Poster Presentation 26th Lorne Cancer Conference 2014

Evaluation of Novel HDAC Inhibitors against Mouse and Human Brain Metastatic Breast Cancer In Vitro and In Vivo (#182)

Soo Hyun Kim 1 , David Fairlie 2 , Delphine Denoyer 3 , Normand Pouliot 1 4 5
  1. Research Division, Peter MacCallum Cancer Centre, East Melbourne, VIC, Australia
  2. Institute for Molecular Bioscience, University of Queensland, Brisbane, Queensland, Australia
  3. Centre for Cellular and Molecular Biology, Deakin University, Melbourne, VIC, Australia
  4. Sir Peter MacCallum Department of Oncology, University of Melbourne, Melbourne, VIC, Australia
  5. Pathology Department, University of Melbourne, Melbourne, VIC, Australia

One in nine Australian women are diagnosed with breast cancer each year and nearly 3,000 will die of metastatic disease, most commonly to bone, liver, lung and brain. Once brain metastases are established, prognosis for these patients is extremely poor, with a median survival of ~ 1-2 months if untreated. The limited efficacy of current systemic and targeted therapies against triple negative (ER-/PR-/HER2-) metastatic breast tumours is contributing to the increase in incidence of metastasis to brain. We have developed a robust mouse model of triple negative breast cancer metastasis to brain (4T1Br4) that is suited for testing the efficacy of anti-metastatic drugs. Recent in vitro and animal studies have shown that brain permeable histone deacetylases (HDAC) inhibitors such as SAHA enhance the radiosensitivity of brain metastatic breast cancer and reduce brain metastasis in experimental metastasis models.

Here, we investigated the inhibitory and radiosensitising properties of novel HDAC inhibitors (SB939 and 1179.4b) against 4T1Br4 (mouse) and MDA-MB-231Br (human) brain metastatic cells in vitro and in vivo. Specifically, we report that SB939 and 1179.4b are significantly more potent than SAHA at inhibiting proliferation of both 4T1Br4 and MDA-MB-231Br cells in vitro. In colony forming assays, SAHA (1 μM) did not inhibit 4T1Br4 colony formation whereas at the same concentration, SB939 partially, and 1179.4b completely blocked colony formation. In combination with radiation, SB939 or 1179.4b enhanced radiosensitivity of brain metastatic cells. This response was accompanied by potent and sustained induction of γ-H2AX foci, a marker of DNA double strand breaks. Preliminary in vivo metastasis assays showed that 1179.4b, at concentration 5 - 20 times lower than SAHA, inhibited primary tumour growth, reduced metastatic burden in lung and decreased the incidence of spontaneous brain metastases. Taken together, our results demonstrate the superior potency of SB939 and 1179.4b against brain metastatic cells and warrant further investigation in vivo.