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Centre for Cancer Biomarkers CCBIO

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.

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Karl-Henning Kalland in his office.
Photo:
Ingvild Melien

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 important molecular targets.

Currently, the group is focused on prostate cancer. One approach is based on an experimental model of stepwise prostate carcinogenesis. 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 presented in a series of publications. Currently, manuscripts and work are in progress regarding mechanisms of stem cell differentiation and asymmetric division. A drug discovery and developmental program is ongoing based upon the model, and this has identified novel small compounds and their molecular targets in cancer cells.

The studies on reprogramming plasticity have yielded increased insight into sources of cancer cell heterogeneity. This has resulted in a Phase I Clinical Trial of cryoimmunotherapy against metastatic prostate cancer, in order to exploit the tumor neo-antigenome and address subcellular heterogeneity. The cryoimmunotherapy module will be combined with specific molecular targeting of gene expression that is preferentially activated in tumor initiating cell subpopulations in ongoing innovative strategies against prostate cancer.

 

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."

PubMed Publications