Rectal Cancer – Functional Molecular Profiling and Targeting of Tumor Hypoxia in Radiation Response and Metastasis
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AbstractRectal cancer is common a disease. For patients with locally advanced rectal cancer (LARC), chemoradiotherapy (CRT) is commonly given prior to surgical resection to optimize local control and improve long-term outcome. Still, a substantial number of patients will develop metastatic disease. Tumor hypoxia is an important hallmark of solid tumors and is recognized as a common determinant of resistance to radiotherapy and metastatic disease progression. In this thesis, methods from experimental and clinical cancer research were used to detect and counteract hypoxic tumor mechanisms involved in poor radiation response and metastasis, with the ultimate goal of improving the outcome for rectal cancer patients. Recognizing that adaptive cellular responses to hypoxic stress involve kinase signaling pathways contributing in the metastatic process, tumor kinase activity was studied in LARC patients participating in a prospective CRT study. Dysfunctional angiogenic tumor signaling, particularly the signaling activity mediated by PDGFR receptor tyrosine kinases, was associated with early systemic disease dissemination. Next, the molecularly targeted agent vorinostat, a histone deacetylase inhibitor, was found to enhance radiation response of experimental colorectal carcinoma models when examined both under hypoxic conditions and in combination with standard CRT. Biomarkers of vorinostat activity were quested by gene expression profiling in patients participating in a prospective study of vorinostat in combination with pelvic radiotherapy. Finally, in the prospective CRT study for LARC patients, neoadjuvant chemotherapy led to substantial tumor volume reduction with particularly good response in the less advanced cases and without compromising CRT response. The biological principle was confirmed in experimental models. Taken together, treatment of rectal cancer should be further individualized by tailoring the multimodal therapy to the specific tumor biology of each patient.
List of papers
|Paper I: Saelen MG, Flatmark K, Folkvord S, de Wijn R, Rasmussen H, Fodstad O, Ree AH: Tumor kinase activity in locally advanced rectal cancer: angiogenic signaling and early systemic dissemination. Angiogenesis 2011, 14:481-489. The published version of this paper is available at: https://doi.org/10.1007/s10456-011-9231-3|
|Paper II: Saelen MG, Ree AH, Kristian A, Fleten KG, Furre T, Hektoen HH, Flatmark K: Radiosensitization by the histone deacetylase inhibitor vorinostat under hypoxia and with capecitabine in experimental colorectal carcinoma. Radiat Oncol 2012, 7:165. This is an Open Access article distributed under the terms of the Creative Commons Attribution License. The published version of this paper is available at: https://doi.org/10.1186/1748-717X-7-165|
|Paper III: Ree AH, Saelen MG, Kalanxhi E, Østensen IHG, Schee K, Røe K, Abrahamsen TW, Dueland S, Flatmark K: Biomarkers of histone deacetylase inhibitor activity in a phase 1 combinedmodality study with radiotherapy. Accepted version. Published as: PLoS ONE 9(2): e89750. This is an open-access article distributed under the terms of the Creative Commons Attribution License. The published version of this paper is available at: https://doi.org/10.1371/journal.pone.0089750|
|Paper IV: Flatmark K, Saelen MG, Seierstad T, Hole KH, Abrahamsen TW, Fleten KG, Røe K, Dueland S, Ree AH: Is oxaliplatin-containing neoadjuvant chemotherapy an alternative to radiation in T3 rectal cancer? Manuscript. The paper is removed from the thesis in DUO due to publisher restrictions.|