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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.

Portrait photo.
Photo:
Ingvild Festervoll Melien Illustration: Gaute Hatlem/Eli Vidhammer

Research focus

The Gjertsen group focuses on intracellular signal transduction in conventional and targeted therapy and questions how signal transduction in cancer cells and stromal or immune cells may act as biomarkers. These represent biomarkers for response or non-response in patients before and early after start of therapy. Such an aim calls for special infrastructure of patient selection and sample logistics. Clinical trials with strict sample procedures and logistics have proven to be necessary to test these hypotheses.

The group’s projects

Subprojects include single cell immune and signaling profiling of patients with chronic myeloid leukemia, acute myeloid leukemia and selected solid cancers, using samples of peripheral blood from patients in clinical trials. The group’s data indicate that chronic myeloid leukemia responds homogenously to kinase inhibitors directed to their driver oncogene BCRABL1. Acute myeloid leukemia is a heterogenous disease where the spread in responde to a single kinase inhibitor is wide, however, the response to intensive chemotherapy is more homogenous. Lymphocytes in both leukemia and solid cancers may contain information of response to immune therapy, and this should be determined more in detail.

Important research results

Optimalization of protein-based biomarker panels for mass cytometry has been reported (Gullaksen SE et al. Cytometry A 2019). This technology was used in acute myeloid leukemia for multi-parametric single cell evaluation. The group defined distinct ex vivo drug responses in healthy hematological cells that are retained in corresponding malignant cell types (Majunder MM et al. Haematologica 2019). Based on ex vivo drug responses, the group tested the therapeutic effect of a novel combination with interferon alpha and valproic acid (Forthun RB et al. J Cancer Res Clin Oncol 2019). Interestingly, in vivo experiments in rat and mouse showed no benefit of the combination valproic acid and interferon alpha, in contrast to similar tumor cells treated in culture. This is an example of how in vivo experiments demonstrate a lack of effect, or even detrimental effect on overall survival, similar to what has been seen repeatedly in clinical trials. These results ended the group’s ambitions for clinical development of this combination of interferon alpha and valproic acid. However, biomarkers based on phosphorylated proteins appeared optimal for following therapy.

Plans for the future

The group’s focus in the coming years will be to examine if tumor cells, support cells or immune cells comprise the most useful information for response determination in AML patients treated with the AXL inhibitor bemcentinib. Preliminary results based on clinical trials in chronic and acute myeloid leukemia, as well as immune therapy in various solid tumors, are now evaluated and validating mass cytometry experiments will be performed on clinical samples collected from specific clinical trials.

Current challenges in the field

The costliest cancer therapy is the therapy that does not work. Based on examples from small subsets of leukemic diseases like chronic myeloid leukemia and acute promyelocytic leukemia, biomarkers may secure targeted therapy for responders with high accuracy. Contemporary biomarkers are dominated by genomic tests, and to some degree, single proteins detected in histopathological tumor sections. The Gjertsen group addresses functional biomarkers and biomarker panels in tumor and contextual cell types, seeking a more precise response prediction.

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