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

项目摘要 肺癌是一种全球祸害，在全世界造成约150万人死亡，在世界各地造成约13万人死亡 2022年美国。尽管我们了解相关的危险因素，如香烟、石棉和氡，但肺 癌症导致的美国公民死亡人数超过了排在其后的四种癌症的总和。虽然临床情况是 具有挑战性的基础癌症研究表明，肺癌可以从基因上细分为- 基于驱动癌基因突变的确定的子集，这些突变反过来作为临床的预测生物标记物 在肺癌患者中部署FDA批准的通路靶向治疗。特别是，FDA的批准 癌蛋白靶向疗法，如索托拉西布或达普拉非尼加曲美替尼治疗KRASG12C或 分别由BRAFV600E驱动的肺癌已经对具有这些亚群的患者产生了重要影响 这种疾病的危害。然而，尽管如此，以及最近在部署免疫疗法方面的进展，只有少数人 的肺癌患者从这些进步中受益，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、放射和/或常规化疗 对肿瘤细胞无效，对患者有毒性。因此，这一总体的、长期的目标是 研究旨在为开发新的综合疗法提供合理的科学依据 治疗KRAS或BRAF驱动的肺癌患者的策略：1.提高总体缓解率 和深度的每个患者的初步反应；2。最大限度地安全和耐受性，同时最小化毒性和； 3.防止出现致命性耐药性。为此，我们的短期目标是阐明不同的 信号通路在肺癌的发生和维持中与致癌的KRAS或BRAF协同作用。 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.人或小鼠肺癌来源的细胞系，其异常行为是由相关因素驱动的 基因异常；3.通路靶向抑制物，其中许多是FDA批准的或临床上的 开发和；4.一个由科学家和医生组成的优秀合作团队，他们将就 设计、执行和解释我们的研究结果。因此，在坚实的基础上 已发表的或初步的数据，我们将使用KRAS或BRAF驱动的肺癌模型来阐明： 1.ERBB/HER信号的自分泌激活是促进肺癌进展和 自噬作为一种保护肺癌细胞免受细胞毒作用的细胞保护机制 途径靶向抑制和；3.AKT蛋白激酶作为进展因子或药理学的作用 肺癌发生或维持的靶点。因此，我们的研究具有重要意义，并可能 在新的组合路径的设计和评估中具有持久和重要的翻译影响- 有针对性的战略，以治疗这种无处不在、毁灭性和鲜为人知的疾病的患者。

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.