Abstract 2016: HDAC inhibition significantly reduces primary and lung metastatic osteosarcoma progression
Authors: Nerlakanti Niveditha , McGuire Jeremy , Yu Diana , Reed Damon R. , Lynch Conor C. 
Published: August 2019

Osteosarcoma (OS) is the most common bone malignancy in adolescents. At the time of initial diagnosis, approximately 15% of the patients present with metastatic disease in lungs. Prognosis for this cohort is grim with 5-year overall survival rates at 30%. Frustratingly, these statistics have changed little over the past three decades, in part due to the lack of progress in identifying effective therapies and difficulty in coordinating robust clinical trials in this relatively rare malignancy. To address this, we previously screened 54 FDA approved drugs against 5 different OS cell lines and identified the histone deacetylase inhibitor (HDAC), panobinostat (Pano) as having potent effects in vitro. Here, we explore whether Panobinostat is effective in preventing multiple stages of OS progression in vivo using the K7M2 and SAOS2LM7 pre-clinical models of the disease. Pano prevents the growth of primary OS and lung metastasis. Mice were intratibially inoculated with K7M2-Luc cells and then treated with vehicle (n=11) or panobinostat (n=10; 10 mg/kg for all in vivo studies). Tumor growth was measured by bioluminescence (RLU). The clinical endpoint was 1x106RLU (IVIS-200). Primary OS growth was significantly slower in the panobinostat treated group (p&lt;0.05 by day 17) with the median time to clinical endpoint being 2.5-fold longer than the controls (control median: 21 days vs. Pano median: 53 days, p&lt;0.05). Micro-CT analysis demonstrated panobinostat limited OS induced bone disease. Panobinostat also impacted spontaneous lung metastasis (Time to detection; control, 10 days vs. Pano, 21 days). Histological analyses showed significantly lower metastatic burden and growth rates (pHistone-H3/cleaved caspase-3) in the panobinostat group. Pano pretreatment prevents OS lung seeding. Mice were pretreated with vehicle (n=9) or panobinostat (n=5) for 5 days prior to tail vein inoculation of 1x106K7M2-Luc cells. Bioluminescence demonstrated that panobinostat significantly (p&lt;0.05) delayed tumor growth compared to control animals. This translated into higher overall survival rates (Control median: 54 days vs. Pano median: 93 days, p&lt;0.05). Despite halting panobinostat treatment at day 38, 44% (4/9) of the mice remained alive at day 100. Pano halts the growth of established lung metastases. Mice were tail-vein inoculated with 1x106K7M2-Luc cells and randomized after three days into control (n=12) and panobinostat (n=15) treated groups. Bioluminescence readings demonstrated that panobinostat significantly reduced the growth of established OS lung metastases (p&lt;0.05). These data were confirmed using the SAOS2LM7 model. Mechanistically, we are now exploring the contribution of individual HDACs to the progression of OS. Taken together we demonstrate that panobinostat is effective for the treatment of OS and our findings provide rationale for the initiation of broad spectrum HDAC inhibitor focused clinical trials.

Citation Format: Niveditha Nerlakanti, Jeremy McGuire, Diana Yu, Damon R. Reed, Conor C. Lynch. HDAC inhibition significantly reduces primary and lung metastatic osteosarcoma progression [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 2016.