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Interrogating the role of mutant KRAS allelic imbalance and co-mutated genes in targeted therapy response of NSCLC

探究突变 KRAS 等位基因失衡和共突变基因在 NSCLC 靶向治疗反应中的作用

基本信息

批准号：
10672963
负责人：
Bianca Diaz
金额：
$ 4.77万
依托单位：
WEILL MEDICAL COLL OF CORNELL UNIV
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-08-09 至 2025-08-08
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10672963
关键词：
Affect Aftercare Alleles Allelic Imbalance Apoptosis Binding Biology CDKN2A gene CRISPR library Cancer Etiology Cancer Patient Cancer cell line Cell Nucleus Cells Cessation of life Clinic Clinical Clinical Management Clustered Regularly Interspaced Short Palindromic Repeats Codon Nucleotides Combined Modality Therapy Data Development Diagnosis Disease EGFR inhibition Environment Epidermal Growth Factor Receptor Evaluation Failure Farnesyl Transferase Inhibitor Future GTP Binding Genes Genetic Genetic Determinism Genotype Guanosine Triphosphate Phosphohydrolases Human Immune checkpoint inhibitor Immunophenotyping KRAS oncogenesis KRAS2 gene Knock-out Libraries Lung Adenocarcinoma Lung Neoplasms MAP Kinase Gene MEKs Malignant Neoplasms Malignant neoplasm of lung Measures Mediating Modeling Mus Mutate Mutation Non-Small-Cell Lung Carcinoma Oncogenic Organoids Outcome Pancreas Pathway interactions Patients Persons Pharmacotherapy Prognosis Proliferating Proliferation Marker Resistance Role STK11 gene Series Signal Pathway Signal Transduction Silent Mutation TP53 gene Technology Testing Therapeutic Toxic effect Tumor Burden Tumor Promotion Tumor Suppressor Genes Tumor Suppressor Proteins Work cancer type cell growth chemotherapy clinically relevant cohort early phase clinical trial extracellular gain of function genetic approach genome editing immune cell infiltrate improved in vivo in vivo Model inhibitor loss of function loss of function mutation lung tumorigenesis mouse model mutant mutant mouse model novel therapeutics pre-clinical predictive marker prevent resistance mechanism response standard of care targeted treatment therapeutically effective treatment response tumor tumor growth tumor microenvironment tumor progression tumor-immune system interactions tumorigenesis vector

项目摘要

PROJECT SUMMARY Nearly 2 million people are diagnosed with lung cancer each year and it is the leading cause in cancer related death worldwide. Standard of care for non-small cell lung cancer (NSCLC) patients has changed little over the past several years however targeted therapies and immune checkpoint inhibitors have recently become a promising option. The most common oncogenic drivers in NSCLC are mutations in EGFR and KRAS which upregulate a myriad of downstream signaling pathways that promote tumor cell growth. Until recently, efforts to develop therapeutics that directly target EGFR or KRAS have largely been met by failure. Specifically, development of farnesyl transferase inhibitors and downstream pathway inhibitors like MEK and RAF, have not shown improvement in survival in the clinic and resistance mechanisms are described. The discovery of KRASG12C mutant inhibitors like AMG 510 and MRTX849 is encouraging as they have both shown promising signs of clinical activity and promise to transform treatment of KRAS mutant cancer. These inhibitors work by covalently binding to the reactive Cys12 locking KRAS in its inactive GDP-bound state. However, as with previously targeted therapies, mechanisms of resistance are beginning to be described. Utilizing precision modeling in mice, I will test the hypothesis that KRAS allelic imbalance and genetic determinants in NSCLC drive tumor progression and confer unique responses to targeted therapies. Since our lab has developed LSL-Kras allelic series that allows for selective targeting of the WT Kras allele, in Aim 1, I will use CRISPR-based genome editing technology to knockout WT Kras in vivo and measure effects in tumor burden and G12C inhibitor response. Further, I aim to understand how WT KRAS signaling contributes to the tumor immune microenvironment and how it affects targeted treatment response. In Aim 2, I will use a patient data guided approach to elucidate how cooperative mutations in tumor suppressors effect tumor progression and G12C inhibitor response. This powerful genetic approach will allow me to directly interrogate ways in which KRASG12C targeted therapy can be affected. Identifying an effective approach to disrupt KRASG12C mutant NSCLC will have a profound impact on the clinical management of these patients. Thus, we believe our work will contribute significant pre-clinical data to developing safe and effective targeted therapies for NSCLC and other cancer types.

项目总结