Targeting ER+ Breast Cancer Through Induced Viral Mimicry

通过诱导病毒模仿来靶向 ER 乳腺癌

• 批准号: 10416945
• 负责人: CHARLES H. SPRUCK
• 金额: $ 44.17万
• 依托单位: SANFORD BURNHAM PREBYS MEDICAL DISCOVERY INSTITUTE
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-04-01 至 2027-03-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10416945
• 关键词: Biological Assay; Bone Metastases Prevention; Breast Cancer Cell; Breast Cancer Model; Breast Cancer Treatment; Cells; Chromatin Remodeling Factor; Clinical; Clinical Trials; Complex; Cytotoxic T-Lymphocytes; DNA Damage; DNA Double Strand Break; DNA Repair; DNA Replication Induction; DNA Single Strand Break; DNA biosynthesis; DNA replication fork; Data; Detection; Development; Diagnosis; Disease; Effectiveness; Endogenous Retroviruses; Epigenetic Process; Estrogen Receptors; Estrogen Therapy; Gene Silencing; Genetic Transcription; Genetically Engineered Mouse; Goals; Growth; Histone Deacetylase; Histone H3; Hormones; Human; Human Genome; Immune; Immunotherapy; Infiltration; Interferons; Lead; Ligands; Lysine; Malignant Bone Neoplasm; Mammary Neoplasms; Mediating; Metastatic Neoplasm to the Bone; Methyltransferase; Molecular Target; Mus; Mutation; Natural Killer Cells; Normal Cell; NuRD complex; Nucleosomes; Organ; Pathway interactions; Pharmaceutical Preparations; Proteins; RNA interference screen; Recurrence; Refractory; Relapse; Repetitive Sequence; Resistance development; Retrotransposon; Signal Transduction; Somatic Cell; Stimulator of Interferon Genes; Therapeutic; Transcriptional Silencer Elements; Tumor Subtype; Tumor-Infiltrating Lymphocytes; Tumorigenicity; Viral; antitumor effect; base; bone; brca gene; cancer cell; cancer therapy; chemotherapy; clinical application; cytotoxic; genome integrity; homologous recombination; immune checkpoint blockade; immunogenicity; in silico; inhibitor; inhibitor therapy; malignant breast neoplasm; mimicry; mortality; mouse model; mutant; pre-clinical; preclinical study; prevent; recombinational repair; recruit; replication stress; synergism; therapeutically effective; treatment response; triple-negative invasive breast carcinoma; tumor; tumor growth; ubiquitin ligase

PROJECT SUMMARY Repetitive elements (REs) compose ~45% of the human genome and are normally transcriptionally silenced in somatic cells, although the mechanism had remained elusive. Through a high-content RNAi screen, we identified the largely uncharacterized protein FBXO44 as an essential repressor of REs in breast cancer cells. FBXO44 bound repressive histone H3 lysine 9 trimethylated (H3K9me3) nucleosomes at the replication fork and recruited H3K9me3 methyltransferase SUV39H1, ubiquitin ligase CRL4RBBP4/7, and histone deacetylase and chromatin- remodeling complex Mi-2/NuRD to transcriptionally silence REs post-DNA replication. FBXO44/SUV39H1 inhibition transcriptionally reactivated endogenous retroviruses (ERVs) and retrotransposons (e.g. Alu, LINE-1) in breast cancer cells, leading to extensive DNA replication stress and stimulation of RIG-I/MDA5-MAVS and cGAS-STING intracellular antiviral pathways to promote enhanced immunogenicity and decreased tumorigenicity. In silico analysis revealed the FBXO44/SUV39H1 pathway inversely correlated with DNA replication stress, antiviral pathways, and cytotoxic T and natural killer (NK) cell infiltration in human breast tumors. Importantly, FBXO44/SUV39H1 were found dispensable for RE silencing in normal cells and their inhibition had no effect on H3K9me3 levels, DNA replication stress, or viability, suggesting a therapeutic window. Our hypothesis is that FBXO44/SUV39H1-mediated RE silencing is an epigenetic vulnerability of breast cancer cells that could be targeted to inhibit tumor growth/progression and enhance the efficacy of certain antitumor therapies through the unique mechanism of induced viral mimicry. In this proposal, we will evaluate 3 potential therapeutic applications of FBXO44/SUV39H1 pathway targeting in the treatment of estrogen receptor (ER)+ breast cancers based on our preliminary data: 1) prevention of bone metastasis relapse through stimulation of NK cell recognition and killing of dormant breast cancer cells; 2) enhancement of immune checkpoint blockade (ICB) therapy through stimulation of IFN signaling and intratumoral infiltration of cytotoxic T cells; and 3) synergy with PARP inhibitors through induction of DNA replication stress and double-strand breaks (DSBs) at REs. These studies could lead to the development of a safe and effective therapeutic approach that selectively induces viral mimicry in ER+ breast cancer cells to prevent bone metastasis relapse and enhance the efficacy of ICB and PARP inhibitor therapies, undoubtedly leading to a significant reduction in disease mortality.

项目摘要 重复元件（RE）占人类基因组的约45%，通常在转录过程中沉默。 体细胞，尽管其机制仍然难以捉摸。通过高含量的RNAi筛选，我们鉴定了 在乳腺癌细胞中，大部分未表征的蛋白FBXO 44作为RE的基本阻遏物。FBXO44 在复制叉处结合抑制性组蛋白H3赖氨酸9三甲基化（H3 K9 me 3）核小体， H3 K9 me 3甲基转移酶SUV 39 H1、遍在蛋白连接酶CRL 4 RBBP 4/7以及组蛋白脱乙酰酶和染色质- 重塑复合物Mi-2/NuRD以在DNA复制后转录沉默RE。FBXO44/SUV 39H1 抑制转录再激活的内源性逆转录病毒（ERV）和逆转录转座子（例如Alu、LINE-1） 在乳腺癌细胞中，导致广泛的DNA复制应激和RIG-I/MDA 5-MAVS的刺激， cGAS-STING细胞内抗病毒途径，以促进增强的免疫原性和降低的 致瘤性计算机模拟分析显示FBXO 44/SUV 39 H1通路与DNA负相关 人乳腺中的复制应激、抗病毒途径和细胞毒性T和自然杀伤（NK）细胞浸润 肿瘤的重要的是，发现FBXO 44/SUV 39 H1在正常细胞中不具有RE沉默作用， 抑制对H3 K9 me 3水平、DNA复制应激或存活力没有影响，这表明了治疗窗口。 我们的假设是FBXO 44/SUV 39 H1介导的RE沉默是乳腺癌的表观遗传脆弱性， 可以靶向癌细胞以抑制肿瘤生长/进展并增强 某些抗肿瘤疗法通过诱导病毒模仿的独特机制。在本提案中，我们 将评估FBXO 44/SUV 39 H1通路靶向治疗的3种潜在治疗应用， 雌激素受体（ER）+乳腺癌的基础上，我们的初步数据：1）预防骨转移复发 通过刺激NK细胞识别和杀死休眠的乳腺癌细胞; 2）增强免疫 检查点阻断（ICB）治疗通过刺激IFN信号传导和肿瘤内浸润的细胞毒性 T细胞;和3）通过诱导DNA复制应激和双链DNA复制应激与PARP抑制剂的协同作用。 这些研究可能会导致开发一种安全有效的治疗方法 在ER+乳腺癌细胞中选择性诱导病毒模拟，以防止骨转移复发并增强 ICB和PARP抑制剂治疗的疗效，无疑会显著减少疾病 mortality.