Preclinical studies of KRAS and EGFR mutations in lung cancer PDXs

肺癌 PDX 中 KRAS 和 EGFR 突变的临床前研究

• 批准号: 10582478
• 负责人: Luis Guillermo Carvajal Carmona
• 金额: $ 20万
• 依托单位: UNIVERSITY OF CALIFORNIA AT DAVIS
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-07-01 至 2024-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10582478
• 关键词: Affect; African; African American; African American population; American; Americas; Asia; Asian; Asian Pacific Islander; Asian population; Biological; Biological Markers; California; Cancer Etiology; Cancer Model; Cancer Patient; Cancer Therapy Evaluation Program; Clinical Trials; Color; Common Neoplasm; Communities; Development; Diagnosis; Epidermal Growth Factor Receptor; Epidermal Growth Factor Receptor Tyrosine Kinase Inhibitor; Ethnic group; Etiology; Feasibility Studies; Female; Frequencies; Future; Genetic; Glycolysis Inhibition; Goals; Hawaiian; Incidence; Indigenous American; Infrastructure; KRAS2 gene; Latino; Latino Population; Link; Lung; Lung Adenocarcinoma; Lung Neoplasms; Malignant Neoplasms; Malignant neoplasm of lung; Minority; Minority Groups; Modeling; Mutate; Mutation; Non-Small-Cell Lung Carcinoma; Patients; Pharmaceutical Preparations; Pharmacodynamics; Pharmacotherapy; Prevalence; Progression-Free Survivals; Race; Research; Resistance; Resistance development; Resources; Samoan; Signal Pathway; Smoking; TP53 gene; Universities; Woman; cancer diagnosis; cancer health disparity; caucasian American; clinically relevant; former smoker; inhibitor; interest; men; minority patient; mortality; mutant; never smoker; patient derived xenograft model; precision medicine; preclinical study; response; single cell sequencing; targeted treatment; therapeutic development; treatment response; tumor; tumor growth

PROJECT SUMMARY/ABSTRACT This application is being submitted in response to the Notice of Special Interest (NOSI) identified as NOT-CA- 22-039. Lung cancer is the leading cause of cancer incidence and mortality in all Americans but disproportionally high in communities of color. Compared to Whites, for example, African Americans and Latinos are 18% and 16% less likely to have an early lung cancer diagnosis, respectively. The 5-year survival of African Americans and Latinos is also 21% and 16% lower than White patients. However, the incidence and mortality rates in US minority populations are closely linked to their smoking rates. In African American and some Asian/Pacific Islander groups such as Hawaiian and Samoan, lung cancer is the top cause of cancer mortality. Lung cancer disproportionally affects African American men, who have incidence and mortality rates of 15% and 18% higher than White men. Even in Latinos, the ethnic group with the lowest smoking rates in the nation, lung cancer remains the first cause of cancer mortality in men. EGFR and KRAS are the most common mutations in lung tumors and are strongly associated with race, smoking, and genetic ancestry. KRAS is commonly diagnosed in Whites and African Americans, in men and smokers/former smokers. Asians and Latinos, on the other hand, have a significantly lower frequency of KRAS mutations but are enriched with mutations in EGFR. EGFR mutations in Asian and Latino patients are prevalent in never smoker women. Until recently, most of the targeted therapies for lung cancer were developed for EGFR mutant tumors, while KRAS was considered “undruggable.” This, however, changed in the last 12 months with the FDA approval of sotorasib, a molecule that increases overall response rate and progression-free survival in tumors carrying the KRAS G12C mutation. Despite these important advances, a significant fraction of patients either lack response or develop resistance to EGFR and KRAS targeted therapies. In this supplement, we are leveraging the resources of our minority PDX (MPDX) center to investigate mechanisms associated with response to inhibitors for KRAS and EGFR in models from White and minority patients. Our Specific Aims are as follows: Aim 1. To determine the activity of direct KRAS G12C inhibition of sotorasib in the presence or absence of dual inhibition of glycolysis and glutaminolysis with sapanisertib and telaglenastat (CB839) in KRAS G12C mutant PDXs with clinically relevant co-alterations (p53/Keap1). Aim 2. To carry out a feasibility study for identifying biomarkers associated with EGFR inhibitor resistance in lung PDXs from Asian and White patients. This project will increase our understanding of responses to targeted therapies for lunch cancer and serve as a springboard for future clinical trials on precision medicine in white and minority patients.

项目摘要/摘要 该申请是为了响应特殊利益通知（NOSI）而提交 22-039。肺癌是所有美国人的癌症事件和死亡率的主要原因，但 有色人种社区的高度高。与白人相比，非洲裔美国人和 拉丁美洲人的早期肺癌诊断的可能性降低了18％和16％。 5年生存 在非洲裔美国人和拉丁美洲人中，比白人患者低21％和16％。但是，事件和 美国少数民族的死亡率与他们的吸烟率密切相关。在非裔美国人和 一些亚洲/太平洋岛民群体，例如夏威夷和萨摩亚人，肺癌是癌症的主要原因 死亡。肺癌不成比例地影响非洲裔美国男性，他们患有事件和死亡率 比白人高15％和18％。即使在拉丁美洲人，吸烟率最低的种族 国家，肺癌仍然是男性癌症死亡率的第一个原因。 EGFR和KRAS是最常见的 肺部肿瘤的突变与种族，吸烟和遗传血统密切相关。克拉斯是 通常在白人和非裔美国人，男性和吸烟者/以前的吸烟者中被诊断出来。亚洲人和 另一方面，拉丁美洲人的KRAS突变频率明显较低，但充满了 EGFR中的突变。亚洲和拉丁裔患者的EGFR突变在永不吸烟的女性中普遍存在。直到 最近，针对EGFR突变肿瘤开发了大多数针对肺癌的靶向疗法，而KRAS则开发了 被认为是“不可能的”。但是，随着FDA的批准，这在过去的12个月内发生了变化 Sotorasib，一种分子，可提高携带肿瘤中的总体反应率和无进展生存率 KRAS G12C突变。尽管有这些重要的进步，但很大一部分患者要么缺乏 对EGFR和KRAS靶向疗法的反应或发育抗性。在这种补充中，我们正在利用 我们少数PDX（MPDX）中心的资源调查与反应相关的机制 来自白人和少数族裔患者模型中KRAS和EGFR的抑制剂。我们的具体目的如下： 目的1。确定在存在或不存在双重的情况下直接kras g12c抑制sotorasib的活性 用sapanisertib和telaglenastat（CB839）在KRAS G12C突变体中抑制糖酵解和谷氨酰胺溶解（CB839） 具有临床相关共同变化的PDX（p53/keap1）。目标2。进行可行性研究以识别 来自亚洲和白人患者的肺PDX中与EGFR抑制剂耐药性相关的生物标志物。这 项目将提高我们对午餐癌靶向疗法的反应的理解，并充当 在白人和少数族裔患者的精密医学临床试验的跳板。