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

基本信息

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
项目类别：
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

项目摘要

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.

项目概要口腔鳞状细胞癌 (OSCC) 是全球第六大常见人类癌症，约占 30%。的口腔癌前病变 (OPL) 进展为 OSCC，这一过程可能具有多灶性起源，并且可能我们的长期目标是确定遗传因素。促进 OPL 高风险进展的改变，并确定这些改变如何调节 OPL 对预防策略的反应最明显的是 TP53 基因（也称为 p53）和 CDKN2A。口腔癌中经常发生突变的基因，还发现 OPLs 的 p53 GOF 突变和基因组改变发生了改变。导致 OPL 和 OSCC 中与“冷”免疫微环境相关的 CDKN2A 基因丢失，进展为癌症的风险很高，并且 OSCC 患者的预后极差。 p53 突变和 CDKN2A 失活的早期出现调节口腔组织为了验证这一假设，我们将研究小鼠模型。在 p53 和/或 CDKN2A 存在的情况下，暴露于烟草替代品 4NQO 后会产生 OPL 患有高风险 OPL 的患者可以从旨在阻止恶性突变的预防策略中受益。然而，之前使用不同化学预防剂的尝试尚未得到证实。最近，针对程序性细胞死亡蛋白 1 的抗体阻断了免疫检查点。 (PD-1) 已在临床试验中被证明可以改善晚期 OSCC 患者的生存率，证实了此外，我们之前的研究表明，免疫系统在遏制侵袭性肿瘤进展方面的重要性。经多个独立小组证实，抗 PD-1 抗体还可以预防我们的初步研究表明，在 4NQO 小鼠口腔癌模型中，OPL 进展为 OSCC。 OPL 的 p53 和 CDKN2A 状态可能决定对抗 PD-1 介导的反应在本提案中，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进行的 PD-1 阻断是否可以带来生存益处，并评估 p53 和 CDKN2A 突变如何影响对 PD-1 阻断的持续反应。克服抗 PD-1 耐药性，我们勇敢地面对携带 p53 突变的 OPL 中 p53 的重新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。