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通路的改变发生在40%-60%的ER+乳腺癌或AR+乳腺癌中，这代表了 在这种肿瘤中最常见的基因组改变，并表明PI3K信号通路在 在激素依赖性肿瘤发生中的重要作用。有重要的双向监管 乳腺癌和前列腺癌中PI3K和ER或AR信号之间的串扰导致肿瘤 当任何一种单一途径被药物抑制时，它们就会适应并存活下来。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， 通过组蛋白甲基转移酶KMT2D的调控。KMT2D被PI3K效应器磷酸化 AKT1/SGK1抑制其向染色质募集及其作为乳腺ER靶基因共激活因子的作用 癌症。一旦PI3K被抑制，这种抑制的磷酸化就会丢失，从而允许KMT2D驱动ER依赖 抄写。我们推测KMT2D可能是控制核激素的一种常见机制 乳腺和前列腺中受体功能、PI3K通路串扰与ER和AR腔细胞分化 模型分别为。初步数据表明，KMT2D是ER和AR转录活动所必需的 分别在乳腺癌和前列腺癌中抑制PI3K。此外，KMT2D缺失会使癌症变得敏感 细胞抑制PI3K/AKT在细胞、肿瘤和患者来源的器官中的作用。我们现在的目标是描述 KMT2D作为AR/ER核受体活性的关键调节因子在细胞和细胞中的表观遗传和转录作用 使用大量表观基因组和单细胞测序的有机化合物(目标1)。我们还鉴定了赖氨酸 甲基转移酶SMYD2作为KMT2D和ER/AR活性调节的新水平。我们现在计划澄清 SMYD2催化的甲基化对乳腺和乳腺中KMT2D活性和辅因子相关性的影响 前列腺癌模型(AIM 2)。更多的初步数据表明，SMYD2缺失可以使肿瘤增敏 进一步抑制PI3K/AKT。为此，我们的目标是确定基因操纵或 SMYD2的药理抑制对PI3K/AKT抑制剂的治疗作用 前列腺癌(目标3)。总之，这项提议受益于i)多学科的合作者团队 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)强劲的初步数据，由至少7年的势头推动，在 核受体调节领域，这将是设计新的和改进的激素疗法的关键- 依附性肿瘤。