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Centre for Cancer Biomarkers CCBIO

Signaling-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

About the group and its research focus

The Signaling-Targeted Therapy Group 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 and indicated the therapeutic potential of small molecule activators and inhibitors of signaling. 

The group sees CCBIO as an ideal platform for extensive biomarker and functional sensitivity testing for individualized signal transduction therapy.

The group’s projects

During treatment, the clonal repertoire of acute myeloid leukemia is usually highly remodeled, and the most dangerous clones may be hardly detectable at diagnosis but strongly amplified during the intensive chemotherapy. The group is currently analyzing sensitivity screens, exome sequencing and functional signaling analyses from patients in the phase I trial BGBC003 testing the per-oral AXL inhibitor BGB324 (Hellesøy M. et al. ASH Meeting Abstract 2016). This is an exciting trial where the group contributed with the first of 24 dosed patients, and has fortunately been able to follow two long-term survivors.

Signaling-targeted therapy is the cornerstone in treatment of chronic myeloid leukemia. The group has developed a method for monitoring leukemia cells and immune cells early after start of chemotherapy. Material collected from one of several small clinical trials in chronic myeloid leukemia (Nordic CML Study Group) has been analyzed and is prepared for publication in 2017. This experience is applied in analyses of patients treated with AXL inhibitor and conventional chemotherapy of acute myeloid leukemia.

Research results

Intercellular communication in the leukemic bone marrow participates in disease development, progression and chemo resistance. Tunneling nanotubes (TNTs) are intercellular communication structures, and in 2016, the group published that the NF-kB pathway was involved in the regulation and formation of TNTs in AML cells (Omsland M et al. Oncotarget 2016). Standard AML therapy downregulated TNTs and inhibited NF-kB. Interestingly, the widely used chemotherapy daunorubicin was found to be transported through TNTs connecting AML cells indicating a novel function of TNTs as drug transporting devices. TNT communication in the bone marrow compartment could reflect important biological features of AML representing a target for future therapy development.

Plans for the future

In autum 2016, the group was able to test a novel low-toxic combination therapy towards NFkB, a prosurvival pathway in AML. The combination is carefully selected based on in vitro and in vivo experiments. Two patients are dosed at increasing level and a wider inclusion is planned if these pilot patients tolerate the drug combination and possibly indicate response.

The AXL inhibitor BGB324 will likely have to be part of a combination therapy regimen. In addition to test selected anti-metabolite combinations within the clinical trial, the group is also performing a wider combination screen in vitro. The small molecular inhibitor combinations are examined in view of the single cell signaling profile observed in treated patients. The goal is to develop effective combinations that may respond to detrimental clonal evolution.

Development of single cell signaling and immune profiling allow monitoring of immune responses in signaling targeted therapy, and a combination of real time monitoring of clonality and immune state may be central for future determination of responders versus non-responders.

The CCBIO Annual Symposium and the joint CCBIO and Oslo Cancer Cluster meeting on repurposing and in vitro drug screens have been important venues for development of future projects. Together with the CCBIO Junior Scientist Symposia, this creates an active environment for training of young scientists.

 

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