Targeting the EGFR-PI3K/mTOR Signaling Circuitry: A Network-Based Approach for Oral Cancer Precision Therapy

靶向 EGFR-PI3K/mTOR 信号通路：基于网络的口腔癌精准治疗方法

基本信息

批准号：
10214590
负责人：
Jorge Silvio Gutkind
金额：
$ 46.71万
依托单位：
UNIVERSITY OF CALIFORNIA, SAN DIEGO
依托单位国家：
美国
项目类别：
财政年份：
2018
资助国家：
美国
起止时间：
2018-08-01 至 2023-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10214590
关键词：
Automobile Driving Biological Process CRISPR screen Cancer Remission Catalytic Domain Cells Cessation of life Cetuximab Chemicals Clinical Combined Modality Therapy DNA Sequence Alteration Data Development Disease Disease remission Drug resistance Epidermal Growth Factor Receptor Exhibits FDA approved FRAP1 gene Future Genetic Genetic Determinism Genetic Engineering Genetic Variation Genomics Goals Health Human Papillomavirus Immune Immune checkpoint inhibitor Immunooncology Individual Knock-in Mouse Knowledge Lesion Malignant Neoplasms Modeling Molecular Mus Mutate Mutation Neoadjuvant Therapy Network-based Oncogenes Oncogenic Oropharyngeal PD-1 blockade PIK3CA gene PIK3CG gene Pathway interactions Patient Selection Patients Phase II Clinical Trials Population Precision therapeutics Predictive Value Prevention Resistance Series Signal Pathway Signal Transduction Sirolimus Stratification System Therapeutic Treatment Efficacy Treatment Failure Tumor Suppressor Genes Validation base cancer cell cancer subtypes deep sequencing drug repurposing falls genome editing humanized monoclonal antibodies immune checkpoint inhibiting antibody mTOR Inhibitor mTOR inhibition malignant mouth neoplasm mouth squamous cell carcinoma new therapeutic target novel novel therapeutics oncology trial patient population precision oncology predictive marker prevent research clinical testing resistance mechanism response response biomarker targeted treatment therapeutic target tumor tumor microenvironment tumor-immune system interactions

项目摘要

Project Summary There are currently no effective targeted therapies for oral squamous cell carcinoma (OSCC), which includes cancers of the oral cavity and oropharynx, a disease that results in ~300,000 deaths each year worldwide. There is an urgent need to develop new therapeutic options to prevent and treat OSCC. A striking finding from the recent deep sequencing of the OSCC genomic landscape was the remarkable multiplicity and diversity of genetic alterations in this malignancy. The emerging picture, however, is that most fall within only a few major driver biological processes, including mitogenic signaling with particular emphasis on aberrant activation of the PI3K/mTOR pathway. Among them, PIK3CA, encoding the PI3Kα catalytic subunit, is the most commonly mutated oncogene in OSCC (~20%), with a significant enrichment in (HPV)-associated tumors (25%). Our team has focused on the study of oncogenic signaling circuitries driving OSCC initiation and progression, aimed at identifying novel druggable targets for OSCC prevention and treatment. These efforts led to our early discovery that the persistent activation of the PI3K/mTOR signaling circuitry is the most frequent dysregulated signaling mechanism in OSCC, and that PI3K/mTOR inhibition exerts potent antitumor activity in a large series of genetically-defined and chemically-induced OSCC models. These findings provided the rationale for launching a multi-institutional Phase II clinical trial (NCT01195922), targeting mTOR in OSCC, which was recently completed and achieved encouraging results. However, 80% of the OSCC lesions lack driver PIK3CA mutations, and to date, we cannot predict the sensitivity or resistance to EGFRi and PI3K/mTORi in the context of an individual tumor, which may help explain prior treatment failures with PI3K/mTORi in unselected advanced OSCC patients. We have also shown that PIK3CA mutations may underlie cetuximab resistance, which can be overcome by mTOR inhibition. We will investigate the therapeutic potential of co-targeting the EGFR- PI3K/mTOR signaling circuitry based on the genetic stratification of PI3K/mTOR network subtypes, alone or combined with immune oncology agents with the goal to develop novel precision therapeutic approaches for OSCC. To this end, we will exploit the emerging information about the OSCC genomic landscape to a) identify alterations driving PI3K/mTOR activation in the OSCC lesions that lack PIK3CA mutation and explore their contribution to cetuximab resistance and sensitivity, b) identify novel systems vulnerabilities associated with cetuximab and PI3K/mTORi sensitization and c) establish the impact of targeting and co-targeting the EGFR- PI3K/mTOR signaling network on the tumor and immune microenvironment, and response to novel immune oncology agents. Ultimately, our efforts will a) overcome EGFR-PI3K/mTORi resistance mechanisms via network-based co-targeting strategies, b) increase the efficacy of novel immune checkpoint inhibitors by targeting oncogenic circuities, and c) inform the molecular stratification of OSCC for patient selection in future precision and immune oncology trials.

项目摘要目前尚无口服鳞状细胞癌（OSCC）的有效靶向疗法，其中包括口腔和口咽的癌症，这种疾病每年在全球造成约300,000人死亡。那里迫切需要开发新的治疗选择来预防和治疗OSCC。从 OSCC基因组景观的最新深度测序是通用的显着多样性和多样性这种恶性肿瘤的改变。但是，新兴的图片是，大多数人只属于几个主要驱动程序生物过程，包括有丝分裂信号传导，特别强调异常激活 PI3K/mTOR途径。其中，编码PI3Kα催化亚基的PIK3CA是最常见的在OSCC中突变的癌基（约20％），在（HPV）相关的肿瘤（25％）中显着富集。我们的团队专注于驱动OSCC计划和进展的致癌信号圈的研究，针对确定可用于预防OSCC的新型可药物靶标。这些努力导致了我们的早期发现 PI3K/MTOR信号传导电路的持续激活是最常见的信号传导 OSCC中的机制，PI3K/MTOR抑制在一系列大量的抗肿瘤活动中执行潜在的抗肿瘤活性遗传定义和化学诱导的OSCC模型。这些发现提供了启动的理由一项多机构II期临床试验（NCT01195922），针对OSCC的MTOR，最近是完成并取得了令人鼓舞的结果。但是，80％的OSCC病变缺乏驱动器PIK3CA突变，迄今为止，我们无法预测对EGFRI和PI3K/MTORI的敏感性或抵抗力单个肿瘤，这可能有助于解释未选择的高级pi3k/mtori的先前治疗失败 OSCC患者。我们还表明，PIK3CA突变可能是西妥昔单抗抗性的基础，这可以是克服MTOR抑制。我们将研究共同靶向EGFR-的治疗潜力基于PI3K/MTOR网络亚型的遗传分层的PI3K/MTOR信号传导电路，单独或结合免疫肿瘤剂，其目标是开发新的精确疗法方法 OSCC。为此，我们将利用有关OSCC基因组景观的新兴信息a）确定在缺乏PIK3CA突变的OSCC病变中驱动PI3K/MTOR激活的变化并探索它们对西妥昔单抗的耐药性和灵敏度的贡献，b）确定与之相关的新型系统脆弱性西妥昔单抗和PI3K/mTORI敏感性，c）建立靶向和靶向EGFR-的影响肿瘤和免疫微环境上的PI3K/MTOR信号网络，以及对新免疫的反应肿瘤学代理。最终，我们的努力将a）通过通过基于网络的共同目标策略，b）通过靶向致癌电路，c）告知OSCC的分子分层以将来选择患者选择精度和免疫肿瘤学试验。