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Centre for Cancer Biomarkers CCBIO

Signalling-targeted therapy

Professor Gjertsen’s research interest has its background in the study of intracellular signal transduction by protein phosphorylation in regulation of cell death (apoptosis). Early works included the first proof-of- principle concept of apoptosis-resistance mechanism in myeloid leukemia through point mutation in protein kinase A.

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Portrait of Bjørn Tore Gjertsen
Photo:
Ingvild Melien

Following this observation, studies of protein phosphorylation in chemotherapy induced apoptosis in vitro and in patients have elucidated novel mechanisms of cell death regulation. The tumor suppressor protein p53 is tightly regulated through protein modifications, and the impact of this key protein was described by analysis of p53 protein isoforms modulation and p53 directed gene expression in patients during high dose chemotherapy of acute myeloid leukemia (AML). The concept of phosphoprotein signaling response and phenotypic profiling for prognostic information in cancer and as biomarkers in clinical trials was later proposed.

In collaboration with Emmet McCormack, state-of-the-art animal models and advanced molecular imaging of acute myelogen leukemia has been established for development of p53-and signaling-targeted therapy. The research has focused on the aggressive blood cancer acute myeloid  leukemia (AML), affecting approximately 150 new cases in Norway per year. Because of limited therapeutic advances the last two decades and a two-year survival below 20% in patients above 65 years of age,  several clinical trials for Norwegian patients have been established.

The CCBIO Centre of Excellence forms an ideal platform for extensive biomarker and functional sensitivity testing for individualized signal transduction therapy. During treatment, the clonal repertoire of AML is usually highly remodeled, and the most dangerous clones may be hardly detectable at diagnosis but strongly amplified during the intensive chemotherapy.

In the ongoing phase I trial BGBC003 we are currently employing sensitivity screen, exome sequencing, functional signaling analyses and avatar creation of enrolled patients. Several of these techniques allow precise evaluation of clonal evolution during therapy. This early phase clinical trial of the orally available Axl kinase inhibitor BGB324 is the first trial of Axl inhibitor in cancer patients. Through CCBIO and the Helse Bergen clinical trials units, the team will continue to develop new therapy options and novel diagnostics for cancer patients.

 

2016 Spring Interview

Professor Gjertsen and his group have great success with research on the aggressive blood cancer acute myeloid leukemia, AML. Important lessons have also been learned through their exciting research on targeted therapy of chronic myeloid leukemia.

You work with signaling-targeted therapy; can you elaborate on your research?

"Our research group addresses how to understand the signaling inside single tumor cells and we are focusing on biomarkers that may represent future diagnostics. A new machine, a mass cytometer, allows us to pick up more than 50 signals from a single cell. We use this technique to map the various cells in blood cancer. That also includes many normal cells that form essential parts of the immune system. The effects of signaling targeted therapy do not only affect cancer cells, but immune cells as well. Likely, the sum of these effects predicts the outcome of cancer therapy."

What do you hope for in the future when it comes to your research?

"We have two main long-term goals. Firstly, we hope that our new diagnostic tests will increase the precision of leukemia therapy: more correct dose and less adverse effects. Maybe we can tell if a medicine is effective in hours or days, rather than months. Secondly, we currently have, in an early development stage, several molecules that act directly on signaling in cancer cells. The long term goal is that these molecules will be made available for patients, and represent more effective and less toxic therapy compared to contemporary medicines."

What are your coming plans, scientifically speaking?

"We are working on development of «liquid biopsies» in cancer diagnostics and follow-up of cancer patients. Blood samples from cancer patients will be analyzed for small amounts of DNA that has been leaking from tumors and into the blood. This DNA could unravel a spectrum of mutations that are unique to the type of disease, unique for the patients, and unique for the various daughter tumors in metastatic disease. In the future we think this will allow us a more precise picture of the disease, and a better monitoring of therapy effect. For each patient this will implicate more personalized therapy and hopefully better survival."

PubMed Publications