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Persistence for resistance
VANCOUVER, British Columbia—Two Vancouver researchers are tackling the deadliest forms of prostate cancer, the most commonly diagnosed male cancer in Canada. Drs. Art Cherkasov and Paul Rennie of the Vancouver Prostate Centre are using "chemogenomics"—the study of genomic responses to chemical compounds—to develop a novel class of prostate cancer drugs in order to provide new treatment options.
The goal is the rapid identification of novel drugs and drug targets, embracing multiple early-phase drug discovery technologies ranging from target identification and validation, through compound design and chemical synthesis, to biological testing and ADME profiling.
This new approach uses computer modeling in virtual 3D to predict how different chemicals or drugs will affect cancer tumors.
Currently, prostate cancer afflicts about one in six men in Canada, notes Rennie, and about one in eight in the United States, or about 5,000 cases reported annually in Canada and 50,000 here.
Since 1946, the disease has been treated by targeting the androgen receptor with drugs that either block or bind the male hormone receptor thereby effectively shrinking the tumor.
Unfortunately, for many men, the effectiveness of this type of treatment is temporary and the cancer cells become treatment-resistant. With no alternative curative treatment options available, the average life expectancy for men whose bodies resist this type of treatment is less than 18 months.
"The impact of this project on patient survival could be tremendous if we can develop a new drug that avoids this resistance issue," says Cherkasov.
To achieve this goal, the Vancouver researchers have "moved upstream," Rennie explains, "from the ligand binding site to the BF3 region."
The goal is to target a different region of the androgen receptor. X-ray crystallography is used to determine the structure of the binding site, Cherkasov explains.
The team will then use virtual screening, with docking being used as one tool, to narrow a set of more than 10 million compounds or chemicals looking for potential new drugs, and then use computational chemogenomics to screen the compounds to gauge their potential effectiveness in targeting prostate tumors.
"This type of 'virtual screening' is expected to shave years off the typical discovery process for new drug candidates and will allow us to identify 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 the stage of testing in humans. This new high-tech approach could significantly shorten the wait for novel prostate cancer treatments."
Initially, Cherkasov estimates that the process will narrow the candidate molecules to a few hundred for testing in the wet lab.
"High-throughput screening is very labor-intensive. What we are seeing is that with virtual screening, we are able to narrow down what drugs we should be taking through to testing in the laboratory or the clinical trial 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 and get a success rate of about 0.01 percent. The use of virtual screening offers the potential for a much higher success rate—from 10 to 60 percent—which would be an enormous improvement in the field."
In addition, the much faster process, which utilizes software Cherkasov developed and 500 processors at the Centre—with access to thousands more—is expected to generate clinic-ready candidates in as little as two years.
"In this type of work, getting funding is difficult," Rennie states, "and Genome BC jumped in."
The organization funded the project as part of its Strategic Opportunities Fund (SOF), which provides funding to key life sciences initiatives in British Columbia. The project, has received $324,000 in funding, with $161,500 from Genome BC and the rest from other partners including the Canadian Institutes of Health Research and the Vancouver Prostate Centre.
"Chemogenomics is becoming an accepted part of drug discovery and promises to revolutionize the field in a manner comparable to how bioinformatics transformed biology research 10 years ago," says Dr. Alan Winter, president and CEO of Genome BC. "This project is groundbreaking, and we are excited by the potential impact it could have on prostate cancer research."