Signaling-targeted therapy

Research focus

The Gjertsen group focuses on how intracellular signal transduction is altered in cancer cells of patients treated with conventional or targeted therapy. The experimental framework is based on tumor cells collected in clinical trials, examining how signaling in tumor cells is related to therapy response. The signaling systems wire the cells and orchestrate a complex regulation of cell proliferation and cell fate. The group has chosen the transcription factor and tumor suppressor p53 as a model for a molecular integrator of cell signaling metabolism and cell stress.

Signal transduction is directly involved in leukemogenesis in 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 RAS-genes, receptor tyrosine kinases like FLT3, c-KIT and CSF3R and tyrosine phosphatases. AML is compared with chronic myeloid leukemia (CML), characterized by a BCR-ABL1 fusion where the ABL1-part comprise a leukemogenic tyrosine kinase.

Subprojects

Subprojects include single cell immune and signaling 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 kinase inhibitors directed to their driver oncogene BCRABL1. Acute myeloid leukemia is a heterogenous stem cell disease, and preliminary data with the AXL inhibitor bemcentinib reflects this manifold genetic background. Lymphocytes in both leukemia and solid cancers may contain information on response to immune therapy, and this will be examined in greater detail.

The p53 research aims to examine whether the p53 system is a ubiquitous biomarker for diagnosis and response evaluation. Ongoing work address how AXL may regulate the p53 protein in AML.

Recent important results

Identifying the impact of sex in prognostication of mutated receptor tyrosine kinase in AML, drawing an outline of complex biological
confounders.

Current challenges

We need better biomarkers for early identification of responders in aggressive cancer. Differences in prognostication by mutations based on sex may be drawing an outline of how confounders may make precision therapy even harder to reach.

Future plans

The group is preparing publications of several extensive research projects in 2022 and 2023. This includes the study of the AXL inhibitor bemcentinib in acute myeloid leukemia, a phase I/II clinical trial that was fully recruited in September 2021 with more than 80 patients in part A and B (ClinicalTrials. gov Identifier: NCT02488408). This work includes single cell immune and signaling profiling and examination of tumor cell fate.

The research will examine how signal transduction modulate the tumor suppressor p53 in myeloid leukemia. The group has shown that wild type p53 is strongly activated 2-4 hrs after start of therapy, with extensive p53 induced gene expression. How signal systems orchestrate p53 in tumor cells during therapy is not known, and whether the manifold pre-mRNA splice forms of p53 play a more important role than the multitude of p53 post-translational modifications, is not known. The connection between signaling systems and p53 will be studied in AML treated with conventional chemotherapy, the AXL inhibitor bemcentinib, or the BTK inhibitor ibrutinib, in search for a biomarker panel that may inform on therapy response.