Nicholas A Vitanza1,2, Matt C Biery1, Carrie Myers1, Eric Ferguson1, Ye Zheng3, Emily J Girard1, Justyna M Przystal4, Giulia Park1, Alyssa Noll1,5, Fiona Pakiam1, Conrad A Winter1, Shelli M Morris1, Jay Sarthy1, Bonnie L Cole6,7, Sarah E S Leary1,2, Courtney Crane8, Nicole A P Lieberman7, Sabine Mueller4,9, Javad Nazarian4,10, Raphael Gottardo3,11,12, Mi-Youn Brusniak1, Andrew J Mhyre1, James M Olson1,2. 1. Fred Hutchinson Cancer Research Center, Seattle, Washington, USA. 2. Division of Pediatric Hematology/Oncology, Department of Pediatrics, Seattle Children's Hospital, University of Washington, Seattle, Washington, USA. 3. Vaccine and Infectious Disease Division, Fred Hutchinson Cancer Research Center, Seattle, Washington, USA. 4. University Children's Hospital Zurich, Zurich, Switzerland. 5. Molecular and Cellular Biology Graduate Program and Medical Scientist Training Program, University of Washington, Seattle, Washington, USA. 6. Department of Laboratories, Seattle Children's Hospital, Seattle, Washington, USA. 7. Department of Laboratory Medicine and Pathology, University of Washington School of Medicine, Seattle, Washington, USA. 8. Ben Towne Center for Childhood Cancer Research, Seattle Children's Research Institute, Seattle, Washington, USA. 9. University of California San Francisco, San Francisco, California, USA. 10. Department of Genetic Medicine Research, Children's National Medical Center, Washington DC, USA. 11. Public Health Sciences Division, Fred Hutchinson Cancer Research Center, Seattle, Washington, USA. 12. Department of Statistics, University of Washington, Seattle, Washington, USA.
Abstract
BACKGROUND: Diffuse midline gliomas (DMGs), including diffuse intrinsic pontine gliomas (DIPGs), have a dismal prognosis, with less than 2% surviving 5 years postdiagnosis. The majority of DIPGs and all DMGs harbor mutations altering the epigenetic regulatory histone tail (H3 K27M). Investigations addressing DMG epigenetics have identified a few promising drugs, including the HDAC inhibitor (HDACi) panobinostat. Here, we use clinically relevant DMG models to identify and validate other effective HDACi and their biomarkers of response. METHODS: HDAC inhibitors were tested across biopsy-derived treatment-naïve in vitro and in vivo DMG models with biologically relevant radiation resistance. RNA sequencing was performed to define and compare drug efficacy and to map predictive biomarkers of response. RESULTS: Quisinostat and romidepsin showed efficacy with low nanomolar half-maximal inhibitory concentration (IC50) values (~50 and ~5 nM, respectively). Comparative transcriptome analyses across quisinostat, romidepsin, and panobinostat showed a greater degree of shared biological effects between quisinostat and panobinostat, and less overlap with romidepsin. However, some transcriptional changes were consistent across all 3 drugs at similar biologically effective doses, such as overexpression of troponin T1 slow skeletal type (TNNT1) and downregulation of collagen type 20 alpha 1 chain (COL20A1), identifying these as potential vulnerabilities or on-target biomarkers in DMG. Quisinostat and romidepsin significantly (P < 0.0001) inhibited in vivo tumor growth. CONCLUSIONS: Our data highlight the utility of treatment-naïve biopsy-derived models; establishes quisinostat and romidepsin as effective in vivo; illuminates potential mechanisms and/or biomarkers of DMG cell lethality due to HDAC inhibition; and emphasizes the need for brain tumor-penetrant versions of potentially efficacious agents.
BACKGROUND: Diffuse midline gliomas (DMGs), including diffuse intrinsic pontine gliomas (DIPGs), have a dismal prognosis, with less than 2% surviving 5 years postdiagnosis. The majority of DIPGs and all DMGs harbor mutations altering the epigenetic regulatory histone tail (H3 K27M). Investigations addressing DMG epigenetics have identified a few promising drugs, including the HDAC inhibitor (HDACi) panobinostat. Here, we use clinically relevant DMG models to identify and validate other effective HDACi and their biomarkers of response. METHODS:HDAC inhibitors were tested across biopsy-derived treatment-naïve in vitro and in vivo DMG models with biologically relevant radiation resistance. RNA sequencing was performed to define and compare drug efficacy and to map predictive biomarkers of response. RESULTS:Quisinostat and romidepsin showed efficacy with low nanomolar half-maximal inhibitory concentration (IC50) values (~50 and ~5 nM, respectively). Comparative transcriptome analyses across quisinostat, romidepsin, and panobinostat showed a greater degree of shared biological effects between quisinostat and panobinostat, and less overlap with romidepsin. However, some transcriptional changes were consistent across all 3 drugs at similar biologically effective doses, such as overexpression of troponin T1 slow skeletal type (TNNT1) and downregulation of collagen type 20 alpha 1 chain (COL20A1), identifying these as potential vulnerabilities or on-target biomarkers in DMG. Quisinostat and romidepsin significantly (P < 0.0001) inhibited in vivo tumor growth. CONCLUSIONS: Our data highlight the utility of treatment-naïve biopsy-derived models; establishes quisinostat and romidepsin as effective in vivo; illuminates potential mechanisms and/or biomarkers of DMG cell lethality due to HDAC inhibition; and emphasizes the need for brain tumor-penetrant versions of potentially efficacious agents.
Authors: Tabitha Cooney; Adam Lane; Ute Bartels; Eric Bouffet; Stewart Goldman; Sarah E S Leary; Nicholas K Foreman; Roger J Packer; Alberto Broniscer; Jane E Minturn; Chie-Schin Shih; Murali Chintagumpala; Tim Hassall; Nicholas G Gottardo; Hetal Dholaria; Lindsey Hoffman; Brooklyn Chaney; Joshua Baugh; Renee Doughman; James L Leach; Blaise V Jones; Maryam Fouladi; Katherine E Warren; Michelle Monje Journal: Neuro Oncol Date: 2017-09-01 Impact factor: 12.300
Authors: Paul J Wood; Robyn Strong; Grant A McArthur; Michael Michael; Elizabeth Algar; Andrea Muscat; Lin Rigby; Melissa Ferguson; David M Ashley Journal: Cancer Chemother Pharmacol Date: 2018-07-09 Impact factor: 3.333
Authors: Nalin Gupta; Liliana C Goumnerova; Peter Manley; Susan N Chi; Donna Neuberg; Maneka Puligandla; Jason Fangusaro; Stewart Goldman; Tadanori Tomita; Tord Alden; Arthur DiPatri; Joshua B Rubin; Karen Gauvain; David Limbrick; Jeffrey Leonard; J Russel Geyer; Sarah Leary; Samuel Browd; Zhihong Wang; Sandeep Sood; Anne Bendel; Mahmoud Nagib; Sharon Gardner; Matthias A Karajannis; David Harter; Kanyalakshmi Ayyanar; William Gump; Daniel C Bowers; Bradley Weprin; Tobey J MacDonald; Dolly Aguilera; Barunashish Brahma; Nathan J Robison; Erin Kiehna; Mark Krieger; Eric Sandler; Philipp Aldana; Ziad Khatib; John Ragheb; Sanjiv Bhatia; Sabine Mueller; Anu Banerjee; Amy-Lee Bredlau; Sri Gururangan; Herbert Fuchs; Kenneth J Cohen; George Jallo; Kathleen Dorris; Michael Handler; Melanie Comito; Mark Dias; Kellie Nazemi; Lissa Baird; Jeff Murray; Neal Lindeman; Jason L Hornick; Hayley Malkin; Claire Sinai; Lianne Greenspan; Karen D Wright; Michael Prados; Pratiti Bandopadhayay; Keith L Ligon; Mark W Kieran Journal: Neuro Oncol Date: 2018-10-09 Impact factor: 12.300
Authors: William G B Singleton; Alison S Bienemann; Max Woolley; David Johnson; Owen Lewis; Marcella J Wyatt; Stephen J P Damment; Lisa J Boulter; Clare L Killick-Cole; Daniel J Asby; Steven S Gill Journal: J Neurosurg Pediatr Date: 2018-06-01 Impact factor: 2.375
Authors: Peter Larsson; Hanna Engqvist; Jana Biermann; Elisabeth Werner Rönnerman; Eva Forssell-Aronsson; Anikó Kovács; Per Karlsson; Khalil Helou; Toshima Z Parris Journal: Sci Rep Date: 2020-04-02 Impact factor: 4.379
Authors: Ye Sun; Kun Yan; Yi Wang; Cheng Xu; Dan Wang; Wei Zhou; Shuning Guo; Yujie Han; Lei Tang; Yanqiu Shao; Shaobo Shan; Qiangfeng C Zhang; Yujie Tang; Liwei Zhang; Qiaoran Xi Journal: Nat Cancer Date: 2022-08-01
Authors: Jeppe Thorlacius-Ussing; Christina Jensen; Emilie A Madsen; Neel I Nissen; Tina Manon-Jensen; Inna M Chen; Julia S Johansen; Hadi M H Diab; Lars N Jørgensen; Morten A Karsdal; Nicholas Willumsen Journal: Int J Mol Sci Date: 2022-04-08 Impact factor: 6.208
Authors: Matt C Biery; Alyssa Noll; Carrie Myers; Shelli M Morris; Conrad A Winter; Fiona Pakiam; Bonnie L Cole; Samuel R Browd; James M Olson; Nicholas A Vitanza Journal: J Exp Neurol Date: 2020-12
Authors: Lydia T Tam; Kristen W Yeom; Jason N Wright; Alok Jaju; Alireza Radmanesh; Michelle Han; Sebastian Toescu; Maryam Maleki; Eric Chen; Andrew Campion; Hollie A Lai; Azam A Eghbal; Ozgur Oztekin; Kshitij Mankad; Darren Hargrave; Thomas S Jacques; Robert Goetti; Robert M Lober; Samuel H Cheshier; Sandy Napel; Mourad Said; Kristian Aquilina; Chang Y Ho; Michelle Monje; Nicholas A Vitanza; Sarah A Mattonen Journal: Neurooncol Adv Date: 2021-03-05
Authors: Izac J Findlay; Geoffry N De Iuliis; Ryan J Duchatel; Evangeline R Jackson; Nicholas A Vitanza; Jason E Cain; Sebastian M Waszak; Matthew D Dun Journal: Oncogene Date: 2021-11-10 Impact factor: 9.867
Authors: Maria B Garcia-Fabiani; Santiago Haase; Andrea Comba; Stephen Carney; Brandon McClellan; Kaushik Banerjee; Mahmoud S Alghamri; Faisal Syed; Padma Kadiyala; Felipe J Nunez; Marianela Candolfi; Antonela Asad; Nazareno Gonzalez; Marisa E Aikins; Anna Schwendeman; James J Moon; Pedro R Lowenstein; Maria G Castro Journal: Front Oncol Date: 2021-06-08 Impact factor: 5.738