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 PRECLINICAL CANCER MODELS
Preclinical models are essential for cancer research. We developed and characterized neuroblastoma patient-derived orthotopic xenograft (PDX) models which retain the protein markers, chromosomal copy number changes, invasive growth pattern, and metastatic capacity of high-risk patient tumors (Braekeveldt et al., Int J Cancer, 2015). Serial in vivo passaging revealed that PDXs also retain temporal genetic stability including mutational profile, copy number changes and transcriptome profile. Interestingly, PDXs obtained from different parts of a single patient tumor can result in divergent tumor phenotypes, indicating a significant functional intratumor heterogeneity in neuroblastoma (Braekeveldt et al., Cancer Res, 2018). PDX models are clinically relevant models which can be used to decipher cancer treatment resistance and for preclinical drug testing. There are however still many opportunities to further develop and improve preclinical cancer models (Braekeveldt & Bexell, Cell Tissue Res, 2018).
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 respond initially to treatment but treatment-resistant relapse is not uncommon. Intra- and intertumor heterogeneity are significant challenges in this context (Karlsson et al., Nature Genetics, 2018). The aim of the project is 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 will be helpful to identify novel treatment regimens.
3. IDENTIFICATION OF NOVEL THERAPIES AGAINST NEUROBLASTOMA
We seek 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).