Newswire (Published: Tuesday, October 1, 2019, Received: Tuesday, October 1, 2019, 5:32:04 PM CDT)
Word Count: 848
2019 OCT 01 (NewsRx) -- By a
“Prostate cancer is defined by its pathology - you take a biopsy, give it to a pathologist, and they score it, for example they will characterize it as ‘pathological stage 3 disease.’ What we want to do is to understand how genetics contributes to driving aggressive pathology. By understanding what pathways and processes are dysregulated by distinct genetic alterations, we can start to explore therapeutic options to match the genetic alterations,” says
In cancers like melanoma, there tends to be a single genetic driver.
“You have mutations in oncogenes such as BRAF or RAS that drives disease,” says
The field of cancer research is getting better and better at turning off oncogenes that cause cancer. However, the field is far less adept at therapeutically targeting cancers where good genes are lost. This means that in prostate cancer and other cancers created by loss of tumor suppressors, treatment isn’t as simple as switching these lost genes back on. Instead, this project hopes to discover what else happens in prostate cancers with loss of these tumor suppressor genes - possibly, in this tangled network of cause-and-effect, turning off a tumor suppressor like TP53 may turn on another gene that aids cancer growth. And if that’s the case, Costello, Cramer, and colleagues would have a target they could do something about - a target gene they could turn off.
Likewise, “In prostate, you get big deletions in chromosomes - there are multiple genes in there and we need to know which ones are the causal drivers of aggressive disease,” Cramer says.
In other words, deleted along with these known tumor-suppressor genes like TP53, may be the loss of many other genes. Some of these losses are unimportant - only about 1.2 percent of our genome is actually manufactured into proteins. But some losses may be additional drivers of cancer.
To discover these genetic drivers of prostate cancer, Costello and Cramer will turn off various combinations of genes in mouse models of the disease to see which combinations grow into aggressive cancers. Then the team will look inside these models of aggressive cancer to see which genetic pathways are affected.
“We end up with the genetically altered cells that drive the disease, which allows us to ask what is the most likely therapeutic target? Then we can treat mouse models with drugs and see if it’s successful,” Costello says. If these studies are promising the next step may be clinical trials in men with this aggressive form of prostate cancer.
Until recently, the project would have struggled to find funding.
“When you submit a grant, it gets evaluated by a ‘study section,’” says Cramer. “Most study sections are very focused - you submit this project to a pathology study section and they might not get the computational modeling that is used to help make sense of genome-wide measurements to identify therapeutic targets. But if you submit the grant to a computational modeling study section, they don’t get the pathology side and tend to score it poorly. The balance is tricky.”
With only 8 percent of cancer research project grant applications earning funding, even perceived weakness or misinterpretations by a reviewer in the study section can be fatal.
“The National Institutes of Health recognized there were research areas they wanted to fund that weren’t getting funded in standard study sections, so they developed the
Despite decades of effort, no one set of tools has been able to point to the genes driving prostate cancer. Now with three sets of tools - genomics, computational modeling, and pathology - Cramer, Costello and
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