Studying the initiation, progression and therapy of lung cancer in mouse models

研究小鼠模型肺癌的发生、进展和治疗

• 批准号: 10819026
• 负责人: MARTIN MCMAHON
• 金额: $ 1.13万
• 依托单位: UNIVERSITY OF UTAH
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-04-01 至 2027-11-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10819026
• 关键词: Asbestos; Autophagocytosis; BRAF gene; Behavior; Cancer Patient; Cell Line; Cessation of life; Cigarette; Clinical; Consult; Cytoprotection; Data; Development; Disease; Drug resistance; EGFR gene; Evaluation; FDA approved; Foundations; Goals; Human; Immunotherapy; KRAS oncogenesis; KRAS2 gene; Maintenance; Malignant neoplasm of lung; Minority; Modeling; Molecular Abnormality; Mus; Mutation; Natural Killer Cells; Oncogenes; Oncoproteins; Operative Surgical Procedures; Pathway interactions; Patients; Physicians; Pre-Clinical Model; Protein Kinase; Proto-Oncogene Proteins c-akt; Proto-Oncogenes; Publishing; Radiation; Radon; Research; Risk Factors; Role; Safety; Scientist; Scourge; Signal Pathway; Signal Transduction; Solid; Therapeutic; Toxic effect; anticancer research; autocrine; cancer initiation; cancer therapy; cancer type; chemotherapy; clinical development; design; ineffective therapies; inhibitor; lung cancer cell; mouse model; neoplastic cell; new combination therapies; pharmacologic; pre-clinical; predict responsiveness; predictive marker; response; statistics; targeted treatment; translational impact; tumor progression

PROJECT ABSTRACT Lung cancer is a global scourge responsible for ~1.5 million deaths worldwide, and ~130,000 deaths in the USA in 2022. Despite our understanding of relevant risk factors such as cigarettes, asbestos and radon, lung cancer kills more US citizens than the next four cancer types combined. Although the clinical situation is challenging, fundamental cancer research has revealed that lung cancers can be subdivided into genetically- defined subsets based on driver oncogene mutations that, in turn, serve as predictive biomarkers for the clinical deployment of FDA-approved pathway-targeted therapies in lung cancer patients. In particular, FDA approval of oncoprotein-targeted therapies such sotorasib or dabrafenib plus trametinib as treatments for KRASG12C or BRAFV600E-driven lung cancer respectively are already having an important impact on patients with these subsets of the disease. However, despite this, and recent advances in the deployment of immunotherapy, only a minority of lung cancer patients have benefitted from such advances such that treatment options for many patients remain limited to conventional approaches including surgery, radiation, and/or conventional chemotherapy that are ineffective against tumor cells and toxic to the patient. Consequently, the overarching, long-term goal of this research is to provide a rational scientific foundation for the development of new combination therapeutic strategies to treat patients with KRAS- or BRAF-driven lung cancer that: 1. Increase the overall response rate and depth of each patient's primary response; 2. Maximize safety and tolerability, while minimizing toxicity and; 3. Forestall the onset of lethal drug resistance. To that end, our short-term aims are to elucidate how various signaling pathways cooperate with oncogenic KRAS or BRAF in the genesis and maintenance of lung cancer. To do so we will leverage: 1. State-of-the-art preclinical mouse models (GEM or PDX) of KRAS- or BRAF-driven lung cancer; 2. Human or mouse lung cancer-derived cell lines whose aberrant behavior is driven by relevant genetic abnormalities; 3. Pathway-targeted inhibitors, many of which are FDA-approved or in clinical development and; 4. An outstanding collaborative team of scientists and physicians who will consult on the design, execution and interpretation of the results of our research. Hence, building on a solid foundation of published or preliminary data, we will use models of KRAS- or BRAF-driven lung cancer to elucidate the role of: 1. Autocrine activation of ERBB/HER signaling as a mechanism that promotes lung cancer progression and maintenance; 2. Autophagy as a cytoprotective mechanism that protects lung cancer cells from the cytotoxic effects of pathway-targeted inhibition and; 3. AKT protein kinases as progression factors or pharmacological targets in the genesis or maintenance of lung cancer. Consequently, our research is significant and likely to have lasting and important translational impact in the design and evaluation of new combination pathway- targeted strategies to treat patients with this ubiquitous, devastating and poorly understood disease.

项目摘要 肺癌是一种全球性祸害，导致全球约 150 万人死亡，其中约 13 万人死于肺癌 2022 年美国。尽管我们了解香烟、石棉和氡气等相关风险因素，但肺 癌症导致的美国公民死亡人数比接下来四种癌症类型的总和还多。虽然临床情况是 具有挑战性的基础癌症研究表明，肺癌可以根据基因细分为： 基于驱动癌基因突变定义的子集，这些突变反过来又作为临床的预测生物标志物 在肺癌患者中部署 FDA 批准的通路靶向治疗。特别是 FDA 批准 癌蛋白靶向疗法（例如 sotorasib 或 dabrafenib 加曲美替尼）作为 KRASG12C 或 BRAFV600E 驱动的肺癌已经对这些亚型的患者产生了重要影响 的疾病。然而，尽管如此，而且免疫疗法部署的最新进展，只有少数人 的肺癌患者已从这些进步中受益，因此许多患者的治疗选择仍然存在 仅限于常规方法，包括手术、放疗和/或常规化疗 对肿瘤细胞无效并且对患者有毒。因此，本次会议的总体、长期目标 研究的目的是为开发新的联合治疗药物提供合理的科学基础 治疗 KRAS 或 BRAF 驱动的肺癌患者的策略： 1. 提高总体缓解率 每个患者的主要反应的深度； 2. 最大限度地提高安全性和耐受性，同时最大限度地降低毒性； 3. 阻止致命耐药性的发生。为此，我们的短期目标是阐明不同的 信号通路与致癌 KRAS 或 BRAF 共同参与肺癌的发生和维持。 为此，我们将利用： 1. KRAS 或 BRAF 驱动的最先进的临床前小鼠模型（GEM 或 PDX） 肺癌； 2. 人或小鼠肺癌衍生细胞系，其异常行为是由相关因素驱动的 遗传异常； 3.通路靶向抑制剂，其中许多已获得FDA批准或已进入临床 发展和； 4. 一个由科学家和医生组成的优秀合作团队，他们将就该问题提供咨询 设计、执行和解释我们的研究结果。因此，建立在坚实的基础上 根据已发表或初步数据，我们将使用 KRAS 或 BRAF 驱动的肺癌模型来阐明以下作用： 1. ERBB/HER 信号的自分泌激活是促进肺癌进展的机制 维护; 2. 自噬作为一种细胞保护机制，保护肺癌细胞免受细胞毒性的影响 通路靶向抑制的影响； 3. AKT蛋白激酶作为进展因子或药理学 肺癌发生或维持的靶标。因此，我们的研究意义重大，并且可能 对新组合途径的设计和评估具有持久且重要的转化影响- 制定有针对性的策略来治疗患有这种普遍存在、具有破坏性且人们知之甚少的疾病的患者。