Current assessment of prostate cancer aggressiveness is not sufficient in predicting disease aggressiveness. Tumor hypoxia, i.e. low tumor oxygen level, is associated with aggressive disease, radioresistance and worse clinical outcome in several cancer forms. Thus, by examining the molecular background of hypoxic prostate tumors, we aimed to discover new methods for stratification and treatment.
We analyzed whole-genome transcriptional programs in index tumor biopsies from a surgical prostate cancer patient cohort and related these to hypoxic fraction determined by pimonidazole staining. Hypoxia was associated with increased aggressiveness, including lymph node metastasis at diagnosis and higher tumor stage. We identified a hypoxia gene signature, where the expression showed relation to disease aggressiveness in our own and in validation cohorts, including independent prognostic information. We hope this gene signature can be further developed into a test to improve stratification of patients to correct treatment intensity.
A large fraction of the transcriptional program was controlled by the protein hypoxia inducible factor 1 (HIF1). We further examined HIF1 and HIF1-dependent gene expression in experimental model systems and tissue samples from patients undergoing androgen deprivation prior to radiation therapy. HIF1 protein and associated gene expression was downregulated by androgen deprivation despite equal hypoxic fraction, complicating their use as hypoxic biomarkers in this setting.
As a possible adjunct to radiation therapy for patients with the most aggressive, hypoxic tumors, radiosensitizing properties of the drug vorinostat was examined. Vorinostat increased the efficacy of radiation in two cell lines, also when the cell lines were irradiated under hypoxic conditions, and is as such a promising radiosensitizer that should be further validated in vivo.
List of papers. The papers are removed from the thesis due to publisher restrictions.
Paper I: Ragnum HB, Vlatkovic L, Lie AK, Axcrona K, Julin CH, Frikstad KAM, Hole KH, Seierstad T, Lyng H. The hypoxia marker pimonidazole reflects a transcriptional program associated with aggressive prostate cancer. Manuscript.
Paper II: Ragnum HB, Røe K, Holm R, Vlatkovic L, Nesland JM, Aarnes EK, Ree AH, Flatmark K, Seierstad T, Lilleby W, Lyng H. Hypoxia-independent downregulation of hypoxia-inducible factor 1 targets by androgen deprivation therapy in prostate cancer. Int J Radiat Oncol Biol Phys. 2013; 87: 753-60. doi:10.1016/j.ijrobp.2013.07.023
Paper III: Ragnum HB, Jonsson M, Julin CH, Frikstad KAM, Clancy T, Wennerstrøm AB, Stokke T, Røe K, Ree AH, Flatmark K, Lyng H. Vorinostat-mediated radiosensitization and transcriptional effects in hypoxia-treated prostate cancer cell lines. Manuscript.