DDDR-11. TREATING DIPG WITH A MITOCHONDRIALLY TARGETED PLATINUM(IV)-BASED PRODRUG

Abstract

Abstract Diffuse intrinsic pontine glioma (DIPG) is a universally fatal childhood cancer of the brain with 5-year survival rates of < 2%. Despite the introduction of conventional chemotherapy and radiotherapy, improvements in survival have been marginal and long-term survivorship is rare. We previously developed MP-Pt(IV), monoamine oxidase B (MAOB) sensitive, mitochondrial targeting platinum-(IV) based prodrug derived from the chemotherapeutic cisplatin. MP-Pt(IV) is well tolerated and is highly effective in a mice xenograft GBM brain tumour model. Unlike in GBM, the expression levels of MAOB in DIPG are unknown. We tested MP-Pt(IV) against DIPG to test whether DIPG exhibit a similar sensitivity to mitochondrially targeted Pt(IV)-based prodrugs. METHODS In-vitro cell growth inhibition studies were conducted on DIPG cells using MP-Pt(IV). Labeling studies were carried out with MitoSox, MitoTracker, and H2DCFAM. Oxygen consumption studies were performed to show mitochondrial targeting. Clonogenic survival assay and scratch assay were performed. RESULTS MP-Pt(IV) shows potent growth inhibition of DIPG in cell culture studies. Mechanistic studies indicate mitochondrial targeting of the prodrug. Significant increases in cellular super-oxide and hydrogen peroxide levels are observed upon MP-Pt(IV) treatment. Oxygen consumption studies confirm mitochondrial targeting of MP-Pt(IV). MP-Pt(IV) strongly inhibits clonogenic survival and cell migration in treated cells. CONCLUSIONS We demonstrate that MP-Pt(IV) is highly effective in DIPG in vitro and is a good candidate for testing in a DIPG xenograft animal model and further development.