Abstract
Background Pre-clinical studies have demonstrated that natural and synthetic histone deacetylase (HDAC) inhibitors can impede the in vitro and in vivo growth of cell lines from a variety of gynecologic and other malignancies. We investigated the anti-tumor activity of panobinostat (LBH589) both in vitro and in vivo as either a single agent or in combination with conventional cytotoxic chemotherapy using patient-derived xenograft (PDX) models of primary serous ovarian tumors.
Highlights
Pre-clinical studies have demonstrated that natural and synthetic histone deacetylase (HDAC) inhibitors can impede the in vitro and in vivo growth of cell lines from a variety of gynecologic and other malignancies
We compared the potency of LBH589 to the only established FDA approved HDAC inhibitor suberoylanilide hydroxamic acid (SAHA, Vorinistat) and observed that the concentrations required for inhibition of OVCAR8 and SKOV3 cell growth were approximately 2-fold less for LBH589
We analyzed the effect of LBH589 on acetylation of these proteins to validate that LBH behaves like other HDAC inhibitors and compared any observed effect to that obtained with SAHA
Summary
Pre-clinical studies have demonstrated that natural and synthetic histone deacetylase (HDAC) inhibitors can impede the in vitro and in vivo growth of cell lines from a variety of gynecologic and other malignancies. We investigated the anti-tumor activity of panobinostat (LBH589) both in vitro and in vivo as either a single agent or in combination with conventional cytotoxic chemotherapy using patient-derived xenograft (PDX) models of primary serous ovarian tumors. 75 % of patients present with advanced stage disease, a factor largely attributed to the absence of effective screening strategies [2]. The combination of carboplatin and paclitaxel is standard first line chemotherapy in the US and, while effective at generating responses in approximately 80 % of women, it is seldom curative [4]. Despite advances in therapy and delivery, recurrence and chemotherapy resistance are still formidable problems as the majority of patients with ovarian cancer who achieve a complete remission with first line platinum-based chemotherapy will develop recurrent disease that is less responsive to cytotoxic chemotherapy [5]. Finding new molecular targets and exploiting cellular pathways involved in the onset and progression of platinum resistant ovarian cancer will be essential to innovating the treatment of women with this lethal disease [6]
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