MENLO PARK, CalifIn 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.
To create the new agent, the researchers first identified the regulatory element of the PSA gene, known as prostate-specific enhancer (PSE). This element was then inserted into adenovirus type 5 DNA next to the E1A tumor suppressor gene, so as to put the virus’ E1A under the control of PSE.
Tests of E1A expression showed that CN706 produced E1A expression selectively in a PSA-producing human prostate cancer cell line (LNCaP) but not in a non-PSA-producing prostate cancer cell line (DU145).
More than 95% of prostate cancers are PSA-positive, the researchers said, and the targeted virus replicates only in cells expressing PSA. This replication amplifies the therapeutic effect of a single CN706 dose.
According to Calydon, the technology used to create CN706known as an attenuated replication-competent adenovirus (ARCA) (see diagram)could potentially be extended to any cancer for which a unique cellular marker exists, such as liver, breast, and ovarian cancers.
The researchers have now reported laboratory and animal studies of the viral construct (Cancer Research, July 1, 1997). To test the selectivity of CN706, a number of different cells lines were treated. In these in vitro tests, CN706 showed a marked preference for replicating in PSA-producing prostate 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. Titers of the two constructs were similar in LNCaP cell lines, but titers of CN706 were reduced in the other human cell lines studied.
For example, the ratio of CN702 to CN706 was 20:1 in PANC-1, a human pancreatic carcinoma line; 2000:1 in DU145, a non-PSA-producing prostate cancer 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 CN706 was able to shrink human prostate cancer tumors in immunodeficient mice by an average of 84% after six weeks, and half the mice (5 of 10) became visually free of tumor.
The tumors induced in the mice (LNCaP) were known to be resistant to chemotherapy, radiation therapy, and hormone therapy. They were allowed to grow to approximately 1 cm in diameter before being injected with CN706.
Serum PSA levels also fell rapidly after the injection, preceding the reduction in tumor volume by one week. All treated animals had undetectable PSA 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 at The Johns Hopkins Oncology Center, under the direction of Jonathan W. Simons, MD, assistant professor of oncology and urology.