New treatment for glioblastoma: Regulation of general resistance mechanisms and opportunities for development of new therapeutic protocols.

Glioblastoma multiforme (GBM) is the most malignant primary brain tumor. The cancer cells vary between more treatment-resistant and more treatment- sensitive cell-states. Current studies aim to uncover forces that drives these phenotypically linked cell-state transitions changes to develop efficient treatment.  


To improve the prognosis for patients with glioblastoma by development of means to identify and manipulate cell-states linked to treatment response, including sensitization towards conventional treatment.


GBM is the most malignant primary brain tumor and efficient treatment is essentially lacking. As most solid tumors GBM is heterogenous and the tumor cells vary in therapy response and molecular characteristics. We believe the chances for curative treatment would improve if this diversity was diminished. By raising cell cultures from single tumor cells from the same patient tumor (clones) we partly capture this variation. We have linked drug and radiation resistance (RES) to a cell state of mesenchymal (MES) character and sensitivity (SENS) to proneural (PN) characteristics (Segerman et al., Cell Reports, 2016) Importantly, these cell state appears epigenetically regulated and reversible. Also, the cancer cells seem to naturally, but at low speed, slide back and forth between more treatment-resistant (RES/MES) and more treatment- sensitive (SENS/PN) cell-states and the MES cell-state coincides with the inducible inflammatory profile of reactive astrocytes (Niklasson et al., J. of Pathol. 2019).

Project plan 

Current studies aim to uncover forces that drives the change in treatment resistance/cell state. The general approach is to by various means stimulate and/or antagonize pathways that appear to be more active in sensitive and resistant clones, respectively. Natural ligands, drugs, genetic techniques or other means, coupled to induction

We then monitor for changes in drug and radiation response as well as molecular profile to link phenotype to molecular changes. Molecular profiling can reveal new therapeutic opportunities and identify markers predicitve of treatment-response. Molecular profiling is done on the RNA and protein level. We aim to establish pyrosequencing for detection of selected DNA methylation markers linked to the RES/MES or SENS/PN cell-state, which might be part of the project.
Preliminary results indicate that combinatory treatments will be needed to reverse the MES-like cell state and sensitize resistant clones. The studies concern GBM but this type of general, epigenetically regulated, resistance mechanism is seen in diverse malignancies; the concept of antagonizing such general resistance mechanisms, if successful, might well be applicable on other tumor types.

Contact details

Anna Segerman, MD PhD
Research group: Bengt Westermark (IGP) and Rolf Larsson (IMV)