Sydney Cancer conference July 9-10

Assoc. Prof Dun is giving a guest presentation today on precision medicine.

Here is a paper in the abstracts for the conference (note that Matt Dun has an interest in more than 1 paper, but this is the only one of interest for us).

Paper ID 114
Combination of Paxalisib and ONC201 for the Treatment of Diffuse Intrinsic Pontine
Glioma
Evangeline Jackson1,2
Ryan Duchatel3,4, Abdul Mannan5,6,7, Sridevi Yadavilli8,9, Mika Persson10, Padraic Kearney1,2, Sarah
Parackal11, Alicia Douglas3,4, David Skerrett-Byrne12, Esther Hulleman13, Angel Carcaboso14, Michelle
Monje15, Geoff McCowage16, Frank Alvaro4,17, Sebastian Waszak18, Martin Larsen19, Javad Nazarian8
,
Jason Cain11, Carl Koschmann20
, Sabine Mueller21 and Matthew Dun3,4
1 Cancer Signaling Research Group, School of Biomedical Sciences and Pharmacy, Faculty of Health and
Medicine, University of Newcastle
2 Priority Research Centre for Cancer Research Innovation and Translation, Hunter Medical Research Institute
3 University of Newcastle, Faculty of Health and Medicine
4 Hunter Medical Research Institute, Cancer Research Program
5 Hunter Cancer Research Alliance, Faculty of Health & Medicine, University of Newcastle, New Lambton Heights,
NSW, Australia
6 Cancer Research Program, Hunter Medical Research Institute, New Lambton Heights, NSW, Australia
7 Priority Research Centre for Cancer Research, Innovation and Translation, Faculty of Health & Medicine,
University of Newcastle, Callaghan, NSW, Australia
8 Center for Genetic Medicine Research, Children’s National Hospital
9 Brain Tumor Institute, Children’s National Hospital
10 Karolinska Institutet
11 Monash Institute of Medical Research, Monash Medical Centre
12 Priority Research Centre for Reproductive Science, Discipline of Biological Sciences, The University of
Newcastle
13 Princess Máxima Center for Pediatric Oncology
14 Institute de Recerca Sant Joan de Deu
15 Departments of Neurology, Neurosurgery, Pediatrics, and Pathology, Stanford University School of Medicine
16 Department of Oncology, The Children's Hospital at Westmead
17 John Hunter Children's Hospital, Newcastle
18 Centre for Molecular Medicine Norway (NCMM), Nordic EMBL Partnership, University of Oslo and Oslo
University Hospital
19 Department of Molecular Biology and Biochemistry, Protein Research Group, University of Southern Denmark
20 Pediatric Hematology-Oncology and Neurology, UCSF Benioff Children’s Hospital
21 Division of Pediatric Hematology/Oncology, Department of Pediatrics, University of Michigan
Background: Diffuse intrinsic pontine glioma (DIPG), is a highly aggressive, childhood brain cancer with
a median overall survival of 9-11 months. Remarkably, 80-90% of patients harbour a recurring point
mutation in histone H3 encoding genes, resulting in a lysine-to-methionine substitution (H3K27M). Recent
clinical reports in DIPG have shown that ONC201 increases survival by ~6 months, however patients
invariably become resistant or do not respond to treatment.
Aim: To improve response to ONC201 treatment.
Methods: Using H3K27M patient derived DIPG cell lines, ten of thirteen responded to ONC201 treatment.
Quantitative proteomics was performed on the ONC201 resistant line, SU-DIPG-VI, +/- ONC201 to
determine mechanisms of resistance.
Results: Pathway analysis of proteomic profiling revealed that cells treated with ONC201, upregulated
the AKT signalling pathway. ONC201 is a known agonist of CLPP, degrading SDHA, leading to
mitochondrial dysfunction, therefore ONC201 resistance may be driven by reprogramming to anaerobic
glycolysis, underpinned by PI3K/AKT. To exploit this therapeutic vulnerability, we utilised the blood-brain
barrier permeable PI3K inhibitor, paxalisib, currently in clinical trials (NCT03696355) in combination with
143
ONC201. In vitro combination treatment induced synergistic cell death in both ONC201 sensitive and
resistant H3K27M DIPG cell lines. To confirm the clinical utility of this combination, we examined the
efficacy of ONC201 and paxalisib in a SU-DIPG-VI, H3K27M DIPG, patient derived orthotopic xenograft
model. ONC201 (p=0.01) and paxalisib (p=0.01) both increased overall survival as monotherapies.
However, in combination, ONC201 and paxalisib and induced a significant synergistic effect on overall
survival (p=0.0043).
Conclusions: These data highlight the clinical and therapeutic promise of the combination of ONC201
and paxalisib.