Here are two contrasting but connected epidemiologies: In the U.S., approximately 23,000 new cases of ovarian cancer (OC) are diagnosed per year and more than 15,000 women die from the disease. This high lethality is due in part to the late stage at which woman are usually diagnosed, and the inherent aggressive biology of the malignancy.

Ovarian cancer cells initially respond with sensitivity to cisplatin, the chemotherapeutic of choice for this particular tumor. But over time, OC turns refractory and its drug sensitivity changes lethally to drug resistance.

Fanconi anemia (FA), a horrendous disorder of young children, is much rarer than CO. It combines cancers typical of adults with a full-body spectrum of destructive juvenile symptoms that become apparent at age 7. Among these varied features: short stature, small head and genitalia, crossed and squinting eyes, anomalies of blood cells, thumbs, wrists, kidneys and urinary tracts, plus mental retardation. FA's victims usually die of leukemia between 3 and 13 years of age.

Ovarian Cases To Fanconi: 23,000 to 500

Some 500 cases of FA among Americans are recorded at the Rockefeller University in an international registry that estimates the disease's worldwide incidence in the thousands. FA strikes one in 360,000 live births. Pediatric oncologist Alan D'Andrea at Harvard-affiliated Dana Farber Cancer Institute in Boston has been studying FA for more than a decade. "Seven genes that encode proteins associated with FA have been cloned," he told BioWorld Today. Six of the seven are labeled, in alphabetical order, FANCA, FANCC, FANCD2, FANCE, FANCF and FANCG. The seventh, FANCD2, subsequently interacts with the two terminal genes of the FA cascade, namely BRCA1 and BRCA2. These encode the two BRCA proteins responsible for most of the 10 percent of mammary carcinomas of genetic, or familial, inheritance. The other 90 percent, he pointed out, "are sporadic and carry mutations in the tumors of ovarian cancers - whence the FA connection."

D'Andrea is senior author of a paper in the May 2003 issue of Nature Medicine, titled "Disruption of the Fanconi anemia-BRCA pathway in cisplatin-sensitive ovarian tumors."

"That chromosome breakage," D'Andrea explained, "fragments the ovarian cells' chromosomes into pieces, which generate cancerous tumors. Our results," he continued, "suggest a model for the progression of some ovarian epithelial cancers. Early in tumor growth, the FANCF gene is methylated and inactivated. This results in chromosome instability and accumulation of other tumorigenic mutations.

"Most of the expanding tumor cells," he reported, "remain hypersensitive to cisplatin because of their underlying defect in the Fanconi anemia pathway. Thus, that chemotherapeutic drug is able to cause pronounced tumor lysis in those cells. However," D'Andrea noted, "in rare tumor cells, FANCF becomes demethylated, resulting in restoration of the Fanconi anemia pathway and outgrowth of cisplatin-resistant tumor cells. Such a model suggests possible therapeutic approaches for cisplatin-resistant ovarian cancers.

"Design of a specific small-molecule inhibitor of the Fanconi anemia pathway," he went on, "may prevent FANCD2 action and chemosensitize the relapsed tumor to cisplatin. Such a drug, which my co-authors and I are engaged in developing, could also enhance the cytotoxicity of cisplatin in normal human cells, however, unless it is selectively delivered only to the tumor cells.

"One of the two cisplatin-hypersensitive, FANCF-methylated lines was established as a primary culture from an untreated ovarian tumor," D'Andrea recounted. "Our results suggest that FANCF may be methylated in a higher percentage [21 percent] of surgically resected primary tumors. Partial demethylation of FANCF in selected cell lines may single out cells with a restored FANCF-BRCA pathway during cisplatin treatment in vitro or in vivo, and may reflect the reversible nature of methylation."

In ongoing research beyond the Nature Medicine article, D'Andrea allowed, "We are interested in trying to find small-molecule inhibitors that block or break the pathway. But we would like such drugs that do so only in the cancer cells. If we could do that, if we could come up with an inhibitor of mono-ubiquitation - an event in the Fanconi-BRCA pathway - we would keep this pathway shut off.

"That means," he pointed out, "that these cancers would be infinitely sensitive to a drug like cisplatin. They couldn't grow back. Not only would the tumor go away when we treat the initial malignancy with cisplatin but it wouldn't be able to grow back a year later. You'd have to be able to deliver that drug specifically to the cancer cell and not to the normal cells around it. We're designing such drugs. Conceptually, its an enzymatic step. Just like Novartis' Gleevec is a drug that inhibits a protein phosphorylation event. Gleevec is a small-molecule inhibitor, which binds to a kinase and blocks protein phosphorylation."

Companies Fond Of Inhibiting Enzymes

"We would like to come up with the Gleevec of this Fanconi-ovarian pathway, which puts a ubiquitin onto a protein and thereby blocks the pathway. It's pretty big," he commented, "but small-molecule inhibitors are in vogue right now. Companies like to inhibit enzymes and develop a pill rather than a needle. We are doing this work right now in our own laboratory. The recent success of Millennium," he concluded, "around its proteome inhibitor is also lending credence to the idea that drug manipulation of this kind of ubiquination is a valid target for drug design."