PCM-22: A NEW APPROACH OF PRECLINICAL TESTING OF CHEMOTHERAPIES - AN EXAMPLE OF BRAIN TUMOUR THERAPY

Choroid plexus carcinomas (CPC) are rare tumours with a dismal prognosis. The role of surgical treatment is well established, but the benefit of either chemotherapy or radiotherapy remains controversial. Therefore, we developed a new preclinical approach that integrates resection surgery and radiation therapy with a novel drug development pipeline using our recently published CPC mouse model. Testing new drugs in concert with neurosurgery or radiation is important since this should increase the predictive power of likely clinical benefit. Our mice first underwent resection surgery to debulk tumours, demonstrating a significant increase in survival (P = 0.0168). Also similar to many clinical situations, single-modality fractionated irradiation (20Gy as 2Gy/dayx5) did not show increase survival of our Tp53 deficient mouse model. Next we combined resection surgery with adjuvant chemotherapy that included lead compounds identified by high throughput drug screening of repurposed chemotherapies. Several highly active drugs were taken into preclinical, pharmacokinetically guided single agent studies but failed to show efficacy. Only Gemcitabine given as 3 hour infusion at 0.805 mg/kg/min prolonged survival of CPC bearing mice (p < 0.0001). To test our lead compound in a clinically relevant setting we randomized cohorts of mice to receive sequential surgery and gemcitabine or surgery alone leading to significant better outcome in the combination arm (p < 0.0001). By closely mimicking clinical trials we hope to identify more efficacious treatments for these devastating paediatric cancers.