panobinostat and Neoplasm-Metastasis

Epigenetic alterations by histone/protein deacetylases (HDACs) are one of the many mechanisms that cancer cells use to alter gene expression and promote growth. HDAC inhibitors have proven to be effective in the treatment of specific malignancies, particularly in combination with other anticancer agents. We conducted a phase I trial of panobinostat in patients with unresectable stage III or IV melanoma. Patients were treated with oral panobinostat at a dose of 30 mg daily on Mondays, Wednesdays, and Fridays (Arm A). Three of the six patients on this dose experienced clinically significant thrombocytopenia requiring dose interruption. Due to this, a second treatment arm was opened and the dose was changed to 30 mg oral panobinostat three times a week every other week (Arm B). Six patients were treated on Arm A and 10 patients were enrolled to Arm B with nine patients treated. In nine patients treated on Arm B, the response rate was 0% (90% confidence interval [CI]: 0-28%) and the disease-control rate was 22% (90% CI: 4-55%). Among all 15 patients treated, the overall response rate was 0% (90% CI: 0-17%) and the disease-control rate was 27% (90% CI: 10-51%). There was a high rate of toxicity associated with treatment. Correlative studies suggest the presence of immune modifications after HDAC inhibition. Panobinostat is not active as a single agent in the treatment of melanoma. Further exploration of this agent in combination with other therapies may be warranted.

Topics: Antineoplastic Agents; Combined Modality Therapy; Female; Histone Deacetylase Inhibitors; Humans; Hydroxamic Acids; Indoles; Male; Melanoma; Neoplasm Metastasis; Neoplasm Staging; Panobinostat; Retreatment; Treatment Outcome

To evaluate the activity of panobinostat in refractory renal carcinoma.. Patients with advanced clear cell renal carcinoma who had received previous therapy with at least one angiogenesis inhibitor and one mTOR inhibitor were treated with panobinostat 45 mg orally twice a week, and were reevaluated after 8 weeks.. Twenty patients were treated with no objective responses. All patients progressed or stopped treatment prior to the 16-week reevaluation. Panobinostat was generally well-tolerated.. Panobinostat had no activity in this group of patients with refractory renal carcinoma. Further development of panobinostat in renal carcinoma is not recommended.

Topics: Aged; Carcinoma, Renal Cell; Female; Histone Deacetylase Inhibitors; Humans; Hydroxamic Acids; Indoles; Kidney Neoplasms; Male; Middle Aged; Neoplasm Metastasis; Panobinostat

Histone deacetylase inhibitors have demonstrated anticancer activity against a range of tumors. We aimed to define the maximum tolerated dose, toxicity, activity, and pharmacokinetics of oral panobinostat, a pan-deacetylase inhibitor, alone and in combination with docetaxel for the treatment of castration-resistant prostate cancer (CRPC).. Sixteen patients were enrolled, eight in each arm. Eligible patients had CRPC and adequate organ function. In arm I, oral panobinostat (20 mg) was administered on days 1, 3, and 5 for 2 consecutive weeks followed by a 1-week break. In arm II, oral panobinostat (15 mg) was administered on the same schedule in combination with docetaxel 75 mg/m(2) every 21 days.. Dose-limiting toxicities were grade 3 dyspnea (arm I) and grade 3 neutropenia >7 days (arm II). In arm I, all patients developed progressive disease despite accumulation of acetylated histones in peripheral blood mononuclear cells. In arm II, five of eight patients (63%) had a >or=50% decline in prostate-specific antigen (PSA), including one patient whose disease had previously progressed on docetaxel.. Oral panobinostat with and without docetaxel is feasible, and docetaxel had no apparent effect on the pharmacokinetics of panobinostat. Since preclinical studies suggest a dose-dependent effect of panobinostat on PSA expression, and other phase I data demonstrate that intravenous panobinostat produces higher peak concentrations (>20- to 30-fold) and area under the curve (3.5x-5x), a decision was made to focus the development of panobinostat on the intravenous formulation to treat CRPC.

Topics: Acetylation; Administration, Oral; Aged; Aged, 80 and over; Antineoplastic Combined Chemotherapy Protocols; Docetaxel; Drug Resistance, Neoplasm; Fluorodeoxyglucose F18; Histone Deacetylase Inhibitors; Histones; Humans; Hydroxamic Acids; Indoles; Male; Maximum Tolerated Dose; Middle Aged; Neoplasm Metastasis; Neoplastic Cells, Circulating; Panobinostat; Positron-Emission Tomography; Prostate-Specific Antigen; Prostatic Neoplasms; Taxoids; Treatment Outcome

Gastric cancer is the fifth most common cancer and the third leading cause of cancer-related deaths worldwide. Histone deacetylase (HDAC) inhibitors are a new class of cytostatic agents available for the treatment of various cancers and diseases. Although numerous clinical and pre-clinical trials on the anticancer effects of panobinostat have been conducted, only a few reports have investigated its efficacy in gastric cancer. The present study aimed to investigate the effects of panobinostat in gastric cancer cells. Panobinostat significantly inhibited the cell viability and proliferation of the gastric cancer cell lines SNU484 and SNU638 in a dose-dependent manner; it reduced the colony-forming ability of these cells. Moreover, it induced apoptosis as indicated by increased protein levels of cleaved poly ADP-ribose polymerase and cleaved caspase-3. Panobinostat induced the G2/M cell cycle arrest in SNU484 and SNU638 cells and subsequently decreased the G2/M phase regulatory-associated protein expression of p-Wee1, Myt1, and Cdc2. Furthermore, panobinostat significantly inhibited the metastasis of SNU484 and SNU638 cells by regulating the expression of MMP-9 and E-cadherin. Further, it decreased the protein levels of p-Akt and forkhead box protein M1 (FOXM1). These effects were reversed by the Akt agonist SC79 and were accelerated by the Akt inhibitor LY2940002. Moreover, tumor growth in xenograft animal experiments was suppressed by panobinostat. These results indicated that panobinostat inhibits the proliferation, metastasis, and cell cycle progression of gastric cancer cells by promoting apoptosis and inactivating Akt/FOXM1 signaling. Cumulatively, our present study suggests that panobinostat is a potential drug for the treatment of gastric cancer.

Topics: Animals; Antineoplastic Agents; Apoptosis; Cell Line, Tumor; Cell Proliferation; Cell Survival; Female; Forkhead Box Protein M1; G2 Phase Cell Cycle Checkpoints; Humans; Mice; Neoplasm Metastasis; Panobinostat; Proto-Oncogene Proteins c-akt; Signal Transduction; Stomach Neoplasms

PI3K (phosphoinositide 3-kinase)/AKT and RAS/MAPK (mitogen-activated protein kinase) pathway coactivation in the prostate epithelium promotes both epithelial-mesenchymal transition (EMT) and metastatic castration-resistant prostate cancer (mCRPC), which is currently incurable. To study the dynamic regulation of the EMT process, we developed novel genetically defined cellular and in vivo model systems from which epithelial, EMT and mesenchymal-like tumor cells with Pten deletion and Kras activation can be isolated. When cultured individually, each population has the capacity to regenerate all three tumor cell populations, indicative of epithelial-mesenchymal plasticity. Despite harboring the same genetic alterations, mesenchymal-like tumor cells are resistant to PI3K and MAPK pathway inhibitors, suggesting that epigenetic mechanisms may regulate the EMT process, as well as dictate the heterogeneous responses of cancer cells to therapy. Among differentially expressed epigenetic regulators, the chromatin remodeling protein HMGA2 is significantly upregulated in EMT and mesenchymal-like tumors cells, as well as in human mCRPC. Knockdown of HMGA2, or suppressing HMGA2 expression with the histone deacetylase inhibitor LBH589, inhibits epithelial-mesenchymal plasticity and stemness activities in vitro and markedly reduces tumor growth and metastasis in vivo through successful targeting of EMT and mesenchymal-like tumor cells. Importantly, LBH589 treatment in combination with castration prevents mCRPC development and significantly prolongs survival following castration by enhancing p53 and androgen receptor acetylation and in turn sensitizing castration-resistant mesenchymal-like tumor cells to androgen deprivation therapy. Taken together, these findings demonstrate that cellular plasticity is regulated epigenetically, and that mesenchymal-like tumor cell populations in mCRPC that are resistant to conventional and targeted therapies can be effectively treated with the epigenetic inhibitor LBH589.

Topics: Animals; Blotting, Western; Cell Line, Tumor; Disease Models, Animal; Epithelial-Mesenchymal Transition; Gene Expression Profiling; Gene Expression Regulation, Neoplastic; Histone Deacetylase Inhibitors; Humans; Hydroxamic Acids; Indoles; Male; Mice, Inbred NOD; Mice, Knockout; Mice, SCID; Mice, Transgenic; Mitogen-Activated Protein Kinases; Neoplasm Metastasis; Panobinostat; Phosphatidylinositol 3-Kinases; Prostatic Neoplasms, Castration-Resistant; Proto-Oncogene Proteins c-akt; Proto-Oncogene Proteins p21(ras); PTEN Phosphohydrolase; Reverse Transcriptase Polymerase Chain Reaction; Signal Transduction

Ewing sarcoma (ES) is a form of primary bone cancer, with few treatment options for patients who develop relapse with an overall 5-year survival of 13%. New treatment options are needed and histone deacetylase (HDAC) inhibitors show encouraging results in preclinical studies. Our patient developed inoperable progressive lung metastases and was treated with the HDAC inhibitor panobinostat. During 18 months of treatment, no new lesions appeared; the treatment was stopped due to progression. This clinical observation warrants further evaluation of HDAC inhibitors in ES. Combination with chemotherapy and biomarker studies could improve the therapeutic index of these classes of compounds.

Topics: Antineoplastic Agents; Bone Neoplasms; Female; Histone Deacetylase Inhibitors; Humans; Hydroxamic Acids; Indoles; Middle Aged; Neoplasm Metastasis; Panobinostat; Sarcoma, Ewing

Triple-negative breast cancer (TNBC) is a highly aggressive breast cancer subtype that lacks effective targeted therapies. The epithelial-to-mesenchymal transition (EMT) is a key contributor in the metastatic process. We previously showed the pan-deacetylase inhibitor LBH589 induces CDH1 expression in TNBC cells, suggesting regulation of EMT. The purpose of this study was to examine the effects of LBH589 on the metastatic qualities of TNBC cells and the role of EMT in this process. A panel of breast cancer cell lines (MCF-7, MDA-MB-231, and BT-549), drugged with LBH589, was examined for changes in cell morphology, migration, and invasion in vitro. The effect on in vivo metastasis was examined using immunofluorescent staining of lung sections. EMT gene expression profiling was used to determine LBH589-induced changes in TNBC cells. ZEB overexpression studies were conducted to validate requirement of ZEB in LBH589-mediated proliferation and tumorigenesis. Our results indicate a reversal of EMT by LBH589 as demonstrated by altered morphology and altered gene expression in TNBC. LBH589 was shown to be a more potent inhibitor of EMT than other HDAC inhibitors, SAHA and TMP269. Additionally, we found that LBH589 inhibits metastasis of MDA-MB-231 cells in vivo. These effects of LBH589 were mediated in part by inhibition of ZEB, as overexpression of ZEB1 or ZEB2 mitigated the effects of LBH589 on MDA-MB-231 EMT-associated gene expression, migration, invasion, CDH1 expression, and tumorigenesis. These data indicate therapeutic potential of LBH589 in targeting EMT and metastasis of TNBC.

Topics: Animals; Antineoplastic Agents; Apoptosis; Breast; Cell Line, Tumor; Cell Movement; Cell Proliferation; Epithelial-Mesenchymal Transition; Female; Histone Deacetylase Inhibitors; Homeodomain Proteins; Humans; Hydroxamic Acids; Indoles; MCF-7 Cells; Mice; Mice, SCID; Neoplasm Invasiveness; Neoplasm Metastasis; Panobinostat; Repressor Proteins; Transcription Factors; Triple Negative Breast Neoplasms; Xenograft Model Antitumor Assays; Zinc Finger E-box Binding Homeobox 2; Zinc Finger E-box-Binding Homeobox 1