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In human and mouse tumors, he found four versions of KLF6 messenger RNA (mRNA). Cells read the gene like a choose-your-own-adventure story, skipping some parts and transcribing the others into mRNA.
Protein made from the shortest version, called KLF6-SV1, drives cellular changes that speed the spread of tumor cells in mice.
In 2005, the team studied the DNA of more than 3,400 men and found that some have a hereditary variation, in KLF6 that changes how cells read the gene. As a result, they make more KLF6-SV1 and less full-length mRNA. A man born with the variation is twice as likely to develop prostate cancer as someone without it. “He makes a little more KLF6-SV1, and over his lifetime that drives the process of cancer development forward,” Narla says.
Genetic testing for this variation may predict a man's chance of developing prostate cancer.
The researchers also found, in 2008, that patients whose tumors had high concentrations of KLF6-SV1 had a greater chance of disease recurrence. This finding may lead to a test on a patient's tumor biopsy that could inform treatment decisions.
Narla and colleagues also managed to reverse the effects of KLF6-SV1 in the lab. After inducing prostate-derived tumors in mice, they injected the tumors with small RNA segments, called siRNA, that attach specifically to KLF6-SV1 and prevent it from being translated into protein. The tumors regressed. These siRNA also killed prostate cancer cells in culture. The study was published in the Journal of Clinical Investigation in August 2008.
“It was really Goutham's work that led us into an understanding of [the gene's] role in cancer,” says Friedman, who adds that he's gratified to see his student emerging as an independent scientist. The early career physician-scientist award, part of HHMI's effort to support young scientists working to translate scientific discoveries into better treatment for patients, will provide five years of funding to Narla's lab.
Narla believes he's finally getting close to his goal of helping patients. “As a clinician I was struggling to find a way to apply this information to the patients we see every day with metastatic cancer. When we identified KLF6-SV1 and were able to actually target it and see tumors shrink, I was extraordinarily excited.”
Photo: The Mount Sinai Medical Center