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Chemoprevention with Cyclooxygenase and Epidermal Growth Factor Receptor Inhibitors in Familial Adenomatous Polyposis Patients

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Chemoprevention with Cyclooxygenase and Epidermal Growth Factor Receptor Inhibitors in Familial Adenomatous Polyposis Patients Published OnlineFirst November 6, 2017; DOI: 10.1158/1940-6207.CAPR-17-0130 Research Article Cancer Prevention Research Chemoprevention with Cyclooxygenase and Epidermal Growth Factor Receptor Inhibitors in Familial Adenomatous Polyposis Patients: mRNA Signatures of Duodenal Neoplasia Don A. Delker1, Austin C. Wood2, Angela K. Snow2, N. Jewel Samadder1,2, Wade S. Samowitz2,3, Kajsa E. Affolter2,3, Kenneth M. Boucher1,2, Lisa M. Pappas2, Inge J. Stijleman2, Priyanka Kanth1, Kathryn R. Byrne1, Randall W. Burt1,2, Philip S. Bernard2,3, and Deborah W. Neklason1,2 Abstract To identify gene expression biomarkers and pathways tar- pared with paired baseline normal for patients on placebo geted by sulindac and erlotinib given in a chemoprevention and drug show that pathways activated in polyp growth and trial with a significant decrease in duodenal polyp burden at proliferation are blocked by this drug combination. Directly 6months(P < 0.001) in familial adenomatous polyposis comparing polyp gene expression between patients on drug (FAP) patients, we biopsied normal and polyp duodenal and placebo also identified innate immune response genes tissuesfrompatientsondrugversusplaceboandanalyzed (IL12 and IFNg) preferentially expressed in patients on drug. the RNA expression. RNA sequencing was performed on Gene expression analyses from tissue obtained at endpoint of biopsies from the duodenum of FAP patients obtained at the trial demonstrated inhibition of the cancer pathways baseline and 6-month endpoint endoscopy. Ten FAP patients COX2/PGE2, EGFR, and WNT. These findings provide molec- on placebo and 10 on sulindac and erlotinib were selected for ular evidence that the drug combination of sulindac and analysis. Purity of biopsied polyp tissue was calculated from erlotinib reached the intended tissue and was on target for RNA expression data. RNAs differentially expressed between the predicted pathways. Furthermore, activation of innate endpoint polyp and paired baseline normal were determined immune pathways from patients on drug may have contrib- for each group and mapped to biological pathways. Key genes uted to polyp regression. Cancer Prev Res; 11(1); 4–15. Ó2017 in candidate pathways were further validated by quantitative AACR. RT-PCR. RNA expression analyses of endpoint polyp com- See related editorial by Shureiqi, p. 1 Introduction nocarcinoma occurring in up to 12% (3–8). As mutations in the APC gene are central to the initiation and development of colo- Familial adenomatous polyposis (FAP) is an autosomal dom- rectal cancer with 80% of sporadic colorectal cancers having APC inant inherited disorder due to germline mutations in the APC loss or inactivation, FAP is an excellent model to study the (adenomatous polyposis coli) gene (1, 2). FAP is characterized by molecular events leading to development of colorectal cancer the formation of hundreds to thousands of adenomatous polyps and other intestinal cancers. in the colorectum and a nearly 100% lifetime risk of colorectal Chemoprevention studies in FAP patients can provide clues as cancer if left untreated (3). Prophylactic colectomy has become to how drugs modify tumor progression. Multiple studies have the standard of care once the extent of colorectal polyposis is shown that sulindac, a cyclooxygenase (COX) inhibitor and beyond endoscopic control. FAP patients are also at greatly NSAID, significantly inhibits colorectal adenomatous polyps in increased risk for duodenal neoplasia, with duodenal adenomas FAP patients (9, 10). However, sulindac has failed to show a signi- eventually forming in >50% of FAP patients and duodenal ade- ficant reduction in duodenal adenomas in FAP patients (11, 12). This is thought to be due to increased COX2 expression in the duodenal tissue compared with colonic tissue of FAP patients 1 Department of Internal Medicine, University of Utah, Salt Lake City, Utah. (13). Studies have suggested that APC inactivation and EGFR 2 3 Huntsman Cancer Institute, University of Utah, Salt Lake City, Utah. Depart- signaling promote COX2 expression, leading to the development ment of Pathology, University of Utah, Salt Lake City, Utah. of intestinal neoplasms (14, 15). The convergence between the Note: Supplementary data for this article are available at Cancer Prevention WNT and EGFR signaling pathways and COX2 activity was dem- Research Online (http://cancerprevres.aacrjournals.org/). onstrated in a mouse model of FAP in which a combination of a Corresponding Author: Deborah W. Neklason, Huntsman Cancer Institute at COX and an EGFR inhibitor diminished small intestinal adenoma University of Utah, 1950 Circle of Hope, Salt Lake City, UT 84112. Phone: 801-587- development by 87% (16). These results led us to test the hypoth- 9882; Fax: 801-585-5763; E-mail: [email protected] esis that a combination of COX and EGFR inhibition would doi: 10.1158/1940-6207.CAPR-17-0130 impede adenoma formation in the duodenum of subjects with Ó2017 American Association for Cancer Research. FAP. We recently reported on a positive clinical study where 4 Cancer Prev Res; 11(1) January 2018 Downloaded from cancerpreventionresearch.aacrjournals.org on September 29, 2021. © 2018 American Association for Cancer Research. Published OnlineFirst November 6, 2017; DOI: 10.1158/1940-6207.CAPR-17-0130 Sulindac–Erlotinib Effect on Duodenal Polyp mRNA Expression manufacturer's instructions and including the on-column RNase- Translational Relevance free DNase treatment. RNA quantity and quality was determined Familial adenomatous polyposis (FAP) patients have a using a Thermo Fisher Scientific NanoDrop Spectrophotometer 100% lifetime risk of colorectal cancer and are also at increased and Agilent Bioanalyzer. risk for duodenal neoplasia, with duodenal adenomas even- tually forming in >50% of FAP patients. In most cases, pro- RNA sequencing phylactic colectomy and frequent endoscopy is the standard of Fifty-two endpoint (20 uninvolved, 32 adenomas) and 17 care for these patients. We recently completed a phase II baseline (all uninvolved) total RNA samples were treated with clinical trial of sulindac and erlotinib in a FAP patient cohort RiboZero Gold (Illumina) to remove ribosomal RNA prior to and found a significant decrease in duodenal polyp burden at cDNA library preparation using the Illumina TruSeq Stranded 6 months for patients on drug versus placebo. Here, we present Total RNA Sample Prep Protocol. PCR-amplified libraries were the duodenal polyp RNA expression data from this cohort, sequenced on Illumina HiSeq 2500 instrument using 50-cycle which show almost complete inhibition of the tumor signal- single-read chemistry. Sequencing datasets are deposited to NCBI ing pathways WNT, EGFR, and COX2/PGE2 and activation of GEO submission #GSE94919. Sequencing reads were aligned to innate immunity signaling pathways IL12 and IFNg in ade- the RefSeq Hg38 human genome using the Novoalign application nomas from patients on drug. The drug combination of (Novocraft). Differentially expressed genes were calculated using sulindac and erlotinib provides a promising alternative treat- the USeq application "DefinedRegionsDifferentialSeq" (DRDS) ment of duodenal polyps in FAP patients. as described previously (20, 21). The DRDS application uses DESeq2 negative binomial statistics together with a Benjamini and Hochberg FDR to identify differentially expressed genes (22). For paired sample comparisons, the DESeq2 paired analysis application in R was used. patients with FAP were treated with either placebo or sulindac and Total RNA from 12 endpoint polyps (6 from placebo and 6 erlotinib (sulindac–erlotinib). At 6 months, the median total from drug endpoint) of similar 3 to 4 mm size, noted in Table 1, duodenal polyp burden had increased by 6 mm from baseline in was further evaluated by targeted gene expression using the the placebo arm and decreased by 9 mm in the sulindac–erlotinib Human Inflammation and Immunity Transcriptome 475 gene arm (P < 0.001; ref. 17). panel (Qiagen # RHS-005Z). This targeted approach improves Here, we report the gene expression analyses from duodenal sequencing depth and reduces biases in amplification. The panel tissue at endpoint compared with baseline for those subjects includes a diverse set of cytokines, growth factors, and transcrip- enrolled in the trial. We show that the EGFR and COX2 pathways tion factors important in mediating general and specialized are activated in duodenal polyps and that the drug combination immune responses. RNA is converted to cDNA and amplified of sulindac–erlotinib blocks this activation. In addition, we found with a multiplex primer panel that labels each cDNA molecule evidence for activation of IFNg and IL12 signaling pathways, with a unique molecular tag. The quantified indexed library DNA suggesting that the recruitment of both Th1 and natural killer was pooled to an equimolar concentration alongside other sam- (NK) T cells may have contributed to the polyp regression (size ples. The pooled library DNA was amplified by emulsion PCR and and number) observed in the drug-treated arm (18, 19). enriched for positive ion sphere particles (ISP) using the Ion Torrent One Touch System II (Life Technologies) and the Ion PI Materials and Methods Hi-Q OT2 Kit (Life Technologies).Templated ISPs were sequenced Patient cohort on a PIv3 micro-chip using the Ion Torrent Proton Machine (Life This study was approved by the University of Utah Institutional Technologies) and the Ion PI Hi-Q Sequencing 200 Kit (Life Review Board (IRB#39278), conducted in accordance with
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