LNP siRNA can silence target genes in vivo and enable inhibition of traditionally non-druggable genes like CLU and other promising cotargeting approaches in ENZ-R CRPC therapeutics.
Cotargeting the AR (with MDV3100) and CLU (with OGX-011) synergistically enhanced apoptotic rates over that seen with MDV3100 or OGX-011 monotherapy and delayed CRPC LNCaP tumor and prostate-specific antigen (PSA) progression in vivo.
Together, our findings indicate that Hsp90 inhibitor-induced activation of the heat shock response and CLU is attenuated by OGX-011, with synergistic effects on delaying CRPC progression.
The progress of clinical application of two ASOs showing promise in treatment of human cancers--Oblimersen (G3139), targeting BCL2 for the treatment of metastatic melanoma, and Custirsen (OGX-11), targeting clusterin for the treatment of hormone refractory prostate cancer (HRPC)--is examined.
These findings suggest that combined treatment with antisense clusterin oligodeoxynucleotide and Ad5CMV-p53 could be a novel strategy to inhibit progression of hormone-refractory prostate cancer and that further addition of chemotherapeutic agents may help to enhance the efficacy of this combined regimen.
Collectively, these findings demonstrate that TRPM-2 overexpression helps confer a chemoresistant phenotype through inhibition of apoptosis, and that antisense TRPM-2 ODN may be useful in enhancing the effects of cytotoxic chemotherapy in hormone-refractory prostate cancer.
These findings confirm that TRPM-2 overexpression confers resistance to cytotoxic chemotherapy in prostate cancer cells and illustrates the potential utility of combined treatment with AS TRPM-2 ODN plus chemotherapeutic agents for patients with hormone-refractory prostate cancer.