Föreläsningar och seminarier Pediatric Oncology seminar

Nikolas Herold, MD, PhD, Docent, Assistant Professor  

Title: Overcoming resistance to chemotherapy and immunotherapy in paediatric oncology  

Summary: Nikolas’s group focuses on understanding the molecular mechanisms of resistance to chemotherapy and immunotherapy in paediatric cancers. As such, the group is interested in multiple aspects of pharmacokinetic and pharmacodynamic drug resistance, the cancer-host interactions both with respect to germline vs somatic genetics and the role of the tumour microenvironment. The group has a translational profile spanning all the way from identification of resistance factors, developing strategies to target the resistance factor and implementing those findings in clinical trials. Examples of the group’s projects are targeting resistance to cytarabine and nelarabine in haematological malignancies, targeting cancer fusion genes in Ewing’s sarcoma, exploiting drug synergy for more efficacious drug combinations in osteosarcoma, and development of novel immunotherapeutic strategies against solid tumours in children. 

Hala Habash, PhD student (Herold group) 

Title: Identification and characterization of a novel family of endogenous SAMHD1 inhibitors 

Summary: Our group has previously discovered SAMHD1 as a major resistance factor for cytarabine (ara-C) treatments in haematological cancers, in particular acute myeloid leukaemia (AML). We have furthermore identified the non-competitive ribonucleotide reductase inhibitors gemcitabine and hydroxyurea as allosteric inhibitors of SAMHD1 with promising preliminary results from our HEAT-AML trial exploring safety and efficacy of ara-C-enhanced standard therapy against adult AML. Prognostication of which patients might benefit most from SAMHD1-directed AML therapy is important in particular for paediatric patients treated with even more intensive chemotherapy as compared to adults. Efforts are being made to predict ara-C responses based on up to 13 single nucleotide polymorphisms including SAMHD1. 

In collaboration with Birgitte Sander, we have recently found a new protein family that directly interacts with SAMHD1. This interaction inhibits SAMHD1’s enzymatic activity towards ara-C triphosphate, and Kaplan-Meyer analyses as well as Cox regression models in both adult and paediatric AML cohorts resulted in unprecedented prediction of treatment outcomes. 

Moderator: Carlos Rodrigues