Abstract 3485: Inhibition of Notch signaling enhances the antitumor efficacy of chemotherapy in triple negative breast cancer through reduction of cancer stem cells

Proceedings: AACR 103rd Annual Meeting 2012‐‐ Mar 31‐Apr 4, 2012; Chicago, IL Triple negative breast cancer (TNBC) is characterized by lack of estrogen receptor (ER), progesterone receptor (PR) or Her2/neu. It is known to be particularly aggressive and refractory to current chemotherapies. Tumor-initiating cells (TICs) have been postulated as responsible for treatment failure for this type of cancer. Recent evidence suggests that Notch signaling may play a role in regulation of TIC self-renewal and differentiation hence present a promising target for development of novel therapies for TNBC. We previously discovered a mouse monoclonal Ab (mu-hN1) that produces robust efficacy in both T-cell acute lymphoblastic leukemia and TNBC by specifically blocking human Notch1 signaling in tumor cells. We subsequently produced a humanized Notch1 mAb (hu-hN1) that retained similar characteristics and activities compared to the mouse prototype mu-hN1. To gain insights into the mechanisms of Notch1 blockade on TNBC tumor grow inhibition (TGI), we evaluated the effect of hu-hN1 on apoptosis, proliferation and TIC self-renewal in Notch-driven Sum149 and a patient derived xenograft (PDX) TNBC models. We showed that hu-hN1 inhibited Notch signaling by reduction of NICD (Notch intracellular domain) and target genes Hes-1 and cMyc in Sum149 tumors. Inhibition of Notch signaling led to significant TGI either as a single agent or in combination with Docetaxel. TGI of hu-hN1 appeared to be in part due to induction of apoptosis in the tumor cells. More interestingly, treatment with this Ab caused reduction in mammosphere formation and CD44+/CD133+/ESA+ cell population. It also resulted in decrease in tumor incidence and delay in tumor recurrence, suggesting an anti-TIC activity of the agent. Further investigation in a PDX TNBC model confirmed the robust tumor efficacy and anti-TIC effect of hu-hN1. Taken together, our findings suggest that anti-Notch1 mAbs may provide novel therapies to improve the efficacy of conventional treatments by directly targeting the TIC niche. They may also delay tumor recurrence and hence have a major impact on cancer patient survival. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 3485. doi:1538-7445.AM2012-3485