MP14-18 MODELING BLADDER CANCER IN DOWN SYNDROME ANIMALS FOR DISCOVERY OF NOVEL THERAPEUTICS

Abstract

You have accessJournal of UrologyCME1 Apr 2023MP14-18 MODELING BLADDER CANCER IN DOWN SYNDROME ANIMALS FOR DISCOVERY OF NOVEL THERAPEUTICS Binh Vo, Erika Abbott, Carolyn Vivian, Xena Moore, Ganeshkumar Rajendran, Scott Weir, Katie Dennis, Benjamin Woolbright, and John Taylor Binh VoBinh Vo More articles by this author , Erika AbbottErika Abbott More articles by this author , Carolyn VivianCarolyn Vivian More articles by this author , Xena MooreXena Moore More articles by this author , Ganeshkumar RajendranGaneshkumar Rajendran More articles by this author , Scott WeirScott Weir More articles by this author , Katie DennisKatie Dennis More articles by this author , Benjamin WoolbrightBenjamin Woolbright More articles by this author , and John TaylorJohn Taylor More articles by this author View All Author Informationhttps://doi.org/10.1097/JU.0000000000003234.18AboutPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareFacebookLinked InTwitterEmail Abstract INTRODUCTION AND OBJECTIVE: Down syndrome (DS) is the most common chromosomal abnormality in humans and results in an increased risk for hematologic cancers, despite a paradoxically lower rate of adult solid tumors. Epidemiological evidence supports the idea that DS patients have a lower risk for bladder cancer (BCa) in spite of reduced environmental exposures. We sought to evaluate potential protective mechanisms against cancer formation in the Ts65Dn mouse model of DS, and hypothesized Ts65Dn mice would be protected against (BCa) formation and progression. METHODS: Tumors were initiated in Ts65Dn and WT mice using N-butyl-N-(4-hydroxybutyl)-nitrosamine (BBN). Ts65Dn or WT animals were given 0.05% BBN for 16 weeks before sacrifice. Bladders were weighed at time of death. For Reactome pathways, Gene Set Enrichment Analysis (GSEA) was performed after RNA-seq. Proliferation was assessed using the hexosaminidase assay on HTB-9, HTB-5 and T24 BCa cells. HTB-9 cells (5×105) xenografts were implanted in the flank of nude mice in 50% Matrigel/saline and allowed to develop over two weeks. When mean tumor sizes per cage reached 50-100 mm3 determined using calipers, treatment with 25 mg/kg barasertib, i.p., Q1D for 5 days per week was started. Tumors were excised and weighed on the final day. RESULTS: After 16 weeks of 0.05% BBN exposure, Ts65Dn mice had smaller bladder tumors which trended towards lower stage tumors compared to WT mice. Although Ds mice and patients are known to have higher expression of anti-angiogenic proteins as such DSCR1, we did not see a decrease in angiogenesis in the Ds tumors, indicating potentially novel mechanisms of protection. RNA-sequencing indicated pathways associated with the cell cycle were most affected in the Ts65Dn mice, including downregulation of the cell cycle regulator Aurora Kinase B (AURKB). We evaluated drug sensitivity in a set of BCa cell lines using the AURKB specific inhibitor barasertib-HQPA. HTB-9 cells were highly susceptible to barasertib (IC50 ∼30-50 nM) whereas T24/HTB-5 cells had dramatically higher IC50 values (∼50 µM). Drug efficacy was assessed by evaluating phosphorylation of the AURKB substrate histone H3. Phospho-histone H3 levels were reduced in all cell lines and inhibition of a known transporter of barasertib using the compound valspodar minimally enhanced barasertib toxicity in T24 cells, indicating the potential for a novel mechanism of resistance. CONCLUSIONS: Our results indicate Ts65Dn mice have reduced tumor formation when exposed to BBN. Using Ts65Dn mice as a model may be a means for finding new drug targets as demonstrated by our results targeting AURKB. Source of Funding: Leo and Anne Albert Institute for Bladder Cancer and Institute for Advancing Medical Innovation at KUMC © 2023 by American Urological Association Education and Research, Inc.FiguresReferencesRelatedDetails Volume 209Issue Supplement 4April 2023Page: e189 Advertisement Copyright & Permissions© 2023 by American Urological Association Education and Research, Inc.MetricsAuthor Information Binh Vo More articles by this author Erika Abbott More articles by this author Carolyn Vivian More articles by this author Xena Moore More articles by this author Ganeshkumar Rajendran More articles by this author Scott Weir More articles by this author Katie Dennis More articles by this author Benjamin Woolbright More articles by this author John Taylor More articles by this author Expand All Advertisement PDF downloadLoading ...