Non-small cell lung cancer (NSCLC) comprises over 80% of all lung cancer cases. More than two-thirds of NSCLC are diagnosed at a late stage, when current treatments are largely ineffective and only benefit a small portion of patients. Clinical variables alone cannot satisfactorily predict patients'outcomes. Biomarkers are urgently needed to assist in the patient stratification for personalized cancer therapy. Novel therapeutic agents are also highly desired to give patients alternative options after improved prediction of outcomes of treatments. The goals of this project are to identify germline genetic and circulating biomarkers related to microRNA (miRNA) as predictors of survival in late stage NSCLC patients. MiRNAs can regulate up to a third of human genes and play important roles in human carcinogenesis. The inherited genetic variants, mostly in the form of single nucleotide polymorphisms (SNPs), particularly SNPs in miRNA regulatory pathways (miR-SNPs), can also affect expression and/or function of their host and target genes. We propose to conduct a systematic study of miR-SNPs and circulating miRNAs in lung cancer. This proposal builds upon a lung cancer population at MD Anderson Cancer Center, with comprehensive epidemiological and clinical data and rich bio specimens. There are three specific aims: 1) to identify novel germline genetic loci in miR-SNPs that predict survival in patients with late-stage NSCLC. We will use a discovery and validation design with each phase consisting of 1,200 patients for platinum-treated patients;2) to identify circulating miRNAs as predictors of survival in late- stage NSCLC patients using a testing and a validation set with a total of 800 plasma samples;and 3) to determine the potential disease-causative structural context, biological function, and molecular mechanism of the identified epigenetic miR-SNP and circulating miRNA biomarkers. This is a significant and innovative project incorporating epidemiology, inherited genetics, circulating biomarkers, biological and mechanistic studies, and preclinical therapeutic development.

Public Health Relevance

Primary lung cancer (LC) is the most common cancer and the leading cause of cancer death and non small cell lung cancer (NSCLC) accounts for over 80% of LC cases. This project aims to identify genetic variants and circulating biomarkers that will predict survival in late stage NSCLC patients receiving platinum-based chemotherapy. Being able to predict patients'outcome before therapy would allow personalized cancer treatment, giving the right therapy to the right patient at the right time.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
1R01CA176568-01A1
Application #
8697324
Study Section
Clinical Oncology Study Section (CONC)
Program Officer
Verma, Mukesh
Project Start
2014-04-01
Project End
2019-02-28
Budget Start
2014-04-01
Budget End
2015-02-28
Support Year
1
Fiscal Year
2014
Total Cost
$519,312
Indirect Cost
$194,742
Name
University of Texas MD Anderson Cancer Center
Department
Public Health & Prev Medicine
Type
Schools of Medicine
DUNS #
800772139
City
Houston
State
TX
Country
United States
Zip Code
77030
Lin, Moubin; Zhang, Liren; Hildebrandt, Michelle A T et al. (2017) Common, germline genetic variations in the novel tumor suppressor BAP1 and risk of developing different types of cancer. Oncotarget 8:74936-74946
Li, Rong; Gu, Jiang; Heymach, John V et al. (2017) Hypoxia pathway genetic variants predict survival of non-small-cell lung cancer patients receiving platinum-based chemotherapy. Carcinogenesis 38:419-424
Shen, Jie; Ye, Yuanqing; Chang, David W et al. (2017) Circulating metabolite profiles to predict overall survival in advanced non-small cell lung cancer patients receiving first-line chemotherapy. Lung Cancer 114:70-78
Xie, Kunlin; Ye, Yuanqing; Zeng, Yong et al. (2017) Polymorphisms in genes related to epithelial-mesenchymal transition and risk of non-small cell lung cancer. Carcinogenesis 38:1029-1035
Lin, Jing; Zandi, Roza; Shao, Ruping et al. (2017) A miR-SNP biomarker linked to an increased lung cancer survival by miRNA-mediated down-regulation of FZD4 expression and Wnt signaling. Sci Rep 7:9029
Gentile, Emanuela; Oba, Taro; Lin, Jing et al. (2017) Cationic liquid crystalline nanoparticles for the delivery of synthetic RNAi-based therapeutics. Oncotarget 8:48222-48239
Zhang, Liren; Lin, Jing; Ye, Yuanqing et al. (2017) Serum MicroRNA-150 Predicts Prognosis for Early-Stage Non-Small Cell Lung Cancer and Promotes Tumor Cell Proliferation by Targeting Tumor Suppressor Gene SRCIN1. Clin Pharmacol Ther :
Lin, Jing; Xu, Kai; Roth, Jack A et al. (2016) Detection of siRNA-mediated target mRNA cleavage activities in human cells by a novel stem-loop array RT-PCR analysis. Biochem Biophys Rep 6:16-23
Xu, Kai; Lin, Jing; Zandi, Roza et al. (2016) MicroRNA-mediated target mRNA cleavage and 3'-uridylation in human cells. Sci Rep 6:30242
Lin, Jing; Xu, Kai; Wei, Jun et al. (2016) MicroRNA-124 suppresses tumor cell proliferation and invasion by targeting CD164 signaling pathway in non-small cell lung cancer. J Gene Ther 2:

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