PSMA-homing dsRNA chimeric protein vector kills prostate cancer cells and activates anti-tumor bystander responses

Abstract

The treatment of metastatic androgen-resistant prostate cancer remains a challenge. We describe a protein vector that selectively delivers synthetic dsRNA, polyinosinic/polycytidylic acid (polyIC), to prostate tumors by targeting prostate specific membrane antigen (PSMA), which is overexpressed on the surface of prostate cancer cells.The chimeric protein is built from the double stranded RNA (dsRNA) binding domain of PKR tethered to a single chain anti-PSMA antibody. When complexed with polyIC, the chimera demonstrates selective and efficient killing of prostate cancer cells. The treatment causes the targeted cancer cells to undergo apoptosis and to secrete toxic cytokines. In a bystander effect, these cytokines kill neighboring cancer cells that do not necessarily overexpress PSMA, and activate immune cells that enhance the killing effect. The strong effects of the targeted polyIC are demonstrated on both 2D cell cultures and 3D tumor spheroids.

Nanoparticle Delivery of RIG-I Agonist Enables Effective and Safe Adjuvant Therapy in Pancreatic Cancer

“…Recent studies showed in vitro that polyinosinic:polycytidylic acid (poly I:C), a broad-spectrum PAMP interacting with dsRNA-dependent protein kinase (PKR), RIG-I, and melanoma differentiation-associated gene 5 (MDA5), can induce growth arrest in prostate cancer cells for up to about 15 days post-treatment. 31 We demonstrated a similar pattern of tumor growth arrest with the ppp dsRNA encapsulating LCP-AEAAs. Further, with this formulation strategy, we avoided the requirement of repeated administration and could enhance the survival of mice bearing KPC tumor.…”

My journey from tyrosine phosphorylation inhibitors to targeted immune therapy as strategies to combat cancer

“…By changing the "homing head" of our vectors, we have targeted HER-2-overexpressing breast cancer and prostate-specific membrane antigen (PSMA)-overexpressing prostate cancer xenografts (106)(107)(108). The involvement of multiple pathways in the response to targeted polyIC, the induction of a direct apoptotic effect that leads to rapid cell death, and the recruitment of the innate and adaptive immune systems to attack heterogeneous tumors and hunt out even distant metastases have combined to produce very impressive preclinical results (100,106,107).…”

Synthetic Biology Approaches in Immunology

“…Cells have been engineered to kill target cells in several ways. One approach involves using a chimeric recombinant protein vector 47 that targets the prostate-specific membrane antigen, found primarily in prostate cancer cells. The protein vector then delivers dsRNA and polyinosinic/polycytidylic acid to activate apoptosis pathways that killed cancer cells in monolayer and 3D cultures.…”