Research team Ourania Kostopoulou
Studies on targeted therapy against childhood cancer and especially neuroblastoma and medulloblastoma.
Childhood cancer is still the most common cause of death in the ages 1–14 years, although today the survival rate is over 85%. Leukaemia is the most common cancer in childhood (30% of paediatric malignancies), while brain and central nervous system (CNS) tumours are the most frequent among the solid tumours (20% of childhood cancers).
MBs, one of the main focuses of our studies, are among the most common malignant brain tumours, accounting for 16-25% of all central nervous system (CNS) tumours in children, and they usually arise in the cerebellum. MB is treated with surgery and radiotherapy (RT) and survival is around 60% so improvement of survival as well as quality of life is warranted.
NB, the other important cancer of our studies, is the most common extracranial solid tumour occurring in childhood. NB can have a diverse clinical presentation and of course depending on variable tumour biology. Despite intensive CT, the survival of high-risk NB for those with recurrent or relapsed disease is low. Thus, new therapies are in need.
Phosphoinositide 3-kinase (PI3K) is linked to pathological cell growth and oncogenesis, and somatic mutations in the PI3K subunit, PIK3CA have been reported frequent in adult cancers, and therapies with PI3K inhibitors in adult cancer (with/without PI3K mutations) have been attempted. PIK3CA mutations are rare in NBs, but PI3K inhibitors together with other drugs have been tested experimentally in NB/MB, and initial reports were promising.
Furthermore, another signalling pathway that has been found to be involved in solid tumors is initiated by fibroblast growth factor receptors (FGFR). FGFRs are a family of tyrosine kinase receptors that are deregulated in many cancers, leading to more aggressive growth. This has also been shown by the T. Dalianis group in human papillomavirus (HPV) positive tonsillar and base of tongue cancer, where FGFR3 mutations/deregulation are associated with worse survival. For childhood cancer, knowledge regarding the FGFR protein family is limited, but FGFR inhibitors may also be of use. Recently, FGFR4 mutations were reported in 7.5% primary human rabdomyosarcomas and FGFR3 and FGFR1 expression was analysed in ependymomas and pilocytic astrocytomas, and increased FGFR3 and FGFR1 expression was reported in aggressive ependymomas.
The objectives of our studies are to:
- Identify whether targeted therapy with PI3K and FGFR inhibitors could be useful for NB or MB patients with PI3K and FGFR mutations
- Identify whether targeted therapy using FGFR and PI3K inhibitors could be useful to treat children, especially in cases where there is resistance to conventional therapies
- Examine if combinational treatments could decrease drug concentrations, and along with the possibility to increase survival also be able to decrease side effects.
Recently, we have very promising results using PI3K and FGFR inhibitors on NB and MB cell lines. We found dose dependent responses to both PI3K and FGFR inhibitors and when we combined the two inhibitors, synergistic effects were obtained. We are presently exploring these data further and testing additional inhibitors alone and in combination with the above.
Ourania Kostopoulou, PhD, docent, team leader
Monika Lukoseviciute MSc student (stud.)
Eleni Papa MSc (Erasmus stud.)