PI3K/mTOR is a therapeutically targetable genetic dependency in diffuse intrinsic pontine glioma
Authors
Ryan J. Duchatel, Cancer Signalling Research Group, School of Biomedical Sciences and Pharmacy, College of Health, Medicine and Wellbeing, University of Newcastle, Callaghan, New South Wales, Australia.
Evangeline R. Jackson, Cancer Signalling Research Group, School of Biomedical Sciences and Pharmacy, College of Health, Medicine and Wellbeing, University of Newcastle, Callaghan, New South Wales, Australia.
Sarah G. Parackal, Centre for Cancer Research, Hudson Institute of Medical Research, Clayton, Victoria, Australia.
Dylan Kiltschewskij, Precision Medicine Research Program, Hunter Medical Research Institute, New Lambton Heights, New South Wales, Australia.
Izac J. Findlay, Cancer Signalling Research Group, School of Biomedical Sciences and Pharmacy, College of Health, Medicine and Wellbeing, University of Newcastle, Callaghan, New South Wales, Australia.
Abdul Mannan, Cancer Signalling Research Group, School of Biomedical Sciences and Pharmacy, College of Health, Medicine and Wellbeing, University of Newcastle, Callaghan, New South Wales, Australia.
Dilana E. Staudt, Cancer Signalling Research Group, School of Biomedical Sciences and Pharmacy, College of Health, Medicine and Wellbeing, University of Newcastle, Callaghan, New South Wales, Australia.
Bryce C. Thomas, Cancer Signalling Research Group, School of Biomedical Sciences and Pharmacy, College of Health, Medicine and Wellbeing, University of Newcastle, Callaghan, New South Wales, Australia.
Zacary P. Germon, Cancer Signalling Research Group, School of Biomedical Sciences and Pharmacy, College of Health, Medicine and Wellbeing, University of Newcastle, Callaghan, New South Wales, Australia.
Sandra Laternser, DIPG/DMG Research Center Zurich, Children's Research Center, Department of Pediatrics, University Children's Hospital Zürich, Zurich, Switzerland.
Padraic S. Kearney, Cancer Signalling Research Group, School of Biomedical Sciences and Pharmacy, College of Health, Medicine and Wellbeing, University of Newcastle, Callaghan, New South Wales, Australia.
M Fairuz Jamaluddin, School of Biomedical Science and Pharmacy, College of Health, Medicine and Wellbeing, University of Newcastle, Callaghan, New South Wales, Australia.
Alicia M. Douglas, Cancer Signalling Research Group, School of Biomedical Sciences and Pharmacy, College of Health, Medicine and Wellbeing, University of Newcastle, Callaghan, New South Wales, Australia.
Tyrone Beitaki, Cancer Signalling Research Group, School of Biomedical Sciences and Pharmacy, College of Health, Medicine and Wellbeing, University of Newcastle, Callaghan, New South Wales, Australia.
Holly P. McEwen, Cancer Signalling Research Group, School of Biomedical Sciences and Pharmacy, College of Health, Medicine and Wellbeing, University of Newcastle, Callaghan, New South Wales, Australia.
Mika L. Persson, Cancer Signalling Research Group, School of Biomedical Sciences and Pharmacy, College of Health, Medicine and Wellbeing, University of Newcastle, Callaghan, New South Wales, Australia.
Emily A. Hocke, Duke Molecular Physiology Institute, Duke University School of Medicine, Durham, North Carolina, USA.
Vaibhav Jain, Duke Molecular Physiology Institute, Duke University School of Medicine, Durham, North Carolina, USA.
Michael Aksu, Duke Molecular Physiology Institute, Duke University School of Medicine, Durham, North Carolina, USA.
Elizabeth E. Manning, School of Biomedical Science and Pharmacy, College of Health, Medicine and Wellbeing, University of Newcastle, Callaghan, New South Wales, Australia.
Heather C. Murray, Precision Medicine Research Program, Hunter Medical Research Institute, New Lambton Heights, New South Wales, Australia.
Nicole M. Verrills, Precision Medicine Research Program, Hunter Medical Research Institute, New Lambton Heights, New South Wales, Australia.
Claire Xin Sun, Centre for Cancer Research, Hudson Institute of Medical Research, Clayton, Victoria, Australia.
Paul Daniel, Centre for Cancer Research, Hudson Institute of Medical Research, Clayton, Victoria, Australia.
Ricardo E. Vilain, Precision Medicine Research Program, Hunter Medical Research Institute, New Lambton Heights, New South Wales, Australia.
David A. Skerrett-Byrne, Infertility and Reproduction Research Program, Hunter Medical Research Institute, New Lambton Heights, New South Wales, Australia.
Brett Nixon, Infertility and Reproduction Research Program, Hunter Medical Research Institute, New Lambton Heights, New South Wales, Australia.
Susan Hua, Precision Medicine Research Program, Hunter Medical Research Institute, New Lambton Heights, New South Wales, Australia.
Charles E. de Bock, Children's Cancer Institute, University of New South Wales (UNSW) Sydney, Kensington, New South Wales, Australia.
Yolanda Colino-Sanguino, Children's Cancer Institute, University of New South Wales (UNSW) Sydney, Kensington, New South Wales, Australia.
Fatima Valdes-Mora, Children's Cancer Institute, University of New South Wales (UNSW) Sydney, Kensington, New South Wales, Australia.
Maria Tsoli, Children's Cancer Institute, University of New South Wales (UNSW) Sydney, Kensington, New South Wales, Australia.
Document Type
Journal Article
Publication Date
2-6-2024
Journal
The Journal of clinical investigation
Keywords
Brain cancer; Drug therapy; Oncogenes; Oncology; Therapeutics
Abstract
Diffuse midline glioma (DMG), including tumors diagnosed in the brainstem (diffuse intrinsic pontine glioma; DIPG), are uniformly fatal brain tumors that lack effective treatment. Analysis of CRISPR/Cas9 loss-of-function gene deletion screens identified PIK3CA and MTOR as targetable molecular dependencies across patient derived models of DIPG, highlighting the therapeutic potential of the blood-brain barrier-penetrant PI3K/Akt/mTOR inhibitor, paxalisib. At the human-equivalent maximum tolerated dose, mice treated with paxalisib experienced systemic glucose feedback and increased insulin levels commensurate with patients using PI3K inhibitors. To exploit genetic dependence and overcome resistance while maintaining compliance and therapeutic benefit, we combined paxalisib with the antihyperglycemic drug metformin. Metformin restored glucose homeostasis and decreased phosphorylation of the insulin receptor in vivo, a common mechanism of PI3K-inhibitor resistance, extending survival of orthotopic models. DIPG models treated with paxalisib increased calcium-activated PKC signaling. The brain penetrant PKC inhibitor enzastaurin, in combination with paxalisib, synergistically extended the survival of multiple orthotopic patient-derived and immunocompetent syngeneic allograft models; benefits potentiated in combination with metformin and standard-of-care radiotherapy. Therapeutic adaptation was assessed using spatial transcriptomics and ATAC-Seq, identifying changes in myelination and tumor immune microenvironment crosstalk. Collectively, this study has identified what we believe to be a clinically relevant DIPG therapeutic combinational strategy.
APA Citation
Duchatel, Ryan J.; Jackson, Evangeline R.; Parackal, Sarah G.; Kiltschewskij, Dylan; Findlay, Izac J.; Mannan, Abdul; Staudt, Dilana E.; Thomas, Bryce C.; Germon, Zacary P.; Laternser, Sandra; Kearney, Padraic S.; Jamaluddin, M Fairuz; Douglas, Alicia M.; Beitaki, Tyrone; McEwen, Holly P.; Persson, Mika L.; Hocke, Emily A.; Jain, Vaibhav; Aksu, Michael; Manning, Elizabeth E.; Murray, Heather C.; Verrills, Nicole M.; Sun, Claire Xin; Daniel, Paul; Vilain, Ricardo E.; Skerrett-Byrne, David A.; Nixon, Brett; Hua, Susan; de Bock, Charles E.; Colino-Sanguino, Yolanda; Valdes-Mora, Fatima; and Tsoli, Maria, "PI3K/mTOR is a therapeutically targetable genetic dependency in diffuse intrinsic pontine glioma" (2024). GW Authored Works. Paper 4380.
https://hsrc.himmelfarb.gwu.edu/gwhpubs/4380