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New drug containers help decrease resistance to neuroblastoma treatment

Drs Jaume Mora and Angel Montero-Carcaboso from the NEUROBLASTOMA CHEMO Marie-Curie action talk about their work in designing pharmacological treatments capable of circumventing some of the known drug resistance mechanisms.

Drug resistance is a growing concern for society, affecting many treatments ranging from antibiotics to cancer drugs. Researchers have set out to tackle this phenomenon in children diagnosed with neuroblastoma, a cancer affecting the peripheral nervous system. As the most common form of solid tumor amongst children, neuroblastoma is responsible for 15 % of deaths in under 15-year-olds, with only 30 % of stage 4 (metastatic) patients surviving the disease. These mitigated results can easily be explained. Fighting neuroblastoma involves complex treatments whose results are threatened by rapidly developing drug resistance. It is generally considered that this resistance is due to the biological properties of the affected cells, but what if inadequate drug penetration could also be held responsible? This is the lead followed by Drs Jaume Mora and Angel Montero-Carcaboso from Hospital Sant Joan de Déu under the EU-backed NEUROBLASTOMA CHEMO (Chemotherapy of neuroblastoma) Marie-Curie action. The project, which ran for four years and was completed last month, aimed to design pharmacological treatments capable of circumventing some of the known drug resistance mechanisms, while more efficiently penetrating the neuroblastoma tumour cells. In spite of facing some unexpected difficulties, the team managed to develop a new drug delivery system made of biocompatible polymer nanofibres and container anticancer agents. They agreed to unveil the project results and discuss future research in this exclusive interview with the research*eu results magazine. What are the main objectives of this project? Dr Angel Montero-Carcaboso: Our proposal 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. Thus, we designed a combined microdialysis-tumour homogenate technique to characterise intra-tumour drug distribution in ‘Patient-derived xenografts’ (PDX) created at Hospital Sant Joan de Déu (HSJD) in Barcelona. We also wanted to understand whether recurring tumours after clinical treatments evolve towards what we call ‘drug-impenetrable phenotype’. To address this question, we established PDX from the same patients at different stages of treatment (diagnosis and relapse) and applied the techniques mentioned. The third question behind our work was related to the design of new drug-delivery systems (DDS) to enhance drug penetration in highly chemoresistant tumours. Dr Jaume Mora: Most importantly, the strategic goal of our proposal was to establish a 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. What are the main reasons behind the poor results of current treatments? JM: Developmental cancers, otherwise known as children’s tumours, are generally highly sensitive to conventional chemotherapeutic agents. However, 20-30 % of cases remain incurable. These include subtypes of cancers like central nervous system tumours, relapsed cases or metastatic cases. Acquisition of drug resistance is primarily responsible for treatment failure in these patients, because many tumours respond well to initial chemotherapy but eventually progress towards an intractable disease. Several factors are thought to contribute to the emergence of multidrug resistance in neuroblastoma. Loss of function of the gatekeeper protein p53 has been shown to confer a broad multidrug-resistant phenotype in neuroblastoma cells. Accordingly, increased frequencies of mutations in the TP53 gene as well as aberrations that result in inappropriately increased activity of the p53 inhibitor MDM2 have been observed in neuroblastoma cell lines that were established from patients in relapse. Elevated expression of drug efflux pumps has been implicated as a second group of mechanisms by which neuroblastoma cells evade therapeutic intervention. The combination of both factors may lead to the inadequate penetration of chemotherapy to the solid tumour cells, what we call the ‘drug-impenetrable’ phenotype. That functional barrier is what we set out to measure. Did you find a solution to ensure a better penetration of drugs into tumorous cells? How so? AMC: Yes. We have developed a local DDS consisting of a tissue made of biocompatible polymer nanofibres containing pure drug particles of a potent anticancer agent. After the nanofibres was deposited on the surgical bed following tumour resection surgery, we found potentially active drug concentrations in the surgical bed 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 drug. What were the main difficulties you faced during the project and how did you resolve them? AMC: As with every new project in a new host institution, the project evolved to take advantage of the strengths provided by the host. Also, we found that several of the initial objectives of the project were not feasible due to technical reasons (for instance, the model drug did not encapsulate in micelles as initially planned), practical reasons (no providers for specific drugs), or experimental reasons (lack of activity of the initially proposed drugs). We overcame all the difficulties and improved the project as compared to its original version. So now that the project is coming to an end, would you qualify it as a success? JM: Yes. The project produced three patent applications related to the DDS. We published one manuscript and two more are in preparation. The project provided the basis for many other projects currently ongoing in the lab. 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. When do you expect your research to start benefitting patients? AMC: There is a plan at the host institution to bring the DDS technology to clinical trials in the medium term (three years). We are running other projects in parallel that will lead to three clinical trials at the host institution within the next two years. Do you have any follow-up plans after the end of the project? JM: We are currently developing a new targeted nanomedicine for neuroblastoma. Our research is always guided by the feedback of the clinical team and patient advocates. Together, we identify the unmet medical needs that we should focus on in future translational projects.

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