Genetic Alterations That Confer High Risk to Oral Premalignant Lesions

导致口腔癌前病变高风险的基因改变

• 批准号: 10656537
• 负责人: CARLOS CAULIN
• 金额: $ 47.29万
• 依托单位: UNIVERSITY OF ARIZONA
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-07-01 至 2027-06-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10656537
• 关键词: Affect; Alleles; Antibodies; Appearance; CDKN2A gene; Carcinogens; Carcinoma; Cells; Chemopreventive Agent; Clinical Trials; Combined Modality Therapy; Cre lox recombination system; DNA Sequence Alteration; Development; Epithelial Cells; Epithelium; Future; Genes; Genetic; Genetically Engineered Mouse; Goals; Histologic; Human; Immune; Immune system; Immunoprevention; Immunosuppression; Lead; Lesion; Malignant - descriptor; Malignant Neoplasms; Mediating; Molecular; Monitor; Mouth Neoplasms; Mus; Mutate; Mutation; Oral; Outcome; Patients; Prevention; Prevention strategy; Preventive; Primary Neoplasm; Process; Relapse; Resistance; Risk Assessment; Role; Survival Rate; TP53 gene; Testing; Tobacco; Tumor Immunity; Tumor Promotion; anti-PD-1; anti-PD1 antibodies; cell type; checkpoint inhibition; design; gain of function mutation; high risk; immune checkpoint blockade; improved; in vivo; malignant mouth neoplasm; mouse model; mouth squamous cell carcinoma; mutant; novel strategies; oral cancer prevention; oral carcinogenesis; oral cavity epithelium; oral lesion; oral status; oral tissue; premalignant; prevent; preventive intervention; programmed cell death protein 1; progression risk; response; tobacco exposure; transcriptome; tumor; tumor-immune system interactions

PROJECT SUMMARY Oral squamous cell carcinoma (OSCC) is the sixth most common human cancer worldwide. Approximately 30% of the oral premalignant lesions (OPLs) progress to OSCC, a process that may have a multifocal origin and can be promoted by carcinogens such as those found in tobacco. Our long-term goal is to identify the genetic alterations that promote high risk of progression to OPLs and to determine how those alterations modulate the response of OPLs to preventive strategies. The TP53 gene (also known as p53) and CDKN2A are the most frequently mutated genes in oral cancer, also found altered in OPLs. p53 GOF mutations and genomic alterations that result in loss of the CDKN2A gene associate with “cold” immune microenvironments in OPLs and OSCCs, with high risk of progression to carcinoma, and with extremely poor outcomes in OSCC patients. We hypothesize that the early appearance of mutations in p53 and CDKN2A inactivation modulate the oral tissue microenvironment and predispose OPLs to progress to OSCC. To test this hypothesis we will study mouse models that develop OPLs upon exposure to the tobacco-surrogate 4NQO, in the presence of p53 and/or CDKN2A mutations. Patients with high-risk OPLs could benefit from preventive strategies designed to block the malignant progression of OPLs. However, previous attempts with different chemopreventive agents have not been successful. Recently, immune checkpoint blockade with antibodies directed at programmed cell death protein 1 (PD-1) has been shown to improve the survival of patients with advanced OSCC in clinical trials, confirming the importance of the immune system in containing progression of invasive tumors. Moreover, our previous studies, confirmed by multiple independent groups, demonstrated that anti-PD-1 antibodies can also prevent the progression of OPLs to OSCC, in a 4NQO mouse model for oral carcinogenesis. Our preliminary studies indicate that the p53 and CDKN2A status of the OPLs may determine the response to anti-PD-1-mediated immunoprevention. In this proposal, we will assess the long-term benefits of anti-PD-1-mediated oral cancer prevention, to determine whether PD-1 blockade, administered in a preventive setting, can confer survival benefits, and to assess how p53 and CDKN2A mutations affect the sustained response to PD-1 blockade. To overcome resistance to anti-PD-1 we hypothesize that reactivation of p53 in OPLs carrying p53 mutations sensitizes the oral lesions to anti-PD-1. Our mouse models will allow us to test this hypothesis in vivo.

项目摘要 口腔鳞状细胞癌（OSCC）是世界上第六大常见的人类癌症。约30% 的口腔癌前病变（OPL）进展为口腔鳞状细胞癌，这一过程可能具有多灶性起源， 致癌物质，如烟草中发现的致癌物质。我们的长期目标是找出 促进进展为OPL的高风险的改变，并确定这些改变如何调节 OPL对预防战略的反应。TP 53基因（也称为p53）和CDKN 2A是最常见的。 在口腔癌中经常发生突变的基因，在OPL中也发现了改变。p53 GOF突变和基因组改变 导致OPL和OSCC中与“冷”免疫微环境相关的CDKN 2A基因丢失， 发展为癌的风险高，并且在OSCC患者中具有极差的结果。我们假设 p53和CDKN 2A失活突变的早期出现调节了口腔组织 微环境和易患OPL进展为OSCC。为了验证这一假设，我们将研究小鼠模型， 在p53和/或CDKN 2A存在下，暴露于烟草替代物4 NQO时产生OPL 突变。高风险OPL患者可以从旨在阻断恶性肿瘤的预防策略中获益。 OPL的发展。然而，先前使用不同化学预防剂的尝试尚未被证实。 成功最近，针对程序性细胞死亡蛋白1的抗体的免疫检查点阻断 在临床试验中，PD-1已被证明可以改善晚期OSCC患者的生存率，证实了PD-1的治疗作用。 免疫系统在抑制侵袭性肿瘤进展中的重要性。此外，我们以前的研究， 经多个独立小组证实，证明抗PD-1抗体也可以预防 OPL向OSCC的进展，在4 NQO小鼠口腔癌发生模型中。我们的初步研究表明 OPL的p53和CDKN 2A状态可能决定对抗PD-1介导的免疫应答。 免疫预防在本提案中，我们将评估抗PD-1介导的口腔癌的长期益处 预防，以确定在预防性环境中给予PD-1阻断剂是否可以提供生存 研究目的是评估p53和CDKN 2A突变如何影响对PD-1阻断的持续反应。到 我们假设携带p53突变的OPL中p53的再激活 使口腔病变对抗PD-1敏感。我们的小鼠模型将使我们能够在体内测试这一假设。