Prostate cancer is the second leading cause of death in American men, and often requires the male hormone testosterone in order to grow. When caught early, most prostate cancer can be cured through surgery and hormone reduction. But there is no treatment for so-called “castration-resistant” prostate cancer, which does not respond to testosterone depletion and will continue to grow.
Now a molecular biologist at the University of Texas Southwestern Medical Center is trying to understand how DNA breaks at specific locations contribute to the progression of prostate cancer. Ultimately, these studies could lead to new therapies for prostate cancer, including castration-resistant forms.
Ram Madabhushi was recruited in 2017 from the Massachusetts Institute of Technology, where he was a postdoctoral fellow, with the help of a First-Time Tenure-Track Award from CPRIT.
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Prostate cancer is the second leading cause of death in American men, and often requires the male hormone testosterone in order to grow. When caught early, most prostate cancer can be cured through surgery and hormone reduction. But there is no treatment for so-called “castration-resistant” prostate cancer, which does not respond to testosterone depletion and will continue to grow.
Now a molecular biologist at the University of Texas Southwestern Medical Center is trying to understand how DNA breaks at specific locations contribute to the progression of prostate cancer. Ultimately, these studies could lead to new therapies for prostate cancer, including castration-resistant forms.
Ram Madabhushi was recruited in 2017 from the Massachusetts Institute of Technology, where he was a postdoctoral fellow, with the help of a First-Time Tenure-Track Award from CPRIT.
More than 50 percent of all prostate cancers are associated with gene fusions. These don’t in themselves cause cancer, but they define a distinct class of prostate cancers and drive progression and metastasis.
Gene fusions arise when DNA breaks occur simultaneously in different parts of the genome and are repaired improperly, so that parts of the genome that do not belong together become fused. In prostate cancer, these fusions often form between the same sets of genes.
“Our goal is to try to understand how the DNA breaks that lead to gene fusions in prostate cancer arise in the first place,” Madhabushi says. “We’d like to find regulators that would prevent the breaks from happening; if you don’t have breaks you won’t have fusion events.”
There are two possibilities: find a way to reduce the frequency of breaks and modify the progression of cancer, or perturb DNA repair mechanisms in ways that would kill cancer cells, he says. “We don’t yet know which is more promising.”
It may seem odd that a researcher in the Department of Psychiatry is working on prostate cancer. But as a postdoctoral researcher in neuroscience, Madabhushi found that when neurons are stimulated, as in response to new sensory experiences, they also incur DNA breaks at specific locations within their genomes.
He mapped the locations of these DNA breaks and identified the molecular mechanisms that underlie their formation. Faulty repair of these DNA breaks in neurons could contribute to the deterioration of neuronal functions in the aging brain and in age-related neurological disorders.
Madabhushi believes his knowledge of DNA breaks in neurons could help illuminate the molecular mechanisms leading to gene fusions in prostate cancer. Likewise, studying DNA repair mechanisms and how they go awry in prostate cancer could help understand how neuronal functions in the aging brain become altered, and suggest ways to preserve them.
Insights gained from these studies could also help discern the role of hormones in other cancers, like insulin in liver cancer and estrogen in breast cancer; systems Madabhushi is also studying.
He credits CPRIT for providing the resources he needs for cutting-edge technologies to help map the DNA breaks as well as study changes in DNA sequences and their effects on gene expression. He’s also able to perform high-throughput screens of small-molecule drug candidates that might eventually provide treatment options for castration-resistant prostate cancer.
Madabhushi received his undergraduate education in biology at the University of Bridgeport, Conn., and his Ph.D. in molecular biology from Weill-Cornell Graduate School of Cornell University. He began his postdoctoral fellowship in neuronal physiology at MIT in 2010.
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