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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 Signaling-Targeted Therapy Group focuses on signaling-targeted therapy in chronic myeloid leukemia (CML) and acute myeloid leukemia (AML), two blood cancers derived from the myeloid cell lineage of the bone marrow. The goal has been to employ single cell analysis to risk stratify patients, and to measure effect of target inhibitors of signaling. An underlying hypothesis is that tumor suppressors, with particular focus on p53, is tightly regulating intracellular signaling.

The group’s projects

• Single cell signaling profiling is hypothesized to predict optimal disease control after serial testing of peripheral blood cells before and within one week of first dosing with kinase inhibitor monotherapy. CML is used as a model disease, where signal transduction inhibitors of the Abl kinase provide superior disease control and a long time overall survival that equal healthy comparators.

• Phase Ib/II trial in AML with Axl inhibitor BGB324. This inhibitor does not target a particular driver mutation, but may represent intrinsic resistance against such targeted therapy. Additionally, BGB324 seems to address the tumor-host interaction, and it will be particularly important to determine to which degree this occurs in AML.

• The tumor suppressor p53 is tightly regulated through cell signaling, and additional complexity is added through its multiple expressed isoforms. The group has previously observed that p53 isoform profiles reflect recurrent mutations in genes encoding for signaling molecules. They are currently addressing this relation of intracellular signaling to p53 regulation in cancer.

Important research results

• A wide phosphoprotein screen in AML patient cells was performed using phosphoprotein-enriching columns and differential gel electrophoresis (Forthun et al. 2017). The data supports the impact of intracellular phospho-signaling pathways in reflecting differentiation stage and recurrent mutations. The identified proteins represent a possibility for further development of protein based biomarkers in AML.

• The group’s key publication from 2017 indicated how single cell profiling can be used in CML treated with the kinase inhibitor nilotinib (Gullaksen et al. 2017).

 

Plans for the future

The most important work of 2018 will be to examine single cell analysis of BGB324 treated AML. Two grants were secured in 2017 for startup in 2018. In collaboration with the biotech company BCI Pharma, the group has piloted preclinical development of new kinase inhibitors for the FLT3 kinase. This project is now supported by the Norwegian Cancer Society for four years, where BCI Pharma has the ambition to initiate a phase I early trial in 2019. FLT3-ITD mutations are found in approximately 25% of AML patients, and are strong negative prognostic markers for these patients.

Current challenges in the field

Clonal evolution during cancer therapy is likely the most important challenge in low intensity therapy of acute myeloid leukemia. If single cell immune and signaling profiling could be used to monitor clonal evolution, future therapy could be guided to efficiently keep the disease in check.

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