Abstract C63: The Pelvic Radiation and Vorinostat (PRAVO) phase 1 study identifying MYC repression as biomarker of histone deacetylase inhibitor activity.

Abstract

Abstract In modern radiation oncology, new insights into molecular radiobiology provide an opportunity for the rational integration of molecularly targeted therapeutics to optimize clinical radiation effects. One example is the use of histone deacetylase (HDAC) inhibitors as potentially radiosensitizing drugs. Conveyed by histone acetylation, HDAC inhibition causes perturbations in gene regulation implicated in cell cycle progression, DNA damage signaling and repair, and apoptosis. Following the demonstration that HDAC inhibitors enhanced radiation-induced clonogenic suppression in human colorectal carcinoma cell lines and xenograft models [1-3], the PRAVO study was conducted [4-5]. This trial, undertaken in patients treated with pelvic palliative radiotherapy (30 Gy in 3-Gy daily fractions) combined with the HDAC inhibitor vorinostat (administered once daily, three hours before radiation) for advanced gastrointestinal malignancy, was the first to report on the use of an HDAC inhibitor in clinical radiotherapy. It was designed to demonstrate that vorinostat reached the specific target (detection of tumor histone acetylation), the applicability of non-invasive tumor response assessment (using functional imaging), and importantly, that this combined-modality therapy was safe and tolerable. In the present report, potential biomarkers of vorinostat radiosensitizing action, not simultaneously manifesting molecular perturbations elicited by the radiation itself, were explored by gene expression array analysis of the PRAVO study patients’ peripheral blood mononuclear cells (PBMC), sampled at baseline (T0) and on-treatment two and 24 hours (T2 and T24) after the patients had received vorinostat. This strategy revealed 1,600 array probes that were common for the comparisons T2 versus T0 and T24 versus T2 across all of the patients, and furthermore, that no significantly differential expression was observed between the T0 and T24 groups. Functional annotation analysis of the array data showed that a significant number of the identified genes were implicated in biological processes and pathways comprising gene regulation (transcription, RNA processing), cell cycle progression (including p53 signaling, commonly involved in the DNA damage response), and chromatin biology. Of five genes that were selected both for verification of patients’ PBMC expression and for validation of vorinostat-regulated expression in human colorectal carcinoma xenograft models, transient repression of MYC was consistently observed in all conditions. In conclusion, within the design of the PRAVO study, all of the identified genes showed rapid and transient induction or repression and therefore, in principle, fulfilled the requirement of being pharmacodynamic biomarkers of vorinostat activity in fractionated radiotherapy, possibly underscoring the regulatory role of myc in this therapeutic setting. Citation Information: Mol Cancer Ther 2013;12(11 Suppl):C63. Citation Format: Anne Hansen Ree, Marie G. Saelen, Erta Kalanxhi, Ingrid H. G. Ostensen, Kristina Schee, Kathrine Roe, Torveig W. Abrahamsen, Svein Dueland, Kjersti Flatmark. The Pelvic Radiation and Vorinostat (PRAVO) phase 1 study identifying MYC repression as biomarker of histone deacetylase inhibitor activity. [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2013 Oct 19-23; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2013;12(11 Suppl):Abstract nr C63.