Cancer Cells and Reprogramming Plasticity
Professor Kalland is directing the Prostate Cancer Therapy Research Group at the Department of Clinical Science. The current research focus of the Prostate Cancer Therapy Research Group is to improve ongoing cryoimmunotherapy (CryoIT) by molecular immunomodulation and development of a dendritic cell based booster vaccine.
Drug Discovery and Developmental Program. The group’s newly developed model of stepwise prostate tumorigenesis was used in two different approaches in a drug discovery and development strategy. According to a repurposing strategy, a panel of more than 600 commercially available FDAapproved drugs was screened in an assay to detect compounds with the novel features of inhibition of WNT-β-catenin signaling pathway. Several candidate compounds were found and were extensively experimentally characterized using additional suitable methods.
In a different drug discovery strategy, a large panel of compounds isolated from Chinese plants and herbs has been screened using a STAT3 activity reporter. Potential STAT3 inhibiting compounds have been found and characterization continues.
Dendritic cell based cryoimmunotherapy (CryoIT). The ongoing autologous dendritic cell based CryoIT Phase I Clinical trial has by the end of 2017 treated 15 patients with metastatic castration resistant prostate cancer (mCRPC). Interim laboratory, radiological, clinical and research biobank patient data were plotted into a new WebCRF database locked September 15th. Analyses continue into 2018.
The identification of nitazoxanide as a compound that binds to the enzyme PAD2 followed by citrullination and degradation of β-catenin is a novel mechanism of modulation of β-catenin signaling and was published in Nature Chemical Biology. Additional experimental work on new compounds, molecular targets and molecular mechanisms of β-catenin regulation was published in PNAS and reviewed in Cell Cycle. The generation and examination of fluorescent and luminescent reporter systems of androgen receptor directed transcriptional regulation was published in PLoS ONE. An interim analysis of patients treated in the CryoIT Phase I clinical trial was conducted with encouraging results. In particular, ultradeep TCR-seq indicated that CryoIT was followed by several prevalent new T-cell clonotypes as a reflection of new immunity.
The CryoIT clinical trial with advanced monitoring and research biobank expansion will continue. A booster strategy of CryoIT immunity will be prioritized if funding of applications will eventually be successful in 2018. The strategy includes development of a dendritic cell based booster vaccine and molecular enhancement of immunity and inhibition of immune tolerance with focus on β-catenin and STAT3 inhibition. Control of immunogenic cell death is one important integrated issue.
Current challenges in the field
The ability to turn tumor associated antigens into new, effective targets of the immune system on a personalized basis remains a critical challenge. There is a need to enhance anti-cancer immunity to sufficient therapeutic efficacy and at the same time to control induction of autoimmunity. Biomarker development to improve immunomonitoring is important.
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.