Abstract
Glioblastoma (GBM) is the most aggressive primary brain cancer with an average survival time after diagnosis of only 12-14 months, with few (<5%) long-term survivors. A growing body of work suggests that GBMs contain a small population of glioma stem cells (GSCs) that are thought to be major contributors to treatment resistance and disease relapse. Identifying compounds that modulate GSC proliferation would provide highly valuable molecular probes of GSC-directed signaling. However, targeting GSCs pharmacologically has been challenging. Patient-derived GSCs can be cultured as neurospheres, and in vivo these cells functionally recapitulate the heterogeneity of the original tumor. Using patient-derived GSC-enriched cultures, we have developed a 1536-well spheroid-based proliferation assay and completed a pilot screen, testing ~3300 compounds comprising approved drugs. This cytotoxic and automation-friendly assay yielded a signal-to-background (S/B) ratio of 161.3 ± 7.5 and Z' of 0.77 ± 0.02, demonstrating its robustness. Importantly, compounds were identified with anti-GSC activity, demonstrating the applicability of this assay for large-scale high-throughput screening (HTS).
References
Oct 7, 2004·Cancer Research·Rossella GalliAngelo Vescovi
Nov 19, 2004·Nature·Sheila K SinghPeter B Dirks
Jan 28, 2005·Journal of Neuro-oncology·Tim Demuth, Michael E Berens
Apr 16, 2005·Neuro-oncology·Caterina GianniniC David James
Oct 20, 2006·Nature·Shideng BaoJeremy N Rich
Nov 3, 2007·Genes & Development·Frank B FurnariWebster K Cavenee
Feb 9, 2008·Molecular and Cellular Biochemistry·Chen Lu, Amal Shervington
Sep 16, 2008·Bioconjugate Chemistry·Thomas Tyrel GoodmanSuzie Hwang Pun
Oct 25, 2008·Stem Cells·Rosaria Maria Rita GangemiGiorgio Corte
Jun 6, 2009·Cell Stem Cell·Steven M PollardPeter Dirks
Dec 8, 2010·Journal of Clinical Oncology : Official Journal of the American Society of Clinical Oncology·Albert LaiTimothy Cloughesy
Nov 21, 2012·Oncotarget·Parvinder HothiGreg Foltz
Mar 26, 2013·Biochemical and Biophysical Research Communications·Xiong JinHyunggee Kim
Jun 22, 2013·Bioorganic & Medicinal Chemistry Letters·Mathieu BibianWilliam R Roush
Apr 15, 2014·Cell·Mario L SuvàBradley E Bernstein
May 20, 2014·Cell Stem Cell·Zhe ZhuHai-Kun Liu
Jul 24, 2014·Cancer Epidemiology, Biomarkers & Prevention : a Publication of the American Association for Cancer Research, Cosponsored by the American Society of Preventive Oncology·Jigisha P ThakkarJohn L Villano
Aug 15, 2014·Biotechnology Advances·Xian XuXinqiao Jia
Mar 26, 2015·Anatomy & Cell Biology·Maryam RahmanBrent A Reynolds
Jun 26, 2015·Genes & Development·Justin D LathiaJeremy N Rich
Dec 17, 2015·JAMA : the Journal of the American Medical Association·Roger StuppZvi Ram
Feb 16, 2016·Expert Opinion on Therapeutic Targets·Laura Garros-RegulezAnder Matheu
Dec 21, 2016·Current Cancer Drug Targets·Drew A SpencerMaciej S Lesniak
Nov 1, 2011·Australasian Journal of Ultrasound in Medicine·Cindy Oakenful, Andreas L Lambrianides
Citations
Jan 30, 2019·Journal of Neuro-oncology·Ahmed Musah-Eroje, Sue Watson
Sep 10, 2019·SLAS Discovery·Olivia W LeeMatthew D Hall
May 1, 2019·SLAS Discovery·Peter WorthingtonSigrid A Langhans
Jun 7, 2020·Cells·Philip Dao TrongRolf Warta
Mar 16, 2019·Annals of the New York Academy of Sciences·M Catarina Silva, Stephen J Haggarty
Aug 30, 2020·Nanomaterials·Kyle Bromma, Devika B Chithrani
Jun 23, 2019·Scientific Reports·BanuPriya SridharanTimothy P Spicer
Mar 7, 2021·Cancers·Sreenivasulu GuntiNyall R London