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Chemoprevention with Cyclooxygenase and Epidermal Growth Factor Receptor Inhibitors in Familial Adenomatous Polyposis Patients: mRNA Signatures of Duodenal Neoplasia.

Authors :
Delker DA
Wood AC
Snow AK
Samadder NJ
Samowitz WS
Affolter KE
Boucher KM
Pappas LM
Stijleman IJ
Kanth P
Byrne KR
Burt RW
Bernard PS
Neklason DW
Source :
Cancer prevention research (Philadelphia, Pa.) [Cancer Prev Res (Phila)] 2018 Jan; Vol. 11 (1), pp. 4-15. Date of Electronic Publication: 2017 Nov 06.
Publication Year :
2018

Abstract

To identify gene expression biomarkers and pathways targeted by sulindac and erlotinib given in a chemoprevention trial with a significant decrease in duodenal polyp burden at 6 months ( P < 0.001) in familial adenomatous polyposis (FAP) patients, we biopsied normal and polyp duodenal tissues from patients on drug versus placebo and analyzed the RNA expression. RNA sequencing was performed on biopsies from the duodenum of FAP patients obtained at baseline and 6-month endpoint endoscopy. Ten FAP patients on placebo and 10 on sulindac and erlotinib were selected for analysis. Purity of biopsied polyp tissue was calculated from RNA expression data. RNAs differentially expressed between endpoint polyp and paired baseline normal were determined for each group and mapped to biological pathways. Key genes in candidate pathways were further validated by quantitative RT-PCR. RNA expression analyses of endpoint polyp compared with paired baseline normal for patients on placebo and drug show that pathways activated in polyp growth and proliferation are blocked by this drug combination. Directly comparing polyp gene expression between patients on drug and placebo also identified innate immune response genes (IL12 and IFNγ) preferentially expressed in patients on drug. Gene expression analyses from tissue obtained at endpoint of the trial demonstrated inhibition of the cancer pathways COX2/PGE2, EGFR, and WNT. These findings provide molecular evidence that the drug combination of sulindac and erlotinib reached the intended tissue and was on target for the predicted pathways. Furthermore, activation of innate immune pathways from patients on drug may have contributed to polyp regression. Cancer Prev Res; 11(1); 4-15. ©2017 AACR See related editorial by Shureiqi, p. 1 .<br /> (©2017 American Association for Cancer Research.)

Details

Language :
English
ISSN :
1940-6215
Volume :
11
Issue :
1
Database :
MEDLINE
Journal :
Cancer prevention research (Philadelphia, Pa.)
Publication Type :
Academic Journal
Accession number :
29109117
Full Text :
https://doi.org/10.1158/1940-6207.CAPR-17-0130