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Centre for Cancer Biomarkers CCBIO
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Scientific Activities and Progress 2019

CCBIO has a two-armed portfolio of biomedical (Team I-III) and societal (Team IV) projects. The Centre has a focus on biomarkers of tumor-microenvironment interactions in primary and metastatic cancers, including the expanding field of tumor immune biology, and how these properties can define aggressive tumor phenotypes and predict tumor progression and treatment response. Studies on ethics and economics represent an integrated part of CCBIO. All activities are performed in a context of interactive education and communication efforts.

Microscope photo
Photo:
CCBIO/Lorens group

During 2019, the CCBIO Research School for Cancer Studies has increased its activities. In addition to the basic course curriculum CCBIO901-906, a new course, CCBIO907 – Cancer Related Vascular Biology, was run and funded by INTPART. This is a collaboration with the Vascular Biology Program at Boston Children’s Hospital and Harvard Medical School, with visiting faculty to Bergen. A new course, Clinical Trials in Cancer Research, with integrated Good Clinical Practice certification was introduced. The very successful two-days’ Scientific Writing Seminar was repeated in 2019.

In TEAM I, projects are focusing on how tumor cells interact with and instruct the surrounding microenvironment, by influencing angiogenesis, cancer associated fibroblasts, immune cell participation, and matrix involvement, favoring tumor growth and metastatic spread, and explaining development of treatment resistance.

The Gullberg group has been working on fibroblast biology and the characterization of novel integrin α11 function blocking antibodies and development of a mouse model to explore the role of α11 in tumor stroma. In 2019, the group reported an interaction between α11 and PDGFR-beta and the importance in breast cancer progression (Primac et al., J Clin Invest 2019).
In the Kalland group, focus has been on two strategies: drug discovery and development by repurposing, and the concept of cryo-immunotherapy (CryoIT). Some of the screened drugs have been shown to inhibit either β-catenin or STAT3 signaling. These are important regulators of tumor-initiating prostate cancer cells. During 2019, a phase I clinical trial for CryoIT for patients with advanced prostate cancer was completed. Treatment effects were suggested according to radiology, circulating tumor cell enumeration, large-scale serum auto-antibody profiling and ultradeep T-cell receptor sequencing, and the results are prepared for submission.
The McCormack group has had a major focus on the importance of studying appropriate preclinical models (organoids, PDX) before clinical trials are performed. Such models have been developed and explored for gynecologic cancers, leukemias, pancreatic cancers, and others. Several imaging techniques have been studied, for example against CD24 in high-grade ovarian cancers in PDX-models, aiming for increased sensitivity in tumor detection and more precise surgery. Strategies for improved drug delivery have been examined, for example by using sonoporation, showing how this might impact the intracellular signaling of cancer cells with identification of biomarkers (Haugse et al., Pharmaceutics 2019).

In TEAM II, studies are being performed on biomarker discovery and validation in several tumor types, with additional work on how such markers are related to underlying mechanisms for tumor progress, tumor immune responses, and development of resistance to various treatments. Efforts are made to map tumor diversity and associations with clinico-pathologic phenotypes and patient outcome.

The Akslen group concentrates on tissue-based biomarkers for better molecular grading of malignant tumors and improved prediction of prognosis and treatment response. The main focus is now on proteomics profiling of luminal-like and basal-like breast cancers, with particular attention to hypoxia responses and metabolic differences as well as markers for a neuroangiogenic phenotype in aggressive tumors. Here, laser captured microdissected samples of the tumor cell and microenvironment compartments are studied separately. Imaging mass cytometry (IMC) is used to map the breast cancer tissue landscapes for high-order co-expression patterns with particular focus on vascular and immune cell components. In addition, markers such as Nestin and Stathmin are studied in more detail. During 2019, a report on tissue structure by radiologic analysis of breast cancers was presented (Hofvind et al., Lancet Oncol 2019).
The Lorens group has been studying various aspects of how the Axl receptor tyrosine kinase is involved as a key regulator of normal adult epithelial progenitor cells and a determinant of carcinoma cell plasticity and interactions at the tumor-immune interface. The results have shown an important role of Axl in epithelial-mesenchymal transition (EMT) and immune evasion. Mechanisms of acquired resistance to targeted treatment in malignant tumors have been uncovered, and studies have demonstrated how anti-Axl treatment (by bemcentinib) can reverse these processes. In one project, Axl inhibition drove tumor cell differentiation and reversed gemcitabine resistance and potentiated an immune stimulatory microenvironment by targeting immune suppressive myeloid cell types. Thus, Axl targeting affects pathways that improve treatment efficacy. During 2019, the group showed that Axl is a key factor in acquired resistance to EGFR targeted treatment in lung cancer (Lotsberg et al., J Thor Onc 2019). Lorens and his team focus on highdimensional single cell studies using the established imaging mass cytometry platform. Axl immunohistochemistry is being developed in collaboration with BerGenBio as a companion diagnostic test for bemcentinib treatment. 
The Costea group studies tumorstroma interactions in oral and vulvar squamous carcinoma, with particular focus on metabolic reprogramming of carcinoma associated fibroblasts (CAFs), and the association with genetic alterations, including HPV subtypes and their role for tumor progression. The group previously demonstrated transcriptional heterogeneity among CAFs. During 2019, the group showed how a novel metabolic coupling between oral carcinoma cells and normal neighboring fibroblasts are induced to export mitochondria towards carcinoma cells through direct contact or indirect mechanisms (Zhang et al., Cell Mol Life Sci. 2019). In studies of gynecologic cancers by the Krakstad group, tissue and serum-based biomarkers have been further explored, with special focus on estrogen regulated pathways and their prognostic value. The international MOMATEC2 study (NCT02543710), a phase 4 implementation trial for validation of ER/PR status to stratify for lymphadenectomy in endometrial cancer, is ongoing and coordinated by the group. Novel PDX models for endometrial cancer have been established, and integration of molecular and radiologic data with clinical phenotypes is ongoing. During 2019, the group reported that PIK3CA amplification is associated with aggressive phenotypes but not markers of AKT-mTOR signaling in endometrial cancer (Holst et al., Clin Cancer Res 2019). 
The Wik group has a focus on breast cancer of the young and why these patients often experience a more aggressive disease behavior. A large cohort has been established with multiple molecular and clinico-pathologic annotations, including primary tumors and metastases, and further genetic and imaging mass cytometric profiling is ongoing. So far, studies have been performed on estrogen related signaling networks and transcriptomic profiles with particular attention to aggressive patient subgroups.

In TEAM III, the main focus is to perform clinical trials with associated biomarker studies, and to promote novel findings on markers and treatments for clinical implementation and change of practice.

The Gjertsen group has been focusing on single cell biomarker profiling of leukemia and solid cancer cells and immune cells following treatment with novel targeted therapy or conventional drugs in a trial setting, to stratify between responders and non-responders. The group has reported how single cell analysis can be used to monitor early responses in AML. In a new project, the CSF1R signaling system in stromal cells is studied, and inhibition of CSF1R may represent a novel resistance mechanism. The group is also active in the p53 field, with particular attention to the importance of p53 isoforms. During 2019, the team presented results on multiparametric single cell evaluation related to drug responses in hematological cells (Majumder et al., Haematologica 2019).
The Straume group is focusing on tissue biomarker studies in clinical trials. The group has also reported the association between surgical tissue trauma and recurrence dynamics in high risk breast cancer patients. A national academic trial combining anti-Axl treatment with immunotherapy is ongoing in patients with advanced melanoma, aiming to analyze efficacy and identify potential predictive markers. A national interventional study of patients with aggressive melanoma (IPI4; ipilimumab) is also being analyzed. During 2019, the group reported a relationship between circulating tumor DNA and response to bevacizumab monotherapy in patients with malignant melanoma (Forthun et al., Sci Rep 2019).
The Bjørge group is engaged in novel multicenter trials with translational research programs related to high-grade ovarian cancer. The group also has a focus on improved imaging guided cytoreduction surgery in this disease. In addition to clinical studies, PDX models and organoid cultures are being established. High-dimensional tissue profiling of ovarian cancer samples have been initiated with special attention to immune responses. During 2019, Bjørge and colleagues reported a proof-of concept study of niraparib-bevacizumab combination therapy against niraparib monotherapy in recurrent platinumsensitive ovarian cancer (Mirza et al., Lancet Oncol 2019).

In TEAM IV, the projects on ethics and economics of biomarker-based therapy are expanding and are being integrated in clinical trials. As CCBIO performs research on cancer biomarkers along the entire chain from studies of biological mechanism to clinical projects, the main societal impact resides in this sense in the improvement of cancer diagnostics and therapies and in medical innovation. The main measure of this impact is ultimately its effect on the quality and cost-effectiveness of cancer management, whereas it cannot be precisely measured in the short-term. Better knowledge of cancer biomarkers is likely to affect the prioritization dilemmas, although the nature of that effect depends on the nature of the knowledge to be discovered. CCBIO integrates work on societal perspectives and has established a team structure led by Strand to improve interdisciplinary humanities and social science programs to study the opportunities and challenges of precision cancer medicine. The team will continue their collaborations on the more conceptual research into RRI and the coproduction of science, technology and society.

The Strand group contributes to intellectual understanding and awareness within the Centre. A key insight is that the quality of a biomarker is a complex issue with scientific and technical but also clinical, economic, ethical and political dimensions. Collaboration has increased with CCBIO ethicists (Norheim group) and economists (Cairns group). Work on a second book project is ongoing (Bremer & Strand, eds: Precision Oncology: Issues at Stake and Matters of Concern. The team is responsible for the basic course CCBIO903 – Cancer Research: Ethical, Economic and Social Aspects. 
The main health economic projects performed by the Cairns group are the PhD projects by Kelly Seo (cost-effectiveness modelling of predictive biomarkers in targeted oncology therapies) and Ana Beatriz Luis (incentives for developing new cancer biomarkers and targeted therapies). The candidates have recently collaborated on a paper assessing the impact of cancer biomarkers on health outcomes in Norway, and their results suggest that biomarker tests improve health by ensuring that the right treatment is given to the right patient and that the effect is stronger for cancer types for which fewer drugs are available. During 2019, a new PhD project has been undertaken by Jiyeon Kang (improving economic evaluation and decision-making for oncology drugs using real-world data). A paper on the cost-effectiveness profile of HSP27 in response prediction for bevacizumab in advanced melanoma was published (Seo et al., Pharmacoecon Open 2019).
In the Norheim group, an aim has been to map how cancer biomarkers can inform and hopefully improve health care priority setting, in addition to factors such as patient age. The group’s findings suggest that age is widely used, directly or indirectly, to guide clinical decisions (published in 2018). Further work will investigate how information from cancer biomarkers will blend into this decision-making process and if, as predicted by many, it will lead to fairer priority setting decisions. During 2019, the Global Health Priorities Research Group directed by Ole Frithjof Norheim has grown and developed into a center - the Bergen Centre for Ethics and Priority Setting (BCEPS), with funding from the Bill & Melinda Gates Foundation among others.

Altogether in TEAMS I-IV, a range of projects have been conducted and reported on since 2013. In addition, multiple new initiatives have been conceived, in part based on increasing intramural collaboration. In addition to many publications and two books presented by CCBIO, several educational activities are being performed, and we continue to reflect on the core concept and integrated activities in CCBIO and the transition to real life impact.

In addition to the activities in these teams, the Jonassen group has been actively collaborating across different groups on the systems biology features of many projects and processing of big data. During 2019, his team initiated a new ERAPerMed project, AML_PM - Improved Treatment of Acute Myeloid Leukemia, with partners including Gjertsen from CCBIO and Ursula Klingmüller (recruited to the CCBIO International Faculty) and others. Postdoc Dimitrios Kleftogiannis, linked to this project, is also using part of his time to work with the Akslen and Wik groups in CCBIO. Within the AML_PM project, the group will analyze single-cell data together with gene and protein expression information and develop machine learning based approaches to predict drug responses and aid in personalized treatment of leukemia.