Genetic Modifiers such as Fas Regulate Tumor-Cell Dependence on Mutant EGFR

Fas 等基因修饰剂调节肿瘤细胞对突变 EGFR 的依赖

• 批准号: 8188777
• 负责人: Trever G Bivona
• 金额: $ 16.85万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-09-21 至 2016-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8188777
• 关键词: Apoptosis; Automobile Driving; CASP8 and FADD-like apoptosis regulating protein; Cancer Etiology; Cancer Model; Cancer Patient; Cell Death; Cell Line; Cessation of life; Clinical; Clinical Data; Clinical Trials; Companions; Critiques; Data; Dependence; Development; Diagnosis; Doctor of Philosophy; Drug Delivery Systems; Environment; Epidermal Growth Factor Receptor; Epidermal Growth Factor Receptor Tyrosine Kinase Inhibitor; Erlotinib; Genetic; Growth; Heterogeneity; Human; Individual; International; K-Series Research Career Programs; Laboratories; Lead; Lung Adenocarcinoma; Malignant neoplasm of lung; Medical Oncologist; Memorial Sloan-Kettering Cancer Center; Mentors; Modeling; Mus; Mutation; Oncogene Proteins; Oncogenes; Outcome; Output; Pathway interactions; Patient Care; Patients; Physicians; Public Health; RNA Interference; Research; Resistance; Science; Scientist; Screening procedure; Signal Transduction; Structure; TNFRSF6 gene; Testing; Thoracic Oncology; Transgenic Organisms; Translating; Tumor Necrosis Factor Ligand Superfamily Member 6; Up-Regulation; Writing; Xenograft Model; addiction; base; cancer cell; experience; gene function; human disease; improved; in vivo Model; inhibitor/antagonist; insight; meetings; mutant; neoplastic cell; oncology; overexpression; patient oriented; research study; response; therapeutic target; treatment response; tumor; tumor xenograft

DESCRIPTION (provided by applicant): This five-year mentored career development award is structured to facilitate my development into an independent, laboratory-based physician scientist in the field of translational thoracic oncology. As an MD-PhD physician scientist, my clinical experiences as a medical oncologist caring for patients with lung cancer inspire the bench science in which I engage. These clinical experiences also provide opportunities to translate scientific discoveries to improve the treatment of patients with lung cancer. My primary mentor is Dr. Charles Sawyers, an international leader in translational oncology. Memorial Sloan-Kettering Cancer Center provides an ideal setting in which to perform patient-oriented, lab-based research. In the laboratory we investigate the mechanism(s) by which some cancer cells acquire dependence upon signaling by an oncoprotein for their survival ("oncogene addiction"). We have focused on human lung cancers that harbor activating mutations in the epidermal growth factor receptor (EGFR). Human lung adenocarcinomas with activating mutations in EGFR often respond to treatment with EGFR tyrosine kinase inhibitors (TKIs) but the magnitude of tumor regression is variable and transient. We hypothesized that the heterogeneity of treatment response may result from genetic modifiers that regulate the degree to which tumor cells are dependent on the mutant EGFR and, hence, the magnitude and duration of response in patients treated with EGFR TKIs. We used an RNA- interference (RNAi) screening strategy to rationally identify companion therapeutic targets that, when inhibited, might enhance the response of EGFR-mutant lung cancers to the EGFR TKI erlotinib. In initial experiments, we showed that knockdown of CD95/Fas and several components of the NF?B pathway specifically enhanced cell death induced by the EGFR TKI erlotinib in EGFR-mutant lung cancer cells. Activation of NF?B through overexpression of the intermediates c-FLIP or IKK, or silencing of I?B, rescued EGFR-mutant lung cancer cells from EGFR TKI. Genetic or pharmacologic inhibition of NF?B enhanced erlotinib-induced apoptosis in erlotinib-sensitive and erlotinib-resistant EGFR-mutant lung cancer models. Increased expression of the NF?B inhibitor I?B predicted for improved response and survival EGFR-mutant lung cancer patients treated with EGFR TKI. These data identify NF?B as a potential companion drug target, together with EGFR, in EGFR-mutant lung cancers. We propose to further test the hypothesis that the CD95/Fas-NF?B pathway and EGFR are rational companion therapeutic targets in EGFR-mutant lung cancers using state-of- the-art murine models, additional human clinical data, and pathway-selective NF?B pharmacologic inhibitors in the following Specific Aims: 1) Determine if CD95/Fas-NF?B signaling is sufficient to induce EGFR TKI resistance using in vivo models of EGFR- mutant lung cancer, 2) Determine if increased CD95/Fas-NF?B signaling occurs in EGFR-mutant transgenic lung cancer models and patients that are resistant to EGFR TKI, 3) Determine if pathway-selective NF?B inhibitors enhance EGFR TKI responses in EGFR-mutant lung cancer models as a prelude to a clinical trial in appropriately selected patients. More broadly, these studies provide insight into the mechanisms by which tumor cells acquire oncogene dependence and escape from oncogene inhibition. PUBLIC HEALTH RELEVANCE: Lung cancer is a major public health problem because it is the most common cause of cancer-related death in the US. Most lung cancer patients die within 5 years of diagnosis since treatments are ineffective because we do not fully understand the mechanisms driving the growth of lung cancer cells. Our research aims to characterize the functions of genes that drive lung cancer growth. These efforts may lead to improved personalized therapies for patients with lung cancer to enhance outcomes. The written critiques and criteria scores of individual reviewers are provided in essentially unedited form in the "Critique" section below. Please note that these critiques and criteria scores were prepared prior to the meeting and may not have been revised subsequent to any discussions at the review meeting. The "Resume and Summary of Discussion" section above summarizes the final opinions of the committee.

描述（由申请人提供）：这项为期五年的指导职业发展奖的结构是促进我成为转化胸部肿瘤学领域的独立，实验室医师科学家的发展。作为MD-PHD医师科学家，我作为医学肿瘤学家照顾肺癌患者的临床经验激发了我参与的基准科学。这些临床经验还提供了翻译科学发现以改善肺癌患者治疗的机会。我的主要导师是转化肿瘤学的国际领导者查尔斯·索耶斯（Charles Sawyers）博士。纪念斯隆 - 凯特林癌症中心提供了一个理想的环境，可以在其中进行以患者为基础的，基于实验室的研究。在实验室中，我们研究了某些癌细胞对癌蛋白生存的信号传导的依赖性的机制（“癌基因成瘾”）。我们专注于携带表皮生长因子受体（EGFR）激活突变的人类肺癌。 EGFR中具有激活突变的人肺腺癌通常会对EGFR酪氨酸激酶抑制剂（TKIS）响应，但肿瘤回归的幅度是可变且瞬时的。我们假设，治疗反应的异质性可能是由于调节肿瘤细胞依赖于突变体EGFR的程度的遗​​传修饰剂，因此，用EGFR TKIS治疗的患者的大小和持续时间。我们使用RNA干扰（RNAI）筛查策略来合理地识别伴随的治疗靶标，这些靶标在被抑制时可能会增强EGFR突变肺癌对EGFR TKI Erlotinib的反应。在最初的实验中，我们表明CD95/FAS的敲低和NF？B途径的几个成分特异性增强了EGFR TKI Erlotinib在EGFR-突变肺癌细胞中诱导的细胞死亡。通过中间体C-Flip或Ikk的过表达激活NF？B，或从EGFR TKI中救出EGFR突变的肺癌细胞的I？B的沉默。 NF？B的遗传学或药理抑制增强了厄洛替尼诱导的厄洛替尼敏感和耐厄洛替尼的EGFR-突变肺癌模型的凋亡。 NF？b抑制剂I？B的表达增加，预计用EGFR TKI治疗的反应和生存EGFR突变肺癌患者的表达增加。这些数据将NF？b与EGFR突变肺癌中的EGFR一起识别为潜在的伴随药物靶标。我们建议进一步检验以下假说：CD95/FAS-NF途径和EGFR是EGFR-突变肺癌中理性伴侣治疗靶标的 - ART-ART鼠模型，其他人类临床数据，途径临床数据和途径 - 选择性NF nf？ TKI resistance using in vivo models of EGFR- mutant lung cancer, 2) Determine if increased CD95/Fas-NF?B signaling occurs in EGFR-mutant transgenic lung cancer models and patients that are resistant to EGFR TKI, 3) Determine if pathway-selective NF?B inhibitors enhance EGFR TKI responses in EGFR-mutant lung cancer models as a prelude to a clinical trial in适当选择的患者。从更广泛的角度来看，这些研究提供了对肿瘤细胞获得癌基因依赖并摆脱癌基因抑制的机制的见解。 公共卫生相关性：肺癌是一个主要的公共卫生问题，因为它是美国与癌症相关死亡的最常见原因。大多数肺癌患者在诊断的5年内死亡，因为治疗无效，因为我们不完全了解推动肺癌细胞生长的机制。我们的研究旨在表征促进肺癌生长的基因的功能。这些努力可能导致改善肺癌患者的个性化疗法，以提高预后。 以下“批评”部分提供了基本未经编辑的审稿人的书面批评和标准评分。请注意，这些批评和标准分数是在会议之前准备的，并且在审查会议上的任何讨论之后可能没有修订。上面的“简历和摘要”部分总结了委员会的最终意见。