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.

项目总结/摘要 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ER+乳腺癌和AR+乳腺癌的发病率。 这是此类肿瘤中最常见的基因组改变，并表明PI 3 K信号通路在肿瘤中起着重要作用。 在肿瘤发生中起重要作用。有重要的双向监管 乳腺癌和前列腺癌中PI 3 K与ER或AR信号传导之间的串扰，导致肿瘤 当任何一条通路受到抑制时，它们都能适应并存活下来。机械地，我们 证明PI 3 K抑制激活ER活性以驱动ER+/PIK 3CA突变体肿瘤的生长， 通过调节组蛋白甲基转移酶KMT 2D。KMT 2D被PI 3 K效应子磷酸化 AKT 1/SGK 1，抑制其向染色质的募集及其作为乳腺癌ER靶基因共激活剂的作用 癌在PI 3 K抑制后，这种抑制性磷酸化丧失，使得KMT 2D驱动ER依赖性的细胞凋亡。 转录。我们推测KMT 2D可能是核激素调控的一个共同机制 乳腺和前列腺中的受体功能、PI 3 K通路串扰以及ER和AR管腔细胞分化 模型分别。初步数据表明，KMT 2D是ER和AR转录活性所必需的 分别在乳腺癌和前列腺癌中抑制PI 3 K。此外，KMT 2D缺失使癌症敏感化 在细胞、肿瘤和患者来源的类器官中，PI 3 K/AKT抑制对细胞的影响。我们现在的目标是描述 KMT 2D作为细胞中AR/ER核受体活性的关键调节剂的表观遗传和转录作用， 使用批量表观基因组和单细胞测序的类器官（Aim 1）。我们还鉴定了赖氨酸 甲基转移酶SMYD 2作为KMT 2D和ER/AR活性的新水平调节剂。我们现在计划阐明 SMYD 2催化介导的甲基化对乳腺癌中KMT 2D活性和辅因子相关性的作用， 前列腺癌模型（Aim 2）。额外的初步数据表明，SMYD 2缺失可以使肿瘤敏感， 进一步抑制PI 3 K/AKT。为此，我们的目标是确定基因操纵或 SMYD 2的药理学抑制在乳腺中对PI 3 K/AKT抑制剂的治疗反应中具有作用， 前列腺癌（Aim 3）。总的来说，这一建议得益于i）一个多学科的合作者团队 他们是乳腺癌和前列腺癌研究、蛋白质甲基化和表观遗传学方面的专家，ii）独特的患者 资源和试剂，iii）至少7年的领先势头推动了强劲的初步数据， 核受体调控领域，这将是关键的设计新的和改进的治疗激素- 依赖性肿瘤