Precision medicine is the new paradigm of modern cancer treatment and gives hope to an increasing number of cancer patients. Unfortunately, fibroblast growth factor receptor (FGFR) aberrant cancers seem to lag behind this development mainly because FGFR inhibitors often fail or only give transient effects in clinical trials. To answer these challenges, we investigate how FGFR signalling is rewired in cancer cells in order to improve and develop novel strategies to target the FGFRs. We use a combination of functional proteomics, cell biological approaches and appropriate cancer cell and mouse models to achieve this. These results are integrated with data from patient biobanks in order to establish the relevance of our findings.

At present, we are focusing mainly on osteosarcoma and rhabdomyosarcoma.

Cancer cell migration, invasion and metastasis

Metastasis is the leading cause of cancer deaths. In the process of metastasis, cancer cells spread from the primary tumor to the surrounding tissue and to distant organs. One important trait of metastasizing cancer cells, is their ability to migrate and invade nearby and distant tissue. Our research goal is to gain better insight into the processes of metastasis with special focus on cell migration and invasion.

Rhabdomyosarcoma is a rare childhood cancer (approximately 5 new cases each year in Norway) originating in soft tissues of mesenchymal origin. The survival rate for rhabdomyosarcoma patients has increased in recent years. However, as for many cancers, the survival rates for children with metastatic rhabdomyosarcoma is still poor. We want to identify factors involved in metastatic rhabdomyosarcoma.

Another important feature of cancer metastasis is the ability of cancer cells in the primary tumor to secrete factors reaching distinct organs. These factors are thought to aid cancer cells homing in the distant organs by priming a metastatic niche before the cancer cells have reached the site. The project group is also part of a project aiming to identify such factors.

To study cancer cell migration and invasion, we use several assays such as scratch/wound assay, 2D cell migration, transwell assays and inverted invasion assays. We are also developing tools, together with Børge Holme (SINTEF), to automatically track migrating cells (Holme et al). We will combine these methods with drug screening and CRISPR knockout screens.

for more information:

https://www.ous-research.no/haugsten

The NoSarC project, initiated in 2014, has inspired the Norwegian sarcoma environment, and stimulated the interest also for clinical research. This inter­disciplinary consortium of academic scientists and clinicians, representing all health regions grew out of the Norwegian Cancer Genomics Con­sortium (NCGC, cancergenomics.no). With the support from the Cancer Society, Helse Sørøst, The Research Coun­cil and private funds, NoSarC is accruing an inter­nationally unique biobank containing material from several annual popu­lation-based cohorts of Norwe­gian sarcoma patients. The value of our biobank has already been proven through inter­national collabo­rations (ref). The NoSarC projects has several objectives:

1. Collection of a population-based biobank of tumor, blood, plasma and serum samples from sarcoma patients in all health regions of Norway over 3+ years, resulting in approximately 600 samples
2. Next generation sequencing (NGS) analysis of all genes to identify possibly targetable mutated driver mechanisms and possible genetic predisposing factors
3. Establishing in vivo and in vitro models from the most aggressive tumors
4. Preclinical investigations to determine efficacy of available drugs in sarcoma cells in vitro, based on targets found by NGS analysis
5. Medium-throughput drug screens to identify drugs with in vitro efficacy against sarcoma cells
6. In vivo validation of promising drugs in sarcoma xenograft models
7. Initiation of small-scale national and international clinical trials to evaluate the efficacy of new drugs in sarcoma patients

Read more about the project on NCGC Sarcoma.

Many are contributing to the sucess of the NoSarc project!

Read more about the project and "Jakten på en kreftkur" i A-Magasinet.

Many of the research activities and projects at our group involve cutting edge high-throughput -OMICS, including genomics, transcriptomics and epigenomics profiling. In close collaboration with the Oslo University Hospital Genomics and Bioinformatics Core Facilities, our group has extensively characterized a large number of preclinical model systems, including over 40 osteosarcoma and liposarcoma cell lines and xenografts, as well as tumour specimens using next-generation sequencing (NGS) and microarray technology. Our preclinical sarcoma panels have been extensively characterized, describing expression profiles for mRNA, non-coding RNA, miRNA, as well as genomic aberrations including mutations, rearrangements and DNA copy number changes and methylation. The molecular data has been further integrated with detailed phenotypic information, support the selection of models to use for specific preclinical investigations.

Further we have established advanced analysis for clinically relevant parameters as mutational signatures, fusion gene identification and functional annotation of mutations. These well-described model systems represent a unique resource to investigate the efficacy of known and novel therapies, and identification of predictive biomarkers for the development of new therapeutic strategies.

One of the concepts of NCGC, taken further in NoSarC, is the sequencing of all available cell lines representing the various tumour types. Although the xenografts and cell lines established as part of NoSarC are the best to use, since we know the genetic status, many candidate target mutations can be identified also in the older lines by bioinformatic analysis. Over the years we have characterised these lines extensively, and we have initially pursued some of the most interesting ones in preclinical studies.

Our main ongoing preclinical studies are:

• Targeting BRCA-ness osteosarcomas with PARP inhibitor
• Preclinical evaluation of potential targets for personalized treatment of sarcoma
• Therapeutic potential of Axl inhibitor in sarcoma cells
• BRAF inhibition in sarcoma

Blood plasma has been shown to carry small amounts of fragmented circulating cell-free DNA of tumour origin (ctDNA), which has been released to the blood stream through necrosis and apoptosis. These blood samples can be regarded as a non-invasive “liquid biopsies”, providing a real-time insight into the tumour’s genome, and can thus be used to monitor disease progression. By investigating ctDNA from cancer patients, the tumour heterogeneity can be better accounted for, since ctDNA in principle contains DNA representing every cancer cell within the body. As part of the Norwegian Cancer Genomics Consortium, our group collaborates with multiple groups in Norway to establish sequencing-based liquid biopsies analysis for research and clinical use.

 In 2014, our group has initiated a prospective study on circulating DNA in sarcomas (CircSarc). Plasma has been collected before and after surgery, and we are currently monitoring the patients over time, collecting plasma at routine controls and before and after each treatment cycle. This study aims to provide new insights into the clinical utility of liquid biopsies in soft tissue sarcomas, where somatic mutations in circulating cfDNA will be used to detect disease progression, monitor treatment response, study resistance mechanisms and possible therapeutic targets. Patients are begin recruited at Oslo and Haukeland University Hospitals.

You can read more about the study in Sarkomer from the Norwegian sarcoma patient advocacy group.   

A dedicated CircSarc project for gastrointestinal stromal tumours has been established with Dr. Boye at OUH in 2016, to analyse cfDNA from all recruited patients in the NoSarc study. In addition, longitudinal plasma samples are collected for metastatic patients and at selected time points during follow-up and before starting new treatments.

Our group is also establishing new sequencing-based technologies to detect RNA fusion transcripts in exosomes and platelets of cancer patients. Recent studies have shown that cancer cells can release microvesicles in the form of exosomes that might contain dsDNA and RNA. Similarly, “tumour-educated platelets” may contain tumour-derived RNAs. The aim of these studies is to show that cancer specific fusion transcripts can be successfully detected in the exosome or tumour-educated platelets in sarcomas, and further establish the use of fusion transcripts as a biomarker for non-invasive disease monitoring in fusion-driven sarcomas.

Sarcomas are difficult to classify because of their rarity and diversity. Morphological and immunophenotypic criteria are used to subclassify cases, and several subgroups have unclear properties, and even undetermined malignancy. Some subgroups carry pathognomonic genetic aberrations, but at present the diagnostic tests are low-throughput and time-consuming. New techniques, including next-generation sequencing (NGS), are promising and may improve the understanding and diagnostics in sarcomas.

We have set up a translational project on sarcomas to bridge routine molecular pathology with targeted sequencing in a research setting.

Aim

• Assess molecular pathology including NGS based analysis of mutations and sarcoma-specific translocations as a tool for classification and malignancy grade staging and to identify prognostic and predictive biomarkers in sarcoma.
• Participate in the development of new approaches to evaluate genome-based diagnostics for routine clinical practice.

The study will mainly focus on three specific histological subgroups among sarcomas:  leiomyosarcoma (LMS), solitary fibrous tumor (SFT) and undifferentiated pleomorphic sarcoma (UPS).

Gene fusions are somatic events pathognomonic for specific cancer subtypes, aiding in their classification, as well as predictive biomarkers for targets for therapies.  In collaboration with the Section of Molecular Pathology at Oslo University Hospital we are implementing and evaluating sequencing-based approaches to screen for multiple gene fusion, and facilitate the implementation of novel technologies for fusion gene detection in routine clinical diagnostics. 

The molecular assays currently used in a clinical diagnostics can only detect one specific fusion at a time. However, an increasing number of genes have been shown to recombine with several different partners. We are using targeted RNA-sequencing approaches for fusion detection which give the benefit not only to detect a large set of fusions including all possible combinations, but also the fusion partner (known or novel), the expression of the fusion gene and the exact breakpoint at the RNA level.

Sarcomas are especially suited for fusion gene detection, harbouring over 30 histological subtypes with known fusion genes associated with different clinical, prognostic and therapeutic properties. In collaboration with pathologist Dr. Bjerkehagen at OUH, we aim to improve fusion transcript detection in sarcomas, aiding sarcoma classification and differential diagnosis, as well as detecting therapeutic targets.

A study by Baumhoer and co-workers in 2015 showed that many osteosarcomas have a mutation signature that suggests similarity to BRCA-deficient breast and ovarian cancer. Such “BRCA-ness” could indicate a deficiency in the homologous recombination repair (HRR) pathway, and suggests that PARP-inhibitors might have a therapeutic potential. The concept “synthetic lethality” is based on PARP-inhibitors inducing cell death in cancer cells with a deficient HRR pathway by blocking the alternative repair pathway, whilst normal cells can repair damage and remain viable. In this project we are combining the genomics approach with preclinical drug testing, and have found striking effect of PARP inhibition in osteosarcoma cells with defects in the HRR pathway. These studies are being taken further in our patient-derived mouse models.

In a previous study we investigated the case of a patient with high-grade metastatic DDLPS who had several rounds of surgery and been treated with a variety of chemotherapeutic agents. Previously confirmed amplifications of MDM2 and CDK4 were unsuccessfully treated with Nutlin-3a and Palbociclib, inhibitors of each of these targets, respectively. In the study we investigated the possible causes for therapy failure and identified other targets potentially suited for targeted therapy in liposarcoma. We characterized three metastases from that patient by exome and transcriptome sequencing as well as DNA copy number analysis. We identified genomic aberrations of several potentially therapeutically targetable genes. Of particular interest was amplification of KITLG and FRS2, in addition to the characteristic amplification of CDK4 and MDM2. We evaluated the efficacy of drugs targeting these aberrations or the corresponding signaling pathways in a patient-derived cell line (NRH-LS1). Interestingly, the pan-FGFR inhibitor NVP-BGJ398, which targets FGFR upstream of FRS2, strongly inhibited cell proliferation in vitro and induced an accumulation of cells into the G₀ phase of the cell cycle.

In an ongoing investigation we have been able to demonstrate the potential of combining personal genomic characterization of the patient’s tumor with the therapeutic evaluation of potential targets in cells from a patient-derived xenograft. This study indicates that FGFR inhibitors have therapeutic potential in the treatment of DDLPS with amplified FRS2.

The aim of our personalized therapy studies is to combine the potential of high-throughput sequencing and targeted therapy for the development of novel and individualized treatment strategies for sarcoma patients who fail to respond to traditional therapies.