https://openworks.mdanderson.org/sumexp22/1066/thumbnail.jp

Gadalla, Ramy Safwat Tawfik

Huse, Jason

Malgulwar, Prit

English

OpenWorks @ MD Anderson

MethodsConclusions• Inhibition of HOXA cluster genes using HRX9peptide, suggest its translational role in preclinicalsetting.• Increase in apoptosis and reduced proliferation inHXR9 treated gliomas, open opportunity for in-vivoexperiments.References1) Arunachalam et al.  BMC Cancer 2022;22(400)2) Morgan et al. Oncotarget 2015;8(19)3) Goncalves et. Nature 2020;77:3797-38214) TCGA et al. NEJM 2015;372(26):2481-2498Fig. 1 ATRX-deficient cell lines overexpress HOX, suppressing cFOS, an apoptosispromoting factor. By competitively inhibiting the HOX-PBX complex, HXR9 mayrestore caspase-mediated apoptosis. (Made with Biorender.com)Table 1 Patient-derived glioma stem cells (GSCs) treated were the GS5-22 and TS603 cell lines.Introduction• Primary brain tumors rank as the #1 cancer in termsof years of life lost• Gliomas represent the majority (80%) of brain tumorsand ATRX-deficient gliomas, i.e., astrocytoma, havethe worst prognosis - average six years of survival.• ATRX-loss gliomas cooccur with IDH-mut, Tp53-mut,and 1p/19q non-co-deletion.• Current treatments include surgery, radiation andchemotherapy with significant side effects, includinghigh morbidity and mortality.• ATRX is a globally repressive chromatin remodelerthrough complexing with H3.3 and DAXX, depositinghistone groups on chromatin.• HOX genes are upregulated in developing fetuses topromote cell proliferation for development of thehindbrain and somites• HOX is overexpressed in ATRX deficient gliomas.• Research into the mechanism of ATRX deficiencies inthese tumors will have great implications for survival.• HXR9 is small peptide sequence that inhibitsheterodimerization of HOX:PBX, inhibiting cellproliferation• HXR9 is potent, clinically effective and blood-brain-barrier permeable peptide• Our aim is to establish HXR9 validity in promotingglioma stem cells apoptosis and elucidate themechanism of action to better understand therole of HOX in gliomagenesisHXR9 Inhibits the HOX-PBX Cluster, Inducing Glioma Apoptosis and Cell Cycle Arrest Ramy Safwat Tawfik Gadalla1,2, Prit Malgulwar, PhD2, Jason Huse, MD, PhD2,31Georgetown University School of Medicine, 2Department of Translational Molecular Pathology, 3Department of Pathology, University of Texas MD Anderson Cancer Center • rsgadalla@mdanderson.orgResultsFig. 3 HXR9 increases late apoptosis by 17% (5 µM) and 30% (20 µM) in GS5-22 ATRX-mut (a) and 34% (20 µM) with 2% increase in early apoptosis (5 µM) in TS603 ATRX-wt (b) glioma stem cellsFig. 2 HOX is overexpressed in ATRX-mut, IDH1-mut, 1p/19q non-co-deleted backgrounds (a) and correlates with lower overall survival (b). * <0.5, ** <0.01, ***<0.001, ****<0.0001RNA-seq analysis shows increased expression of HOXA cluster genes in ATRX deficient gliomas High expression of HOXA cluster genes is associated with poor prognosis in ATRX deficient gliomas Dose dependent escalation of HXR9 drives patient derived gliomas towards apoptosisababFig. 4 HXR9 induces cell cycle arrest by reducing the % of GS5-22 cells in thesynthetic (S)-phase by 4% and 5% (a) and the % of TS603 cells in both the Sand growth 2 (G2) phases by 1.5% and 6% (b), at 5 µM and 20 µM, respectivelyDecrease in S-Phase of cell cycle upon treatment with HRX9 in patient derived gliomasTwitter: @RamyGadallaLinkedIn: ramy-gadallaFuture Directions• I plan to do qPCR to check if the HOX issuppressed.• I can do western of a wide variety of proteins toconfirm apoptosis.• I can check the global transcriptional profilethrough RNA sequencing to detect differentpathways the HXR9 peptide modulates.• I can test HXR9 in TMZ-resistant, CD133+ stemcell lines.AcknowledgementsWe thank the MD Anderson Flow Core for cell cycleanalysis, Sharvhari Dharmaiah and Jeffrey Ackroyd forlab introduction, Ben Whitfield and Bhargavi Barathi forhelpful explanations and advice.ab

HXR9 Inhibits the HOX-PBX Cluster, Inducing Glioma Apoptosis and Cell Cycle Arrest

https://openworks.mdanderson.org/cgi/viewcontent.cgi?article=1066&context=sumexp22

HXR9 Inhibits the HOX-PBX Cluster, Inducing Glioma Apoptosis and Cell Cycle Arrest

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