DR5-targeted, chemotherapeutic drug-loaded nanoparticles induce apoptosis and tumor regression in pancreatic cancer in vivo models

• Published in: Journal of controlled release Vol. 324; pp. 610 - 619
• Main Authors: Johnston, Michael C., Nicoll, Julie A., Redmond, Kelly M., Smyth, Peter, Greene, Michelle K., McDaid, William J., Chan, Darren K.W., Crawford, N., Stott, Katie J., Fox, Jennifer P., Straubinger, Ninfa L., Roche, Sandra, Clynes, Martin, Straubinger, Robert M., Longley, Daniel B., Scott, Christopher J.
• Format: Journal Article
• Language: English
• Published: Netherlands Elsevier B.V 10.08.2020
• Subjects: Apoptosis; CASP8 and FADD-Like Apoptosis Regulating Protein; Cell Line, Tumor; Drug Carriers; Humans; Nanoparticles; Pancreatic Neoplasms - drug therapy; Receptors, TNF-Related Apoptosis-Inducing Ligand - metabolism
• ISSN: 0168-3659; 1873-4995
• DOI: 10.1016/j.jconrel.2020.05.046

Pancreatic cancer is usually advanced and drug resistant at diagnosis. A potential therapeutic approach outlined here uses nanoparticle (NP)-based drug carriers, which have unique properties that enhance intra-tumor drug exposure and reduce systemic toxicity of encapsulated drugs. Here we report that patients whose pancreatic cancers express elevated levels of Death Receptor 5 (DR5) and its downstream regulators/effectors FLIP, Caspase-8, and FADD had particularly poor prognoses. To take advantage of elevated expression of this pathway, we designed drug-loaded NPs with a surface-conjugated αDR5 antibody (AMG 655). Binding and clustering of the DR5 is a prerequisite for efficient apoptosis initiation, and the αDR5-NPs were indeed found to activate apoptosis in multiple pancreatic cancer models, whereas the free antibody did not. The extent of apoptosis induced by αDR5-NPs was enhanced by down-regulating FLIP, a key modulator of death receptor-mediated activation of caspase-8. Moreover, the DNA topoisomerase-1 inhibitor camptothecin (CPT) down-regulated FLIP in pancreatic cancer models and enhanced apoptosis induced by αDR5-NPs. CPT-loaded αDR5-NPs significantly increased apoptosis and decreased cell viability in vitro in a caspase-8- and FADD-dependent manner consistent with their expected mechanism-of-action. Importantly, CPT-loaded αDR5-NPs markedly reduced tumor growth rates in vivo in established pancreatic tumor models, inducing regressions in one model. These proof-of-concept studies indicate that αDR5-NPs loaded with agents that downregulate or inhibit FLIP are promising candidate agents for the treatment of pancreatic cancer. [Display omitted] •The death receptor 5 pathway is upregulated in pancreatic cancer and correlates with poorer prognosis.•AMG 655 conjugated to nanoparticle surface facilitates death receptor 5 apoptosis induction in pancreatic cancer cell lines•FLIP downregulation increases response to TRAIL and nanoparticle conjugated AMG 655•Camptothecin causes downregulation of FLIP•CRISPR targeting shows conjugated AMG 655 efficacy is FADD and caspase 8 dependent