Investigating a new vulnerability in oral squamous cell carcinoma

研究口腔鳞状细胞癌的新脆弱性

基本信息

批准号：
10714352
负责人：
CHRISTINE M. EISCHEN
金额：
$ 53.58万
依托单位：
THOMAS JEFFERSON UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2023
资助国家：
美国
起止时间：
2023-07-01 至 2028-04-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10714352
关键词：
Affinity Apoptosis Automobile Driving Belief Binding Biochemical Cell Cycle Cell Death Cell Death Signaling Process Cell Line Cells Cessation of life Clustered Regularly Interspaced Short Palindromic Repeats DNA DNA Damage DNA Double Strand Break DNA Repair Data Dentists Dependence Development Effectiveness Embryonic Development Generations Genes Growth Head and Neck Cancer Human Human Papillomavirus Immune Immune Cell Suppression Immune checkpoint inhibitor Immunocompetent Incidence Interferon Type I Knockout Mice Laboratories Malignant Epithelial Cell Malignant Neoplasms Metabolic Molecular Mus Mutation Normal Cell Oncogenes Oral Pathway interactions Patients Positioning Attribute Preclinical Testing Proliferating Protac Proteins Quality of life Reagent Relapse Resistance Sampling Signal Transduction Site Stimulator of Interferon Genes Survival Rate TP53 gene Testing The Cancer Genome Atlas Therapeutic Therapeutic Intervention Translating Validation Xenograft procedure cancer cell carcinogenesis cell killing checkpoint inhibition chemokine cytokine cytotoxicity design effective therapy experience immunogenic immunogenicity improved in vivo innovation insight knock-down mouse model mouth squamous cell carcinoma mutant mutant mouse model neoplastic cell novel novel therapeutic intervention preclinical evaluation response routine care small hairpin RNA targeted treatment therapy resistant three dimensional cell culture tumor tumor-immune system interactions tumorigenic

项目摘要

SUMMARY Oral squamous cell carcinoma (OSCC) is the most common oral malignancy and subtype of head and neck cancer and frequently identified by dentists during routine care. OSCC is the sixth most common cancer globally with incidence continuing to rise. Current therapies for OSCC are inadequate and OSCC are resistant to immune checkpoint inhibition (ICI), resulting in frequent reoccurrence and poor rates of patient survival. The development of targeted therapies for OSCC is hampered by the lack of common driving oncogene mutations, but inactivation of the p53 tumor suppressor is frequent in human papillomavirus (HPV) negative OSCC, which contributes to treatment resistance, immune cell suppression, and reduced patient survival. Therefore, new and innovative treatment approaches are desperately needed for OSCC and particularly those with inactivated p53. Thus, we sought to identify new vulnerabilities in HPV-negative OSCC. It was believed that if p53 was inactivated, cancer cells did not require Mdm2, which binds and regulates p53. However, challenging this long-held belief, our results with cancers arising in p53-null mice showed that the Mdm2 oncogene was required for the survival of p53-null murine cancers. Capitalizing on our paradigm-shifting discovery in mice, our preliminary data reveal Mdm2 is a previously unknown and unexpected vulnerability in p53-inactivated human OSCC. We propose that targeted loss of Mdm2 will effectively eliminate OSCC cells by activating p53- independent mechanisms that signal for apoptosis and pathways that contribute to increasing immunogenicity. Preliminary results with a novel Mdm2-targeted degrader we designed and synthesized support this hypothesis. To further test our hypothesis, we propose to 1) investigate the cytotoxicity mechanism(s), the required pathways, and in vivo efficacy with targeted Mdm2 loss with our Mdm2 PROTAC in OSCC cells with various p53 alterations; and 2) investigate improving the immunogenicity of OSCC tumors and overcoming ICI resistance with several approaches that include our Mdm2 PROTAC and immune competent syngeneic mouse models. Completion of this study will uncover the specific requirements of Mdm2 in OSCC, significantly increasing the mechanistic understanding of the p53-independent functions of Mdm2, and provide critical pre-clinical evaluation of potential novel therapy approaches for OSCC that increase immunogenicity and overcome ICI resistance.

概括口腔鳞状细胞癌（OSCC）是最常见的口腔恶性肿瘤，也是头颈部的亚型癌症，经常被牙医在日常护理中发现。 OSCC 是第六大常见癌症全球范围内发病率持续上升。当前 OSCC 的治疗方法不足且 OSCC 具有耐药性免疫检查点抑制（ICI），导致频繁复发和患者生存率低。这口腔鳞癌靶向治疗的开发因缺乏共同的驱动癌基因突变而受到阻碍，但 p53 肿瘤抑制因子的失活在人乳头瘤病毒 (HPV) 阴性 OSCC 中很常见，这会导致治疗抵抗、免疫细胞抑制并降低患者的生存率。所以， OSCC 迫切需要新的和创新的治疗方法，特别是那些患有 OSCC 的患者 p53 失活。因此，我们试图找出 HPV 阴性 OSCC 的新漏洞。人们相信，如果 p53失活，癌细胞不需要结合并调节p53的Mdm2。然而，具有挑战性根据这一长期持有的信念，我们对 p53 缺失小鼠中发生的癌症的研究结果表明，Mdm2 癌基因是 p53 缺失的小鼠癌症的生存所需。利用我们在小鼠身上的范式转变发现，我们的初步数据显示 Mdm2 是 p53 失活中先前未知且意外的漏洞人类口腔鳞癌。我们认为，Mdm2 的靶向缺失将通过激活 p53- 有效消除 OSCC 细胞。发出细胞凋亡信号的独立机制和有助于增加细胞凋亡的途径免疫原性。我们设计和合成的新型 Mdm2 靶向降解剂的初步结果支持这个假设。为了进一步检验我们的假设，我们建议 1）研究细胞毒性使用我们的 Mdm2 PROTAC 确定 Mdm2 丢失的机制、所需途径和体内功效在具有各种 p53 改变的 OSCC 细胞中； 2) 研究提高 OSCC 肿瘤的免疫原性并通过多种方法克服 ICI 耐药性，包括我们的 Mdm2 PROTAC 和免疫有能力的同基因小鼠模型。完成本研究将揭示 Mdm2 的具体要求在 OSCC 中，显着增加对 Mdm2 的 p53 独立功能的机制理解，并为 OSCC 的潜在新治疗方法提供关键的临床前评估，以增加免疫原性并克服 ICI 耐药性。