Highly specific targeting of the TMPRSS2/ERG fusion gene using liposomal nanovectors.
OBJECTIVE
The TMPRSS2/ERG (T/E) fusion gene is present in half of all prostate cancer tumors. Fusion of the oncogenic ERG gene with the androgen-regulated TMPRSS2 gene promoter results in expression of fusion mRNAs in prostate cancer cells. The junction of theTMPRSS2- and ERG-derived portions of the fusion mRNA constitutes a cancer-specific target in cells containing the T/E fusion gene. Targeting the most common alternatively spliced fusion gene mRNA junctional isoforms in vivo using siRNAs in liposomal nanovectors may potentially be a novel, low-toxicity treatment for prostate cancer.


METHODS
We designed and optimized siRNAs targeting the two most common T/E fusion gene mRNA junctional isoforms (type III or type VI). Specificity of siRNAs was assessed by transient co-transfection in vitro. To test their ability to inhibit growth of prostate cancer cells expressing these fusion gene isoforms in vivo, specific siRNAs in liposomal nanovectors were used to treat mice bearing orthotopic or subcutaneous xenograft tumors expressing the targeted fusion isoforms.


RESULTS
The targeting siRNAs were both potent and highly specific in vitro. In vivo they significantly inhibited tumor growth. The degree of growth inhibition was variable and was correlated with the extent of fusion gene knockdown. The growth inhibition was associated with marked inhibition of angiogenesis and, to a lesser degree, proliferation and a marked increase in apoptosis of tumor cells. No toxicity was observed.


CONCLUSIONS
Targeting the T/E fusion junction in vivo with specific siRNAs delivered via liposomal nanovectors is a promising therapy for men with prostate cancer.
Department of Pathology and Immunology and Michael E. DeBakey Department of Veterans Affairs Medical Center, Baylor College of Medicine, Houston, Texas 77030, USA.
Longjiang
L
Shao
Ibrahim
I
Tekedereli
Jianghua
J
Wang
Erkan
E
Yuca
Susan
S
Tsang
Anil
A
Sood
Gabriel
G
Lopez-Berestein
Bulent
B
Ozpolat
Michael
M
Ittmann
D000818:Animals; D045744:Cell Line, Tumor; D055785:Gene Knockdown Techniques; D006801:Humans; D008081:Liposomes; D008297:Male; D051379:Mice; D008819:Mice, Nude; D009368:Neoplasm Transplantation; D015514:Oncogene Proteins, Fusion / Q000235:genetics* / Q000378:metabolism; D011471:Prostatic Neoplasms / Q000628:therapy; D020033:Protein Isoforms / Q000235:genetics / Q000378:metabolism; D034622:RNA Interference; D034741:RNA, Small Interfering / Q000235:genetics*; D015534:Trans-Activators / Q000235:genetics / Q000378:metabolism; D000071230:Transcriptional Regulator ERG; D014162:Transfection / Q000379:methods*
C072312:ERG protein, human; D008081:Liposomes; D015514:Oncogene Proteins, Fusion; D020033:Protein Isoforms; D034741:RNA, Small Interfering; C515553:TMPRSS2-ERG fusion protein, human; D015534:Trans-Activators; D000071230:Transcriptional Regulator ERG