Experimental Radiosensitization and Molecular Prediction of Chemoradiotherapy Response in Rectal Cancer
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AbstractIn Norway, the annual incidence of rectal cancer exceeds 1000 cases. Although surgery remains the principal treatment modality in this common disease, recent studies have highlighted the central role of chemoradiotherapy (CRT) in conjunction with surgical resection to optimize local control and improve outcome. Nevertheless, in locally advanced rectal cancer (LARC), tumor response to preoperative CRT may vary considerably; in addition, this treatment delays surgery and has substantial acute and long-term adverse effects. Hence, in the contemporary management of LARC, the possibility of improving CRT efficacy and predicting CRT response to enable treatment stratification would be a critical achievement.
The study aims were to evaluate new drugs for radiosensitizing efficacy in relevant preclinical models and to identify functional biomarkers predictive of tumor responsiveness to preoperative CRT in LARC.
Oxaliplatin is a chemotherapeutic currently under investigation in CRT trials for rectal cancer. In an experimental in vivo model of human colorectal carcinoma, however, this drug did not convincingly improve the radiosensitizing effect of a standard CRT regimen, implying that integration of oxaliplatin into combined modality treatment of rectal cancer should remain controversial when conclusive clinical evidence is lacking.
On the contrary, vorinostat, a histone deacetylases inhibitor, enhanced radiation response of experimental colorectal carcinoma models as evaluated by in vitro clonogenicity and in vivo tumor growth delay, suggesting that this class of therapeutics might be a supplement to current CRT strategies in rectal cancer.
Finally, recognizing that kinase activity is a predictor of radiation response in tumor models, multiplex kinase activity profiles of diagnostic tumor biopsies from LARC patients were correlated with the individual tumor responses to preoperative CRT, and kinase pathways descriptive of poor-responding tumors were identified.
List of papers
I Folkvord S, Flatmark K, Seierstad T, Røe K, Rasmussen H, Ree AH. Inhibitory effects of oxaliplatin in experimental radiation treatment of colorectal carcinoma: does oxaliplatin improve 5-fluorouracil-dependent radiosensitivity? Radiother Oncol, 2008, 86 (3):428-34
II Folkvord S, Ree AH, Furre T, Halvorsen T, Flatmark K. Radiosensitization by SAHA in experimental colorectal carcinoma models – in vivo effects and relevance of histone acetylation status. Int J Radiat Oncol Biol Phys, 2009, 74 (2):546-52 Int J Radiat Oncol Biol Phys, 2009, 74 (2):546-52
III Ree AH, Folkvord S, Flatmark K. HDAC2 deficiency and histone acetylation. Nat Genet, 2008, 40 (7):812-3 Nat Genet, 2008, 40 (7):812-3
IV Folkvord S, Flatmark K, Dueland S, Wijn R, Grøholt KK, Nesland JM, Hole KH, Boender PJ, Johansen M, Giercksky KE, Ree AH. Prediction of response to preoperative chemoradiotherapy in rectal cancer by multiplex kinase activity profiling. Manuscript.