A combination of DR5 agonistic mAb with gemcitabine targets pancreatic cancer stem cells, and results in long-term disease control in human pancreatic cancer model.
Molecular cancer therapeutics 2010 Jul 26; In press
Rajeshkumar N NV, Rasheed Z ZA, García-García E, Lopez-Rios F, Fujiwara K, Matsui W WH, Hidalgo M
1Medical Oncology, Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University.
Pancreatic ductal adenocarcinoma (PDA) is an aggressive malignancy with one of the worst outcomes among all cancers. PDA often recurs after initial treatment to result in patient death despite the use of chemo-/radiation therapy. PDA contains a subset of tumor-initiating cells capable of extensive self-renewal known as cancer stem cells (CSCs), which may contribute to therapeutic resistance and metastasis. At present, conventional chemotherapy and radiotherapy are largely ineffective in depleting CSC pool, suggesting the need for novel therapies that specifically target the cancer-sustaining stem cells for tumor eradication and to improve the poor prognosis of PDA patients. In this study, we report that death receptor-5 (DR5) is enriched in pancreatic CSCs compared to the bulk of the tumor cells. Treating a collection of freshly generated patient-derived PDA xenografts with gemcitabine (GEM), the first-line chemotherapeutic agent for PDA, is initially effective in reducing tumor size, but largely ineffective in diminishing the CSC populations, and eventually culminated in tumor relapse. However, a combination of tigatuzumab, a fully humanized DR5 agonist mAb, with GEM prove to be more efficacious by providing a double hit to kill both CSCs and bulk tumor cells. The combination therapy produced remarkable reduction in pancreatic CSCs, tumor remissions and significant improvements in time to tumor progression in a model which is considered more difficult to treat. These data provides the rationale to explore the DR5 directed therapies in combination with chemotherapy as a therapeutic option to improve the current standard of care for pancreatic cancer patients.
Keywords: DR5 gemcitabine pancreatic cancer