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Targeting the cytokine circuitry of KRAS-driven lung cancer

靶向 KRAS 驱动肺癌的细胞因子回路

基本信息

批准号：
9263834
负责人：
David A Barbie
金额：
$ 39.46万
依托单位：
DANA-FARBER CANCER INST
依托单位国家：
美国
项目类别：
财政年份：
2015
资助国家：
美国
起止时间：
2015-04-01 至 2020-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9263834
关键词：
Alleles Autophagocytosis Basic Science Biological Markers Biology Biopsy Cancer Etiology Cancer Model Cancer Patient Cancer cell line Cell Proliferation Cell Survival Cessation of life Clinical Clinical Trials Colorectal Cancer Combined Modality Therapy Data Development Disease Drug Targeting Feedback Genetic Genetic Crosses Genetic Determinism Genetic study Genetically Engineered Mouse Genotype Goals Grant Homologous Gene Human Immune signaling Impairment In Vitro Inflammation Interleukin-6 Investigation JAK1 gene Janus kinase KRAS2 gene Laboratories MEK inhibition MEKs Malignant Neoplasms Malignant neoplasm of lung Mediator of activation protein Molecular Mus Mutate Mutation Non-Small-Cell Lung Carcinoma Oncogenes Oncogenic Pancreatic Ductal Adenocarcinoma Pathway interactions Patients Pharmaceutical Preparations Pharmacodynamics Pharmacogenetics Pharmacology Study Phase Phosphotransferases Production Proto-Oncogene Proteins c-akt Public Health RANTES Research Research Project Grants Resistance Role Serum Signal Pathway Signal Transduction Subgroup TBK1 gene TP53 gene Time Toxic effect Translational Research Tumorigenicity United States Work autocrine base bench to bedside cancer cell cell motility cell transformation chemotherapeutic agent cytokine disorder control docetaxel drug development experimental study in vivo inhibitor/antagonist insight kinase inhibitor metaplastic cell transformation migration mortality mouse model mutant neoplastic cell novel novel therapeutics pre-clinical public health relevance research clinical testing resistance mechanism response synergism targeted treatment therapeutic target therapy resistant tumor tumorigenic

项目摘要

DESCRIPTION (provided by applicant): The goal of this research project proposal is to investigate a novel combination therapy for KRAS-driven non-small cell lung cancer (NSCLC) that involves inhibition of pro-tumorigenic cytokine production. Work from this laboratory identified the JAK kinase inhibitor CYT387 (momelotinib) as a potent inhibitor of the immune signaling kinases TBK1/IKK?, disrupting a cytokine circuit that oncogenic RAS engages to promote tumor cell survival and migration. Although efficacious as single agent therapy in Kras-driven murine lung cancer, combination pathway inhibition with a MEK inhibitor resulted in synergy and prolonged tumor regression in an aggressive mouse model of Kras-p53 driven lung cancer. The broad, long term objective is to perform research at the bench to bedside interface to explore further the mechanistic basis that underlies the synergy of this combination therapy, and to identify additional strategies to enhance response and overcome resistance. A unique aspect of this proposal is that it spans basic and translational research and incorporates analysis of an actual clinical trial impacting patients. Specific aims are to: 1) Explore synergy and resistance to TBK1 and MEK inhibition in murine Kras-driven lung cancer through further genetic and pharmacologic studies. 2) Elucidate the molecular circuitry responsible for TBK1/MEK inhibitor synergy, and 3) Evaluate response and resistance to momelotinib/trametinib combination therapy in a phase 1b/2 clinical trial in human KRAS mutant NSCLC. The use of mouse lung cancer models will facilitate pharmacogenetic and pharmacodynamics studies that will define the specific activities of the momelotinib/trametinib combination. Genetic crosses of conditional TBK1 null or kinase dead mice into the oncogenic Kras-driven lung cancer model, together with selective JAK and MEK inhibitor treatment, will identify the unique role of TBK1 in regulating this autocrine cytokine circuit in vivo. Analysis of momelotinib/trametinib efficacy across Kras, Kras-p53, and Kras-Lkb1 murine lung cancer models will determine genetic modifiers of response and de novo resistance. Further investigation of TBK1 signaling in KRAS-dependent human cancer cell lines in vitro will elucidate the mechanism by which its inhibition leads to feedback activation of MEK-ERK signaling, yielding important biologic insights and a better understanding of TBK1/MEK inhibitor synergy. Finally, the determination of resistance mechanisms that develop in mouse models and in patients will further define the key activities of these inhibitors. Through these complementary studies, the ultimate goal is not only to understand mechanism and target this therapy to the appropriate subgroup of patients, but also to identify additional strategies for combination therapy that leads to durable control of this aggressive disease.

描述（由申请人提供）：该研究项目提案的目标是研究一种针对 KRAS 驱动的非小细胞肺癌 (NSCLC) 的新型联合疗法，该疗法涉及抑制促肿瘤细胞因子的产生。该实验室的工作确定了 JAK 激酶抑制剂 CYT387（momelotinib）是免疫信号激酶 TBK1/IKK? 的有效抑制剂，可破坏致癌 RAS 参与促进肿瘤细胞存活和迁移的细胞因子回路。尽管作为单一药物治疗 Kras 驱动的小鼠肺癌有效，但与 MEK 抑制剂的联合途径抑制在 Kras-p53 驱动的侵袭性肺癌小鼠模型中产生了协同作用并延长了肿瘤消退时间。广泛的长期目标是在实验室与床边界面进行研究，以进一步探索这种联合疗法协同作用的机制基础，并确定增强反应和克服耐药性的其他策略。该提案的一个独特之处在于它涵盖了基础研究和转化研究，并结合了对影响患者的实际临床试验的分析。具体目标是： 1) 通过进一步的遗传和药理学研究，探索 TBK1 和 MEK 抑制在小鼠 Kras 驱动的肺癌中的协同作用和耐药性。 2) 阐明负责 TBK1/MEK 抑制剂协同作用的分子回路，以及 3) 在人类 KRAS 突变 NSCLC 的 1b/2 期临床试验中评估对 momelotinib/trametinib 联合疗法的反应和耐药性。小鼠肺癌模型的使用将促进药物遗传学和药效学研究，从而确定莫莫替尼/曲美替尼组合的具体活性。将条件性 TBK1 缺失或激酶死亡小鼠与致癌性 Kras 驱动的肺癌模型进行基因杂交，加上选择性 JAK 和 MEK 抑制剂治疗，将确定 TBK1 在调节体内自分泌细胞因子回路中的独特作用。分析莫莫替尼/曲美替尼在 Kras、Kras-p53 和 Kras-Lkb1 小鼠肺癌模型中的疗效将决定反应和从头耐药的遗传修饰因子。在体外对 KRAS 依赖性人类癌细胞系中的 TBK1 信号传导进行进一步研究，将阐明其抑制导致 MEK-ERK 信号传导反馈激活的机制，从而产生重要的生物学见解并更好地了解 TBK1/MEK 抑制剂的协同作用。最后，确定小鼠模型和患者中产生的耐药机制将进一步确定这些抑制剂的关键活性。通过这些补充研究，最终目标不仅是了解机制并将这种疗法针对适当的患者亚组，而且还确定联合疗法的其他策略，从而持久控制这种侵袭性疾病。