Role of PUMA in EGFR targeted therapy in HNSCC

PUMA 在 HNSCC EGFR 靶向治疗中的作用

• 批准号: 7620091
• 负责人: Jian Yu
• 金额: $ 31.44万
• 依托单位: UNIVERSITY OF PITTSBURGH AT PITTSBURGH
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-08-01 至 2013-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7620091
• 关键词: Animals; Antibodies; Antineoplastic Agents; Apoptosis; Apoptosis Promoter; Binding; Cancer Etiology; Caspase; Cell Culture Techniques; Cell Death; Cell Line; Cells; Cessation of life; Cetuximab; Clinical; Colon Carcinoma; DNA Damage; Data; Down-Regulation; EGFR Protein Overexpression; Epidermal Growth Factor Receptor; Epidermal Growth Factor Receptor Tyrosine Kinase Inhibitor; Erlotinib; Family member; Gefitinib; Head and Neck Squamous Cell Carcinoma; In Vitro; Induction of Apoptosis; Malignant Epithelial Cell; Malignant Neoplasms; Mediating; Mediator of activation protein; Mitochondria; Modeling; Molecular; Pathway interactions; Patients; Protein Family; RNA Interference; Receptor Inhibition; Regulation; Resistance; Role; Sampling; Signal Transduction; Small RNA; Survival Rate; TP53 gene; Testing; Therapeutic; Therapeutic Effect; Transactivation; Transcriptional Regulation; Tyrosine Kinase Inhibitor; United States; Xenograft Model; abstracting; cancer cell; chemotherapeutic agent; conventional therapy; cytotoxic; cytotoxicity; improved; in vivo; mitochondrial dysfunction; novel; outcome forecast; public health relevance; research study; response; small hairpin RNA; therapeutic development; tumor; tumor xenograft

DESCRIPTION (provided by applicant): Abstract Head and neck squamous cell carcinoma (HNSCC) is the sixth leading cause of cancer related death worldwide. The survival rate of HNSCC patients has not been significantly improved over the past 30 years with conventional therapies. More than 80% of HNSCC express high levels of epidermal growth factor receptor (EGFR), which correlate with poor prognosis. Targeting EFGR signaling with tyrosine kinase inhibitors (TKIs) or antibodies has emerged as a promising approach for treating cancers including HNSCC. The antitumor effects of EGFR blockade are thought to involve multiple mechanisms, including induction of apoptosis, whose underlying mechanism is not well understood. We and others previously identified the BH3- only Bcl-2 family member PUMA (p53 unregulated modulator of apoptosis) as an essential mediator of DNA damage-induced apoptosis. Our recent preliminary data showed that PUMA fails to be induced by conventional chemotherapeutic agents, but is induced by clinically approved EGFR targeting agents, gefitinib, erlotinib and cetuximab, in most HNSCC cell lines. PUMA induction is associated with EGFR TKI sensitivity. Knockdown of PUMA by small interference RNA (siRNA) and small hairpin RNA (hsRNA) suppressed gefitinib- induced apoptosis in HNSCC cells. Furthermore, EGFR TKIs induce PUMA through the effects on the p53 family members p63 and p73, but not p53 itself. These observations led us to hypothesize that PUMA induction is an important mechanism of EGFR blockade-induced cytotoxicity in HNSCC cells. We propose to test this central hypothesis using cell culture, animal tumor models and clinical samples. In Aim 1, we will delineate the molecular mechanisms of PUMA induction by EGFR inhibition in HNSCC cells. We will focus on the role of p73 and p63 in the transcriptional regulation of PUMA. In Aim 2, we will investigate the role of PUMA in EGFR inhibition-induced apoptosis in HNSCC cells. We will focus on the role and mechanism of PUMA in the regulation of mitochondrial integrity and other Bcl-2 family proteins. In Aim 3, we will determine whether PUMA levels modulate the therapeutic responses to EGFR targeted therapy in cell culture, xenograft models and clinical samples. PUBLIC HEALTH RELEVANCE: Head and neck squamous cell carcinoma (HNSCC) is a significant cause of cancer related death in the United States. This project seeks to understand the mechanisms by which a novel class of anticancer agent, epidermal growth factor receptor (EGFR) antagonists, exerts their antitumor effects in HNSCC. The results could be useful for developing improved strategies and agents for treatment of HNSCC and possibly other cancers with EGFR overexpression.

描述（由申请人提供）：抽象的头部和颈部鳞状细胞癌（HNSCC）是全球癌症相关死亡的第六个主要原因。在过去的30年中，HNSCC患者的存活率尚未得到显着提高。超过80％的HNSCC表达高水平的表皮生长因子受体（EGFR），这与预后不良相关。用酪氨酸激酶抑制剂（TKI）或抗体靶向EFGR信号传导已成为治疗包括HNSCC在内的癌症的有希望的方法。 EGFR阻滞的抗肿瘤作用被认为涉及多种机制，包括诱导凋亡，其潜在机制尚不清楚。我们和其他人先前以前将BH3-仅BCL-2家族成员PUMA（p53未管制的凋亡调节剂）视为DNA损伤诱导的凋亡的必不可少的介体。我们最近的初步数据表明，在大多数HNSCC细胞系中，PUMA无法由常规化学治疗剂诱导，但由临床批准的EGFR靶向剂，Gefitinib，erlotinib和cetuximab诱导。 PUMA诱导与EGFR TKI敏感性有关。通过小型干扰RNA（siRNA）和小发夹RNA（HSRNA）抑制PUMA，抑制了吉非替尼诱导的HNSCC细胞中的凋亡。此外，EGFR TKI通过对p53家族成员p63和p73的影响诱导PUMA，而不是p53本身。这些观察结果导致我们假设PUMA诱导是HNSCC细胞中EGFR阻断诱导的细胞毒性的重要机制。我们建议使用细胞培养，动物肿瘤模型和临床样品检验该中心假设。在AIM 1中，我们将通过HNSCC细胞中的EGFR抑制来描述PUMA诱导的分子机制。我们将重点介绍p73和p63在PUMA转录调控中的作用。在AIM 2中，我们将研究PUMA在EGFR抑制诱导的HNSCC细胞中的作用。我们将重点关注PUMA在线粒体完整性和其他Bcl-2家族蛋白的调节中的作用和机制。在AIM 3中，我们将确定PUMA水平是否调节细胞培养，异种移植模型和临床样品中对EGFR靶向治疗的治疗反应。公共卫生相关性：头颈鳞状细胞癌（HNSCC）是美国癌症相关死亡的重要原因。该项目旨在了解一种新型的抗癌剂表皮生长因子受体（EGFR）拮抗剂的机制，在HNSCC中发挥了抗肿瘤作用。该结果可能有助于开发改进的策略和代理，以治疗HNSCC以及可能具有EGFR过表达的其他癌症。