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 口服鳞状细胞癌（OSCC）是全球第六大最常见的人类癌症。约30％ 口服前病变（OPLS）的进展到OSCC，该过程可能具有多焦点来源，并且可以 由致癌物（例如在烟草中发现的）促进。我们的长期目标是确定通用 促进OPL进展的高风险并确定这些变化如何调节的改变 OPL对预防策略的反应。 TP53基因（也称为p53）和CDKN2A是最大的 在OPL中，经常发现口腔癌的突变基因也发生了变化。 p53 GOF突变和基因组改变 这导致CDKN2A基因与OPL和OSCC中的“冷”免疫环境的关联丧失， OSCC患者的高风险进展为癌，并且结果极差。我们假设 p53和CDKN2A灭活中突变的早期出现调节口腔组织 微环境和倾向OPL逐渐发展为OSCC。为了检验该假设，我们将研究鼠标模型 在存在p53和/或CDKN2A的情况下，暴露于烟草酸盐4NQO时会产生OPL 突变。具有高风险OPL的患者可能会受益于旨在阻止恶性肿瘤的预防策略 OPL的进展。但是，以前与不同化学预防剂的尝试尚未 成功的。最近，使用针对编程细胞死亡蛋白1 （PD-1）已证明可以改善临床试验中晚期OSCC患者的存活率，确认 免疫系统在含有侵入性肿瘤进展方面的重要性。而且，我们以前的研究， 由多个独立组确认，证明抗PD-1抗体也可以防止 在4NQO小鼠的口服癌变模型中，OPL向OSCC的进展。我们的初步研究表明 OPL的p53和CDKN2A状态可以确定对抗PD-1介导的响应 免疫预防。在此提案中，我们将评估抗PD-1介导的口腔癌的长期益处 预防，确定在预防性环境中给药的PD-1封锁是否可以赋予生存 益处，并评估p53和CDKN2A突变如何影响对PD-1封锁的持续反应。到 克服对抗PD-1的耐药性，我们假设在携带p53突变的OPL中重新激活p53 将口腔病变感知到抗PD-1。我们的鼠标模型将使我们能够在体内检验这一假设。