The PRAVO study

The completed phase I study Pelvic Radiation and Vorinostat (ClinicalTrials NCT00455351; Principal Investigators: Ree, Flatmark, Dueland) for symptom palliation in advanced bowel cancer was designed to identify clinical safety and toxicity markers, and forms a template for early-phase clinical trials in assessing molecularly targeted therapeutics combined with radiotherapy [Ree & Hollywood, 2013]. The PRAVO study evolved within a preclinical program on tumor radiosensitization by histone deacetylase (HDAC) inhibitors in experimental colorectal carcinoma models [Flatmark et al., 2006; Ree et al., 2008]. In human colorectal carcinoma xenografts, significant tumor growth delay was observed following fractionated radiation combined with daily injections of the mice with the HDAC inhibitor vorinostat, compared to radiation treatment alone [Folkvord et al., 2009]. Furthermore, tumor volumes of irradiated hypoxic xenografts in mice given vorinostat were similar to xenograft volumes resulting from irradiation under normoxic conditions, demonstrating that the drug had reversed the radiation-resistant hypoxic phenotype [Saelen et al., 2012].

Completed clinical and biomarker investigations: In the PRAVO study, which was the first to report on the therapeutic use of an HDAC inhibitor in clinical radiotherapy, sequential patient cohorts were exposed to escalating dose levels of vorinostat combined with palliative radiotherapy to pelvic target volumes. Because common side effects of vorinostat single-agent therapy include intestinal toxicities, the primary objective of the study was to determine tolerability in combination with pelvic radiation since the latter may cause an overlapping toxicity profile [Ree et al., 2010; Bratland et al., 2011]. The study was also designed to demonstrate that vorinostat reached the specific target (detection of tumor histone acetylation) and the applicability of non-invasive tumor response assessment using functional magnetic resonance imaging [Ree et al., 2010]. Importantly, molecular markers of vorinostat action in this combined-modality context have been explored in non-irradiated, drug-exposed normal tissue. Following gene expression array analysis of study patients’ serially collected peripheral blood mononuclear cells (PBMC), biomarkers of vorinostat activity related to gene regulation and cell cycle progression, reflecting the appropriate timing of drug administration in the fractionated radiotherapy protocol, have been identified [Ree et al., 2014a].

Ongoing activity: Recently, in PBMC from study patients that specifically experienced dose-limiting toxicity from vorinostat, enrichment of genes reflecting particular molecular aberrations has been found, possibly underscoring a limited range of biological processes as fundamental for intestinal treatment toxicities [Ree et al., 2014b]. These findings are currently being confirmed through vorinostat-induced functional endpoints in a number of experimental intestinal models.

 

Publications:

Kalanxhi E et al. Cancer Res Treat. 2016 Jul 28.
Ree AH et al. PLoS One 2014a; 9, e89750.
Ree AH et al. Int J Mol Sci 2014b; 15, 22835-56.
Ree AH & Hollywood D. Radiother Oncol 2013; 108, 3-16.
Saelen MG et al. Radiat Oncol 2012; 7, 165.
Ree AH et al. Lancet Oncol 2010; 11, 459-64.
Bratland Å et al. Radiat Oncol 2011; 6, 33.
Folkvord S et al. Int J Radiat Oncol Biol Phys 2009; 74, 546-52.
Ree AH et al. Nat Genet 2008; 40, 812-3.
Flatmark K et al. Radiat Oncol 2006; 1, 25.