Journal Article

A patient-derived xenograft pre-clinical trial reveals treatment responses and a resistance mechanism to karonudib in metastatic melanoma

Brynjolfsson, Siggeir F., Nilsson, Lisa M., Söderberg, Elin M. V., Koolmeister, Tobias, Karlsson, Joakim, Einarsdottir, Berglind O., Wallner, Olof, Jespersen, Henrik, Helleday, Thomas, Carstam, Louise, Larsson, Erik, Olofsson Bagge, Roger, Lindberg, Mattias F., Berglund, Ulrika Warpman, Funck-Brentano, Elisa, Scobie, Martin, Stierner, Ulrika, Ny, Lars, Nilsson, Jonas A.

2018

Overview

Karonudib (TH1579) is a novel compound that exerts anti-tumor activities and has recently entered phase I clinical testing. The aim of this study was to conduct a pre-clinical trial in patient-derived xenografts to identify the possible biomarkers of response or resistance that could guide inclusion of patients suffering from metastatic melanoma in phase II clinical trials. Patient-derived xenografts from 31 melanoma patients with metastatic disease were treated with karonudib or a vehicle for 18 days. Treatment responses were followed by measuring tumor sizes, and the models were categorized in the response groups. Tumors were harvested and processed for RNA sequencing and protein analysis. To investigate the effect of karonudib on T-cell-mediated anti-tumor activities, tumor-infiltrating T cells were injected in mice carrying autologous tumors and the mice treated with karonudib. We show that karonudib has heterogeneous anti-tumor effect on metastatic melanoma. Thus, based on the treatment responses, we could divide the 31 patient-derived xenografts in three treatment groups: progression group (32%), suppression group (42%), and regression group (26%). Furthermore, we show that karonudib has anti-tumor effect, irrespective of major melanoma driver mutations. Also, we identify high expression of ABCB1 , which codes for p-gp pumps as a resistance biomarker. Finally, we show that karonudib treatment does not hamper T-cell-mediated anti-tumor responses. These findings can be used to guide future use of karonudib in clinical use with a potential approach as precision medicine.

• Publisher: Nature Publishing Group UK,Springer Nature B.V
• Subject: 13/51 / 59/5 / 64/60 / Animal models / Animals / annotation / Antibodies / Antitumor agents / ATP Binding Cassette Transporter, Subfamily B, Member 1 - metabolism / Biochemistry / Biomarkers / Biomarkers, Tumor - metabolism / Biomedical and Life Sciences / Cancer and Oncology / Cancer och onkologi / cancer-cell survival / Cell and Molecular Biology / Cell Biology / Cell Culture / Cell- och molekylärbiologi / Clinical trials / Drug Evaluation, Preclinical / Drug Resistance, Neoplasm / Enzyme Inhibitors - pharmacology / Enzyme Inhibitors - therapeutic use / exome / expression / guideline / Humans / Immunology / inhibitors / Life Sciences / Lymphocytes T / Melanoma / Melanoma - drug therapy / Melanoma - pathology / Metastases / Metastasis / Mice / mth1 / multidrug-resistance / p-glycoprotein / Patients / Precision medicine / Pyrimidines - pharmacology / Pyrimidines - therapeutic use / Ribonucleic acid / RNA / Transplantation, Heterologous / Tumor Cells, Cultured / Tumors / Up-Regulation / Xenografts