We are dedicated to help children with cancer and our work is focused on neuroblastoma, a cancer derived from the sympathetic nervous system. Our overall goals are to investigate mechanisms of treatment resistance and to identify and test novel therapies against high-risk neuroblastoma. We have three main aims:
1. DEVELOPMENT OF CLINICALLY RELEVANT CANCER MODELS
Clinically relevant models are essential for cancer research. We have developed and characterized neuroblastoma patient-derived orthotopic xenograft (PDX) models which retain the genetic features, transcriptome profiles, protein markers, invasive growth pattern, and metastatic capacity of high-risk patient tumors (Braekeveldt et al., Cancer Res, 2018). PDX models are clinically relevant models which can be used to decipher treatment resistance and for preclinical drug testing. We further established humanized models of neuroblastoma bone marrow metastatic disease (Grigoryan et al., Sci Transl Med, 2022). The models recapitulate many of the features of bone marrow metastatic disease in neuroblastoma patients. These models will therefore be important to understand and target neuroblastoma metastasis.
2. MECHANISMS OF TREATMENT RESISTANCE AND RELAPSE
Current treatment of high-risk neuroblastoma includes a combination of chemotherapies, surgery, targeted therapy, anti-GD2 therapy, and more. Many patients have an initial response to treatment but treatment-resistant relapse is common. Intra- and intertumor heterogeneity are significant challenges in this context (Karlsson et al., Nature Genetics, 2018). We have shown that neuroblastoma chemoresistance is associated with an immature mesenchymal-like phenotype (Manas et al., Sci Adv, 2022). We seek to investigate the molecular mechanisms and pathways underlying neuroblastoma treatment relapse. An integrated understanding of the genetic and non-genetic mechanisms involved in treatment resistant relapse is necessary to identify novel treatment regimens.
3. IDENTIFICATION OF NOVEL THERAPIES AGAINST NEUROBLASTOMA
We work to identify and test novel combination therapies against high-risk neuroblastoma. One such example is triple PIM/PI3K/mTOR inhibition which, in combination with chemotherapy, is a promising anti-neuroblastoma treatment strategy (Mohlin*, Hansson* et al, EMBO Mol Med, 2019). Recently, we performed a high-throughput drug screen and identified several novel anti-neuroblastoma drugs. Using 3D tumor organoids and orthotopic PDX models we showed that KSP-inhibition is a powerful treatment strategy against neuroblastoma. KSP-inhibition leads to abnormal monoastral spindles, mitotic arrest, neuroblastoma cell apoptosis and increased survival in PDX models (Hansson et al. Science Transl Med, 2020). Using molecular characterization of treatment resistance and metastatic relapse we aim to identify new approaches for targeting resistant tumors with novel drugs and drug combinations. We are continuously evaluating new treatments in our clinically relevant, patient-derived models in vitro and in vivo.