Researchers at the University of Michigan have identified a potential new strategy for tackling aggressive prostate cancer that changes its cellular identity to evade treatment, raising hopes for patients whose tumours no longer respond to standard therapies.
In preclinical experiments, combining two classes of drugs significantly slowed tumour growth and reversed many genetic changes associated with treatment resistance.
The findings, published in JCI Insight, could inform future treatments, although clinical trials are needed to establish their safety and effectiveness in humans.
In Nigeria, prostate cancer is the most commonly diagnosed cancer among men and a leading cause of cancer-related deaths. Late diagnosis remains a major challenge, with estimates suggesting that 80 to 86 per cent of patients present with advanced disease. Low awareness, delays in seeking medical care and limited access to screening have been identified as contributing factors.
Most prostate cancers initially depend on androgens, including testosterone, to grow. Consequently, androgen receptor inhibitors, which block these hormones’ signals, are widely used to treat advanced disease. However, cancer cells can eventually develop resistance, allowing the disease to progress despite treatment.
One mechanism behind this resistance is transdifferentiation, a process in which cancer cells lose characteristics associated with prostate gland cells and adopt a different cellular identity.
Previous studies linked the loss of two genes, TP53 and RB1, to this transformation. To understand the underlying mechanisms, the researchers examined prostate cancer cell lines lacking both genes and identified two major changes: the loss of glandular genes and the activation of cellular programmes that promote stem cell-like characteristics.
Joshi Alumkal, a professor of internal medicine in haematology and oncology and a member of the university’s Rogel Cancer Centre, said the transition involves both the loss of the cells’ original identity and the activation of programmes that drive them towards a different one.
The researchers investigated two drug classes that target different aspects of the transformation.
BET bromodomain inhibitors interfere with pathways that enable cancer cells to activate alternative cellular programmes. However, earlier experiments showed that these drugs slowed cancer cell growth without killing the cells or permanently preventing disease progression.
The team therefore added DNA methyltransferase (DNMT) inhibitors, which can reactivate genes that have been switched off, including those associated with glandular identity.
Some DNMT inhibitors are already approved by the United States Food and Drug Administration for certain blood cancers.
Combining the two drug classes suppressed prostate cancer cell growth more effectively than either drug alone. Similar results were observed in mice implanted with prostate tumours.
Will Storck, a research laboratory specialist in the Alumkal laboratory, said the combination reversed a substantial proportion of the gene expression changes associated with the tumours’ altered identity.
The researchers also recorded a significant reduction in tumour growth and reported that the combination was well tolerated by the mice at the doses tested.
The findings suggest that targeting both biological processes could be more effective than addressing either one independently.
Commenting on the findings, Dr Bayo Oladeji, Head of the Department of Radiation Oncology at the University College Hospital, Ibadan, said the research remained at the preclinical stage.
“This is still at the preclinical (research) stage and is not yet available for patient treatment. It will still need to go through several phases of clinical trials to establish its safety and effectiveness before it can be approved for use in patients,” he said.
Oladeji stressed the importance of early detection, noting that the prostate-specific antigen (PSA) blood test can help identify men who require further investigation.
He cautioned that elevated PSA levels do not necessarily indicate cancer but may warrant further assessment by a healthcare professional.
“Feeling healthy doesn’t necessarily mean that prostate cancer isn’t there, as the disease often develops without noticeable symptoms in its early stages,” he said, adding that age- and risk-appropriate testing could improve the chances of detecting the disease early, when treatment may be curative.
Early-stage prostate cancer often causes no noticeable symptoms. As the disease advances, men may experience difficulty urinating, blood in the urine or semen, bone pain, unexplained weight loss and persistent fatigue.
The researchers plan to identify the genes responsible for the observed antitumour effects and develop biomarkers to determine which patients are most likely to benefit.
They also want to establish whether treatment could prevent transdifferentiation before it occurs, rather than reversing the process after cancer cells have changed identity.
The team hopes to develop clinical trials to assess the combination’s effectiveness in patients and investigate whether the approach could also work against certain lung and pancreatic cancers.
For now, the findings offer a potential new direction for tackling treatment-resistant prostate cancer, but further research is essential before the strategy can be considered for routine patient care.
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