Final Report Summary - NEUROBLASTOMA CHEMO (Chemotherapy of neuroblastoma)
The Neuroblastoma Chemo project addressed several questions related to the pharmacology of neuroblastoma, an aggressive paediatric solid tumour. The first question was whether anticancer drug distribution is restricted to more aggressive neuroblastomas. To address such question we had to evaluate precisely drug distribution in tumor compartments (intracellular, extracellular and vascular). Because the techniques to address such studies were not fully developed, we first validated a reproducible microdialysis-tumor homogenate method that overcomes the limitations of the microdialysis technique in hydrophobic drugs and provides a powerful tool to characterize compartmental anticancer drug distribution. With this method we characterised intra-tumour drug distribution in ‘Patient-derived xenografts’ (PDX) created at Hospital Sant Joan de Déu (HSJD) in Barcelona. Specifically, we studied the distribution of the active metabolite of irinotecan, SN-38 –a very potent anticancer agent-, in several PDX models established from the same patients at different stages of treatment (“diagnosis” and “relapse”). We found that the cellular penetration of the drug was more restricted in “relapse” tumors as compared to “diagnosis” counterparts. Such finding is important because it means that the treatment of chemoresistant tumours could be improved by pharmaceutical methods that increase intratumour drug distribution. Thus, we designed a new drug-delivery system (DDS) to achieve increased drug concentration in tumours. Particularly, we developed a local DDS consisting of a tissue made of biocompatible polymer nanofibres containing pure drug microcrystals of SN-38. Such DDS is deposited on the surgical bed following tumour resection surgery, to achieve “local control” of the microscopic residual tumour. In preclinical studies we found potentially active drug concentrations in the surgical bed in which the film was deposited, for up to one week. As a consequence of increasing local drug distribution, our DDS improves control of tumour recurrences in the resected area. We observed promising activity in preclinical models of paediatric solid tumours such as neuroblastoma, Ewing sarcoma and rhabdomyosarcoma. The drug released from the DDS achieves minimal concentrations in blood, as compared to the concentrations achieved after systemic administration of the prodrug irinotecan. The project has produced three patent applications related to the DDS, owned by our host institution. We expect to bring the DDS technology to clinical trials in the medium term (three years).
Importantly, the strategic goal of Neuroblastoma Chemo was to establish a new translational research laboratory in paediatric solid tumours at Hospital Sant Joan de Déu Barcelona, the host institution, focusing on the improvement of therapy for children with solid tumours by means of preclinical studies. The project provided the basis for many other projects currently ongoing in the lab, focused in paediatric tumours such as Ewing sarcoma, retinoblastoma and diffuse intrinsic pontine glioma (DIPG), among others. We set up a very important resource at the host institution and now have six researchers working under the research line ‘Preclinical Therapeutics and Drug Delivery Research Program’, established as a direct result of this Marie Curie action. Our current projects will lead to three clinical trials at the host institution within the next two years.
Importantly, the strategic goal of Neuroblastoma Chemo was to establish a new translational research laboratory in paediatric solid tumours at Hospital Sant Joan de Déu Barcelona, the host institution, focusing on the improvement of therapy for children with solid tumours by means of preclinical studies. The project provided the basis for many other projects currently ongoing in the lab, focused in paediatric tumours such as Ewing sarcoma, retinoblastoma and diffuse intrinsic pontine glioma (DIPG), among others. We set up a very important resource at the host institution and now have six researchers working under the research line ‘Preclinical Therapeutics and Drug Delivery Research Program’, established as a direct result of this Marie Curie action. Our current projects will lead to three clinical trials at the host institution within the next two years.