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123 abc lane, Townsville, ZZ 00000, USA
Funding Progress: $§ / $§§§§§
OLIG2 Targeting in DIPG using the novel small molecular inhibitor CT179
TranslationalDIPG, Childhood (Brain Cancer)
Lay Summary
Diffuse Intrinsic Pontine Glioma (DIPG) is an incurable brain stem glioma predominantly arising in young children, better options to treat this aggressive disease are urgently needed. Oligodendrocyte transcription factor 2 (OLIG2) is mostly expressed in restricted domains of the brain and spinal cord ventricular zone which give rise to oligodendrocytes and specific types of neurons. OLIG2 is well recognised for its importance in cancer, particularly in brain cancers. OLIG2 is universally expressed in glioblastoma (GBM) and other diffuse gliomas such as astrocytomas and oligodendrogliomas. CT179 is a small molecule made by Curtana Pharmaceutical that disrupts OLIG2 dimerisation, thereby inhibiting OLIG2’s transcriptional function, with favourable chemical properties for blood brain barrier penetration. Our research has shown that CT179 inhibits the growth of GBM and medulloblastoma (MB) tumour cells in the dish, while animal studies using CT179 have demonstrated anti-tumour activity against these tumours. These data are highly encouraging; we now propose to better understand the expression and function of OLIG2 in DIPG and further confirm targeting and efficacy in animals transplanted with human DIPG. If our studies are successful, this project could pave the way for clinical testing of CT179 in DIPG patients.
Executive Summary
Scientific leadership capabilities – Prof Bryan Day will lead this project, he is Group Leader of the Sid Faithfull Brain Cancer Laboratory at QIMR Berghofer MRI in Brisbane. The focus of his laboratory is to better understand the molecular mechanisms which drive the most common and aggressive forms of both adult and paediatric brain cancers. His scientific career has centered on brain cancer where he has undertaken several leadership roles. He currently sits on the Directorship for the Centre for Child and Adolescent Brain Cancer Research (CCABCR). He sits on the Management Committee for the Cooperative Trials Group for Neuro-Oncology (COGNO) and Steering Committee for Brain Cancer Biobanking Australia (BCBA). Additionally, he is a past Director for the Australian Society of Medical Research (ASMR). Prof Day is well placed to conduct this study and progress any positive findings to the clinic. He has >1100 career citations and has published >40 scientific articles directly relating to understanding the biology of and designing and testing new therapies for brain cancer.
QIMR Berghofer brain cancer tissue and culture bank – Prof Day and colleagues have collected >350 primary brain cancer specimens from the Royal Brisbane Hospital, from this tissue >60 primary tumour lines have been generated, grown in serum-free conditions. Tumour bank development is ongoing and we typically receive one specimen per week. We have characterised twelve of these models which are publicly available as a resource (Q-Cell) (Stringer et al 2019, Scientific Reports), all models give rise to intracranial tumours in immunocompromised mice. These models can also be cultured as 3D organoid models which better mimic physiological and pathophysiological processes providing more accurate models of human biology and disease. Prof Day's group routinely perform orthotopic engraftment of brain cancer cells into the brains of mice and have performed >3500 intracranial injections to-date. In addition, we have extensive experience in the administration of radiation and numerous chemotherapy and experimental agents in vivo.
DIPG patient-derived model development
In collaboration with A/Prof Andrew Moore and the Queensland Children's Tumour Bank (QCTB), Prof Day and his team have established DIPG primary cultures and engrafted these models into the brainstem of immunocompromised mice. The team are also sourcing additional DIPG models from their collaborator Prof Johns at the Telethon Kids Institute, Perth, Australia.
OLIG2 expression in brain cancer
OLIG2 is a transcription factor that is expressed in neural progenitor cells during embryonic development regulating their oligodendrocyte and motor neuron multi-lineage potential. Importantly, OLIG2 is re-expressed at high levels and drives an oncogenic program that leads to dysregulation of the cell cycle and subsequent gliomagenesis in adult GBM (Greenall et al, submitted). Our preliminary data has shown that OLIG2 is also very highly expressed in our DIPG models and could therefore pose as a viable therapeutic target for the treatment of this disease.
CT179 efficacy in brain cancer
CT179 is a small molecule made by Curtana Pharmaceutical that disrupts OLIG2 dimerisation, thereby inhibiting OLIG2’s transcriptional function, with favourable chemical properties for blood brain barrier penetration (patent number WO2016138479A1). Our research has shown that CT179 inhibits the in-vitro growth of all patient-derived glioma and MB cells. Preliminary in vivo studies have demonstrated anti-tumour activity using GBM and MB orthotopic xenograft models. We now propose to expand the scope of these studies to further investigate OLIG2 expression and function in DIPG. We will also validate if CT179 is effective using relevant DIPG orthotopic animal models, and synergises with the current standards of care. In collaboration with Prof Johns, we have investigated the efficacy of CT179 in brain cancer, we have screened eleven genetically and phenotypically diverse patient-derived GBM cell lines and five medulloblastoma (MB) cell lines. CT179 displayed nanomolar anti-proliferative activity and induced significant apoptosis mediated through disruption of the cell cycle that resulted in mitotic catastrophe at prometaphase (Greenall et al, submitted). CT179 showed enhanced anti-tumour activity in xenograft mouse models of GBM when used in combination with the standards of care. We have also generated encouraging preliminary in-vivo results using an MB xenograft mouse model, tumour burden was significantly decreased when CT179 (50 mg/kg) used in combination with radiation (4 fractionated doses of 2 Gy, total 8 Gy). We now propose to build upon these positive findings and extend our work to DIPG.
Animal ethics and welfare
All animal procedures and experiments have been approved by the QIMR Berghofer animal ethics committee. Animals are monitored daily and will be culled (end-point) once signs of illness occur, weight loss >20%, hunching, rough coat, reduced activity, reluctance to feed. Tumour progression is monitored weekly using live in vivo bioluminescence imaging. A log-rank Mantel-Cox test will be used to determine if changes in overall survival are significant. Power calculations for similar studies have been carried out in our previous work and determined that 8 mice per group provide more than 90% power to determine a 25% difference with statistical significance of p<0.05 (power test, StatMate® V3). We have performed numerous animal studies using the current brain cancer standards of care, including ionising radiation (IR) and various chemotherapy agents and have optimised the most effective doses in vivo.
Description of Research Proposal
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Budget
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Curabitur ut ipsum non odio malesuada vulputate. Morbi maximus, est eu lobortis molestie, tortor sapien hendrerit nisi, in cursus odio diam ut odio. Fusce pulvinar volutpat velit. Aliquam erat volutpat. Integer rhoncus mollis suscipit. Praesent non ipsum mollis, finibus nunc a, scelerisque nibh. In feugiat iaculis velit, eu semper lacus dignissim nec. Praesent vitae nisi leo. Cras venenatis dictum magna ut semper. Sed eget eros nibh. Sed vitae quam sed dolor faucibus elementum. Curabitur interdum porttitor finibus. Nullam tincidunt odio lectus, sit amet rhoncus libero dapibus sed. Sed mollis egestas enim, vel porta tortor volutpat eget.
Morbi orci urna, ornare non pretium eget, pulvinar eget magna. Ut consectetur efficitur varius. Fusce ac aliquet mauris, at mattis ligula. Quisque est libero, interdum id orci et, ornare luctus diam. Proin commodo lectus id accumsan blandit. Nulla eu turpis interdum, luctus ante ac, imperdiet tellus. In semper enim eu tristique aliquam.
Collaborations and Conflicts of Interest
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Curabitur ut ipsum non odio malesuada vulputate. Morbi maximus, est eu lobortis molestie, tortor sapien hendrerit nisi, in cursus odio diam ut odio. Fusce pulvinar volutpat velit. Aliquam erat volutpat. Integer rhoncus mollis suscipit. Praesent non ipsum mollis, finibus nunc a, scelerisque nibh. In feugiat iaculis velit, eu semper lacus dignissim nec. Praesent vitae nisi leo. Cras venenatis dictum magna ut semper. Sed eget eros nibh. Sed vitae quam sed dolor faucibus elementum. Curabitur interdum porttitor finibus. Nullam tincidunt odio lectus, sit amet rhoncus libero dapibus sed. Sed mollis egestas enim, vel porta tortor volutpat eget.