大象传媒

In Kalland麓s Group, one key activity has听been the generation and characterization听of a new experimental model of stepwise听prostate tumorigenesis, comprising听benign cells (EPT1), pre-malignant mesenchymal听type cells (EPT2), tumorigenic听(EPT3-N04/EPT3-PT1) and metastatic听(EPT3-M1) cells in mice, with different听phenotypes and behavior, and applied听in studies of transcriptional reprogramming听and drug discovery. This is the first听experimental prostate cancer model that听derived tumorigenic prostate cells by听using physiological selection pressure听only. Epithelial-to-mesenchymal transition听(EMT) was an early feature of the听model, and tumor initiating cell (TIC)听subpopulations have been characterized听among the tumorigenic cells.

Work on听the experimental tumorigenesis model听has resulted in increased insight into the听potential of gene expression reprogramming听as a source of cell heterogeneity.

Subpopulations of TICs show activation听of the WNT pathway and an autocrine听IL6/STAT3 feedback loop associated听with tumorigenesis. Recently, this model听has been used in a drug discovery and听development program, resulting in 5听WNT/尾-catenin inhibitor candidates听(with patents pending).

Kalland麓s team,听in collaboration with Gjertsen and听others, have initiated an ongoing phase听I clinical trial of cryoimmunotherapy for听advanced prostate cancer, including听an intensive biomarker program with听liquid biopsy projects and collaboration听with Dr. Pantel, tissue-based biomarker听analysis, and mass cytometry profiling.

Within CCBIO, Kalland is collaborating听with Gjertsen, Lorens and Akslen.

Gullberg麓s Group has studied how听different connective tissue cells interact听with tumor cells and the extracellular听matrix, a process that is similar听to wound healing and scarring. In听particular, integrins are important听regulators of these processes. The group听has established a model using A549 lung听cancer cells to study tumor-stromal听interactions, recently reporting that听integrin 伪11 from fibroblasts is important听to stimulate tumor cells to secrete听soluble factors influencing immune cell听recruitment and tumor growth. Also,听integrin 伪11 was found to be important听for stromal stiffness and tumor spread听in non-small cell lung cancer.

Gullberg听and co-workers have found that integrin听伪11尾1 is the receptor on fibroblasts that听mediates contraction of wounds, and听that this mechanism is mediated via听c-jun N-terminal kinase (JNK). This is听an important step forward in the efforts听to delineate the molecular mechanism听of cell-collagen interactions.

The team听is now also working to generate and听characterize novel integrin 伪11 blocking听antibodies with potential use as robust听biomarkers in tissue analyses, and work听is ongoing to establish and characterize听an 伪11 promoter-Cre mouse strain.

Within CCBIO, Gullberg is collaborating听with Reed, Akslen, Johannessen, and听Gjertsen.

In collaboration with Gullberg and听others, Reed麓s Group has a focus on the听dynamic extracellular matrix and on听interstitial fluid pressure (Pif) in tumors听and how this can be modified. This is听relevant for imaging technologies and听for distribution of drugs. Tumors have听an elevated Pif that acts as a functional听barrier towards transcapillary fluid听flux that can block the distribution of听cytostatic anti-cancer agents.

The group听has reported that integrin 伪11 has an听influence on the interstitial pressure,听and subsequently on tumor growth听patterns in mice lacking this integrin听(breast and prostate cancer models). The听results point to important biophysical听features of the tumor microenvironment听and their importance for cancer听progress.

Reed麓s group has also been听working on the use of improved imaging听techniques (DCEMRI)听in determining听tumor vasculature听and transcapillary听transport in preclinical听models. Lately,听the team is studying听the interaction between the genetic听background of integrins (using various听mouse strains) and growth of breast听cancer models. 大象传媒 on the effect听of hyperbaric oxygen on experimental听tumor growth are ongoing.

Within听CCBIO, Reed is collaborating with听Gullberg and Akslen.

on basic and translational aspects of听oral cancer with focus on cancer-host听interactions, particularly between the听surface epithelium and the underlying听connective tissue. The team has established听novel in vitro assays of human听tissue-based 3D cell culture models of听normal mucosa and oral cancer tissue,听and a new rodent oral cancer model.

In听collaboration with听Gullberg麓s group,听integrin 伪11 has been听identified as a key听regulator in stromaendothelial听cross听talk. Johannessen麓s听team now aims to develop a diagnostic听and prognostic biomarker profile听that can stratify patients with oral听premalignant and malignant lesions听for a more individualized therapy,听and they have reported a 鈥渕alignancy听index鈥� signature which is now being听validated.

The group identified two听distinct fibroblast (CAF) subgroups in听oral squamous cell carcinoma based on听transcriptome analysis of primary cells听from human cancers: a CAF subgroup听with a gene expression profile closer to听normal fibroblasts, having a more motile听phenotype and deeper carcinoma cell听invasion; and a CAF subgroup with a听more divergent gene expression profile,听having a more stationary phenotype,听with less tumor formation and invasion.This study points to functional听heterogeneity within tumor associated听fibroblasts.

Within CCBIO, Johannessen听collaborates with Gullberg, as well as听Junior Investigator Costea.

The Lorens Group works on cellular听plasticity, such as stem cell differentiation听and transdifferentiation, a critical听prerequisite for adult tissue homeostasis听and injury repair. Using comparative听functional approaches, the team is听investigating the regulation of tumor听cell plasticity and maintenance of听normal adult stem and progenitor cells.

Recent results highlight the Axl receptor听tyrosine kinase as a key regulator of both听normal adult epithelial stem/progenitor听cells and a determinant of carcinoma cell听plasticity. The studies on Axl signaling听have provided new insights into the听regulation of tumor phenotypic heterogeneity听and form the basis for the recent听clinical translation of novel Axl inhibitors听(e.g. BGB324). Importantly, it was recently听also reported that Axl-activity could be听blocked by low-dose warfarin.

The group听continues to study how microenvironmental听factors and immune cell challenge听illicit tumor cell phenotypic plasticity听that engenders acquired resistance to听both chemo- and immunotherapeutic听agents. On this background, a national听investigator-sponsored trial on metastatic听melanoma with BGB324 anti-Axl therapy听and anti-PD-1 (PI Straume) has been听launched, with an intensive biomarkerprogram听included.

Within CCBIO, Lorens听is collaborating with Gjertsen, Straume听and Akslen.

Akslen麓s Group has focused on the use听of biomarkers for improved molecular听classification and grading of malignant听tumors, as a better guide for targeted听treatment. 大象传媒 of human tumor听samples (primary and metastatic听lesions) are combined with experimental听cell and animal models to improve听translation. The team is concentrating on听studies of the tumor microenvironment,听especially tumor-vascular interactions听and angiogenesis markers, and the use听of precise indicators for tumor proliferation听with clinical applications.

The听team has reported novel tissue-based听angiogenesis biomarkers. As examples,听microvessel proliferation was studied听in several human tumor types and provides听better prognostic information than听vascular density. This marker proved听valid also in xenograft models of breast听cancer. Further, a 32-gene RNA-based听expression signature for microvessel听proliferation gives prognostic information听in endometrial and breast cancer,听and was linked to 6p21 amplification.

An 18-gene s ignature was identified听for vascular invasion by tumor cells,听pointing towards novel mechanisms听involved in early metastatic spread, and听this signature was strongly prognostic听in breast cancer. 大象传媒 on the progenitor听cell marker Nestin indicated an听ability to identify BRCA-1 related breast听cancer and the aggressive basal-like听phenotype.

During the last year, the听team has reported on tumor proliferation听markers in breast cancers and how听these change from primary tumors to听metastases. Data on proliferation is currently听used in definition of Luminal B听breast cancer and treatment decisions.听Whereas 15% of the cases changed听from low (primary tumors) to high听proliferation (metastases), treatment听consequences are currently not clear听in guidelines but are being discussed.

Further, a paper on improved definitions听of extra-nodal growth in lymph node听metastases of breast cancer has led to听new national guidelines.

In a collaborative study with Dr. Watnick (Boston), the听importance of prosaposin (PSAP) and听thrombospondin-1 (TSP-1) for ovarian听cancer progression was reported (Wang,听2016), expanding on previous findings听from this collaboration.

Within CCBIO,听Akslen is collaborating with Kalland,听Gullberg, Reed, Lorens, Straume and听Gjertsen, as well as Junior Investigators听Wik and Krakstad.

Gjertsen麓s Group, supported by the听Early Phase Clinical Trial Unit at听Haukeland University Hospital, has听been the initial center for a phase I trial听(BGBC003; clinicaltrials.gov) in AML听using the novel anti-Axl drug BGB324听(per oral formulation) in collaboration听with BerGenBio. The trial is now also听recruiting in Houston (Texas) and Germany.

In parallel, more focused small听trials in chronic myeloid leukemia has听been performed and completed in collaboration听with the Nordic CML Study听Group, providing a unique material听for proof of principle testing of how to听monitor signaling in cancer cells as biomarkers听for risk and therapy response.听Importantly, new instrumentation听funded by Bergen Research Foundation听in 2015, a mass cytometer, allows听multiparametric analysis of single听tumor cells.

Through CCBIO and the听Helse Bergen Clinical Trials Unit, the听team will address clonal evolution in听AML through mass cytometric analysis.听The team has performed extensive听studies of signaling patterns in CML听cases. There is a need for more direct听biomarker analyses for early kinase听inhibitor therapy, based on increasing听reports of adverse events. The group听has demonstrated that the drug target听can be monitored in the actual cancer听cells, and suggests that cellular signal听systems involved in signaling of BCRABL听outline the long time response. This听single cell analysis of cellular signaling听fit with the blood levels of the drug, and听is likely to be a preferred method for听future precision medicine with signaling听targeted therapy.

In the phase I trial听with BGB324, the concepts of single-cell听biomarker profiling are tested. Different听analysis methods and read-out panels听have been developed during 2016. The听possibility to employ single cell biomarker听technology in drug development听is very promising. The strategy is also to听move these concepts beyond blood cancers听to metastatic solid cancers, based听on strong collaborations within CCBIO,听and several trials are now prepared.

In听collaboration with Kalland, a phase I听clinical trial of cryoimmunotherapy has听been initiated for patients with metastatic听castration resistant prostate cancer.听The trial is based upon a dendritic听cell based immunotherapy protocol in听collaboration with the Haakon Ragde听Foundation in Seattle (USA). The associated听biobank is used for development听of advanced immune-monitoring and听circulating tumor cell enumeration as听well as organoid cell culture isolation.

Within CCBIO, Gjertsen is collaborating听with Lorens, Kalland, Straume, Akslen听and Gullberg, as well as Associate PIs听Bj酶rge and McCormack.

Straume麓s Group is focusing on the听identification of predictive biomarkers听for therapy response in academic trials听of patients with metastatic melanoma听and kidney cancer.

In melanoma,听previous results of a clinical trial听with the anti-VEGF antibody bevacizumab听documented that ~30 % of the听patients experienced clinical benefit听of the treatment. Based on a screen of听multiple candidate markers in tissues听of primary tumors and metastases, as听well as serum markers, HSP27 tissue听expression in metastatic lesions was able听to predict therapy response. The team听continues to screen for serum-based听biomarkers of therapy response, to antiangiogenesis听treatment (bevacizumab)听and immunotherapy (ipilimumab).

Due听to the recently reported role of Axl in听immune evasion, a national听investigatorsponsored trial on metastatic melanoma听with BGB324 anti-Axl therapy and听anti-PD-1, directed by Straume, has听been launched, with an intensive听biomarker-program included. Focus will听be on predictive markers of response.听In a collaboration with national centers,听150 patients with metastatic melanoma听were treated with ipilimumab, a听CTLA-4 antibody (phase IV clinical听trial). Blood and tissue samples are听being studied to identify predictive听markers of response. In a trial series of听45 cases with metastatic clear cell renal听carcinoma treated by VEGF-inhibition听(sunitinib), the team is now working听on a set of candidate biomarkers for听their predictive value.

In a study that听could be of major clinical significance,听the Straume Group reported that breast听cancer recurrence can be influenced by听the timing of surgery. The finding might听lead to increased awareness about the听role of surgery in high risk patients and听increased use of immediate surgery.

Within CCBIO, Straume collaborates听with Lorens, Gjertsen and Akslen.

The Bergen Gynecologic Cancer听Group (previously led by Salvesen)听has made significant efforts in biomarker听discovery and validation in听gynecologic cancers, at the genetic听and protein levels, with special focus听on endometrial cancer and hormone听receptor regulation and impact. For both听estrogen receptor (ER) and progesterone听receptor (PR), loss of expression is linked听to aggressive disease and poor survival.

ATAD2, a cofactor for ER, was strongly听linked to aggressive signatures, while听FOXA1, another ER cofactor, showed an听unexpected switch in expression from听primary tumors to metastatic lesions.听Loss of both ER and PR predicted lymph听node metastases, and this finding led听to determination of ER/PR status for听endometrial cancer as a stratifier for听lymphadenectomy in a phase 4 implementation听trial (MoMaTEC2). Stathmin听expression was found to predict clinical听response to taxane treatment in endometrial听cancer, both in preclinical and听clinical settings. This finding has been听taken to a phase 2 integrated biomarker听trial for paclitaxel treatment in endometrial听and ovarian cancer (MoMaTEC2).

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

In summary, several efforts and听initiatives within CCBIO, with increased听internal and external collaboration, are听now up and running. The projects are听spanning from matrix biology and听plasticity programs, through discovery听and validation of biomarkers and听signatures, to clinical trials with targeted听biomarker panels using liquid听biopsy and single cell analysis. In this听context, the programs on ethics and听economics of biomarker based therapy,听are also expanding and are being听integrated in the recently established听clinical trials.

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