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

• 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
• 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

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 口腔鳞状细胞癌（OSCC）目前尚无有效的靶向治疗方法，包括 口腔和口咽癌，这种疾病每年导致全球约300，000人死亡。那里 因此，迫切需要开发新的治疗选择来预防和治疗OSCC。一个惊人的发现， 最近对OSCC基因组景观的深度测序是遗传多样性的显着多样性和多样性， 这种恶性肿瘤的变化。然而，新出现的情况是，大多数都属于少数几个主要驱动因素 生物学过程，包括促有丝分裂信号传导，特别强调 PI 3 K/mTOR通路。其中，编码PI 3 K α催化亚基的PIK 3CA是最常见的。 突变的癌基因在口腔鳞状细胞癌（~20%），与（HPV）相关的肿瘤（25%）显着富集。我们的团队 一直致力于研究致癌信号通路驱动口腔鳞癌的发生和发展，旨在 确定用于OSCC预防和治疗的新的可药物靶点。这些努力使我们早期发现 PI 3 K/mTOR信号通路的持续激活是最常见的失调信号通路， PI 3 K/mTOR抑制在OSCC中发挥了有效的抗肿瘤活性， 遗传定义和化学诱导的OSCC模型。这些发现为启动 一项多机构II期临床试验（NCT 01195922），目标是OSCC中的mTOR，最近 完成并取得了令人鼓舞的成果。然而，80%的OSCC病变缺乏驱动PIK 3CA突变， 到目前为止，我们还不能预测EGFR i和PI 3 K/mTORi的敏感性或耐药性。 个体肿瘤，这可能有助于解释先前PI 3 K/mTORi治疗晚期胰腺癌失败的原因 OSCC患者我们还发现PIK 3CA突变可能是西妥昔单抗耐药的基础，这可能是一个潜在的原因。 通过mTOR抑制克服。我们将研究共靶向EGFR的治疗潜力- 基于PI 3 K/mTOR网络亚型的遗传分层的PI 3 K/mTOR信号通路，单独或 与免疫肿瘤学药物相结合，目的是开发新的精确治疗方法， 口腔鳞癌。为此，我们将利用有关OSCC基因组景观的新信息， 在缺乏PIK 3CA突变的OSCC病变中驱动PI 3 K/mTOR激活的改变，并探索其 B）识别与下列因素相关的新的系统脆弱性： c）确定靶向和共靶向EGFR-1的影响， PI 3 K/mTOR信号网络对肿瘤和免疫微环境的影响，以及对新型免疫的应答 肿瘤药物。最终，我们的努力将a）通过以下途径克服EGFR-PI 3 K/mTORi抗性机制： 基于网络的共靶向策略，B）通过以下方式增加新型免疫检查点抑制剂的功效 靶向致癌环路，以及c）告知OSCC的分子分层，用于将来的患者选择 精准和免疫肿瘤学试验。