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.

概括口服鳞状细胞癌（OSCC）是头和颈的最常见的口腔恶性肿瘤和亚型癌症，经常在常规护理期间被牙医确定。 OSCC是第六大常见的癌症全球发病率继续上升。 OSCC的当前疗法不足，OSCC具有抵抗力免疫检查点抑制（ICI），导致频繁再次发生和患者存活率较差。这由于缺乏共同的驱动癌基突变，开发针对OSCC的靶向疗法受到阻碍但是，在人乳头瘤病毒（HPV）负OSCC中，p53肿瘤抑制剂的失活经常这有助于治疗耐药性，免疫细胞抑制和降低患者的生存率。所以， OSCC迫切需要新的和创新的治疗方法，尤其是那些灭活的p53。因此，我们试图确定HPV阴性OSCC中的新漏洞。相信如果 p53被灭活，癌细胞不需要MDM2，该MDM2结合和调节p53。但是，具有挑战性这种长期以来的信念，我们在p53-null小鼠中产生的癌症的结果表明MDM2癌基因是 p53-null鼠癌的生存所必需的。利用我们在小鼠中的范式转移发现，我们的初步数据表明，MDM2是p53灭活的先前未知且意外的漏洞人类OSCC。我们提出，靶向MDM2的靶向丢失将通过激活p53-有效消除OSCC细胞。凋亡和途径有助于增加的独立机制免疫原性。我们设计和合成的新型MDM2靶向降解器的初步结果支持这一假设。为了进一步检验我们的假设，我们建议1）研究细胞毒性机理，所需的途径和靶向MDM2损失的体内疗效与我们的MDM2 Protac 在具有各种p53改变的OSCC细胞中； 2）研究改善OSCC肿瘤的免疫原性并通过包括我们的MDM2 Protac和免疫的几种方法克服了ICI抗性合理的合成小鼠模型。这项研究的完成将发现MDM2的具体要求在OSCC中，显着提高了对MDM2的p53独立函数的机械理解，并为OSCC的潜在新型治疗方法提供关键的临床前评估免疫原性并克服ICI耐药性。