Signaling-targeted therapy

Research focus

The signaling networks in cells are heavily dependent on a system of kinases and phosphatases, signaling enzymes that orchestrate regulation of cellular processes including cell proliferation and cell fate. The Gjertsen group focuses on how intracellular signal transduction can be decoded to early tell responders from nonresponders in cancer therapy. The experimental framework is based on single cell profiling of tumor cells collected in clinical trials, dissecting how signaling in tumor cells is related to therapy response. The molecular pathway from cell surface by the receptor tyrosine kinase down to the transcription factor and tumor suppressor p53 is examined by mass cytometry, proteomics and gene expression analyses. The group is hypothesizing that the signaling pathway and the effector protein p53 can be viewed as integrators of information about proliferative activity and cellular fate. Therefore, decoding the signaling pathways and p53 may provide precise information about therapy response.

Signal transduction is directly involved in leukemogenesis of more than 50% of the aggressive blood cancer acute myeloid leukemia (AML). This is reflected in a spectrum of recurrent mutations found in the progenitor cells, including receptor tyrosine kinases like FLT3, RAS-genes, and tyrosine phosphatases. The Gjertsen group has chosen chronic myeloid leukemia (CML) for comparison to AML.

Subprojects

Subprojects include single cell immune and signal profiling of patients with CML, AML and selected solid cancers, using samples of peripheral blood from patients in clinical trials. The group’s data indicate that CML responds homogenously to ABL1 kinase inhibitors. However, the level of phosphorylated STAT3 indicate how effective the CML therapy is.

In AML, the group is examining whether signaling pathways from receptor tyrosine kinases, e.g., the MAP kinase pathway, may contain information about response to therapy and length of survival. Particularly, they examine whether the therapy given to the patients can be used as a stress test to enhance the predictive power of long-term response.

Preliminary data with the AXL inhibitor bemcentinib reflects this manifold genetic background of AML. The complexity of the tumorhost interaction indicate that these comparative analyses will take time.

The group’s p53 research examines whether p53 isoform patterns are biomarkers of response. The wild type p53 protein reacts to most if not all cancer therapies. Ongoing work addresses how AXL may regulate the p53 protein and its isoforms. This may be an elegant link between the known function of p53 in cell differentiation and quiescence and the therapeutic effects of AXL inhibition.

Important results

Together with Nordic collaborators, the group has shown that kinase inhibitor therapy combined with interferon alpha broaden the immune repertoire in CML. For response prediction in AML, a combined gene expression profiling with ex vivo drug sensitivity screens are effective in more than 60% of the patients. This forms a foundation for future functional signaling analysis of single cancer cells.

Future plans

CCBIO version 2.0 could be a platform to evaluate the concept of early signaling response evaluation in solid cancers followed by adaptive treatment, e.g., by developing single cell techniques analyzing circulating tumor cells. CCBIO significance Gjertsen finds that CCBIO has been pivotal to building the projects towards the study of tumor-host interaction, exploring single cell signaling profiles in immune and tumor cells in the same sample. CCBIO has supported and built technical capacities, specifically mass cytometry for both liquid samples and tissue sections.

PubMed Publications

Find Gjertsen's PubMed publication list here.