SCIDOT-32. NEUROSURGICAL DELIVERY OF THE POLY ADP RIBOSE POLYMERASE-1 INHIBITOR OLAPARIB FROM A THERMO-RESPONSIVE BIODEGRADABLE PASTE POTENTIATES RADIOTHERAPY AND PROLONGS SURVIVAL IN HIGH-GRADE GLIOMA

Abstract

Abstract There has been considerable interest in repurposing the poly ADP ribose polymerase inhibitor and purported radiosensitiser olaparib (Lynparza), with a recent dose escalation study of olaparib plus temozolomide in recurrent GBM showing good tolerance (Fulton et al 2018). Due to systemic therapy-associated caveats such as dose-limiting toxicities and blood-brain-barrier penetration, here we assess localised post-surgical delivery of olaparib from our previously developed poly(DL-lactic-co-glycolic acid) (PLGA) and poly(ethylene glycol) (PEG) (PLGA/PEG) thermo-sensitive biodegradable paste. Metabolic and clonogenic assays revealed impaired proliferation and clonal growth respectively, upon acute exposure of high-grade glioma cells to olaparib (3–5µM), an effect dramatically potentiated with 3Gy radiation. Flow cytometry of Annexin V+/Propidium iodide+ rodent and human high-grade glioma cells, revealed a significant cell proportion increase at late stage apoptosis when exposed to 2–3µM olaparib and 3Gy radiation (relative to untreated, olaparib alone or radiation alone). A high-grade glioma orthotopic allograft study is ongoing where we already observe a significant overall survival benefit of locally-delivered 10% and 20% w/w (drug:polymer ratio) olaparib via PLGA/PEG paste post-surgery with adjuvant radiotherapy, compared to surgery/oral temozolomide/radiotherapy (GBM standard-of-care) and surgery/systemic olaparib (120 days vs. 44 vs 30 respectively). A more pronounced survival benefit, as determined by the total number of long-term surviving animals, was observed with combined PLGA/PEG/olaparib/temozolomide/radiotherapy or PLGA/PEG/olaparib/etoposide/radiotherapy. RNAseq data from 10 GBM patients show significantly elevated levels of apoptosis-inducing factor-1 in 5-aminolevulinic acid (5ALA)+ fluorescence–activated cell sorted populations (i.e. purified tumour cells from the invasive margin), relative to 5ALA- cells, confirming PARP-1 activity in infiltrative tumour cells. Collectively our data supports a clinical rationale for localised olaparib delivery with adjuvant radiotherapy.