Abstract 2834: Anti-DLL4 treatment inhibits melanoma tumor growth, recurrence, metastases, and reduces frequency of cancer stem cells in a clinically relevant tumor model in NOD/SCID mice

Abstract

Abstract Metastatic burden at the time of diagnosis is often the cause of death in patients suffering from malignant melanoma. More predictive in vivo animal tumor models are needed to elucidate both the efficacy and mechanism of activity for newly developed anti-cancer therapeutic agents. We have developed an orthotopic melanoma model in NOD/SCID mice with intradermal implant of human melanoma cells that are derived directly from human cancer patient specimens. These tumors retain much of the original human cancer heterogeneity, phenotype, and the ability to form metastases in the lungs, lymph nodes, liver, intestines, and brain _ recapitulating the metastatic invasiveness seen in the clinic. We have developed antibodies against the human and the murine Delta-like Notch ligand DLL4, which target both tumor cells and vasculature, and reduce the frequency of cancer stem cells (CSCs) in human tumors implanted into NOD/SCID mice (Hoey et al., Cell Stem Cell 5:1680177, 2009). In our studies with a human melanoma model, we evaluated the anti-tumor and anti-metastatic activities of anti-DLL4 and found a significant inhibition of both primary tumor and metastases in the lungs, liver, intestine and brain. Moreover, in combination with the standard-of-care Paclitaxel, anti-DLL4 treatment caused a greater reduction of tumor growth than either agent alone and an increase in apoptosis of tumor cells compared to control antibody or paclitaxel alone These data were consistent with the results from the limiting dilution assay experiments that demonstrated a significant reduction of tumor initiating cells by the anti-DLL4 alone (1:15) and a further decrease in combination with paclitaxel (1:33) compared to the control antibody (1:5), but no effect by paclitaxel (1:5). In other studies aimed to examine tumor recurrence after excision of the primary tumors, treatment with anti-DLL4, alone and with paclitaxel, prevented recurrence of the primary tumors. In contrast, paclitaxel alone increased the frequency of tumor relapse when compared to the control and other treatments. In addition, anti-DLL4 alone inhibited metastases to lungs, lymph nodes, liver, brain and intestines and this effect was further enhanced by the combination with paclitaxel in the liver and intestines. The results from these studies demonstrate for the first time a significant inhibition of tumor recurrence and metastases in human melanoma by anti-DLL4 and establish a link between reduction of CSC frequency and the concurrent inhibition of metastases. Therefore our findings reveal great potential of our anti-DLL4 antibody as an effective anti-cancer therapy for melanoma patients. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 2834. doi:10.1158/1538-7445.AM2011-2834