YM155: A Small Molecule Survivin Suppressant with Potent Antitumor Effect in Human Breast Cancer Models. (2009)

Abstract Background: Survivin, a member of the inhibitor of apoptosis (IAP) gene family, is a key regulator of apoptosis and mitosis. Aberrant expression of survivin is detected in various clinical tumors, but not in normal adult tissues. Increased survivin expression in cancer patients is an unfavorable prognostic marker correlating with decreased overall survival in several malignancies. Also, survivin expression has been implicated in tumor growth, progression, and resistance to conventional and targeted anticancer agents. YM155 is a novel small molecule survivin suppressant which has demonstated potent antitumor activity against a wide range of cancer cells and is currently in clinical development in a number of tumor types including breast cancer. In this study, we evaluated the therapeutic potential of YM155 against human breast cancer models.Material and Methods: Antiproliferative effect was evaluated by sulforhodamine B assay. In an assessment of gene expression changes, cell viability and caspase activation, cells were analyzed 48-96h post transfection of survivin siRNA or treatment with YM155. For antitumor experiments, three human triple negative breast cancer (TNBC), MRK-nu-1, MDA-MB-231 and MDA-MB-435 cells were subcutaneously or orthotopically implanted into female BALB/c nu/nu mice. After the tumors were established, YM155 was administered as a 7-day continuous sc infusion. Docetaxel was administered IV bolus.Results: In in vitro panel screening derived from human breast tumors, YM155 showed potent antiproliferative activity against breast cancer cell lines with GI50 values ranging from 0.64 to 32 nM, regardless of ER-alpha, PR, HER-2 expression status. In MRK-nu-1 TNBC cells, YM155 resulted in suppression of survivin expression, caspase-3/7 activation, induction of spontaneous apoptosis, and growth inhibition in the same way that survivin siRNA did. In addition, 7-day continuous infusion of YM155 resulted in the complete regression without body weight loss in an MRK-nu-1 subcutaneous xenograft model, indicating that MRK-nu-1 cells highly depend on survivin for survival. In an MDA-MB-231 human TNBC orthotopic xenograft model, YM155 also induced more durable tumor regression compared with that of the docetaxel treatment group. In the combination study using an MDA-MB-435 orthotopic model, concomitant administration of YM155 and docetaxel showed substantial tumor regression more potently and for longer periods than each single compound administration alone without enhancement of body weight loss.Conclusions: YM155 plus docetaxel showed enhanced antitumor activity as compared to each compound alone without increase in weight loss in breast cancer models, suggesting that survivin suppression may constitute a valuable supplement to current treatment strategies in breast cancer. Since taxanes are commonly utilized in the treatment of breast cancer, these results support evaluating this combination in patients with advanced breast cancer. A phase 2 study of YM155 in combination with docetaxel in women with metastatic HER2 negative breast cancer is planned. Citation Information: Cancer Res 2009;69(24 Suppl):Abstract nr 3140.