Dehm’s gene rearrangement research seeks to turn the tide on deadly prostate cancer
The renowned actor Sidney Poitier died of heart failure in January at age 94. He lived for nearly three decades following treatment for prostate cancer at age 66. Based on modeling estimates published a week after his death, nearly 270,000 men in the U.S. will be diagnosed with prostate cancer and 34,500 will die from the disease this year. Though Poitier was successfully treated, a testament to advances in therapies and patient monitoring, Black men like Poitier are at higher risk for developing and dying from the disease.
In contrast to Poitier, best-selling author and Saint Paul native Vince Flynn died of an aggressive metastatic prostate cancer at age 47 three years after he was diagnosed in 2010.
LMP professor Scott Dehm said in an interview that men die of prostate cancer after it has spread beyond the prostate gland and become resistant to hormone therapy, what is termed castrate-resistant prostate cancer or CRPC. “Many prostate cancer patients are cured by surgery or radiation because these treatments can eradicate early-stage disease and thereby prevent metastasis," said Dehm, a faculty member in the Masonic Cancer Center. "If you’re looking at survival rates, patients diagnosed with localized prostate cancer have five-year survival of 99 percent and ten-year survival rates of 98 percent,” he said. Metastasis, or the spreading of the cancer outside of the prostate, is really the serious event that precedes CRPC and that necessitates hormone therapy. “All metastatic prostate cancer treated with hormonal therapy will eventually develop resistance and become CRPC,” Dehm said.
During the past decade, Dehm has tracked down the cellular, molecular, and genetic basis of CRPC focusing on the genes for androgen receptors, receptors that work in the nucleus of cells to regulate the gene expression programs that allow the body to respond to androgen hormones such as testosterone. “We discovered the first androgen receptor gene rearrangement in a widely used prostate cancer cell line in 2011,” Dehm said. “It was a single cell line – called 22Rv1 – and it’s been available from the ATCC cell line repository for decades. Everybody in the field uses it.”
Since that initial discovery in a ubiquitous prostate cancer cell line, Dehm has expanded his studies to include many additional CRPC models as well as large collections of metastatic CPRC tissues from prostate cancer patients. Through this work, Dehm has revealed in exquisite detail the mechanism by which prostate cancer cells generate active androgen receptor (AR) variants (AR-Vs) that enable malignant cells to circumvent hormone treatment. His laboratory has found that AR-V expression driven by gene rearrangements can generate resistance to hormone therapies because these hormone therapies are not able to inhibit AR-Vs in the same way that they can inhibit normal androgen receptors. Dehm’s perceptive and systematic investigations of diverse AR genomic structural rearrangements, funded by the National Institutes of Health and the Department of Defense among other funding sources, lay the foundation for the development of CRPC biomarkers and AR-V-targeted molecular therapies in a deadly disease.
Asked about what laboratory techniques and methods have been most valuable to his research, Dehm is unequivocal. “It’s really been next-generation DNA sequencing that has enabled this work, just as it has enabled our understanding of global mutational patterns,” he said. “But it’s still imperfect because the short sequence reads we get from DNA sequencing are not optimal for discovering structural variation in the genome. Long-read DNA sequencing technologies are still evolving and have not been fully adopted. That’s the next frontier.”
Prognostic biomarkers, like gene signatures, are already in routine clinical use for localized prostate cancer, Dehm said. The Decipher® prostate cancer gene expression test can predict a patient’s risk of metastasis from prostate tissue following surgical removal of the gland. The prostate-specific antigen (PSA) blood test is a widely used screening test to identify patients who are at higher risk of having prostate cancer and to monitor patients for evidence of recurrence following surgery or radiation therapy.
“We definitely want to detect the aggressive prostate cancers as early as possible,” Dehm said. “The problem is that early detection usually involves identifying ‘indolent’ prostate cancers earlier as well, which often triggers overtreatment in patients.” That was the rationale behind the US Preventative Services Task Force (USPSTF) recommendation in 2015 for not using routine widespread PSA screening. “PSA screening does catch many prostate cancers, both the aggressive ones but also the indolent ones. Sorting out which is which is the ‘Holy Grail’ of prostate cancer detection – a test that would not just detect prostate cancer in its early stages but would detect the aggressive prostate in their earliest stages and differentiate those from the indolent prostate cancers.” [Current USPSTF recommendations are here]
Among the newer laboratory tools Dehm uses in his research is genome editing or engineering with the CRISPR/Cas9 system. “We use it as a way to develop laboratory models of prostate cancer so that we can study those models and understand mechanisms,” he said. “I think it’s likely these new genome engineering approaches will also lead to new therapies for prostate cancer, such as genome engineering of immune cells to train them to attack and kill prostate cancer cells.”
Prostate cancer is an immunogenically “cold” tumor, Dehm said, with few immune cells recognizing and infiltrating prostate malignancies. “There’s a huge amount of activity in the field trying to turn ‘cold’ prostate cancers into ‘hot’ prostate cancers that might be susceptible to immunotherapies, both current and future immunotherapies.”
Indeed, the AR gene rearrangements Dehm has identified can give rise to altered protein forms of the androgen receptor in CRPC cells that have amino acid sequences not found in normal human cells, sequences that could be recognized by immune cells as foreign antigens. “So is there opportunity for this work to contribute to future immunotherapies for treating metastatic prostate cancer and CRPC? Absolutely!”