Persistence for resistance

VANCOUVER, British Columbia—Two Vancouver researchers aretackling the deadliest forms of prostate cancer, the most commonly diagnosedmale cancer in Canada. Drs. Art Cherkasov and Paul Rennie of the VancouverProstate Centre are using "chemogenomics"—the study of genomic responses tochemical compounds—to develop a novel class of prostate cancer drugs in orderto provide new treatment options.

The goal is the rapid identification of novel drugs and drugtargets, embracing multiple early-phase drug discovery technologies rangingfrom target identification and validation, through compound design and chemicalsynthesis, to biological testing and ADME profiling.

This new approach usescomputer modeling in virtual 3D to predict how different chemicals or drugswill affect cancer tumors.

Currently, prostate cancer afflicts about one in six men inCanada, notes Rennie, and about one in eight in the United States, or about5,000 cases reported annually in Canada and 50,000 here.

Since 1946, the diseasehas been treated by targeting the androgen receptor with drugs that eitherblock or bind the male hormone receptor thereby effectively shrinking thetumor.

Unfortunately, for many men, the effectiveness of this type of treatmentis temporary and the cancer cells become treatment-resistant. With noalternative curative treatment options available, the average life expectancyfor men whose bodies resist this type of treatment is less than 18 months.

"The impact of this project on patient survival could betremendous if we can develop a new drug that avoids this resistance issue,"says Cherkasov.

To achieve this goal, the Vancouver researchers have "movedupstream," Rennie explains, "from the ligand binding site to the BF3 region."

The goal is to target a different region of the androgen receptor. X-raycrystallography is used to determine the structure of the binding site,Cherkasov explains.

The team will then use virtual screening, with dockingbeing used as one tool, to narrow a set of more than 10 million compounds orchemicals looking for potential new drugs, and then use computationalchemogenomics to screen the compounds to gauge their potential effectiveness intargeting prostate tumors.

"This type of 'virtual screening' is expected to shave yearsoff the typical discovery process for new drug candidates and will allow us toidentify and test the most promising chemical compounds more rapidly," says Dr.Rennie. "Presently, it can take 10 years or more to bring a compound to thestage of testing in humans. This new high-tech approach could significantlyshorten the wait for novel prostate cancer treatments."

Initially, Cherkasov estimates that the process will narrowthe candidate molecules to a few hundred for testing in the wet lab.

"High-throughput screening is very labor-intensive. What weare seeing is that with virtual screening, we are able to narrow down whatdrugs we should be taking through to testing in the laboratory or the clinicaltrial stage," says Cherkasov. "When trying to create new drugs in the past,you'd make your best guess on what compound you thought might work, test andget a success rate of about 0.01 percent. The use of virtual screening offersthe potential for a much higher success rate—from 10 to 60 percent—which wouldbe an enormous improvement in the field."

In addition, the much faster process, which utilizessoftware Cherkasov developed and 500 processors at the Centre—with access tothousands more—is expected to generate clinic-ready candidates in as little astwo years.

"In this type of work, getting funding is difficult," Renniestates, "and Genome BC jumped in."

The organization funded the project as part of its StrategicOpportunities Fund (SOF), which provides funding to key life sciencesinitiatives in British Columbia. The project, has received $324,000 in funding,with $161,500 from Genome BC and the rest from other partners including theCanadian Institutes of Health Research and the Vancouver Prostate Centre.

"Chemogenomics is becoming an accepted part of drug discovery andpromises to revolutionize the field in a manner comparable to howbioinformatics transformed biology research 10 years ago," says Dr. AlanWinter, president and CEO of Genome BC. "This project is groundbreaking, and weare excited by the potential impact it could have on prostate cancer research."