Research team Ourania Kostopoulou

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 chemotherapy (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:

1. Identify whether targeted therapy with PI3K, FGFR, CDK4/6, PARP and WEE1 inhibitors alone or combined, and with or without CT/RT could be useful for NB or MB patients, especially in cases where there is resistance to conventional therapies.
2. Examine if combinational treatments could decrease drug concentrations and  along with the possibility to increase survival also be able to decrease side effects.
3. In addition, by using barcoding and single cell RNA and DNA sequencing in more detail identify subclonal evolution and resistance patterns, according to specific NB/MB tumour molecular profile.

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 by barcoding the cell lines and testing additional inhibitors alone and in combination with the above and according to tumour molecular profile.

PubMed publications from Ourania Kostopoulou

Group members

Ourania Kostopoulou, PhD, Associate Professor, team leader
Monika Lukoseviciute, PhD student
Amelia Irimies, Bachelor student
Albin Dalipi, Medical student