Epigenetic targeting of LSD1 for OSCC Therapy

口腔鳞状细胞癌(OSCC)，它占头颈部癌症的大部分。治疗 对于口腔鳞状细胞癌来说，通常涉及手术、放疗和化疗的组合。然而， 对治疗的抵抗使治疗复杂化，5年存活率保持在65%左右。 需要了解导致疾病进展和治疗耐药性的因素，以促进患者 结果。我们建议研究一种潜在的口腔鳞状细胞癌的分子调控因子。赖氨酸专一性脱甲基酶1 (LSD1)是一种具有去甲基酶活性的胺氧化酶，与维持 致癌细胞的未分化状态。我们的初步研究表明，LSD1在HSC- 3在小鼠模型中，移植的原位肿瘤抑制了肿瘤的生长和转移，而 LSD1的过表达促进了它的表达。LSD1小分子抑制剂(如GSK-LSD1)减轻疾病 在患者来源的异种移植(PDX)中，EGFR诱导的信号转导和癌基因(MMP13，LOXL4 和PD-L1)。基因芯片和基因集浓缩分析也表明GSK-LSD1抑制了 EGFR信号通路的关键调节因子。我们假设条件性上皮细胞特异性 口腔中LSD1的缺失通过抑制口腔鳞状细胞癌的进展和转移 减少EGFR诱导的致癌信号网络，促进特定靶基因的表达。此外，我们 假设GSK-LSD1与免疫治疗或化疗完全联合 减弱口腔鳞癌。这项研究的具体目的是：1)确定内源性LSD1是否是一个关键的激活剂 2)确定GSK-LSD1是否具有增敏作用 PDOX和4NQO小鼠模型通过抑制EGFR，c-Myc， 和PD-L1信号通路。体外、体外和体内方法以及微阵列和下一步- 将采用世代排序来解决拟议的目标。LSD1抑制剂可能被证明对 口腔鳞状细胞癌免疫治疗和个性化联合治疗。因此，本研究具有很强的翻译性 LSD1作为一种新的药物靶点及其用于抗口腔鳞癌单一疗法和 综合疗法。

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.