Abstract
AB005. Development of tumour specific therapy for treatment of diffuse intrinsic pontine glioma (DIPG)
Jiney Jose1, Peter Choi1, Maria Tsoli2, Anjana Gopalakrishnan2, Carina Lee3, Thomas I. I. Park3, David Ziegler2, William Denny1
1Auckland Cancer Society Research Centre, Faculty of Medical and Health Science, The University of Auckland, Auckland, New Zealand;
2Children’s Cancer Institute Australia, Faculty of Medical and Health Science, The University of Auckland, Auckland, New Zealand;
3Department of Pharmacology, Faculty of Medical and Health Science, The University of Auckland, Auckland, New Zealand
Correspondence to: Jiney Jose, PhD. Auckland Cancer Society Research Centre, Faculty of Medical and Health Science, The University of Auckland, Auckland, New Zealand. Email: j.jose@auckland.ac.nz.
Background: Diffuse intrinsic pontine glioma (DIPG), is an aggressive form of paediatric high-grade glioma (pHGG) that affects children below the age of 10 months. The survival period for a child suffering from DIPG has not changed in decades (approximately 10 months). This pattern is similar for most pHGG; even though the survival period is more extended, tumour recurrence and death are almost inevitable. This is primarily due to the presence of the blood-brain barrier (BBB), which blocks the entry of most therapeutics into the brain, and also due to tumour heterogeneity associated with central nervous system (CNS) tumours that blunt the efficacy of targeted therapy. The development of a meaningful cure for paediatric brain cancer hinges on discovering chemotherapy agents that (I) can cross the BBB; (II) accumulates explicitly in tumour tissues; and (III) can block pathways leading to the escape of cancer stem cells, promoting recurrence.
Methods: This project aims to develop therapeutics that can cross the BBB, a significant hindrance to delivering medicines across the brain, and specifically target cancer cells without affecting normal brain cells. We will accomplish this by attaching novel dyes possessing tumour specificity to various classes of chemotherapy agents. The compounds will be tested on patient-derived paediatric brain cancer cell lines and the most potent compounds will be progressed to an animal model of DIPG.
Results: Several drug-dye conjugates were designed and synthesized to target various aberrant pathways involved in disease initiation and progression of DIPG. These were tested first in patient-derived DIPG cell lines. Several of these drug-dye conjugates showed potent antiproliferative effect in various DIPG cell lines. One of these conjugates is currently undergoing maximum tolerated dose study in an animal model of DIPG.
Conclusions: The present work details an effort to develop BBB crossing tumour specific therapeutic agents for the treatment of DIPG. The work has resulted in several promising drug-dye conjugates showing antiproliferative activity in various patient-derived DIPG cell lines, enabling the progression of such conjugates into animal models of DIPG. Such studies will inform the utility of such drug-dye conjugates for application in difficult to treat pHGGs such as DIPG.
Keywords: High-grade glioma (HGG); blood-brain barrier (BBB); tumour specific drug delivery
Acknowledgments
We thank Dr. Thomas Park, Miss. Carina Lee for establishing the initial cellular testing studies for the compounds.
Funding: This study was supported by the Neurological Foundation (grant No. 2127 PRG) and Cure Kids (No. 3619).
Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://cco.amegroups.com/article/view/10.21037/cco-24-ab005/coif). The authors have no conflicts of interest to declare.
Ethical Statement: The authors are accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved. The study was conducted in accordance with the Declaration of Helsinki (as revised in 2013). The study was approved by the institutional ethics board of University of New South Wales Australia (No. 19/75B) the registration number of the ethics board) and in compliance with national or institutional guidelines for the care and use of animals.
Open Access Statement: This is an Open Access article distributed in accordance with the Creative Commons Attribution-NonCommercial-NoDerivs 4.0 International License (CC BY-NC-ND 4.0), which permits the noncommercial replication and distribution of the article with the strict proviso that no changes or edits are made and the original work is properly cited (including links to both the formal publication through the relevant DOI and the license). See: https://creativecommons.org/licenses/by-nc-nd/4.0/.
Cite this abstract as: Jose J, Choi P, Tsoli M, Gopalakrishnan A, Lee C, Park TII, Ziegler D, Denny W. AB005. Development of tumour specific therapy for treatment of diffuse intrinsic pontine glioma (DIPG). Chin Clin Oncol 2024;13(Suppl 1):AB005. doi: 10.21037/cco-24-ab005
