Therapeutic targeting of Kras-driven Lung Adenocarcinoma

Kras 驱动的肺腺癌的治疗靶向

基本信息

批准号：
9303312
负责人：
Alan P. Fields
金额：
$ 35.8万
依托单位：
MAYO CLINIC JACKSONVILLE
依托单位国家：
美国
项目类别：
财政年份：
2016
资助国家：
美国
起止时间：
2016-07-01 至 2021-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9303312
关键词：
Anchorage-Independent Growth Biochemical Biological Cancer Etiology Cell Maintenance Cells Cessation of life Clinical Clinical Management Clonal Expansion Collaborations Data Development ELF3 gene Epidermal Growth Factor Receptor Epithelial Exhibits Gene Expression Gene Targeting Genetic Genomics Goals Growth Human In Vitro Intervention KRAS2 gene Knockout Mice Lung Lung Adenocarcinoma Lung Neoplasms Maintenance Malignant neoplasm of lung Mediating Modeling Mus NOTCH3 gene Neoplasm Metastasis Non-Small-Cell Lung Carcinoma Oncogenes Pathway interactions Patient-Focused Outcomes Patients Pharmacologic Substance Phenotype Phosphorylation Phosphorylation Site Prognostic Marker Promoter Regions Protein Kinase Publishing Recruitment Activity Role Signal Pathway Signal Transduction Site Squamous Cell Lung Carcinoma Survival Rate TP53 gene Testing Therapeutic Transcriptional Regulation Tumor Initiators United States Xenograft procedure actionable mutation base cancer subtypes cell behavior cell transformation clinical development genome-wide analysis in vivo inhibitor/antagonist insight knock-down mouse model mutant novel novel therapeutic intervention pharmacodynamic biomarker predictive marker promoter public health relevance response biomarker stem stem-like cell targeted treatment therapeutic target transcription factor treatment strategy tumor tumor growth tumor initiation tumor progression tumor xenograft tumorigenesis

项目摘要

DESCRIPTION (provided by applicant): Lung cancer is the leading cause of cancer death in the US, exhibiting a dismal five year survival rate of ~16%, underscoring the need for new therapeutic approaches. The recent development of targeted therapeutics that effectively treat lung cancer subtypes harboring specific driver mutations in EGFR, MET and EML4-ALK have made important inroads in treating these specific subsets of lung cancer. Despite these key advances, treatment options for mutant KRAS-driven lung adenocarcinoma (KRAS LADC), the most prevalent form of lung cancer, remain limited. We have identified protein kinase Cι (PKCι) as an oncogene in KRAS LADC and lung squamous cell carcinoma (LSCC), the two major forms of non-small cell lung cancer (NSCLC). PKCι functions to maintain a tumor-initiating cell (TIC) phenotype in both of these NSCLC tumor types. Surprisingly however, our published and preliminary studies demonstrate that PKCι drives a TIC phenotype in KRAS LADC and LSCC through distinct signaling pathways. Preliminary data demonstrate that: 1) PKCι drives a KRAS LADC TIC phenotype by activating expression of the pluripotent stem factor NOTCH3; 2) PKCι activates NOTCH3 expression by recruiting the ELF3 transcription factor to the NOTCH3 promoter; 3) PKCι phosphorylates ELF3 at Ser68 to regulate ELF3 occupancy and activation of the NOTCH3 promoter; 4) a newly identified, highly potent and selective PKCι inhibitor inhibits LADC TIC cell behavior in vitro. Based on these data, we hypothesize that: 1) PKCι regulates ELF3 promoter occupancy on NOTCH3 and other gene targets involved in maintaining a LADC TIC phenotype; 2) the novel PKCι-ELF3-NOTCH3 signaling axis drives Kras-mediated LADC initiation and progression in mouse models of Kras LADC; 3) our novel, potent and highly selective PKCι inhibitor will exhibit anti-tumor activity in KRAS LADC, and PKCι-ELF3-NOTCH3 signaling intermediates will be useful predictive and pharmacodynamic biomarkers of response. These hypotheses will be tested in three interrelated specific aims to: 1) assess the role of PKCι-mediated ELF3 phosphorylation in NOTCH3 promoter occupancy, NOTCH3 expression and LADC TIC behavior; 2) assess the role of the PKCι- ELF3-NOTCH3 signaling axis in mutant Kras-mediated lung tumor initiation and progression; and 3) assess the potential of a novel highly potent and selective PKCι inhibitor as a therapeutic strategy for treatment of KRAS LADC. Successful completion of these aims will: 1) provide new mechanistic insight into the newly- identified PKCι-ELF3-NOTCH3 signaling axis; 2) assess the importance of this pathway in the maintenance of a LADC TIC phenotype; 3) identify novel targets for PKCι-ELF3-dependent transcriptional regulation; 4) assess the importance of the PKCι-ELF3-NOTCH3 signaling axis in LADC tumor initiation and maintenance; and 5) assess the utility of a newly-developed, highly potent PKCι inhibitor in the treatment of KRAS LADC. Given the poor clinical outcome of patients with KRAS LADC, and the dearth of therapeutic options, these studies may have widespread impact on the clinical management of these patients.

描述（由适用提供）：肺癌是美国癌症死亡的主要原因，其惨淡的五年生存率约为16％，强调了对新治疗方法的需求。靶向疗法的最新发展有效地治疗了EGFR，MET和EML4-ALK中具有特定驱动因素突变的肺癌亚型，这使得在治疗这些特定的肺癌子集方面重要。尽管取得了这些关键进展，但最普遍的肺癌形式的突变体KRAS驱动的肺腺癌（KRAS LADC）的治疗选择仍然有限。我们已经将蛋白激酶Cι（PKC）确定为KRAS LADC和肺鳞状细胞癌（LSCC）的癌基因，这是两种主要形式的非小细胞肺癌（NSCLC）。 PKC的功能可在这两种NSCLC肿瘤类型中维持肿瘤发射细胞（TIC）表型。但是，令人惊讶的是，我们发表的初步研究表明，PKCι通过不同的信号通路在KRAS LADC和LSCC中驱动TIC表型。初步数据表明：1）PKC通过激活多能茎因子Notch3的表达来驱动KRAS LADC TIC表型； 2）PKCι通过将ELF3转录因子募集到Notch3启动子来激活Notch3表达； 3）PKCι在Ser68处磷酸化ELF3，以调节Notch3启动子的ELF3占用和激活； 4）新近鉴定的高潜力和选择性PKCι抑制剂在体外抑制LADC TIC细胞行为。基于这些数据，我们假设：1）PKCι调节Notch3上的ELF3启动子占用者以及其他涉及的基因靶标，涉及维持LADC TIC表型； 2）新型的PKCι-Eff3-Notch3信号轴驱动KRAS介导的LADC计划和KRAS LADC小鼠模型中的进展； 3）我们的新型，潜在和高度选择性的PKCι抑制剂将杀死KRAS LADC中的抗肿瘤活性，而PKCι-FELF3-NOTCH3信号传导中间体将是有用的预测性预测性和药效性生物标志物。这些假设将以三个相互关联的特定目的进行检验：1）评估PKC介导的ELF3磷酸化在Notch3启动子占有，Notch3表达和LADC TIC行为中的作用； 2）评估PKCι-Elf3-Notch3信号轴在突变体Kras介导的肺部肿瘤倡议和进展中的作用； 3）评估新型高潜力和选择性PKCι抑制剂的潜力，作为治疗KRAS LADC的治疗策略。这些目标的成功完成将：1）提供有关新识别的PKCι-Eff3-Notch3信号轴的新机械洞察力； 2）评估该途径在维持LADC TIC表型中的重要性； 3）确定依赖PKCι-Felf 3的新目标； 4）评估PKCι-Felf3-Notch3信号轴在LADC肿瘤倡议和维护中的重要性； 5）评估新开发的，高潜在的PKCι抑制剂在KRAS LADC治疗中的效用。鉴于KRAS LADC患者的临床结果不佳以及治疗选择的死亡，这些研究可能会对这些患者的临床管理产生宽敞的影响。