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 本申请是为了回应被确认为非CA-CA的特殊利益通知(NOSI)而提交的 22-039.肺癌是所有美国人癌症发病率和死亡率的主要原因，但 在有色人种社区中比例很高。例如，与白人相比，非裔美国人和 拉丁裔被早期诊断为肺癌的可能性分别低18%和16%。五年的生存时间 非洲裔美国人和拉美裔患者的比例也分别比白人患者低21%和16%。然而，发病率和 美国少数民族人口的死亡率与他们的吸烟率密切相关。在非洲裔美国人和 一些亚洲/太平洋岛民群体，如夏威夷人和萨摩亚人，肺癌是癌症的首要原因 死亡率。肺癌对非洲裔美国男性的影响不成比例，他们的发病率和死亡率 分别比白人男性高15%和18%。即使在拉丁裔中，吸烟率最低的民族也是世界上 在全国范围内，肺癌仍然是男性癌症死亡的第一大原因。EGFR和KRAS是最常见的 肺癌中的突变与种族、吸烟和遗传血统密切相关。KRAS是 通常在白人和非裔美国人、男性和吸烟者/前吸烟者中被诊断。亚洲人和 另一方面，拉美裔人的KRAS突变频率明显较低，但富含 EGFR基因突变。亚裔和拉丁裔患者的EGFR突变在从不吸烟的女性中很常见。直到 最近，大多数肺癌的靶向治疗都是针对EGFR突变的肿瘤开发的，而KRAS 被认为是“无法下药的”。然而，在过去的12个月里，随着FDA批准 Sotorasib是一种分子，可以提高携带TRAN基因的肿瘤的总体应答率和无进展生存率 KRAS基因G12C突变。尽管有这些重要的进步，但有相当一部分患者要么缺乏 对EGFR和KRAS靶向治疗产生反应或产生抗药性。在本增刊中，我们利用 我们的少数民族PDX(MPDX)中心的资源用于研究与应对 白人和少数族裔患者模型中KRAS和EGFR的抑制剂。我们的具体目标如下： 目的1.测定索托拉西布存在或不存在时直接抑制KRAS G12C的活性 Sapanisertib和telaglenastat(CB839)对KRAS G12C突变株糖酵解和谷氨酰胺分解的抑制作用 具有临床相关共同改变(P53/Keap1)的PDX。目标2.开展可行性研究，以确定 亚裔和白人患者肺PDX中与EGFR抑制剂耐药相关的生物标志物。这 该项目将增加我们对午餐癌症靶向治疗的反应的了解，并作为 未来在白人和少数族裔患者中进行精准医学临床试验的跳板。