No treatment is currently available
for metastatic and androgen-resistant prostate cancer. In our laboratory, we
are developing a novel strategy for targeted prostate cancer therapy. We plan
to selectively deliver synthetic dsRNA, poly-inosine/cytosine acid (PolyIC), to
prostate cancer cells by targeting Prostate Specific Membrane Antigen (PSMA),
which is over-expressed on the surface of prostate cancer cells. This strategy
is based on the fact that when internalized into cells, viral dsRNA activates
multiple killing pathways that promote apoptotic cell death and recruitment of
immune cells to the infected area.
We designed a
chimeric protein that will be used to deliver polyIC into prostate cancer
cells. The chimeric protein, DRBD-9Arg-ScFvJ591, contains the PSMA targeting
single-chain antibody J-591 linked to two dsRNA Binding Domains isolated from
dsRNA- activated protein kinase (PKR DRBD). The 9-Arginine linker was chosen in
order to facilitate endosomal escape following endocytosis. The specific
internalization of the above structure to prostate cancer cells was proved
using live cell imaging. We also confirmed the ability of the structure to bind
dsRNA. Finally, we were able to demonstrate a selective and efficient effect of
DRBD-9Arg-ScFvJ591/PolyIC conjugates on prostate cancer cell apoptosis. This
effect also triggered multiple pathways leading to cytokine induction resulting
in recruitment of immune cells.
The potent
effect of PolyIC delivery on the immune system makes this strategy superior to
other targeted therapeutics. Harnessing the immune system against the tumor
ensures extensive eradication of neighboring tumor cells, even those that do
not over-express PSMA (the bystander effect). This provides an effective
therapy, which should result in lower occurrence of acquired resistance and in
reduced probability of disease recurrence.
