大象传媒

In Kalland's聽group, one key activity has聽been the generation and characterization聽of a new experimental model of stepwise聽prostate tumorigenesis, comprising聽benign cells (EPT1), pre-malignant mesenchymal聽type cells (EPT2), tumorigenic聽(EPT3-N04/EPT3-PT1) and metastatic聽(EPT3-M1) cells in mice, with different聽phenotypes and behavior. Each of the聽different cell types can be passaged聽indefinitely. Epithelial-to-mesenchymal聽transition (EMT) was an early feature聽of the model, and tumor initiating聽cell (TIC) subpopulations have been聽characterized among the tumorigenic聽cells.

Work on the experimental tumorigenesis聽model has resulted in increased聽insight into the potential of gene expression聽reprogramming as a source of cell聽heterogeneity. Subpopulations of TICs聽show activation of the WNT pathway聽and an autocrine ROS/IL6/STAT3 loop聽with increased resistance to apoptosis聽and anoikis. Recently, this model has聽been used in a drug discovery and聽development program, resulting in 5聽WNT/beta-catenin inhibitor candidate聽(with patents pending).

Gullberg's聽group has studied how different聽connective tissue cells interact聽with tumor cells and the extracellular聽matrix, a process which is similar聽to wound healing and scarring. In聽particular, integrins are important聽regulators of these processes.

The聽group has established a model using聽A549 lung cancer cells to study tumorstromal聽interactions, recently reporting聽that integrin alpha-11 from fibroblasts聽is important to stimulate tumor cells聽to secrete soluble factors influencing聽immune cell recruitment and tumor聽growth. Also, integrin alpha-11 was聽found to be important for stromal stiffness聽and tumor spread in non-small cell聽lung cancer.

In collaboration with Gullberg and others,聽Reed's group has a focus on interstitial聽fluid pressure (Pif) in tumors and聽how this can be modified. Tumors have聽an elevated Pif that acts as a functional聽barrier towards transcapillary fluid flux聽that can block the distribution of cytostatic聽anti-cancer agents. The group has聽reported that integrin alpha-11 has an聽influence of the interstitial pressure, and聽subsequently on tumor growth patterns聽in mice lacking this integrin (breast and聽prostate cancer models).

The results聽point to important biophysical features聽of the tumor microenvironment and聽their importance for cancer progress.聽Reed's group has also been working on聽the use of improved imaging techniques聽(DCE-MRI) in determining tumor聽vasculature and transcapillary transport聽in preclinical models.

Johannessen's group has worked聽on basic and translational aspects of聽oral cancer with focus on cancer-host聽interactions, particularly between the聽surface epithelium and the underlying聽connective tissue. The team has established聽novel in vitro assays of human聽tissue-based 3D cell culture models of聽normal mucosa and oral cancer tissue,聽and a new rodent oral cancer model. In聽collaboration with Gullberg麓s group,聽integrin alpha-11 has been identified as聽a key regulator in stroma-endothelial聽cross talk.

Johannessen麓s team also聽aims to develop a diagnostic and聽prognostic tool聽that can stratify聽patients with oral聽premalignant and聽malignant lesions聽for a more individualized聽therapy聽of oral cancer聽patients, and they聽have published a聽鈥渕alignancy index鈥� signature which聽is now being validated.

The group of Lorens works on cellular聽plasticity, such as stem cell differentiation聽and transdifferentiation, a critical聽prerequisite for adult tissue homeostasis聽and injury repair. Using comparative聽functional approaches, the team is聽investigating the regulation of tumor聽cell plasticity and maintenance of聽normal adult stem and progenitor cells.聽Recent results highlight the Axl receptor聽tyrosine kinase as a key regulator of聽both normal adult epithelial stem/progenitor cells and a determinant of聽carcinoma cell plasticity.聽These studies on聽Axl signaling have聽provided new insights聽into the regulation of聽tumor phenotypic聽heterogeneity and聽form the basis for the聽recent clinical translation聽of novel Axl聽inhibitors (e.g. BGB324). Importantly,聽it was recently also reported that聽Axl-activity could be blocked by lowdose聽warfarin.

The group continue to聽study how microenvironmental factors聽and immune cell challenge illicit tumor聽cell phenotypic plasticity that engenders聽acquired resistance to both chemo- and聽immunotherapeutic agents.

Akslen's team has focused on the use聽of biomarkers for improved molecular聽classification and grading of malignant聽tumors, as a better guide for targeted聽and precise treatment. 大象传媒 of human聽tumor samples (primary and metastatic聽lesions) are combined with experimental聽cell and animal models to improve聽translation. The team is concentrating聽on two main programs: first, studies聽of the tumor microenvironment, especially聽tumor-vascular interactions and聽angiogenesis markers; second, genetic聽and molecular markers of aggressive聽tumors, especially related to tumor cell聽proliferation.聽

The team has reported novel tissuebased聽angiogenesis biomarkers. 聽Microvessel proliferation was studied聽in several human tumor types and聽provide better prognostic information聽than vascular density. This marker聽also proved valid in xenograft models聽of breast cancer. By supervised analysis,聽a 32-gene RNA-based expression聽signature for microvessel proliferation聽was prognostically significant in endometrial聽cancer and is now explored in聽other tumor types. An 18-gene signature聽was identified for vascular invasion by聽tumor cells, pointing towards novel聽mechanisms involved in early metastatic聽spread, and was significant in endometrial聽and breast cancer. The progenitor聽cell marker Nestin has been found聽to identify subgroups of aggressive聽tumors in breast cancer and malignant聽melanoma.

In breast cancer, proliferation聽markers in primary tumors and聽metastatic lesions have been reported聽to improve molecular classification, as聽a basis for more precise treatment. Correlations聽between vascular biomarkers聽and imaging features have been performed聽on breast and endometrial cancers聽in collaboration with other teams.聽Genetic markers are being explored in聽melanoma, like CDK4 and BRAF as well聽as others.

Salvesen's group has made significant聽efforts in biomarker discovery and聽validation in gynecologic cancers, with聽special focus on endometrial cancer聽and hormone receptor regulation and聽impact. For both estrogen receptor (ER)聽and progesterone receptor (PR), loss聽of expression is linked to aggressive聽disease and poor survival. ATAD2, a聽cofactor for ER, was strongly linked to 聽aggressive signatures, while FOXA1,聽another ER cofactor, showed an unexpected聽switch in expression from聽primary tumors to metastatic lesions.聽Loss of both ER and PR predicted lymph聽node metastases, and this finding led聽to determination of ER/PR status for聽endometrial cancer as a stratifier for聽lymphadenectomy in a phase 4 implementation聽trial (MoMaTEC2). Stathmin聽expression was found to predict clinical聽response to taxane treatment in endometrial聽cancer, both in preclinical and clinical聽settings. This finding will be taken聽to a phase 2 integrated biomarker trial聽for paclitaxel treatment in endometrial聽and ovarian cancer (MoMaTEC2).

The聽team also continues studies on genetic聽alterations in gynecologic cancer, in a聽collaboration with the Broad Institute.聽In particular, data from an extensive聽molecular profiling of genomic alterations聽in cervical carcinomas were presented聽(published in Nature). Similar聽studies on endometrial cancer, also in聽collaboration with several other teams,聽are ongoing. Further, the team has聽studied different imaging modalities聽in preclinical and clinical settings in聽relation with angiogenesis and clinical聽characteristics. The findings are relevant聽for preoperative patient stratification.

Gjertsen's group, supported by the聽Early Phase Clinical Trial Unit at Haukeland University Hospital, has been the聽initial center for a phase I trial BGBC003;聽clinicaltrials.gov) with the novel聽anti-Axl drug BGB324 (per oral formulation)聽from BerGen-Bio. The trial is now聽also recruiting in聽Houston (Texas) and聽Germany. The trial聽will likely conclude聽at the end of 2016.聽In parallel, more聽focused small trials聽in chronic myeloid聽leukemia has been performed and completed聽in collaboration with the Nordic聽CML Study Group, providing a unique聽material for proof of principle testing聽of how to monitor signaling in cancer聽cells as biomarkers for risk and therapy聽response. Importantly, new instrumentation聽funded by Bergen Research聽Foundation in 2015, a mass cytometer,聽allows multiparametric analysis of聽single tumor cells. Through CCBIO and聽the Helse Bergen clinical trials units, the聽team will address clonal evolution in聽AML through mass cytometric analysis.聽

The team has performed extensive聽studies of signaling patterns in CML聽cases. There is a need for more direct聽biomarker analysis for early kinase聽inhibitor therapy, based on increasing聽reports of adverse events. The group has聽demonstrated that the drug target can聽be monitored in the actual cancer cells,聽and suggest that cellular signal systems聽involved in signaling of BCR-ABL outline聽the long time response. This single cell聽analysis of cellular signaling fit with the聽blood levels of the drug, and is likely聽a preferred method for future precision聽medicine聽with signaling聽targeted therapy.聽In contrast to the聽nearly monogenic聽BCR-ABL positive聽chronic myeloid聽leukemia, acute聽myeloid leukemia聽(AML) usually聽comprise 4-5 mutations. In the phase I聽trial with BGB324, the concepts of single聽cell biomarker profiling is tested. Analysis聽methods and read-out panels have聽been developed during 2015. The possibility聽to employ single cell biomarker聽technology in drug development is very聽promising. The strategy is also to move聽these concepts beyond blood cancers to聽metastatic solid cancers, based on strong聽collaborations within CCBIO, and several聽trials are now prepared.聽In collaboration with Kalland (PI), a phase聽I clinical trial of cryoimmunotherapy at聽Haukeland University Hospital has been聽initiated for patients with metastatic聽castration resistant prostate cancer, so聽far with around 10 patients recruited.聽The trial is based upon a dendritic聽cell based immunotherapy protocol in聽collaboration with the Haakon Ragde聽Foundation in Seattle (USA). One important聽aspect of the research protocol is to聽overcome tumor cell heterogeneity. The聽associated biobank is used for development聽of advanced immune-monitoring聽and circulating tumor cell enumeration聽as well as organoid cell culture isolation.

Straume's group is focusing on the聽identification of predictive biomarkers聽for therapy response in academic trials聽of patients with metastatic melanoma聽and kidney cancer. In melanoma,聽previous results of a clinical trial with聽the anti-VEGF antibody bevacizumab聽documented that ~30 % of the patients聽experienced clinical benefit of the聽treatment. Based on a screen of multiple聽candidate markers in tissues of primary聽tumors and metastases, as well as serum聽markers, HSP27 expression in metastatic聽lesions was able to predict therapy聽response. In metastatic kidney cancer,聽the VEGF receptor inhibitor sunitinib is聽first line treatment, and about 50 % of聽the patients are expected to respond.

In聽a trial series of 45 cases with metastatic聽clear cell renal carcinoma, the team聽is now working on a set of candidate聽biomarkers for their predictive value.聽In a collaboration with national centers,聽150 patients with metastatic melanoma聽were treated with ipilimumab, a CTLA-4聽antibody (phase IV clinical trial). Blood聽and tissue samples are being studied to聽identify predictive markers of response.聽Further, in a collaboration between聽CCBIO and BerGenBio, an investigator聽initiated randomized phase II clinical聽trial in metastatic melanoma will be聽initiated to study the combination of聽the Axl kinase inhibitor BGB324 with聽pembrolizumab or the BRAF inhibitor聽dabrafenib. Focus will be on predictive聽markers of response.