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.

口腔鳞状细胞癌（OSCC），占头颈部癌症的大多数。治疗 口腔鳞状细胞癌的治疗通常包括手术、放疗和化疗的联合治疗。然而，在这方面， 对治疗的抵抗使治疗复杂化，5年生存率保持在65%左右。 需要了解疾病进展和治疗抵抗的因素，以促进患者 结果。我们建议在这里研究一个潜在的分子调控OSCC。赖氨酸特异性脱甲基酶1 （LSD 1）是一种具有脱甲基酶活性的胺氧化酶， 未分化状态的癌症起始细胞。我们的初步研究表明，在HSC中LSD 1敲低- 3移植的原位肿瘤减弱小鼠模型中的肿瘤生长和转移，而 LSD 1的过表达促进了它。小分子抑制剂（例如，GSK-LSD 1）的LSD 1减毒疾病 在患者来源的异种移植物（PDX）中，EGFR诱导的信号传导和原癌基因（MMP 13，LOXL 4） PD-L1）。基因组富集分析后的微阵列也显示GSK-LSD 1抑制了细胞凋亡。 EGFR信号通路的关键介质。我们假设条件性上皮细胞特异性 口腔中LSD 1的缺失通过以下途径减弱上皮OSCC的进展和转移： 降低EGFR诱导的致癌信号网络，促进特异性靶基因的表达。我们还 假设GSK-LSD 1与免疫治疗或化疗完全联合， 减轻OSCC。该研究的具体目的是：1）确定内源性LSD 1是否是关键激活剂 在鼠4 NQO OSCC小鼠模型中的特异性靶基因，和2）确定GSK-LSD 1是否致敏 通过抑制EGFR，c-Myc， 和PD-L1信号通路。体外、离体和体内方法以及微阵列和下一个- 将采用世代排序来实现拟议目标。LSD 1抑制剂可以用于 OSCC免疫治疗和个性化联合治疗。因此，本研究具有较强的翻译性 有可能将LSD 1确定为一种新型可药物靶点，并具有抗OSCC单药治疗的潜力， 联合治疗