Background and Aim: Pancreatic adenocarcinoma remains one of the most deadly and chemo resistant cancers. Emerging data suggest that pancreatic cancer contains a small subset of distinct cancer stem cells that are responsible for tumor initiation, growth and are thought to be the major culprit behind cancer metastasis and recurrence after clinical remission. Treatment with standard chemotherapeutics may result in tumor shrinkage, but majority of the tumors recur, likely because the cancer stem cells survives and fuels tumor regeneration. Agents specifically targeting pancreatic cancer stem cells will likely be needed for tumor eradication and improve the poor prognosis of pancreatic cancer patients. To this end, we evaluated the antitumor potential of a novel humanized death receptor-5 (DR5) agonist antibody, Tigatuzumab (CS-1008), in combination with gemcitabine in pancreatic tumor xenografts. Experimental procedure: Flow cytometry was used to examine the expression of DR5 by pancreas cancer stem cells (ALDH+CD24+CD44+). Ten patient-derived tumor xenografts growing in nude mice were treated with 1) Tigatuzumab 3 mg/kg., i.v once weekly for 4 weeks 2) Gemcitabine 100 mg/kg i.p twice weekly for 4 weeks and 3) Gemcitabine + Tigatuzumab in the above mentioned dose and frequency. Tumor size was measured twice per week and relative tumor growth index and tumor doubling time was calculated versus control mice. Immunohistochemical staining was performed to determine the ALDH and CD24 expression in control and treated tumor samples. Results: Pancreas cancer stem cells are relatively enriched for DR5 expression (94% of ALDH+ cells and 89% of CD24+CD44+ cells) compared to non-stem cell bulk populations (30%). Gemcitabine treatment alone reduced tumor size and resulted in the enrichment of tumor cells that express ALDH+ and/or CD24+CD44+. But tumors reliably recurred after treatment discontinuation. However, treatment with gemcitabine + Tigatuzumab eliminated the pancreas cancer stem cells, significantly increased tumor doubling time and resulted in long term cures in 50% of cases. Conclusion: Pancreas cancer stem cells express DR5. Targeting DR5 with Tigatuzumab eliminates pancreatic cancer stem cell population and potentiates gemcitabine sensitivity. This study supports the rational to test this promising combination in a clinical setting of pancreatic cancer.

Citation Information: In: Proc Am Assoc Cancer Res; 2009 Apr 18-22; Denver, CO. Philadelphia (PA): AACR; 2009. Abstract nr 1069.

100th AACR Annual Meeting-- Apr 18-22, 2009; Denver, CO

American Association for Cancer Research
2009