A Three-dimensional Ex Vivo Viability Assay Reveals a Strong Correlation Between Response to Targeted Inhibitors and Mutation Status in Melanoma Lymph Node Metastases
Although clinical management of melanoma has changed considerably in recent years, intrinsic treatment resistance remains a severe problem and strategies to design personal treatment regimens are highly warranted. We have applied a three-dimensional (3D) ex vivo drug efficacy assay, exposing disaggr...
| Main Authors: | , , , , , , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
| Published: |
Elsevier
2019-07-01
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| Series: | Translational Oncology |
| Online Access: | http://www.sciencedirect.com/science/article/pii/S1936523318306144 |
| _version_ | 1831747212356354048 |
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| author | Vivi Ann Flørenes Karine Flem-Karlsen Erin McFadden Inger Riise Bergheim Vigdis Nygaard Vegard Nygård Inger Nina Farstad Geir Frode Øy Elisabeth Emilsen Karianne Giller-Fleten Anne Hansen Ree Kjersti Flatmark Hans Petter Gullestad Robert Hermann Truls Ryder Patrik Wernhoff Gunhild Mari Mælandsmo |
| author_facet | Vivi Ann Flørenes Karine Flem-Karlsen Erin McFadden Inger Riise Bergheim Vigdis Nygaard Vegard Nygård Inger Nina Farstad Geir Frode Øy Elisabeth Emilsen Karianne Giller-Fleten Anne Hansen Ree Kjersti Flatmark Hans Petter Gullestad Robert Hermann Truls Ryder Patrik Wernhoff Gunhild Mari Mælandsmo |
| author_sort | Vivi Ann Flørenes |
| collection | DOAJ |
| description | Although clinical management of melanoma has changed considerably in recent years, intrinsic treatment resistance remains a severe problem and strategies to design personal treatment regimens are highly warranted. We have applied a three-dimensional (3D) ex vivo drug efficacy assay, exposing disaggregated cells from 38 freshly harvested melanoma lymph node metastases and 21 patient derived xenografts (PDXs) to clinical relevant drugs for 7 days, and examined its potential to evaluate therapy response. A strong association between Vemurafenib response and BRAF mutation status was achieved (P < .0001), while enhanced viability was seen in some NRAS mutated tumors. BRAF and NRAS mutated tumors responded comparably to the MEK inhibitor Cobimetinib. Based on the ex vivo results, two tumors diagnosed as BRAF wild-type by routine pathology examinations had to be re-evaluated; one was subsequently found to have a complex V600E mutation, the other a double BRAF mutation (V600E/K601 N). No BRAF inhibitor resistance mechanisms were identified, but PIK3CA and NF1 mutations were identified in two highly responsive tumors. Concordance between ex vivo drug responses using tissue from PDXs and corresponding patient tumors demonstrate that PDX models represent an indefinite source of tumor material that may allow ex vivo evaluation of numerous drugs and combinations, as well as studies of underlying molecular mechanisms. In conclusion, we have established a rapid and low cost ex vivo drug efficacy assay applicable on tumor tissue from patient biopsies. The 3D/spheroid format, limiting the influence from normal adjacent cells and allowing assessment of drug sensitivity to numerous drugs in one week, confirms its potential as a supplement to guide clinical decision, in particular in identifying non-responding patients. |
| first_indexed | 2024-12-21T21:28:54Z |
| format | Article |
| id | doaj.art-5e33a627a4a3411eb74675f0d94b0c59 |
| institution | Directory Open Access Journal |
| issn | 1936-5233 |
| language | English |
| last_indexed | 2024-12-21T21:28:54Z |
| publishDate | 2019-07-01 |
| publisher | Elsevier |
| record_format | Article |
| series | Translational Oncology |
| spelling | doaj.art-5e33a627a4a3411eb74675f0d94b0c592022-12-21T18:49:41ZengElsevierTranslational Oncology1936-52332019-07-01127951958A Three-dimensional Ex Vivo Viability Assay Reveals a Strong Correlation Between Response to Targeted Inhibitors and Mutation Status in Melanoma Lymph Node MetastasesVivi Ann Flørenes0Karine Flem-Karlsen1Erin McFadden2Inger Riise Bergheim3Vigdis Nygaard4Vegard Nygård5Inger Nina Farstad6Geir Frode Øy7Elisabeth Emilsen8Karianne Giller-Fleten9Anne Hansen Ree10Kjersti Flatmark11Hans Petter Gullestad12Robert Hermann13Truls Ryder14Patrik Wernhoff15Gunhild Mari Mælandsmo16Department of Pathology, Norwegian Radium Hospital, Oslo University Hospital, N-0310 Oslo, NorwayDepartment of Pathology, Norwegian Radium Hospital, Oslo University Hospital, N-0310 Oslo, Norway; Institute for Clinical Medicine, Faculty of Medicine, University of Oslo, NorwayDepartment of Pathology, Norwegian Radium Hospital, Oslo University Hospital, N-0310 Oslo, NorwayDepartment of Cancer Genetics, Institute for Cancer Research, Norwegian Radium Hospital, Oslo University Hospital, N-0310 Oslo, NorwayDepartment of Tumor Biology, Institute for Cancer Research, Norwegian Radium Hospital, Oslo University Hospital, N-0310 Oslo, NorwayDepartment of Core Facilities, Institute for Cancer Research, Norwegian Radium Hospital, Oslo University Hospital, N-0310 Oslo, NorwayDepartment of Pathology, Norwegian Radium Hospital, Oslo University Hospital, N-0310 Oslo, Norway; Institute for Clinical Medicine, Faculty of Medicine, University of Oslo, NorwayDepartment of Tumor Biology, Institute for Cancer Research, Norwegian Radium Hospital, Oslo University Hospital, N-0310 Oslo, NorwayDepartment of Pathology, Norwegian Radium Hospital, Oslo University Hospital, N-0310 Oslo, NorwayDepartment of Tumor Biology, Institute for Cancer Research, Norwegian Radium Hospital, Oslo University Hospital, N-0310 Oslo, NorwayDepartment of Oncology, Akershus University Hospital, N-1478 Lørenskog, Norway; Institute for Clinical Medicine, Faculty of Medicine, University of Oslo, NorwayInstitute for Clinical Medicine, Faculty of Medicine, University of Oslo, Norway; Department of Tumor Biology, Institute for Cancer Research, Norwegian Radium Hospital, Oslo University Hospital, N-0310 Oslo, Norway; Department of Gastroenterological Surgery, Norwegian Radium Hospital, Oslo University Hospital, N-0310 Oslo, NorwayDepartment of Plastic and Reconstructive Surgery, Norwegian Radium Hospital, Oslo University Hospital, N-0310 Oslo, NorwayDepartment of Plastic and Reconstructive Surgery, Norwegian Radium Hospital, Oslo University Hospital, N-0310 Oslo, NorwayDepartment of Plastic and Reconstructive Surgery, Norwegian Radium Hospital, Oslo University Hospital, N-0310 Oslo, NorwayDepartment of Pathology, Norwegian Radium Hospital, Oslo University Hospital, N-0310 Oslo, NorwayDepartment of Tumor Biology, Institute for Cancer Research, Norwegian Radium Hospital, Oslo University Hospital, N-0310 Oslo, Norway; Institute of Medical Biology, Faculty of Health Sciences, UiT-Arctic University of Norway, Tromsø, Norway; Address all correspondence to: Gunhild M. Mælandsmo, Department of Tumor Biology, Norwegian Radium Hospital, Oslo University Hospital, PO Box 4950 Nydalen, 0424 Oslo, Norway.Although clinical management of melanoma has changed considerably in recent years, intrinsic treatment resistance remains a severe problem and strategies to design personal treatment regimens are highly warranted. We have applied a three-dimensional (3D) ex vivo drug efficacy assay, exposing disaggregated cells from 38 freshly harvested melanoma lymph node metastases and 21 patient derived xenografts (PDXs) to clinical relevant drugs for 7 days, and examined its potential to evaluate therapy response. A strong association between Vemurafenib response and BRAF mutation status was achieved (P < .0001), while enhanced viability was seen in some NRAS mutated tumors. BRAF and NRAS mutated tumors responded comparably to the MEK inhibitor Cobimetinib. Based on the ex vivo results, two tumors diagnosed as BRAF wild-type by routine pathology examinations had to be re-evaluated; one was subsequently found to have a complex V600E mutation, the other a double BRAF mutation (V600E/K601 N). No BRAF inhibitor resistance mechanisms were identified, but PIK3CA and NF1 mutations were identified in two highly responsive tumors. Concordance between ex vivo drug responses using tissue from PDXs and corresponding patient tumors demonstrate that PDX models represent an indefinite source of tumor material that may allow ex vivo evaluation of numerous drugs and combinations, as well as studies of underlying molecular mechanisms. In conclusion, we have established a rapid and low cost ex vivo drug efficacy assay applicable on tumor tissue from patient biopsies. The 3D/spheroid format, limiting the influence from normal adjacent cells and allowing assessment of drug sensitivity to numerous drugs in one week, confirms its potential as a supplement to guide clinical decision, in particular in identifying non-responding patients.http://www.sciencedirect.com/science/article/pii/S1936523318306144 |
| spellingShingle | Vivi Ann Flørenes Karine Flem-Karlsen Erin McFadden Inger Riise Bergheim Vigdis Nygaard Vegard Nygård Inger Nina Farstad Geir Frode Øy Elisabeth Emilsen Karianne Giller-Fleten Anne Hansen Ree Kjersti Flatmark Hans Petter Gullestad Robert Hermann Truls Ryder Patrik Wernhoff Gunhild Mari Mælandsmo A Three-dimensional Ex Vivo Viability Assay Reveals a Strong Correlation Between Response to Targeted Inhibitors and Mutation Status in Melanoma Lymph Node Metastases Translational Oncology |
| title | A Three-dimensional Ex Vivo Viability Assay Reveals a Strong Correlation Between Response to Targeted Inhibitors and Mutation Status in Melanoma Lymph Node Metastases |
| title_full | A Three-dimensional Ex Vivo Viability Assay Reveals a Strong Correlation Between Response to Targeted Inhibitors and Mutation Status in Melanoma Lymph Node Metastases |
| title_fullStr | A Three-dimensional Ex Vivo Viability Assay Reveals a Strong Correlation Between Response to Targeted Inhibitors and Mutation Status in Melanoma Lymph Node Metastases |
| title_full_unstemmed | A Three-dimensional Ex Vivo Viability Assay Reveals a Strong Correlation Between Response to Targeted Inhibitors and Mutation Status in Melanoma Lymph Node Metastases |
| title_short | A Three-dimensional Ex Vivo Viability Assay Reveals a Strong Correlation Between Response to Targeted Inhibitors and Mutation Status in Melanoma Lymph Node Metastases |
| title_sort | three dimensional ex vivo viability assay reveals a strong correlation between response to targeted inhibitors and mutation status in melanoma lymph node metastases |
| url | http://www.sciencedirect.com/science/article/pii/S1936523318306144 |
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