panobinostat and Bone-Neoplasms

Overall survival rates for patients with advanced osteosarcoma have remained static for over three decades. An in vitro analysis of osteosarcoma cell lines for sensitivity to an array of approved cancer therapies revealed that panobinostat, a broad spectrum histone deacetalyase (HDAC) inhibitor, is highly effective at triggering osteosarcoma cell death. Using in vivo models of orthotopic and metastatic osteosarcoma, here we report that panobinostat impairs the growth of primary osteosarcoma in bone and spontaneous metastasis to the lung, the most common site of metastasis for this disease. Further, pretreatment of mice with panobinostat prior to tail vein inoculation of osteosarcoma prevents the seeding and growth of lung metastases. Additionally, panobinostat impaired the growth of established lung metastases and improved overall survival, and these effects were also manifest in the lung metastatic SAOS2-LM7 model. Mechanistically, the efficacy of panobinostat was linked to high expression of HDAC1 and HDAC2 in osteosarcoma, and silencing of HDAC1 and 2 greatly reduced osteosarcoma growth in vitro. In accordance with these findings, treatment with the HDAC1/2 selective inhibitor romidepsin compromised the growth of osteosarcoma in vitro and in vivo. Analysis of patient-derived xenograft osteosarcoma cell lines further demonstrated the sensitivity of the disease to panobinostat or romidepsin. Collectively, these studies provide rationale for clinical trials in osteosarcoma patients using the approved therapies panobinostat or romidepsin.

Topics: Animals; Bone Neoplasms; Cell Line, Tumor; Cell Proliferation; Cell Survival; Depsipeptides; Gene Expression Regulation, Neoplastic; Histone Deacetylase 1; Histone Deacetylase 2; Histone Deacetylase Inhibitors; Humans; Lung Neoplasms; Mice; Osteosarcoma; Panobinostat; Survival Analysis; Xenograft Model Antitumor Assays

Mutations in chromatin-modifying proteins and transcription factors are commonly associated with a wide variety of cancers. Through gain- or loss-of-function, these mutations may result in characteristic alterations of accessible chromatin, indicative of shifts in the landscape of regulatory elements genome-wide. The identification of compounds that reverse a specific chromatin signature could lead to chemical probes or potential therapies. To explore whether chromatin accessibility could serve as a platform for small molecule screening, we adapted formaldehyde-assisted isolation of regulatory elements (FAIRE), a chemical method to enrich for nucleosome-depleted genomic regions, as a high-throughput, automated assay. After demonstrating the validity and robustness of this approach, we applied this method to screen an epigenetically targeted small molecule library by evaluating regions of aberrant nucleosome depletion mediated by EWSR1-FLI1, the chimeric transcription factor critical for the bone and soft tissue tumor Ewing sarcoma. As a class, histone deacetylase inhibitors were greatly overrepresented among active compounds. These compounds resulted in diminished accessibility at targeted sites by disrupting transcription of EWSR1-FLI1. Capitalizing on precise differences in chromatin accessibility for drug discovery efforts offers significant advantages because it does not depend on the a priori selection of a single molecular target and may detect novel biologically relevant pathways.

Topics: Antineoplastic Agents; Bone Neoplasms; Cell Line, Tumor; Chromatin; Drug Design; Drug Evaluation, Preclinical; High-Throughput Screening Assays; Histone Deacetylase Inhibitors; Histones; Human Umbilical Vein Endothelial Cells; Humans; Hydroxamic Acids; Indoles; Molecular Targeted Therapy; Nucleosomes; Oncogene Proteins, Fusion; Panobinostat; Phenylbutyrates; Sarcoma, Ewing; Small Molecule Libraries; Transcription, Genetic; Vorinostat

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