Preclinical and phase I studies of phenoxodiol: a translational approach for the development of a novel isoflavone for the treatment of prostate cancer

Abstract

This work presents an investigation of the potential development of phenoxodiol, a novel isoflavone, for the treatment of prostate cancer. The literature concerning isoflavone epidemiology, pharmacology, clinical use and their effect on prostate cancer is reviewed. Isoflavone impact on signal transduction pathways is also reviewed with a particular focus on the Akt / mTOR signal transduction pathway, a key signaling pathway in prostate cancer cells. In vitro experiments and xenograft nude mice studies show that phenoxodiol inhibits the growth of DU145 and PC3 prostate cancer cells, when used alone and in combination with cisplatin or carboplatin. Phenoxodiol in combination with cisplatin is highly synergistic when inhibiting the growth of DU145 cells in particular. We show for the first time, that phenoxodiol and cisplatin or carboplatin, inhibits phosphorylation of Akt and mTOR in DU145 and PC3 cells. A first-in-human study of single dose phenoxodiol investigating its pharmacokinetic properties in cancer patient volunteers was performed. Extensive conjugation of phenoxodiol and a short half-life was noted in this study. A Phase I study of intravenous phenoxodiol administered weekly to patients with advanced cancer was then performed to assess toxicity of a repeated dose schedule, as well as the maximum tolerated dose. This schedule was well tolerated in patients, with lymphocytopenia noted as the main toxicity. Given the short half-life of phenoxodiol and our preclinical studies suggesting that combination with cisplatin and carboplatin synergistically inhibited prostate cancer cell growth, we also undertook a Phase I dose escalation study of oral phenoxodiol administered in combination with cisplatin or carboplatin to patients with advanced cancer. The main adverse events include hyperglycemia, hypocalcemia, mild transaminase rises, as well as nausea, constipation, infusion site reactions and lethargy. Three patients with ovarian cancer responded to treatment according to CA125 criteria, and there was a 45% reduction in prostate specific antigen level in one man with androgen independent prostate cancer. The bioavailability of the oral formulation of phenoxodiol was calculated to be 17.5%. Phenoxodiol shows promise for further development in the potential treatment of prostate cancer.