Abstract 3650: In Vitro and in vivo synergistic anticancer effect of HDAC inhibitor panobinostat (LBH589) plus zoledronic acid in human prostate, breast and multiple myeloma tumor models

Prostate cancer (PCa), multiple myeloma (MM) as well as triple-negative breast cancers (TNBCa) (lacking ER, PR, and ErbB2 receptor) are associated with aggressive behaviour, poor prognosis, and limited response to conventional chemotherapy as well as to molecular targeted drugs, in advanced disease. On this regards, the recent availability of agents able to regulate many signaling pathways, such as HDAC inhibitors (HDAC-Is) as well as bisphosphonates (BPs), can help to overcome the existence limited activity of anticancer strategies. The HDAC-I Panobinostat (LBH589) has shown significant preclinical and clinical anticancer activity in both haematological and solid malignancies, and is currently in phase III for relapsed MM. BPs, such as zoledronic acid (ZOL), inhibit osteoclast-mediated bone resorption and are indicated for the treatment of cancer bone metastasis. In addition a direct and indirect anticancer activity of ZOL in several preclinical models and clinical studies have been observed. In our study, we sought to define preclinically, the potential anticancer effect of Panobinostat in combination with ZOL in several cell models. We showed a potent synergistic antiproliferative effect of Panobinostat/ZOL treatment in PC3, LNCAP and DU145 PCa cells, independently of p53/KRAS status as well as androgen dependency, whatever schedule of administration (simultaneous vs sequential) we used, as demonstrated by median drug effect analysis calculating combination index (CI) according to the method of Chou and Talalay (CI