Lung cancer is the leading cause of cancer mortality worldwide with lung adenocarcinomas representing the subtype that is increasing in incidence. Identification of specific alterations such as EGFR mutations and more recently, ALK kinase gene fusions, have lead to the more efficacious treatment of patients whose lung adenocarcinomas contain these alterations. We have utilized a novel strategy for the identification of gene fusions in lung cancer (Wang et al, Nature Biotechnology) revealing the R3HDM2-NFE2 and more recently the HSPA1A-NFKBIL1 gene fusions in lung adenocarcinomas, as well as nominating many additional potential gene-fusion candidates. We hypothesize that identification of novel gene fusions in lung adenocarcinoma may provide new avenues for highly selective treatments of this cancer as well as specific markers for cancer detection or therapeutic monitoring.
Three specific aims are proposed.
Aim one is to functionally characterize the novel R3HDM2-NFE2 gene fusion utilizing siRNA knockdown in lung cancer lines containing these alterations as well as using lung cell lines engineered to overexpress NFE2. Effects on tumor cell proliferation, invasion and specific transcriptional programs will define the mechanisms underlying R3HDM2-NFE2 oncogenic activity.
Aim two is to define the frequency of occurrence of the novel HSPA1A-NFKBIL1 gene fusion in primary lung cancers using fluorescence in situ hybridization with tissue microarrays, followed by functional analyses of the oncogenic activity of the fusion gene as those utilized for the R3HDM2-NFE2 in Aim one.
Aim three will employ the successful methodologies used for the discovery of the R3HDM2-NFE2 and HSPA1A- NFKBIL1 fusions, to identify, validate and functionally characterize additional novel fusions involving functionally important cellular processes in lung cancer. Priority will be gene fusions that are candidates for targeted therapeutics or that involve genes and critical cellular targets for which therapies may be potentially developed. Higher emphasis will also be placed on candidates occurring at high frequency or within identifiable tumor subgroups. These studies have potential to identify new approaches to treat the leading cause of cancer death.

Public Health Relevance

Lung cancer has the highest mortality of all cancers and best treated when detected early or with therapies directly against cancer-specific alterations. Gene fusions represent a new category of genetic alterations in lung cancer that can demonstrate this cancer-specificity and may be responsive to new therapies. This research proposal will identify new gene-fusions in lung cancer utilizing a newly developed bioinformatics approach combined with next-generation sequencing data. There is great potential that new therapeutic targets may be identified as well as markers for early detection that would directly impact survival of specific patients with lung cancer.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA154365-04
Application #
8618865
Study Section
Cancer Genetics Study Section (CG)
Program Officer
Johnson, Ronald L
Project Start
2011-04-01
Project End
2016-03-31
Budget Start
2014-04-01
Budget End
2015-03-31
Support Year
4
Fiscal Year
2014
Total Cost
$278,426
Indirect Cost
$98,976
Name
University of Michigan Ann Arbor
Department
Surgery
Type
Schools of Medicine
DUNS #
073133571
City
Ann Arbor
State
MI
Country
United States
Zip Code
48109
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