MENLO PARK, Calif-In preclin-ical studies, an attenuated adenovirus engineered to incorporate the regulatory region of the PSA gene has been shown to selectively infect and destroy human prostate cancer cells expressing PSA. The engineered virus, named CN706, was developed by scientists from Calydon, Inc., a California-based biopharmaceutical firm, and the Brady Urological Institute at The Johns Hopkins Oncology Center.
MENLO PARK, CalifIn preclin-ical studies, an attenuated adenovirusengineered to incorporate the regulatory region of the PSA gene has beenshown to selectively infect and destroy human prostate cancer cells expressingPSA. The engineered virus, named CN706, was developed by scientists fromCalydon, Inc., a California-based biopharmaceutical firm, and the BradyUrological Institute at The Johns Hopkins Oncology Center.
To create the new agent, the researchers first identified the regulatoryelement of the PSA gene, known as prostate-specific enhancer (PSE). Thiselement was then inserted into adenovirus type 5 DNA next to the E1A tumorsuppressor gene, so as to put the virus’ E1A under the control of PSE.
Tests of E1A expression showed that CN706 produced E1A expression selectivelyin a PSA-producing human prostate cancer cell line (LNCaP) but not in anon-PSA-producing prostate cancer cell line (DU145).
More than 95% of prostate cancers are PSA-positive, the researcherssaid, and the targeted virus replicates only in cells expressing PSA. Thisreplication amplifies the therapeutic effect of a single CN706 dose.
According to Calydon, the technology used to create CN706known as anattenuated replication-competent adenovirus (ARCA) (see diagram)couldpotentially be extended to any cancer for which a unique cellular markerexists, such as liver, breast, and ovarian cancers.
The researchers have now reported laboratory and animal studies of theviral construct (Cancer Research, July 1, 1997). To test the selectivityof CN706, a number of different cells lines were treated. In these in vitrotests, CN706 showed a marked preference for replicating in PSA-producingprostate cancer cells versus non-PSA-producing human cell lines.
This was shown by comparing replication of CN706 with that of CN702,an adenovirus type 5 construct that does not have the PSE insert. Titersof the two constructs were similar in LNCaP cell lines, but titers of CN706were reduced in the other human cell lines studied.
For example, the ratio of CN702 to CN706 was 20:1 in PANC-1, a humanpancreatic carcinoma line; 2000:1 in DU145, a non-PSA-producing prostatecancer cell line; and 3000:1 in HBL100, a human lung cell line.
In Vivo Testing
In preclinical in vivo testing, a single intratumoral injection of CN706was able to shrink human prostate cancer tumors in immunodeficient miceby an average of 84% after six weeks, and half the mice (5 of 10) becamevisually free of tumor.
The tumors induced in the mice (LNCaP) were known to be resistant tochemotherapy, radiation therapy, and hormone therapy. They were allowedto grow to approximately 1 cm in diameter before being injected with CN706.
Serum PSA levels also fell rapidly after the injection, preceding thereduction in tumor volume by one week. All treated animals had undetectablePSA levels at six weeks, the investigators said. There was no tumor recurrence,and no adverse effects were seen.
A phase I human clinical trial of CN706 is planned for late 1997 atThe Johns Hopkins Oncology Center, under the direction of Jonathan W. Simons,MD, assistant professor of oncology and urology.