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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.

总结口腔鳞状细胞癌（Oral squamous cell carcinoma，OSCC）是口腔最常见的恶性肿瘤，也是头颈部最常见的肿瘤亚型癌症，经常被牙医在日常护理中发现。口腔鳞状细胞癌是第六常见的癌症全球发病率持续上升。目前治疗口腔鳞癌是不够的，口腔鳞癌是耐药的免疫检查点抑制（ICI），导致频繁复发和患者生存率低。的用于OSCC的靶向疗法的开发受到缺乏共同驱动癌基因突变的阻碍，但是p53肿瘤抑制因子的失活在人乳头瘤病毒（HPV）阴性的OSCC中是常见的，其导致治疗抗性、免疫细胞抑制和降低的患者存活率。因此，我们认为，迫切需要新的和创新的治疗方法用于OSCC，特别是那些失活的p53。因此，我们试图确定HPV阴性口腔鳞癌中的新漏洞。据信，如果当p53失活时，癌细胞不需要结合并调节p53的Mdm 2。然而，挑战我们对p53基因缺失小鼠产生的癌症的研究结果表明，Mdm 2癌基因是 p53缺失的鼠癌症的存活所需的。利用我们在老鼠身上的范式转变发现，我们的初步数据显示Mdm 2是p53失活细胞中以前未知和意外的脆弱性，人口腔鳞癌我们认为，靶向的Mdm 2缺失将通过激活p53- 1，有效地消除OSCC细胞。细胞凋亡信号的独立机制和有助于增加免疫原性我们设计和合成的新型Mdm 2靶向降解剂的初步结果支持这一假设。为了进一步验证我们的假设，我们建议1）研究细胞毒性机制、所需途径和我们的Mdm 2 PROTAC靶向Mdm 2损失的体内疗效在具有各种p53改变的OSCC细胞中;和2）研究改善OSCC肿瘤的免疫原性并通过多种方法克服ICI抗性，包括我们的Mdm 2 PROTAC和免疫同基因小鼠模型。本研究的完成将揭示Mdm 2的具体要求在OSCC中，显著增加了对Mdm 2的p53非依赖性功能的机制理解，并为OSCC的潜在新治疗方法提供关键的临床前评估，免疫原性和克服ICI抗性。