Epigenetic targeting of LSD1 for OSCC Therapy

用于 OSCC 治疗的 LSD1 表观遗传靶向

• 批准号: 9766270
• 负责人: Manish Bais
• 金额: $ 20.63万
• 依托单位: BOSTON UNIVERSITY MEDICAL CAMPUS
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-09-01 至 2021-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9766270
• 关键词: Address; Alleles; Antibodies; Attenuated; Biology; Cells; Cessation of life; Chromatin; Combined Modality Therapy; DNA sequencing; Data; Development; Disease; Disease Progression; Environment; Enzymes; Epidermal Growth Factor Receptor; Epigenetic Process; Epithelial; Epithelial Cells; Exhibits; Family member; Future; Genes; Genetic Transcription; Growth; Head and Neck Cancer; Human; Immunosuppression; Immunotherapy; Implant; In Vitro; KDM1A gene; Keratin; Knowledge; Lead; Ligands; Malignant Neoplasms; Mediator of activation protein; Modeling; Molecular; Morbidity - disease rate; Mus; Mutation; Neoplasm Metastasis; Nitroquinolines; Oncogenes; Oncogenic; Operative Surgical Procedures; Oral cavity; Oxides; PDCD1LG1 gene; Pathway interactions; Patient-Focused Outcomes; Patients; Phosphorylation; Play; Publishing; Radiation therapy; Recurrence; Regulation; Role; Signal Pathway; Signal Transduction; Survival Rate; Tamoxifen; Testing; Tumor-Derived; Undifferentiated; Xenograft Model; Xenograft procedure; amine oxidase; attenuation; c-myc Genes; chemotherapy; clinical application; demethylation; effective therapy; epigenetic regulation; in vivo; inhibitor/antagonist; knock-down; loss of function; malignant mouth neoplasm; mortality; mouse model; mouth squamous cell carcinoma; new therapeutic target; next generation sequencing; novel; overexpression; promoter; small molecule inhibitor; synergism; therapeutic target; therapy resistant; transcriptome sequencing; treatment strategy; tumor; tumor growth; tumor progression

Oral squamous cell carcinoma (OSCC), which accounts for the majority of head and neck cancers. Treatment for OSCC frequently involves a combination of surgery, radiotherapy, and chemotherapy. However, resistance to therapy complicates treatment, and the 5-year survival rate remains at ~65 percent. Understanding contributors to disease progression and treatment resistance is needed to promote patient outcomes. We propose here to study a potential molecular regulator of OSCC. Lysine-specific demethylase 1 (LSD1) is an amine oxidase with demethylase activity and has been implicated in maintaining the undifferentiated state of cancer-initiating cells. Our preliminary studies showed that LSD1 knockdown in HSC- 3 implanted orthotopic tumors attenuates tumor growth and metastasis in mouse models, whereas overexpression of LSD1 promotes it. Small molecule inhibitors (e.g., GSK-LSD1) of LSD1 attenuate disease in patient-derived xenografts (PDXs), EGFR-induced signaling, and pro-oncogenic gene (MMP13, LOXL4 and PD-L1). Microarrays followed by gene set enrichment analysis also showed that GSK-LSD1 inhibits the key mediators of EGFR signaling pathways. We hypothesize that conditional epithelial cell-specific deletion of LSD1 in the oral cavity attenuates epithelial OSCC progression and metastasis by reducing EGFR induced oncogenic signaling network to promote specific target genes. Further, we postulate that GSK-LSD1 in combination with immunotherapy or chemotherapy completely attenuates OSCC. The specific aims of the study are to 1) determine if endogenous LSD1 is a key activator of specific target genes in murine 4NQO OSCC mouse model, and 2) determine if GSK-LSD1 sensitizes OSCC to chemotherapy or immunotherapy in PDOX and 4NQO mouse models by inhibiting EGFR, c-Myc, and PD-L1 signaling pathways. In vitro, ex-vivo, and in vivo approaches as well as microarrays and next- generation sequencing will be employed to address the proposed aims. LSD1 inhibitors could prove useful for OSCC immunotherapy and in personalized combination therapies. Thus, this study has a strong translational potential to identify LSD1 as a novel druggable target and its potential for anti-OSCC monotherapy and combination therapies.

口服鳞状细胞癌（OSCC），占头颈癌的大部分。治疗 因为OSCC经常涉及手术，放射疗法和化学疗法的组合。然而， 对治疗的抵抗使治疗复杂化，而5年的存活率仍为约65％。 需要了解促进疾病进展和抗药性的因素来促进患者 结果。我们在这里建议研究OSCC的潜在分子调节剂。赖氨酸特异性脱甲基酶1 （LSD1）是一种具有脱甲基酶活性的胺氧化酶，与维持 癌症引发细胞的未分化状态。我们的初步研究表明，HSC-的LSD1敲低 3植入的原位肿瘤可减弱小鼠模型中肿瘤的生长和转移，而 LSD1的过表达促进它。 LSD1衰减疾病的小分子抑制剂（例如GSK-LSD1） 在患者衍生的异种移植物（PDXS）中，EGFR诱导的信号传导和亲基因（MMP13，LOXL4） 和PD-L1）。微阵列随后进行基因集富集分析还表明，GSK-LSD1抑制了 EGFR信号通路的关键介体。我们假设条件上皮细胞特异性 口腔中LSD1的缺失减弱了上皮OSCC的进展和转移 减少EGFR诱导的致癌信号网络以促进特定的靶基因。此外，我们 假设GSK-LSD1与免疫疗法或化学疗法结合使用 减弱OSCC。研究的具体目的是1）确定内源性LSD1是否是关键激活剂 鼠4NQO OSCC小鼠模型中的特定靶基因，2）确定GSK-LSD1是否敏感 OSCC通过抑制EGFR，C-Myc，在PDOX和4NQO小鼠模型中进行化学疗法或免疫疗法 和PD-L1信号通路。体外，前体和体内方法以及微阵列和下一步 将采用生成测序来解决拟议的目标。 LSD1抑制剂可能对 OSCC免疫疗法和个性化组合疗法。因此，这项研究具有很强的翻译 识别LSD1是一种新型可毒靶的潜力及其对抗OSCC单一疗法的潜力和 组合疗法。