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.