DIPG-08. The development of ACT001 as a novel therapeutic for diffuse intrinsic pontine gliomas

Autor: Dannielle Upton, Sandra George, Jie Liu, Dongpo Doug Cai, Steven Yung-Chang Su, Benjamin Rayner, Maria Tsoli, David Ziegler
Rok vydání: 2022
Předmět:
Zdroj: Neuro-Oncology. 24:i19-i19
ISSN: 1523-5866
1522-8517
Popis: Diffuse Intrinsic Pontine Gliomas (DIPG) are a subset of Diffuse Midline Gliomas (DMG) and are the most devastating of all brain tumours. There are currently no effective treatments. ACT001 is a novel anti-cancer agent in clinical development that is blood-brain-barrier permeable. Previous studies undertaken in adult glioblastoma suggest that ACT001 exerts an anti-tumour effect via induction of oxidative stress and inhibition of NF-kB and STAT3 pathways. In DIPG, we have found that ACT001 demonstrated potent cytotoxic activity against a panel of DIPG neurospheres and also inhibited colony formation. Flow cytometric analysis confirmed the induction of apoptosis in vitro. Interestingly, we also observed increased expression of some markers of the ROS-dependant NRF2 endogenous antioxidant pathway within DIPG neurospheres suggesting an alternative mechanism of inhibition of DIPG cell proliferation involving ROS generation. In vivo testing of ACT001 in a highly aggressive DIPG-orthotopic model showed that ACT001 was well tolerated and significantly improved survival. ACT001 treatment of HSJD-DIPG007 tumour-bearing animals extended median survival from 59 to 78 days (p=0.0005). ACT001 treated mice had significantly decreased proliferating DIPG cells, analysed by Ki67 staining (p=0.01), and significantly increased H3K27me3 staining (p=0.0479). Given the significant effects on H3K27me3 we evaluated two potential drug combinations with known, clinically available epigenetic modifers. Combination of ACT001 with the FACT inhibitor CBL0137 or the HDAC inhibitor SAHA each significantly and synergistically decreased colony formation. These combinations are currently being evaluated in vivo in orthotopic models of DIPG. ACT001 is currently in a Phase 1 paediatric trial for children with DIPG/DMG. Clinical activity has been demonstrated in DIPG/DMG patients, including a reduction in tumour burden and clinical response. These combined preclinical and clinical results suggest that ACT001 is a viable therapy for patients with DIPG/DMG and preclinical combination therapy testing may guide further clinical trials.
Databáze: OpenAIRE
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