Histone deacetylases play important roles in the epigenetic regulation of gene expression, and the therapeutic principle of HDAC inhibition exploits the aberrant epigenetic changes characterizing cancer cells. HDAC inhibitors have demonstrated activity in a variety of malignancies, and currently, a dozen HDAC inhibitors are under investigation in clinical trials. Reports indicating low toxicity and favorable safety profiles suggest HDAC inhibitors as interesting candidates for combinatory regimens with cytotoxic therapy (radiotherapy, chemotherapy). The authors have previously reported that the HDAC inhibitor SAHA (vorinostat) had radiosensitizing activity in preclinical models, as tumor cell radiosensitization was achieved in human colorectal carcinoma cell lines in vitro and in vivo.
The PRAVO phase 1 study was performed to assess whether vorinostat could be administered safely in combination with pelvic palliative radiotherapy. The authors report that, among the 16 patients completing the study (one patient withdrew), most adverse events were grades 1 or 2, with fatigue and gastrointestinal events common to all patients. Grade 3 adverse events included fatigue (five patients), anorexia (three), diarrhea (two), hyponatremia (one), hypokalemia (one), and acneiform rash (one). Dose-limiting toxicities occurred at the 300 mg dose in one of six patients (fatigue and anorexia) and at the 400 mg dose in two of six patients (diarrhea, fatigue, anorexia, hyponatremia, and hypokalemia), suggesting a maximum tolerable daily dose of 300 mg. The researchers observed histone hyperacetylation in tumor biopsies, indicating biological activity of vorinostat in the radiotherapy target volumes.
Strategies for improving therapeutic efficacy in clinical radiotherapy are increasingly focused on targeting molecular mechanisms to increase tumor cell radiosensitivity, and HDAC inhibition is emerging as a promising concept. This study shows that vorinostat can be safely combined with short-term pelvic palliative radiotherapy, emphasizing the potential use of HDAC inhibitors with radiation. Furthermore, these promising results suggest vorinostat to be investigated in combination with long-term curative pelvic radiotherapy, for instance in rectal cancer.
The Lancet Oncology, Early Online Publication, 7 April 2010
Vorinostat, a histone deacetylase inhibitor, combined with pelvic palliative radiotherapy for gastrointestinal carcinoma: the Pelvic Radiation and Vorinostat (PRAVO) phase 1 study
Prof Anne Hansen Ree MD, Svein Dueland MD, Sigurd Folkvord MD, Knut H Hole MD, Therese Seierstad PhD, Marianne Johansen RN, Torveig W Abrahamsen BSc, Kjersti Flatmark MD
Press release from Reuters:
Merck drug shows promise in pelvic cancer patients
Previous news article (from www.rr-research.no) about Ree, Flatmark and co-workers:
Correspondence in Nature Genetics by Ree, Folkvord, and Flatmark