PI3K/mTOR is a therapeutically targetable genetic dependency in diffuse intrinsic pontine glioma.
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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 B, 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, Tsoli Maria, Ziegler David S, Cairns Murray J, Raabe Eric H, Vitanza Nicholas A, Hulleman Esther, Phoenix Timothy N, Koschmann Carl, Alvaro Frank, Dayas Christopher V, Tinkle Christopher L, Wheeler Helen, Whittle James R, Eisenstat David D, Firestein Ron, Mueller Sabine, Valvi Santosh, Hansford Jordan R, Ashley David M, Gregory Simon G, Kilburn Lindsay B, Nazarian Javad, Cain Jason E, Dun Matthew D
Аннотация
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.