A novel anti-metastasis therapy for prostate cancer, utilizing the newly established small-activating RNA (saRNA) technique to up-regulate the expression of the tumor metastasis suppressor gene, dihydropyrimidase-like 3 (DPYSL3).
Metastasis is the main cause of death from prostate cancer. Suppressing cancer progression at a very early stage would prevent the development of metastases and reduce subsequent mortality. Dihydropyrimidase-like 3 (DPYSL3) is a gene that encodes for the protein CRMP4, which was previously identified as a metastatic suppressor in prostate cancers. CRMP4 protein suppresses cell motility or invasion in vitro and reduces tumor metastasis in mouse xenograft models. Based on this, KU researchers have showed that upregulation of DPYSL3 gene expression would suppress metastasis.
This invention prevents prostate cancer metastasis by upregulating the tumor suppressor gene DPYSL3 only in prostate-specific membrane antigen (PSMA) positive prostate cancer cells.
Double-stranded saRNA molecules that are complimentary to the DPYSL3 gene promoter enhance transcription of this gene. Prostate-cancer specific cell delivery used select saRNA molecules for DPYSL3 conjugated with prostate-specific membrane antigen (PSMA). The resulting conjugates successfully upregulated DPYSL3 gene expression in PSMA-positive prostate cancer cells, but not in PMSA-negative cells, thereby confirming specificity. Proof-of-concept for saRNA-driven upregulation of the tumor suppressor gene DPYSL3 in preventing metastasis in a prostate cancer animal model was successful. The results from this study showed that the saRNA conjugates significantly suppressed metastasis in mice with the prostate cancer xenografts compared to those treated with control (non-specific) saRNAs.
Since nearly all mortality associated with prostate cancer is due to metastasis, reducing the occurrence of distant tumor formation would boost survival rates.
Traditionally, therapeutics for prostate cancer included chemotherapy drugs, radiation, and prostate removal. This invention offers a novel approach to therapy by enhancing DPYSL3 gene expression of prostate tumor suppressors in vivo. Suppression of the gene provides a new avenue for effective anticancer therapy.
tumor suppressor gene activation