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

项目摘要 肺癌是一种全球性的祸害，在全球范围内造成约150万人死亡，在世界范围内造成约130，000人死亡。 2022年的美国。尽管我们了解相关的危险因素，如香烟，石棉和氡，肺 癌症杀死的美国公民比接下来的四种癌症的总和还要多。虽然临床情况是 具有挑战性的基础癌症研究表明，肺癌可以细分为遗传- 基于驱动癌基因突变的定义的子集，反过来，这些子集作为临床诊断的预测性生物标志物。 在肺癌患者中部署FDA批准的途径靶向治疗。尤其是FDA批准 癌蛋白靶向治疗，如sotorasib或dabrafenib加曲美替尼作为KRASG 12 C或 BRAFV 600 E驱动的肺癌已经对这些亚群的患者产生了重要影响 疾病。然而，尽管如此，以及最近在免疫疗法的部署方面取得的进展， 的肺癌患者受益于这些进步，因此许多患者的治疗选择仍然存在 局限于常规方法，包括手术、放射和/或常规化疗， 对肿瘤细胞无效并对患者有毒。因此，这一总体的长期目标 研究的目的是为开发新的联合治疗药物提供合理的科学依据 治疗KRAS或BRAF驱动的肺癌患者的策略：1.提高总体答复率 和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.防止致命的抗药性的出现。为此，我们的短期目标是阐明各种 信号通路与致癌KRAS或BRAF在肺癌的发生和维持中协同作用。 为此，我们将利用：1. KRAS或BRAF驱动的最新临床前小鼠模型（GEM或PDX） 肺癌; 2.其异常行为是由相关基因驱动的人或小鼠肺癌衍生细胞系 遗传异常; 3.靶向通路的抑制剂，其中许多是FDA批准的或在临床上 发展; 4。一个由科学家和医生组成的杰出合作团队， 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以下因素的作用： 1. ERBB/HER信号的自分泌激活作为促进肺癌进展的机制， 维护; 2.自噬作为一种细胞保护机制，可保护肺癌细胞免受细胞毒性 通路靶向抑制的作用; 3. AKT蛋白激酶作为进展因子或药理学 肺癌的发生或维持中的靶点。因此，我们的研究具有重要意义，并可能 在设计和评估新的组合途径方面具有持久和重要的转化影响- 有针对性的策略，以治疗这种普遍存在的，毁灭性的和知之甚少的疾病的患者。

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.