Two-step amplification technique delivers gene therapy to refractory prostate cancer

CONTEXT: Under the supervision of Dr. Lily Wu, researchers at the University of California, Los Angeles created a prostate-specific two-step transcription amplification (TSTA) technique to deliver suicide gene therapy to hormone-refractory prostate cancer (HRPC), an aggressive cancer that is stubbornly resistant to conventional therapy.

RESULTS: In a study published in the May 15, 2005, issue of Clinical Cancer Research, lead author Dr. Makoto Sato tested a TSTA-driven adenovirus vector on three androgen-dependent and six HRPC cancers in mice. Optical imaging and PET/CT were used to monitor real-time gene expression. After three weeks of treatment with the adenoviral vector, optical imaging revealed vector activity in the androgen-dependent lines and four of the HRPC cell lines, all of which possess androgen receptors. These HRPC tumors displayed about seven times more luciferase expression than did androgen-dependent tumors. In addition, the HRPC tumors emitted PET signals that were more robust than those from the other tumors. While serum amounts of prostate-specific antigen leveled off in mice that received suicide gene therapy, PSA steadily increased in mice that received only saline. The researchers also treated a set of mice with a similar gene construct under the control of a constitutive viral cytomegalovirus (CMV) promoter. In contrast to mice treated with the TSTA construct, mice that received the CMV promoter revealed a high expression of thymidine kinase in the liver during PET/CT. Liver damage from the thymidine kinase was evidenced by elevated serum levels of liver transaminase.

IMAGE: PET/CT records results of suicide gene therapy. LAPC-4 tumors were injected with 109 infectious units of prostate-targeted AdTSTA-sr39tk or constitutive AdCMV-sr39tk vector. PET/CT imaging performed seven days later and prior to ganciclovir (GCV) treatment shows (top) tumor-limited expression in the TSTA-treated animal (left), but the CMV-treated animal shows strong expression in the liver as well. After GCV treatment (80 mg/kg per day from day eight to 15), fluorine-18-FHBG PET/CT signals at day 22 (bottom) are diminished in the tumors and the liver of the CMV animal. Histology performed at the day 22 endpoint (right) revealed extensive apoptosis, as shown in TUNEL-positive brown staining in the tumor and liver of the CMV-treated animal.

IMPLICATIONS:Data from the study support the conclusion that androgen receptor function is activated in HRPC despite low levels of androgen. Because most recurrent cancers express androgen receptors and PSA, the authors see the TSTA approach as a promising way to administer gene therapy to treat advanced prostate cancer.