By Steve Sternberg

Special To BioWorld Today

Calydon Inc. was created to turn nature against itself.

Sweeping as that aim might sound, the biopharmaceutical firm founded two years ago in Menlo Park, Calif., hopes to achieve it in an exceedingly focused way — by transforming the common adenovirus into a cellular assassin that eradicates prostate cancer.

Prostate cancer ranks second after lung cancer among the killer malignancies in men, claiming 42,000 lives each year. Breast cancer, that most dreaded of diseases among women, kills 2,000 more. And prostate cancer, like breast cancer, is notoriously difficult to treat.

All three currently available therapies, surgery, hormonal ablation and radiation, have serious drawbacks. None of these methods can predictably cure all cancers. Surgery, which is considered the “gold standard“ of the three, often has severe side effects — the loss of sexual function among them.

Calydon’s founder, Daniel Henderson, is an experienced biotech entrepreneur who helped establish Microgenics Corp., of Concord, Calif., which was sold to Boehringer Mannheim Pharmaceuticals Corp. two years ago. Henderson saw in prostate cancer a formidable adversary, a profitable opportunity, and a chance to help thousands of men worldwide, said Richard Fischer, Calydon’s chief financial officer.

Under Henderson’s leadership, Calydon has approached this problem in a novel way. Rather than trying to eradicate only cancer cells, which are difficult targets at best, Calydon aims to destroy all of the prostate’s epithelial cells, the cells that turn cancerous. If it succeeds, this strategy would not only wipe out cells that already are cancerous, it also would eliminate the possibility that other cells might someday turn malignant.

To this end, Calydon has “reengineered“ the adenovirus, a troublesome cause of respiratory illness and cancer. The company’s researchers insert prostate genes at specific loci next to E1A and E1B in the virus’s genome. The genes they have chosen are prostate-specific genes that only function in prostate epithelial cells. When the adenovirus gains entry to these cells, the virus begins to replicate. Once an adenovirus begins to replicate, it continues to churn out thousands upon thousands of offspring.

Within a matter of hours, the epithelial cells — both cancerous cells and healthy ones — become bloated with virus. But the adenovirus, determined to fulfill its biological imperative to reproduce, knows no moderation. It continues to replicate until the cells can no longer contain their infectious cargo. The cells explode, releasing thousands of copies of Calydon virus to infect other prostate cells. This process is repeated until the prostate epithelium is destroyed, along with any cancerous cells it might contain.

Frank McCormick, of Onyx Pharmaceuticals Inc., in Richmond, Calif., has tried a similar approach in cancers spawned by mutations of p53, the tumor suppressor gene that, when it functions normally, prevents damaged cells from replicating or prompts them to commit suicide, a process known as apoptosis. The Onyx team inserted a genetically engineered virus into mouse tumor cells. Cells with normal p53 prevent the virus from reproducing.

Calydon’s Approach Works, Regardless Of p53 Status

In cells with damaged p53, the virus replicates and ultimately bursts the cell. But this approach only works in cells containing nonfunctioning p53. Prostate cancer cells contain only 8 to 20 percent of the p53 found in other tumors. Calydon’s approach, if it proves effective, would wipe out the cells no matter what their p53 status.

Fischer said the therapy has so far worked successfully in trials using nude mice, according to a study published in Nature last spring.

In this experiment, Calydon cultivated human prostate tumors on the flanks of these mice by injecting them with tumor-producing LNCaP cells. Then the mice were injected with Calydon’s doctored adenovirus. After the injections, the visible tumors shrank to less than 20 percent of their original size. The level of prostate-specific antigen (PSA), a protein that betrays the presence of tumor cells, soon dropped to undetectable levels. So far, the mice have gone for six months without a recurrence.

“It looks good,“ Fischer said of the therapy.

He cautioned, however, that no one knows whether the tumors will recur later on. Only time will tell, Fischer said.

The firm plans to submit an investigational new drug application for the first human trial during the first quarter of 1997. That study will be headed by Jonathan Simons, of the Brady Urological Institute at Johns Hopkins Medical Institutions in Baltimore. It will involve just 30 patients, all of whom will receive the drug. The researchers will initially try to determine the maximal safe dose needed to shrink prostate tumors in humans.

Fischer said the trial also should provide “preliminary indications of efficacy.“

Calydon also is attempting to develop a secondary therapy that can further interrupt cancer cell growth. This formulation is intended to provide better results than the current choices, Lupron, made by Takeda Chemical Industries Ltd., in Osaka, Japan, and Eulexin, made by Schering-Plough Corp., of Madison, N.J. These so-called hormonal ablation drugs cut off the supply of testosterone, a male sex hormone that primes prostate cancer cells to multiply, said Eric Schuur, Calydon’s director of molecular biology.

The company declined to release details of its own new therapy, except that it is a substance with a low molecular weight that would initially be administered through an injection into the tumor.

He said the company has not yet explored the possibility of joining forces with a larger pharmaceutical company for development and commercialization of these products, but it may do so in the future.“