A Combination of DR5 Agonistic Monoclonal Antibody with Gemcitabine Targets Pancreatic Cancer Stem Cells and Results in Long-term Disease Control in Human Pancreatic Cancer Model

Abstract

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 chemotherapy or radiation therapy. PDA contains a subset of tumor-initiating cells capable of extensive self-renewal known as cancer stem cells (CSC), 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 with the bulk of the tumor cells. Treating a collection of freshly generated patient-derived PDA xenografts with gemcitabine, 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 monoclonal antibody, with gemcitabine proved 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 that is considered more difficult to treat. These data provide 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.

The anti-Fn14 antibody BIIB036 inhibits tumor growth in xenografts and patient derived primary tumor models and enhances efficacy of chemotherapeutic agents in multiple xenograft models

“…Notably, the TRAIL-R2 receptor DR5 was shown to be enriched in pancreatic CSCs compared with the bulk of tumor cells, and this is thought to account for the particularly potent effect of the anti-DR5 antibody tigatuzimab in combination with gemcitabine. 18 Thus, it is possible that Fn14, too, may be had previously responded to BIIB036 treatment, remained sensitive to a second cycle of treatment with BIIB036. Significantly, BIIB036 enhanced the sensitivity to several chemotherapeutic agents in multiple xenograft models with no overlapping toxicities, supporting the utility of BIIB036 in the combination setting.…”

Stem Cells in Pancreatic Cancer

“…The combination therapy produced remarkable reduction in pancreatic CSCs, tumor remissions, and significant improvements in time to tumor progression [134]. Signaling pathways can also be inhibited by small molecule kinase inhibitors that act downstream of the extracellular domain of the receptor.…”

Trial Watch: Monoclonal antibodies in cancer therapy

“…100,101 The exact mechanisms underlying the cancer-selective toxicity of TRAILR agonists remain to be fully elucidated, but may be related to the differential expression of TRAILRs and downstream signaling proteins in transformed vs. normal cells. 102 Irrespective of these considerations, both conatumumab and tigatuzumab exhibited promising safety and efficacy profiles in preclinical tests and in initial phase I-II studies, 100,[103][104][105] which are now being extended to several oncological indications ( Table 4).…”