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

Einarsdottir, Berglind Osk, 1979 (author)
Gothenburg University,Göteborgs universitet,Institutionen för kliniska vetenskaper, Avdelningen för kirurgi,Sahlgrenska Cancer Center,Institute of Clinical Sciences, Department of Surgery
Karlsson, Joakim (author)
Gothenburg University,Göteborgs universitet,Institutionen för biomedicin, avdelningen för medicinsk kemi och cellbiologi,Institute of Biomedicine, Department of Medical Biochemistry and Cell Biology
Söderberg, Elin, 1988 (author)
Gothenburg University,Göteborgs universitet,Institutionen för kliniska vetenskaper, Avdelningen för kirurgi,Institutionen för kliniska vetenskaper, Avdelningen för onkologi,Sahlgrenska Cancer Center,Institute of Clinical Sciences, Department of Surgery,Institute of Clinical Sciences, Department of Oncology
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Lindberg, Mattias F (author)
Gothenburg University,Göteborgs universitet,Sahlgrenska Cancer Center,Institutionen för kliniska vetenskaper, Avdelningen för kirurgi,Institutionen för kliniska vetenskaper, Avdelningen för onkologi,Institute of Clinical Sciences, Department of Surgery,Institute of Clinical Sciences, Department of Oncology
Funck-Brentano, Elisa (author)
Gothenburg University,Göteborgs universitet,Institutionen för kliniska vetenskaper, Avdelningen för onkologi,Institutionen för kliniska vetenskaper, Avdelningen för kirurgi,Sahlgrenska Cancer Center,Institute of Clinical Sciences, Department of Oncology,Institute of Clinical Sciences, Department of Surgery
Jespersen, Henrik (author)
Gothenburg University,Göteborgs universitet,Sahlgrenska Cancer Center,Institutionen för kliniska vetenskaper, Avdelningen för onkologi,Institute of Clinical Sciences, Department of Oncology
Brynjólfsson, Siggeir Fannar (author)
Gothenburg University,Göteborgs universitet,Institutionen för biomedicin, avdelningen för mikrobiologi och immunologi,Institute of Biomedicine, Department of Microbiology and Immunology
Olofsson Bagge, Roger, 1978 (author)
Gothenburg University,Göteborgs universitet,Institutionen för kliniska vetenskaper, Avdelningen för kirurgi,Sahlgrenska Cancer Center,Institute of Clinical Sciences, Department of Surgery
Carstam, Louise (author)
Scobie, M. (author)
Karolinska Institutet
Koolmeister, T. (author)
Karolinska Institutet
Wallner, O. (author)
Karolinska Institutet
Stierner, Ulrika, 1952 (author)
Gothenburg University,Göteborgs universitet,Sahlgrenska Cancer Center
Berglund, U. W. (author)
Karolinska Institutet
Ny, Lars, 1967 (author)
Gothenburg University,Göteborgs universitet,Sahlgrenska Cancer Center,Institutionen för kliniska vetenskaper, Avdelningen för onkologi,Institute of Clinical Sciences, Department of Oncology
Nilsson, Lisa M, 1976 (author)
Gothenburg University,Göteborgs universitet,Institutionen för kliniska vetenskaper, Avdelningen för kirurgi,Institutionen för kliniska vetenskaper, Avdelningen för onkologi,Sahlgrenska Cancer Center,Institute of Clinical Sciences, Department of Surgery,Institute of Clinical Sciences, Department of Oncology
Larsson, Erik, 1975 (author)
Gothenburg University,Göteborgs universitet,Institutionen för biomedicin, avdelningen för medicinsk kemi och cellbiologi,Institute of Biomedicine, Department of Medical Biochemistry and Cell Biology
Helleday, T. (author)
Karolinska Institutet
Nilsson, Jonas A, 1971 (author)
Gothenburg University,Göteborgs universitet,Institutionen för kliniska vetenskaper, Avdelningen för kirurgi,Sahlgrenska Cancer Center,Institutionen för kliniska vetenskaper, Avdelningen för onkologi,Institute of Clinical Sciences, Department of Surgery,Institute of Clinical Sciences, Department of Oncology
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 (creator_code:org_t)
2018-07-24
2018
English.
In: Cell Death & Disease. - : Springer Science and Business Media LLC. - 2041-4889. ; 9:8
Related links:
https://www.nature.c...
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https://doi.org/10.1...
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  • Journal article (peer-reviewed)
Abstract Subject headings
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  • 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.

Subject headings

MEDICIN OCH HÄLSOVETENSKAP  -- Medicinska och farmaceutiska grundvetenskaper -- Cell- och molekylärbiologi (hsv//swe)
MEDICAL AND HEALTH SCIENCES  -- Basic Medicine -- Cell and Molecular Biology (hsv//eng)
MEDICIN OCH HÄLSOVETENSKAP  -- Klinisk medicin -- Cancer och onkologi (hsv//swe)
MEDICAL AND HEALTH SCIENCES  -- Clinical Medicine -- Cancer and Oncology (hsv//eng)

Keyword

cancer-cell survival
multidrug-resistance
p-glycoprotein
mth1
inhibitors
expression
annotation
guideline
exome
model
Cell Biology

Publication and Content Type

ref (subject category)
art (subject category)

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