Abstract 1215: Identifying new treatment options for metastatic melanoma using patient derived xenografts: Defining the role of Pim kinases
Authors: Berglind Osk Einarsdottir, Roger Olofsson, Joydeep Bhadury, Henrik Jespersen, Jan Mattsson, Lisa Nilsson, Ulrika Stierner, Lars Ny, Jonas Nilsson
Journal: Cancer Research (2014)

Abstract Melanoma is considered to be one of the most aggressive form of human tumors and current therapies are only partly effective. The mutation rate is higher in melanoma compared to other cancer types. The most frequent mutation, BRAFV600E is found in 50-70% of melanomas and promotes proliferation and survival. BRAF inhibitors have shown a good clinical responds rate, however resistance eventually develops. Therefore research into other pathways active in melanoma remains important. Other oncoproteins with limited knowledge about in melanoma are the Pim kinases Pim1, 2 and 3. They are involved in several pro-survival pathways, are weakly oncogenic and found over-expressed in several cancer types. We have found that Pim3 is highly expressed in melanoma compared to other cancer types, while expression of Pim1 and Pim2 are relatively low. Previous work in the lab has shown that PIM3 is regulated by c-MYC, a gene known to be critical for melanoma proliferation and survival. This suggests that Pim kinase inhibitors could have efficacy in tumors expressing high levels of Pim3. We have started the Sahlgrenska Translational Melanoma Group (SATMEG). The goal is to create a platform that can be used amongst other to test the effect of different drugs in mono- or combination therapy in vivo. Tumor biopsies from patients with stage III and IV melanoma are serially transplanted into immunocompromised mice making a patient derived xenograft (PDX) and analyzed for molecular characterization by expression sequencing. The mice can be divided in treatment groups and dosed with different compounds. Tumor growth can be monitored by in vivo imaging (IVIS) for evaluation of drug efficiency. The platform can also be used to increase the prediction value of clinical trials by pre-screening the patients using the PDXs and identifying a common biomarker for the responding PDXs. Thereby patients can be recruited to clinical trials based on molecular characteristics and those how would not benefit from the therapy can be excluded. This study aims at analyzing the effect of Pim kinase inhibition on melanoma cells both in vitro and in vivo. Investigate if Pim kinase inhibition can synergize in a cytotoxic manner with other compounds and analyse Pim kinase downstream targets. The ultimate goal is to define a predictive biomarker to identify patients which would benefit from Pim kinase inhibitor mono- or combination therapy. Since the role of Pim kinases have not been characterized in melanoma it is important to fully explore this option as a new line of treatment. Data on the effect of Pim kinase inhibition on melanoma and the use of the platform will be presented. Citation Format: Berglind Osk Einarsdottir, Roger Olofsson, Joydeep Bhadury, Henrik Jespersen, Jan Mattsson, Lisa Nilsson, Ulrika Stierner, Lars Ny, Jonas Nilsson. Identifying new treatment options for metastatic melanoma using patient derived xenografts: Defining the role of Pim kinases. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 1215. doi:10.1158/1538-7445.AM2014-1215