Histone deacetylase inhibition prevents the growth of primary and metastatic osteosarcoma. Issue 10 (29th June 2020)

• Record Type: Journal Article
• Authors: McGuire, Jeremy J.; Nerlakanti, Niveditha; Lo, Chen Hao; Tauro, Marilena; Utset‐Ward, Thomas J.; Reed, Damon R.; Lynch, Conor C.
• Is Part Of: International journal of cancer. Volume 147:Issue 10(2020)
• Page Start: 2811
• Page End: 2823
• Publication Date: 2020-06-29
• Subjects: histone deacetylase -- lung metastasis -- osteosarcoma -- panobinostat; Cancer -- Periodicals; Cancer -- Prevention -- Periodicals; 616.994
• DOI: 10.1002/ijc.33046
• Languages: English
• ISSNs: 0020-7136

Abstract

Abstract: 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. Abstract : What's new? Clinical trials of osteosarcoma therapies are difficult to conduct given the low incidence of the disease. While in vitro studies have identified histone deacetylase (HDAC) inhibitors as a potential treatment, their efficacy in vivo largely remains untested. This study found that the broad‐spectrum HDAC inhibitor panobinostat blocks spontaneous osteosarcoma metastasis to the lung when used as a single agent. Panobinostat also impaired growth of established lung metastases and improved overall survival. Mechanistically, HDAC1/2 emerged as important drivers of osteosarcoma growth and metastasis. Altogether, the findings provide a strong rationale for the design of clinical trials to test panobinostat in humans.