panobinostat and Sarcoma

Treatment options for sarcoma are limited. Histone deacetylase inhibitors increase the efficacy of topoisomerase II inhibitors by promoting access to chromatin and by down-regulating DNA repair. Thus, combined panobinostat and epirubicin therapy was evaluated to treat refractory sarcoma.. Patients with advanced solid tumors were enrolled in a 3 + 3 dose-escalation phase I trial of panobinostat given on days 1, 3, and 5 followed by 75 mg/m(2) of epirubicin on day 5 in 21-day cycles, with a dose expansion at maximum tolerated dose (MTD) in 20 sarcoma patients. Peripheral blood mononucleocyte histone acetylation was also evaluated.. Forty patients received 20-60 mg panobinostat. Dose-limiting toxicities included thrombocytopenia, febrile neutropenia, and fatigue at 60 mg, defining a panobinostat MTD at 50 mg. Four responses were seen in 37 assessable patients, all after progression on prior topoisomerase II inhibitors. For those with sarcoma, 12 of 20 derived clinical benefit (1 partial response and 11 stable disease, median overall survival 8.3 months), including 8 of 14 previously progressed on topoisomerase II therapy. Treatment benefits correlated with increased histone acetylation and decreased neutrophil count on day 5.. Panobinostat and epirubicin treatment is well tolerated and may reverse anthracycline resistance. Changes in histone acetylation and associated decrease in neutrophil count correlated with clinical benefit and warrant investigation as predictive biomarkers.. This trial is registered at www.Clinicaltrials.gov, Identifier: NCT00878904.

Topics: Adult; Aged; Chromatin; DNA Repair; Dose-Response Relationship, Drug; Drug Therapy, Combination; Epirubicin; Female; Histone Deacetylase Inhibitors; Humans; Hydroxamic Acids; Indoles; Male; Maximum Tolerated Dose; Middle Aged; Panobinostat; Sarcoma; Topoisomerase II Inhibitors

Soft tissue sarcomas (STS) are rare tumours for which treatment options are limited in the advanced setting. Histone deacetylase inhibitors have shown activity in preclinical models of STS.. We conducted a single-arm, open-label, multicentre phase II study to assess the efficacy and tolerability of panobinostat given orally, 40 mg thrice weekly in patients with advanced pretreated STS. The primary endpoint was the 3-month progression-free rate.. Forty-seven STS patients were enrolled between January 2010 and December 2010. Median age was 59 (range 21-79) years, 22 (47%) patients were males. Panobinostat dose was lowered to 20 mg thrice weekly after nine patients were enrolled, based on the recommendation of an independent safety committee. The most common grade 3/4 adverse events were thrombocytopenia, fatigue, lymphopenia and anaemia. Forty-five patients were evaluable for the primary endpoint. Among them, nine patients (20%, 95% CI (10-35%)) were progression-free at 3 months. No partial response was seen, but 17 patients (36%) had stable disease (SD) as their best response. Six patients were progression-free at 6 months.. Panobinostat was poorly tolerated at 40 mg thrice a week. Efficacy in unselected advanced STS was limited, although some patients had prolonged SD.

Topics: Adult; Aged; Antineoplastic Agents; Disease-Free Survival; Female; Humans; Hydroxamic Acids; Indoles; Leiomyosarcoma; Liposarcoma; Liposarcoma, Myxoid; Male; Middle Aged; Nerve Sheath Neoplasms; Panobinostat; Salvage Therapy; Sarcoma; Sarcoma, Alveolar Soft Part; Sarcoma, Endometrial Stromal; Sarcoma, Synovial; Treatment Outcome; Young Adult

Sarcoma is a rare and heterogeneous class of mesenchymal malignancies with poor prognosis. Panobinostat (LBH589) as one of histone deacetylase (HDAC) inhibitors has demonstrated anti-tumor activity in patients with sarcoma, but its mechanisms remains unclear. Here, we found that LBH589 alone inhibited the proliferation and colony formation of soft tissue sarcoma (STS) cell lines. Transcriptome analysis showed that treatment with LBH589 augmented the NK cell-mediated cytotoxicity. Quantitative real-time PCR and flow cytometric analysis (FACS) further confirmed that LBH589 increased the expression of NKG2D ligands MICA/MICB. Mechanistically, LBH589 activated the Wnt/β-catenin pathway by upregulating the histone acetylation in β-catenin promoter. In vitro co-culture experiments and in vivo animal experiments showed that LBH589 increased the cytotoxicity of natural killer (NK) cells while Wnt/β-catenin inhibitor decreased the effects. Our findings suggest that LBH589 facilitates the anti-tumor effect of NK cells, highlights LBH589 an effective assistance drug in NK cell-based immunotherapies.

Topics: Animals; Antineoplastic Agents; Apoptosis; beta Catenin; Cell Line, Tumor; Cell Proliferation; Histone Deacetylase Inhibitors; Hydroxamic Acids; Killer Cells, Natural; Panobinostat; Sarcoma

Epithelioid sarcomas and rhabdoid tumors are rare, aggressive malignancies with poor prognosis. Both are characterized by INI1 alterations and deregulation of growth factor receptors albeit their interaction has not been elucidated.. In this study, we investigated the activity of a panel of epigenetic modulators and receptor tyrosine kinase inhibitors in vitro on respective cell lines as well as on primary patient-derived epithelioid sarcoma cells, and in vivo on xenografted mice. Focusing on histone deacetylase (HDAC) inhibitors, we studied the mechanism of action of this class of agents, its effect on growth factor receptor regulation, and changes in epithelial-to-mesenchymal transition by using cell- and RT-qPCR-based assays.. Pan-HDAC inhibitor panobinostat exhibited potent anti-proliferative activity at low nanomolar concentrations in A204 rhabdoid tumor, and VAESBJ/GRU1 epithelioid sarcoma cell lines, strongly induced apoptosis, and resulted in significant tumor growth inhibition in VAESBJ xenografts. It differentially regulated EGFR, FGFR1 and FGFR2, leading to downregulation of EGFR in epithelioid sarcoma and to mesenchymal-to-epithelial transition whereas in rhabdoid tumor cells, EGFR was strongly upregulated and reinforced the mesenchymal phenotype. All three cell lines were rendered more susceptible towards combination with EGFF inhibitor erlotinib, further enhancing apoptosis.. HDAC inhibitors exhibit significant anticancer activity due to their multifaceted actions on cytotoxicity, differentiation and drug sensitization. Our data suggest that the tailored, tissue-specific combination of HDAC inhibitors with therapeutics which target cellular salvage mechanisms might increase their therapeutic relevance.

Topics: Animals; Apoptosis; Cell Line, Tumor; Cell Proliferation; Epithelial-Mesenchymal Transition; Female; Histone Deacetylase Inhibitors; Humans; Mice; Mice, Nude; Panobinostat; Receptors, Growth Factor; Rhabdoid Tumor; Sarcoma

Undifferentiated pleomorphic sarcoma (UPS) is the second most common soft tissue sarcoma. For patients with unresectable or metastatic disease, chemotherapies are considered, but in many cases they are not curative. There is a need to identify specific molecular dysregulations that can be therapeutic targets. We focused on neurotensin receptor 1 (NTSR1), which belongs to the G-protein-coupled receptor. NTSR1 expression was upregulated in specimens from patients with UPS. Real-time polymerase chain reaction showed that expression of NTSR1 messenger RNA was 5- to 7-fold increased in UPS cells compared with myoblasts. Western blot showed a high expression of NTSR1 protein in UPS cell lines. Knockdown of NTSR1 prevented UPS cell proliferation and invasion. We confirmed that SR48692, an inhibitor of NTSR1, exhibited antitumor activities in UPS cells. The combination index showed that SR48692 and standard chemotherapeutic drugs prevented UPS cell proliferation synergistically. Mouse xenograft models showed that SR48692 inhibited extracellular signal-regulated kinase phosphorylation and enhanced the response to standard chemotherapeutic drugs. Inhibition of NTSR1 improved the effect of standard chemotherapeutic drugs for UPS. SR48692 may be a new drug for targeted UPS therapy.

Topics: Adult; Aged; Aged, 80 and over; Animals; Antineoplastic Agents; Cell Line, Tumor; Cell Proliferation; Cell Survival; Drug Synergism; Female; Gene Expression Regulation, Neoplastic; Humans; Male; Mice, Inbred BALB C; Mice, Nude; Middle Aged; Molecular Targeted Therapy; Panobinostat; Pyrazoles; Quinolines; Receptors, Neurotensin; Sarcoma; Up-Regulation; Xenograft Model Antitumor Assays

Topics: Animals; Apoptosis Regulatory Proteins; Cell Line, Tumor; Cell Proliferation; Cell Survival; Down-Regulation; Gene Expression Regulation, Neoplastic; Histone Deacetylase Inhibitors; Humans; Inhibitory Concentration 50; Mice; Panobinostat; Proto-Oncogene Proteins c-fos; Sarcoma; Treatment Outcome; Xenograft Model Antitumor Assays