EXTH-31 - Exploiting the genetic dependency on PI3K/mTOR signaling for the treatment of H3-altered diffuse midline glioma

Friday, November 17, 2023

3:45 PM – 3:55 PM PT

Location: Room 121-122

Oral Abstract Presenter(s)

Ryan J. Duchatel

University of Newcastle
Callaghan, New South Wales, Australia

Author(s)

Evangeline R. Jackson

University of Newcastle
Callaghan, New South Wales, Australia
SP

Sarah G. Parackal

Hudson Institute of Medical Research
Clayton, Victoria, Australia
CS

Claire Sun

Hudson Institute of Medical Research
Clayton, Victoria, Australia
PD

Paul Daniel

Hudson Institute of Medical Research
Clayton, Victoria, Australia
AM

Abdul Mannan

University of Newcastle
Callaghan, New South Wales, Australia
IF

Izac J. Findlay

University of Newcastle
Callaghan, New South Wales, Australia
DS

Dilana Staudt

University of Newcastle
Callaghan, New South Wales, Australia
ZG

Zacary Germon

University of Newcastle
Callaghan, New South Wales, Australia
SL

Sandra Laternser

University Children’s Hospital Zürich
Zurich, Switzerland
DK

Dylan Kiltschewskij

University of Newcastle
Callaghan, Australia
PK

Padraic S. Kearney

University of Newcastle
Callaghan, New South Wales, Australia
MB

M. Fairuz B. Jamaluddin

University of Newcastle
Callaghan, Australia
AD

Alicia M. Douglas

University of Newcastle
Callaghan, New South Wales, Australia
TB

Tyrone Beitaki

University of Newcastle
Callaghan, New South Wales, Australia
MP

Mika Perrson

University of Newcastle
Callaghan, New South Wales, Australia
BT

Bryce Thomas

University of Newcastle
Callaghan, New South Wales, Australia
EM

Elizabeth E. Manning

University of Newcastle
Callaghan, New South Wales, Australia
HM

Heather C. Murray

University of Newcastle
Callaghan, New South Wales, Australia
NV

Nikki M. Verrills

University of Newcastle
Callaghan, New South Wales, Australia
RV

Ricardo Vilain

University of Newcastle
Callaghan, New South Wales, Australia
DS

David Skerrett-byrne

University of Newcastle
Callaghan, New South Wales, Australia
BN

Brett Nixon

University of Newcastle
Callaghan, New South Wales, Australia
SH

Susan Hua

University of Newcastle
Callaghan, New South Wales, Australia
CD

Charles DeBock

Children's Cancer Institute
Sydney, New South Wales, Australia
FV

Fatima Valdes-Mora

Children's Cancer Institute
Sydney, New South Wales, Australia
MT

Maria Tsoli

Children's Cancer Institute
Sydney, New South Wales, Australia
David S. Ziegler

Kids Cancer Centre, Sydney Children’s Hospital
Randwick, New South Wales, Australia
MC

Murray Cairns

University of Newcastle
Callaghan, New South Wales, Australia
ER

Eric Raabe

Johns Hopkins University
Baltimore, Maryland, United States
Nicholas A. Vitanza

Seattle Children’s
Seattle, Washington, United States
TP

Timothy N. Phoenix

University of Cincinnati
Cincinnati, United States
Carl J. Koschmann

University of Michigan
Ann Arbor, Michigan, United States
FA

Frank Alvaro

University of Newcastle
Callaghan, New South Wales, Australia
CD

Christopher V. Dayas

University of Newcastle
Callaghan, Australia
Christopher Tinkle

St. Jude Children’s Research Hospital
Memphis, Tennessee, United States
David D. Eisenstat

The Royal Children’s Hospital Melbourne
Parkville, Victoria, Australia
RF

Ron Firestein

Hudson Institute of Medical Research
Clayton, Victoria, Australia
Sabine Mueller

University of California, San Francisco
San Francisco, California, United States
Javad Nazarian

University Children’s Hospital Zurich
Zürich, District of Columbia, Switzerland
JC

Jason E. Cain

Hudson Institute of Medical Research
Clayton, Victoria, Australia
Matthew D. Dun

University of Newcastle
Callaghan, New South Wales, Australia

Recurring activating mutations, amplifications and allelic loss of the negative repressors of the phosphatidylinositol-4,5-bisphosphate 3-kinase (PI3K) signaling genes are overarching contributors to the poor survival of patients with H3K27-altered diffuse midline gliomas (DMG) diagnosed in the pons (diffuse intrinsic pontine glioma – DIPG), highlighting the clinical potential of therapies that target this axis. Employing a loss-of-function CRISPR-Cas9 gene deletion screen, we identified PIK3CA and MTOR as survival dependences in DMG/DIPG patient derived cell line models (n=36), highlighting the clinical potential of targeting PI3K/Akt/mTOR. The brain-penetrant, PI3K/mTOR inhibitor paxalisib is currently under clinical investigation in DIPG (NCT03696355 and NCT05009992), but dosing limiting toxicities including hyperglycaemia, mucositis and skin irritation limit patient compliance. To exploit this therapeutic vulnerability, we optimized the preclinical use of paxalisib, identifying both precision medicine combination strategies and systemic interventions that reduced side effects and elicited profound tumor control in vivo. Mimicking the patient experience, paxalisib elevated blood glucose levels, promoting the phosphorylation of the insulin receptor (p-INSR) in patient derived DIPG xenograft models. Combining paxalisib with the anti-glycemic drug metformin, synergistically extended the survival of two DIPG xenograft models, decreasing p-Akt, p-mTOR and p-INSR in vivo. Phosphoproteomic profiling of DIPG cells identified paxalisib induced intracellular calcium-regulated PKC signaling. The brain penetrant PKC inhibitor enzastaurin extended the survival of DIPG xenograft models alone, and synergistically combined with paxalisib, enhanced using metformin in three DIPG xenograft models, as well as the immunocompetent H3f3a^K27M, Pdgfra^D842Vmut, Trp53^-/- murine brainstem glioma model. Mechanisms of adaptation/plasticity were assessed by ATAC-Seq and quantitative proteomic profiling xenograft tumors refractory to treatment. Here we address the intrinsic neoplastic sequela of DIPG, by combined targeting of PI3K/Akt/mTOR using paxalisib, compensatory PKC signaling using enzastaurin, coupled with strategies to manage treatment-related side-effects and reduced efficacy using metformin; providing the preclinical rationale for the addition of metformin to NCT05009992.