title: Influence of a novel histone deacetylase inhibitor panobinostat (LBH589) on the growth of ovarian cancer.
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.
  
  
  METHODS
  The ovarian cancer cell lines OVCAR8, SKOV3 and their paclitaxel-resistant derivatives OVCAR8-TR and SKOV3-TR were treated with increasing doses of LBH589. The effect of LBH589 on cell viability was assessed using the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay. Serially transplanted primary human high-grade serous ovarian adenocarcinoma tissue was utilized to generate xenografts in 6-week old female NOD/SCID mice. The mice were then randomized into one of 4 treatment groups: (1) vehicle control; (2) paclitaxel and carboplatin (P/C); (3) LBH589; or (4) P/C + LBH589. Mice were treated for 21 days and tumor volumes and mouse weights were obtained every 3 days. These experiments were performed in triplicate with three different patient derived tumors. Wilcoxan rank-sum testing was utilized to assess tumor volume differences.
  
  
  RESULTS
  In vitro treatment with LBH589 significantly reduced the viability of both taxol-sensitive and taxol-resistant ovarian cancer cell lines (p < 0.01). In vivo treatment with LBH589 alone appeared tumorstatic and reduced tumor growth when compared to vehicle treatment (p < 0.007) after 21 days. This single agent activity was confirmed in two additional experiments with other PDX tumors (p < 0.03, p < 0.05). A potential additive effect of LBH589 and P/C, manifested as enhanced tumor regression with the addition of LBH589 compared to vehicle (p < 0.02), in one of the three analyzed serous PDX models.
  
  
  CONCLUSIONS
  Our findings suggest that pan-HDAC inhibition with panobinostat precludes the growth of ovarian cancer cell lines in vitro and PDXs in vivo. Added benefit of LBH589 to standard P/C therapy was observed in one of three PDX models suggesting improved response in a subset of serous ovarian cancers.
authors.affiliation: Division of Gynecologic Oncology, Department of OB/GYN, Beth Israel Deaconess Medical Center, 330 Brookline Ave, Kirstein 3rd Floor, Boston, MA, 02215, USA.|Harvard Medical School, Boston, MA, 02114, USA.
authors.forename: Leslie A
authors.initials: LA
authors.lastname: Garrett
authors.affiliation: Division of Gynecologic Oncology, Department of OB/GYN, Massachusetts General Hospital, 55 Fruit Street, Yawkey 9, Boston, MA, 02114-2696, USA.|Vincent Center for Reproductive Biology, Department of OB/GYN, Massachusetts General Hospital, 55 Fruit Street, Their 9, Boston, 02114-2696, USA.|Harvard Medical School, Boston, MA, 02114, USA.
authors.forename: Whitfield B
authors.initials: WB
authors.lastname: Growdon
authors.affiliation: Division of Gynecologic Oncology, Department of OB/GYN, Massachusetts General Hospital, 55 Fruit Street, Yawkey 9, Boston, MA, 02114-2696, USA.|Vincent Center for Reproductive Biology, Department of OB/GYN, Massachusetts General Hospital, 55 Fruit Street, Their 9, Boston, 02114-2696, USA.|Harvard Medical School, Boston, MA, 02114, USA.
authors.forename: Bo R
authors.initials: BR
authors.lastname: Rueda
authors.affiliation: Division of Gynecologic Oncology, Department of OB/GYN, Massachusetts General Hospital, 55 Fruit Street, Yawkey 9, Boston, MA, 02114-2696, USA. Rfoster1@mgh.harvard.edu.|Vincent Center for Reproductive Biology, Department of OB/GYN, Massachusetts General Hospital, 55 Fruit Street, Their 9, Boston, 02114-2696, USA. Rfoster1@mgh.harvard.edu.|Harvard Medical School, Boston, MA, 02114, USA. Rfoster1@mgh.harvard.edu.
authors.forename: Rosemary
authors.initials: R
authors.lastname: Foster
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D015415:Biomarkers; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D004195:Disease Models, Animal; D004353:Drug Evaluation, Preclinical; D005260:Female; D056572:Histone Deacetylase Inhibitors / Q000494:pharmacology*; D006801:Humans; D006877:Hydroxamic Acids / Q000494:pharmacology*; D007211:Indoles / Q000494:pharmacology*; D051379:Mice; D016688:Mice, Inbred NOD; D016513:Mice, SCID; D060787:Neoplasm Grading; D010051:Ovarian Neoplasms / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology; D000077767:Panobinostat; D047368:Tumor Burden / Q000187:drug effects; D023041:Xenograft Model Antitumor Assays
chemical_list: D000970:Antineoplastic Agents; D015415:Biomarkers; D056572:Histone Deacetylase Inhibitors; D006877:Hydroxamic Acids; D007211:Indoles; D000077767:Panobinostat
keywords: Conventional chemotherapy; Histone deacetylase inhibitor; Ovarian cancer; Patient derived xenograft model