancer cell; cofactor; design; epigenetic therapy; epigenomics; genetic manipulation; histone methyltransferase; hormone therapy; improved; inhibitor; malignant breast neoplasm; men; multidisciplinary; mutant; novel; patient population; pharmacologic; pre-clinical; prostate cancer cell; prostate cancer model; receptor function; recruit; research clinical testing; response; single cell sequencing; transcription factor; treatment response; tumor; tumor growth; tumorigenesis

PROJECT SUMMARY/ ABSTRACT 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. Mechanistically, we demonstrated that PI3K inhibition activates ER activity to drive the growth of in ER+/PIK3CA mutant tumors, through regulation of the histone methyltransferase KMT2D. KMT2D is phosphorylated by the PI3K effectors AKT1/SGK1, which inhibits its recruitment to chromatin and its role as a coactivator at ER target genes in breast cancer. Upon PI3K inhibition, this inhibitory phosphorylation is lost, allowing KMT2D to drive ER-dependent transcription. We hypothesized that KMT2D could be a common mechanism in controlling nuclear hormone receptor function, PI3K pathway crosstalk, and ER and AR luminal cell differentiation in breast and prostate models respectively. Preliminary data have shown that KMT2D is required for ER and AR transcriptional activity upon PI3K inhibition in breast and prostate cancers respectively. Furthermore, KMT2D loss sensitizes cancer cells to PI3K/AKT inhibition in cells, tumors, and patient derived organoids. We now aim to characterize the epigenetic and transcriptional role of KMT2D as a key modulator of AR/ER nuclear receptor activity in cells and organoids using bulk epigenomic and single cell sequencing (Aim 1). We have also identified the lysine methyltransferase SMYD2 as a novel level of regulator of KMT2D and ER/AR activity. We now plan to elucidate the role of SMYD2-catalyzed-mediated methylation on KMT2D activity and cofactor associations in breast and prostate cancer models (Aim 2). Additional preliminary data demonstrate that SMYD2 loss can sensitize tumors further to PI3K/AKT inhibition. To this end, we aim to determine the role that the genetic manipulation or pharmacological inhibition of SMYD2 has in the therapeutic response to PI3K/AKT inhibitors in breast and prostate cancer (Aim 3). Altogether, this proposal is benefiting from i) a multidisciplinary team of collaborators who are experts in breast and prostate cancer research, protein methylation, and epigenetics, ii) unique patient resources and reagents, iii) robust preliminary data propelled by at least of 7 years momentum as a leader in the field of nuclear receptor regulation which will be critical to design new and improved therapies for hormone- dependent tumors.

项目摘要/摘要 PI3K途径的改变发生在40-60％的ER+乳腺癌或AR+乳腺癌中，代表 在这种肿瘤中最常见的基因组改变，表明PI3K信号通路的作用 在激素依赖性肿瘤的肿瘤发生中的重要作用。有重要的双向调节 PI3K和ER或AR信号之间的串扰分别在乳腺和前列腺癌中，导致肿瘤 当两种途径在药理上抑制时，这种适应和生存。从机械上讲，我们 证明PI3K抑制激活ER活性以驱动ER+/PIK3CA突变肿瘤的生长， 通过调节组蛋白甲基转移酶KMT2D。 KMT2D被PI3K效应子磷酸化 Akt1/sgk1，它抑制其募集到染色质及其在乳腺癌中的ER靶基因共激活剂的作用 癌症。抑制PI3K后，这种抑制性磷酸化丢失了，允许KMT2D驱动ER依赖性 转录。我们假设KMT2D可能是控制核激素的常见机制 乳腺和前列腺中的受体功能，PI3K途径串扰以及ER和AR腔细胞分化 模型分别。初步数据表明，ER和AR转录活动需要KMT2D 乳腺癌和前列腺癌的PI3K抑制作用后。此外，KMT2D损失使癌症敏感 细胞在细胞，肿瘤和患者衍生的类器官中抑制PI3K/AKT。我们现在的目标是表征 KMT2D作为细胞和ER核受体活性的关键调节剂的表观遗传和转录作用 使用散装表观基因组和单细胞测序的器官（AIM 1）。我们还确定了赖氨酸 甲基转移酶Smyd2是KMT2D和ER/AR活性的新型调节剂。我们现在计划阐明 Smyd2催化介导的甲基化对乳腺和辅助因子的乳腺癌关联的作用 前列腺癌模型（AIM 2）。其他初步数据表明，SMYD2损失可以使肿瘤敏感 进一步可以抑制PI3K/AKT。为此，我们旨在确定遗传操作或 Smyd2的药理抑制作用具有对乳腺和乳腺Akt抑制剂的治疗反应 前列腺癌（AIM 3）。总的来说，该提议从i）合作者的多学科团队中受益 谁是乳腺癌和前列腺癌研究，蛋白质甲基化和表观遗传学的专家，ii）独特的患者 资源和试剂，iii）至少7年的势头推动了强大的初步数据，作为领导者 核受体调节领域，这对于设计新的和改进的激素疗法至关重要 依赖性肿瘤。