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

基本信息

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
项目类别：
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

项目摘要

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.

项目概要/摘要本申请是为了响应被识别为 NOT-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，但与白人相比，例如非裔美国人和非裔美国人的比例高得不成比例。拉丁美洲人早期肺癌诊断的可能性分别低 18% 和 16% 5 年生存率。非裔美国人和拉丁裔患者的发病率也比白人患者低 21% 和 16%。美国少数族裔的死亡率与其吸烟率密切相关。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肺癌对非裔美国男性的影响尤为严重，他们的发病率和死亡率很高。即使在拉丁美洲吸烟率最低的族裔中，这一比例也比白人男性高出 15% 和 18%。肺癌仍然是男性癌症死亡的首要原因，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。常见于白人和非裔美国人、男性和吸烟者/前吸烟者和亚洲人。另一方面，拉丁美洲人的 KRAS 突变频率明显较低，但富含 EGFR 突变在亚洲和拉丁裔患者中普遍存在于从不吸烟的女性中。最近，肺癌的靶向治疗大多针对EGFR突变肿瘤，而KRAS 被认为是“不可成药的”。然而，随着 FDA 的批准，这种情况在过去 12 个月中发生了变化。 sotorasib 是一种分子，可提高携带该药物的肿瘤的总体缓解率和无进展生存期尽管取得了这些重要进展，但仍有相当一部分患者缺乏 KRAS G12C 突变。对 EGFR 和 KRAS 靶向治疗产生反应或产生耐药性在本补充品中，我们正在利用。我们少数族裔 PDX (MPDX) 中心的资源，用于研究与应对相关的机制在白人和少数族裔患者模型中使用 KRAS 和 EGFR 抑制剂我们的具体目标如下：目标 1. 确定在存在或不存在双重作用的情况下 sotorasib 直接 KRAS G12C 抑制的活性在 KRAS G12C 突变体中使用 sapanisertib 和 telaglenastat (CB839) 抑制糖酵解和谷氨酰胺分解具有临床相关共同改变的 PDX（p53/Keap1）。目标 2. 进行可行性研究以鉴定。与亚洲和白人患者肺 PDX 中 EGFR 抑制剂耐药性相关的生物标志物。该项目将增加我们对午餐癌靶向治疗反应的了解，并作为未来针对白人和少数族裔患者进行精准医疗临床试验的跳板。