Improving the efficacy of immunotherapies for the childhood cancer neuroblastoma

Neuroblastoma is a deadly childhood cancer originating from the peripheral nervous system.

Metastatic neuroblastoma is very hard to treat, but about half of the patients respond to immunotherapy. Thus, there is an urgent need to find ways of increasing the number of patients benefiting from this treatment.

This research could benefit children with cancer by increasing their chance of responding successfully to immunotherapy.

A major cause of failure of cancer immunotherapies is the activation of inflammatory cells, which interferes with the antitumour immune response. In neuroblastoma, formation of myeloid derived suppressor cells (MDSCs) or regulatory T-cells reduce the efficacy of immunotherapies with GD2 antibody or CAR-T cells. Therefore, eliminating the immunosuppressive tumour microenvironment is a major priority in paediatric oncology because it could greatly improve the clinical benefits of immunotherapies.

Developing new molecules designed to inactivate immunosuppressive cells may require many years. A better, and more cost-effective, alternative might be drug repurposing.

We propose to use antidepressants (SSRI inhibitors) to increase the efficacy of immunotherapies in neuroblastoma. Preliminary data in our laboratory and in the scientific literature suggest that

1. antidepressant molecules modulate the phenotype and cytokine expression of myeloid cells and have anti-inflammatory activity;
2. the popular antidepressant fluoxetine (Prozac) has direct anti-neuroblastoma activity in vitro and in vivo.

We propose to study the role of antidepressants in modulating immune suppressive cells using multiple neuroblastoma models. The tumour microenvironment composition and trafficking will be characterized using state-of-the-art techniques such as fluorescent intra-vital microscopy. A small mouse trial with GD2mab (Dinutuximab) in combination with an SSRI inhibitor will be implemented to validate the strategy in neuroblastoma. The ultimate goal of the project is to validate the repurposing of antidepressant molecules in children with neuroblastoma to enhance GD2 antibody and CAR-T cell immunotherapies

Publication

S. Bibbo, A. Lamolinara, E.Capone, S. Purgato, A.Tsakaneli, V. Panella, M. Sallese, C. Rossi, P. Ciufici, V. Nieddu, V. De Laurenzi, M. Iezzi, G. Perini, G. Sala and A.Sala REPURPOSING A PSYCHOACTIVE DRUG FOR CHILDREN WITH CANCER: P27KIP1-DEPENDENT INHIBITION OF METASTATIC NEUROBLASTOMAS BY PROZAC. Oncogenesis, 9(1):3 (2020)

Meet the Principal Investigator(s) for the project

Professor Arturo Sala - Trained in Biochemistry and Cellular Biology at the University of Rome and the Italian National Institute of Health, I completed a PhD in Biochemistry at the University of Rome “La Sapienza” on the topic of DNA and RNA methylation in relation to muscle cell differentiation.  After a short postdoctoral training in the National Institute of Health in Rome, I won an international post-doctoral fellowship from the Italian Association for Cancer Research (AIRC) and moved to the Kimmel Cancer Institute, Thomas Jefferson University Philadelphia. Working in the laboratory of Prof. Bruno Calabretta, I was the first to characterize the transcription factor and oncoprotein B-MYB and establish its relationship with key tumour suppressor genes, such as p53 and retinoblastoma family members.  In 2001 I was recruited by the UCL Institute of Child Health as Senior Lecturer and later promoted to Reader. In UCL I continued to pursue the study of oncogenic transcription factors in the context of neuroblastoma, a childhood tumour affecting the peripheral nervous system. I was appointed Professor of Translational Cancer Research and Deputy Director of the Brunel Institute of Cancer Genetics and Pharmacogenomics in September 2011. In 2016 I joined the Synthetic Biology Theme in the Institute of Environment, Health and Societes. 

Project last modified 12/09/2024