Introduction: Of the 12,000 patients diagnosed with breast cancer in Australia annually, nearly 3,000 will die due to 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 ~ 4-6 months if treated with radiotherapy. The poor efficacy of current therapies against brain metastases is contributing to the recent surge in the incidence of advanced breast cancer patients developing brain metastases. We have developed a unique 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 vorinostat enhance the radiosensitivity of brain metastatic breast cancer and reduce brain metastasis in experimental models.
Aim: To test the inhibitory and radiosensitising properties of novel HDAC inhibitors against 4T1Br4 brain metastatic cells in vitro using proliferation and colony forming assays.
Results: Compounds derived from 2-aminosuberic acid , were tested and their efficacy compared to that of vorinostat against 4T1Br4 tumour cells and neonatal foreskin fibroblasts. One of these, 1179.4b, was significantly more potent (IC50 = 72 nM) than vorinostat (IC50 >400 nM) at inhibiting 4T1Br4 cell proliferation. Importantly, inhibition by 1179.4b was 5.6-fold more selective for 4T1Br4 tumour cells compared to normal fibroblasts (IC50 ~ 400 nM). In a colony forming assay, vorinostat (1 μM) did not inhibit 4T1Br4 colony formation but at the same concentration, 1179.4b completely blocked colony formation. In combination with irradiation, 1179.4b (50 nM) even at a concentration 10 times lower than vorinostat enhanced the effect of irradiation. Other 1179.4b-related compounds will be tested and the results presented.
Conclusion: These results demonstrate the potency of aminosuberic acid-derived compounds against brain metastatic cells and warrant further investigation in vivo.