Cancer Cells and Reprogramming Plasticity
Professor Kalland is directing the Prostate Cancer Therapy Research Group at the Department of Clinical Science, and he is engaged in translational cancer research with a focus on molecular mechanisms and regulatory principles underlying reprogramming plasticity that may be exploited by aggressive cancer cells, such as epithelial to mesenchymal transition (EMT), stem cell and neuroendocrine differentiation of prostate cells and asymmetric cell division.
The Prostate Cancer Therapy Research Group is located at the Department of Clinical Science, University of Bergen. It aims to take advantage of recent achievements in order to develop immunotherapy enhanced with molecular targeting and with advanced monitoring of treatment effects, including liquid biopsies and immunoassays.
The group’s projects
Kalland’s research group is engaged in translational cancer research with the focus on molecular mechanisms and regulatory principles underlying reprogramming plasticity that may be exploited by aggressive cancer cells, such as epithelial to mesenchymal transition (EMT), stem cell and neuroendocrine differentiation of prostate cells and asymmetric cell division. The idea is that research using appropriate experimental cell culture, animal models and relevant patient materials will provide insights that may guide innovative cancer therapy and identify useful molecular targets.
One approach is based on the group’s experimental model of stepwise prostate tumorigenesis. This model has been developed by the group starting with a benign human prostate epithelial cell with basal cell features. Using only physiological selection, i.e. different growth conditions and selection over time, gene expression reprogramming gave rise to a series of progeny cells with an accumulating number of malignant features. The model encompasses cells that underwent EMT, acquired ability to grow anchorage independently and eventually formed tumors in mice models. Human prostate tumor cells have been recovered from the animal tumors. All these cell types seem to be relatively stable and can be passaged indefinitely in subconfluent cultures. The passage history is carefully recorded.
The experimental model has generated detailed molecular insight into reprogramming plasticity of prostate derived cells, including EMT, as published in a series of publications. The model was next exploited in a drug discovery and development program. The insight into reprogramming plasticity as one basis of cancer cell heterogeneity has stimulated the initiation of a Phase I Clinical immunotherapy trial that theoretically can confront cancer cell heterogeneity.
The group’s recent publication in PNAS has been broadly covered in scientific commentary journals internationally. Several drugs that inhibited WNT/β-catenin signaling were discovered according to a repurposing strategy. The PNAS manuscript describes a novel mechanism by which one of the leading compounds, the drug axitinib, targets the ubiquitin ligase SHPRH and thereby increases degradation of nuclear β-catenin followed by a shift of malignant symmetrical cell division to asymmetrical cell division. Another publication reports context dependent target genes of the androgen receptor in prostate cells with epithelial versus mesenchymal features with clinical relevance for androgen deprivation therapy, which is the current first line treatment of invasive prostate cancer.
Plans for the future
The drug discovery and development program will continue with follow-up of several leading compounds. By happenstance, evidence has recently emerged that the WNT-β-catenin pathway is important not only for malignant signaling of cancer cells, but additionally for decisions of dendritic cells to react with immune activation or tolerance against neo-antigens. Plans are ongoing to test compounds for combined activity to inhibit cancer cells, to inhibit cancer cell immune evasion and to stimulate immune activation. This work will be used to enhance the ongoing dendritic cell based cryoimmunotherapy and as the basis for development of a vaccination booster strategy.
2016 Spring Interview
Professor Kalland is directing the Prostate Cancer Therapy Research Group at the Department of Clinical Science, and the group has made encouraging progress during the last couple of years.
You work with cryoimmunotherapy, can you tell us about your findings?
"Cryoimmunotherapy can theoretically confront the big problem that cancer cells exist as multiple subtypes due to mutations and gene reprogramming. Unfortunately, in invasive cancer there almost always exist cancer cell types that are resistant to any single specific therapy and these cells will cause relapse after seemingly successful initial treatment. In cryoimmunotherapy, immune cells derived from the patient, called dendritic cells, are injected in high numbers into the cancer tissue that first is killed by freezing inside the body. The dendritic cells may then “see” all the different subtypes of cancer cells and instruct the patient’s immune system to attack all those subtypes. Very recently, we have started a Phase I Clinical Trial of cryoimmunotherapy at Haukeland University Hospital."
Can you tell us about your highlights of 2015?
"One highlight in 2015 was that the Phase I Clinical Trial was started and six patients treated before the New Year. It was a lot of work to assemble the clinical teams, establish the logistics and coordinate and conduct the treatments successfully. Another highlight is that our drug discovery and development program, utilizing an experimental prostate cancer model, identified compounds with the ability to block oncogenic signaling. Patent applications have been filed for several compounds with the ability to block the so-called WNT-beta-catenin pathway, and manuscripts reporting molecular targets of the compounds and novel mechanisms are in the publication process."
What are your plans for further research?
"The research biobank associated with the Phase I Clinical Trial, new methodology for monitoring treatment effects and novel leading compounds, have provided a basis for “next generation” immunotherapy. The times are exciting for innovative combinations of immunotherapy and molecular targeted therapy, and we hope to contribute to the cumulative progress within this field."
Find Kalland's PubMed publication list here.