DIPG-07. INDUCING DNA LETHALITY THROUGH POLO-LIKE KINASE 1 INHIBITION: A NOVEL THERAPEUTIC APPROACH IN DIPG

Abstract

AbstractDiffuse Intrinsic Pontine Glioma (DIPG) is the most aggressive form of malignant glioma to affect children. DIPG tumours cannot be surgically removed, do not respond to chemotherapy and are highly resistant to radiotherapy. Almost all children present with a short history of symptoms, fast neurological decline and rapid tumour progression. With almost all children with DIPG dying within only one year of diagnosis, new and innovative treatment strategies are urgently needed to counter these devastating tumours. We have found multiple regulators of the cell cycle are overexpressed in DIPG. Polo-like Kinase 1 (PLK1) represents the most promising target within the cell cycle apparatus. PLK1 controls cell cycle progression, cellular response to DNA damage and regulates cell cycle re-entry following arrest. We examined the therapeutic potential of 3 blood brain barrier permeable PLK1 inhibitors readily amenable for rapid clinical translation (BI2536/GSK461364/BI6727). Each exhibited unprecedented anti-proliferative effects against our panel of DIPG cultures at exceptionally low nanomolar potency, decreasing clonogenic abilities and increasing arrest at the G2 checkpoint. We found PLK1 inhibition influences one of the major oncogenic pathways in DIPG, the Phosphoinositide 3-kinase (PI3K) pathway. Interestingly, several key tumour promoting aberrations in this pathway were corrected upon PLK1 inhibition. We therefore examined whether the efficacy of PLK1 inhibitors can be further enhanced through combination with agents that target this pathway. We found cytotoxic activity of PLK1 inhibitors are synergistically enhanced upon addition of the PI3K inhibitor BKM120. We also identified a novel highly potent therapeutic approach for DIPG combining PLK1 inhibitors with temsirolimus (an mTOR inhibitor). In our highly aggressive orthotopic model of paediatric supratentorial High Grade Glioma, PLK1 inhibition significantly and potently enhanced animal survival. We are currently testing PLK1 inhibitors in combination with irradiation in our patient-derived in vivo model of DIPG with preliminary results indicating prolonged animal survival.