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：
9977696
负责人：
Jorge Silvio Gutkind
金额：
$ 46.59万
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/9977696
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 Pharmaceutical Preparations 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 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.

项目概要目前尚无针对口腔鳞状细胞癌（OSCC）的有效靶向疗法，其中包括口腔和口咽癌是一种每年导致全球约 30 万人死亡的疾病。迫切需要开发新的治疗方案来预防和治疗 OSCC。最近对 OSCC 基因组图谱进行的深度测序发现，基因组具有显着的多样性和多样性。然而，这种恶性肿瘤的变化大多数都属于少数几个主要驱动因素。生物过程，包括有丝分裂信号传导，特别强调异常激活其中，编码PI3Kα催化亚基的PIK3CA是最常见的。 OSCC 中存在突变癌基因（约 20%），而 (HPV) 相关肿瘤中显着富集（25%）。重点研究驱动 OSCC 发生和进展的致癌信号通路，旨在确定用于 OSCC 预防和治疗的新药物靶标。这些努力使我们取得了早期发现。 PI3K/mTOR 信号通路的持续激活是最常见的失调信号传导 OSCC 中的机制，并且 PI3K/mTOR 抑制在一系列中发挥有效的抗肿瘤活性这些发现为推出基因定义和化学诱导的 OSCC 模型提供了依据。一项多机构 II 期临床试验 (NCT01195922)，针对 OSCC 中的 mTOR，最近完成并取得了令人鼓舞的结果，然而，80％的 OSCC 病变缺乏驱动 PIK3CA 突变，迄今为止，我们无法预测 EGFRi 和 PI3K/mTORi 的敏感性或耐药性个体肿瘤，这可能有助于解释先前使用 PI3K/mTORi 治疗未选择的晚期患者的失败我们还发现 PIK3CA 突变可能是 OSCC 患者对西妥昔单抗耐药的原因。我们将研究共同靶向 EGFR- 的治疗潜力。基于 PI3K/mTOR 网络亚型遗传分层的 PI3K/mTOR 信号通路，单独或与免疫肿瘤药物相结合，目标是开发新的精准治疗方法为此，我们将利用有关 OSCC 基因组景观的新信息来 a) 识别在缺乏 PIK3CA 突变的 OSCC 病变中驱动 PI3K/mTOR 激活的改变并探索其对西妥昔单抗耐药性和敏感性的贡献，b) 识别与以下相关的新系统漏洞 c) 确定靶向和共同靶向 EGFR-的影响 PI3K/mTOR信号网络对肿瘤和免疫微环境的影响以及对新型免疫的反应最终，我们的努力将通过以下方式克服 EGFR-PI3K/mTORi 耐药机制。基于网络的联合靶向策略，b）通过以下方式提高新型免疫检查点抑制剂的功效针对致癌回路，c) 为 OSCC 的分子分层提供信息，以便将来选择患者精准和免疫肿瘤学试验。