Experimental modeling and novel therapeutic strategies in melanoma brain metastasis
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Melanoma patients carry a high risk of developing brain metastases and improvements in survival are still measured in weeks or months. The aim of this thesis was to study the biology of melanoma brain metastasis and find new therapeutic approaches. In Paper I, we reviewed the current literature on animal models of brain metastasis. Many models are available and have provided valuable insights, but technical and biologic limitations have hampered clinical translation. In Paper II, we reported on the development and validation of a new experimental brain metastasis model. This model featured MRI-based automated quantification of nanoparticle-labeled melanoma cells in the mouse brain after intracardiac injection. We proposed that this model could help to increase the reproducibility and predictivity of mechanistic and therapeutic studies of melanoma brain metastasis. In Paper III, we examined the temporal, spatial and functional significance of lactate dehydrogenase A (LDHA) in melanoma brain metastasis. We found that LDHA expression was hypoxia-dependent, but did not affect tumor progression or survival in vivo or in a large patient cohort. In Paper IV, we applied genomics-based drug repositioning and carried out a comprehensive in vitro and in vivo screening of potential anti-melanoma brain metastasis compounds. We found the cholesterol analogue β-sitosterol to inhibit the growth of brain metastases and improve survival in established and preventive scenarios across several in vivo models. β-sitosterol provided broad-spectrum suppression of the important mitogen-activated protein kinase (MAPK) pathway and reduced mitochondrial respiration through Complex I inhibition. Notably, increased mitochondrial respiration is a key mediator of intrinsic and acquired resistance to established MAPK-targeted therapies. Together, Papers I and II showed that the study of melanoma biology and brain metastasis requires reproducible and predictive animal models. By applying such models in Papers III and IV, we revealed novel insights into the biology and therapy of melanoma brain metastasis, and suggested that mitochondrial respiration might play an imperative role in tumor progression and treatment resistance.
Består avPaper I: Daphu I, Sundstrøm T, Horn S, Huszthy PC, Niclou SP, Sakariassen PØ, Immervoll H, Miletic H, Bjerkvig R & Thorsen F. In vivo animal models for studying brain metastasis: value and limitations. Clinical & Experimental Metastasis 2013; 30: 695-710. The article is not available in BORA due to publisher restrictions. The published version is available at: http://dx.doi.org/10.1007/s10585-013-9566-9
Paper II: Sundstrøm T, Daphu I, Wendelbo I, Hodneland E, Immervoll H, Skaftnesmo KO, Lundervold A, Jendelova P, Babic M, Sykova E, Bjerkvig R, Lund-Johansen M & Thorsen F. Automated tracking of nanoparticle-labeled melanoma cells improves the predictive power of a brain metastasis model. Cancer Research 2013; 73: 2445- 2456. The article is not available in BORA due to publisher restrictions. The published version is available at: http://dx.doi.org/10.1158/0008-5472.can-12-3514
Paper III: Sundstrøm T, Espedal H, Harter PN, Fasmer KE, Skaftnesmo KO, Horn S, Hodneland E, Mittelbronn M, Weide B, Beschorner R, Bender B, Rygh CB Lund- Johansen M, Bjerkvig R & Thorsen F. Melanoma brain metastasis is independent of lactate dehydrogenase A expression. Neuro-Oncology 2015; 17: 1374-1385. The article is not available in BORA due to publisher restrictions. The published version is available at: http://dx.doi.org/10.1093/neuonc/nov040
Paper IV: Sundstrøm T, Varughese JK, Prestegarden L, Azuaje F, Røsland GV, Skaftnesmo KO, Ingham E, Even L, Tam S, Tepper C, Petersen K, Ferrara KW, Tronstad KJ, Lund-Johansen M, Bjerkvig R & Thorsen F. β-sitosterol provides broad-spectrum therapeutic suppression of melanoma brain metastasis. Manuscript submitted. The article is not available in BORA.