Hidden Weakness Leads to Self-Destruction of Prostate Cancer

An international team of researchers has discovered a new vulnerability in prostate cancer cells that could lead to more effective treatments for one of the most common cancers in men. The study, published in the Proceedings of the National Academy of Sciences (PNAS), was led by scientists at Flinders University in Australia and South China University of Technology.

Prostate Cancer is One of the Most Common Cancers in Men

Prostate cancer is a malignant tumor of the prostate, a small gland below the bladder that is responsible for producing part of the seminal fluid. The disease develops when cells in the prostate tissue multiply uncontrollably, forming tumors that often grow slowly at first but in some cases can be aggressive and spread to other parts of the body, such as the lymph nodes or bones. Prostate cancer is one of the most common cancers in men in many Western countries; a significant proportion of all men develop changes in the prostate during their lifetime, although many of these changes remain benign or grow so slowly that they do not cause any symptoms during their lifetime. Signs of prostate cancer often only appear at a late stage because the disease usually does not cause any symptoms in its early stages.

The risk of developing prostate cancer increases significantly with age. The disease rarely occurs before the age of 50, but its frequency increases steadily from the fifth decade of life onwards. Most diagnoses are made in men over the age of 60, and the incidence is particularly high from around the age of 70 onwards. Age is therefore considered the most important risk factor. This is related to a number of biological processes: with increasing age, genetic changes accumulate in the body’s cells, repair mechanisms become less reliable, and chronic inflammatory changes occur in the tissue, which increases the likelihood of malignant cell changes.

Age-related changes in male hormone levels, often referred to as andropause, also play a role. This is not an abrupt change like female menopause, but a gradual decline in the concentration of male sex hormones, especially testosterone, which usually begins between the ages of 45 and 55. Although prostate cancer is not caused by low testosterone levels, the long-term effect of androgens—and in particular dihydrotestosterone, which is closely linked to the growth of prostate tissue—is an essential component of prostate biology. Andropause coincides with the phase of life in which prostate cancer is particularly frequently diagnosed, without, however, being considered a direct cause itself. Rather, the increased risk results from the interaction of aging processes, decades of hormonal influence on prostate tissue, and progressive changes in cell metabolism that occur with increasing age. These correlations underscore the importance of regular preventive checkups for men of middle age and older in order to detect possible changes at an early stage and treat them if necessary.

Treatment Options

Common forms of treatment include surgery (removal of the prostate), radiation therapy, hormone therapy, and chemotherapy. Current research highlights two enzymes, PDIA1 and PDIA5, which play a key role in the growth, survival, and resistance to existing treatments of prostate cancer cells. According to experts, PDIA1 and PDIA5 act as molecular bodyguards for the androgen receptor (AR), a protein that drives the growth of prostate cancer. When these enzymes are blocked, the AR loses its stability and disintegrates, causing cancer cells to die and tumors to shrink in both laboratory cultures and animal models. The team also discovered that combining drugs that inhibit PDIA1 and PDIA5 with enzalutamide, a standard prostate cancer drug, made the treatment significantly more effective. “We have discovered a previously unknown mechanism by which prostate cancer cells protect the androgen receptor, which is an important driver of the disease,” explains lead author Professor Luke Selth, Head of Prostate Cancer Research and Co-Director of the Cancer Impact Program at the Flinders Health and Medical Research Institute. “By targeting these enzymes, we can destabilize the AR and make tumors more susceptible to existing therapies such as enzalutamide.”

A Promising Combination Therapy

Lead author Professor Jianling Xie, who began the research at Flinders University, said the combination therapy worked well in both patient tumor samples and mouse models, showing great potential for clinical use. “This is an exciting step forward,” said Dr. Xie, who is now at South China University of Technology. “Our findings show that PDIA1 and PDIA5 not only support cancer growth, but are also promising targets for new treatments that could work in combination with existing drugs.”

The study also found that PDIA1 and PDIA5 do more than just protect the AR. They help cancer cells cope with stress and maintain their energy production systems. When the enzymes are blocked, the mitochondria—the powerhouses of the cells—are damaged, leading to oxidative stress that further weakens the cancer cells. “This dual effect, which targets both the AR and the cancer’s energy supply, makes these enzymes particularly attractive targets. It’s like turning off the fuel and the engine at the same time.

Professor Selth notes that while current PDIA1 and PDIA5 inhibitors are promising, they need further development before they can be used in patients. Some of the existing compounds can affect healthy cells, so future studies will focus on developing safer and more selective versions. Prostate cancer is the second most common cancer in men worldwide. Although treatments such as hormone therapy and AR-targeted drugs have significantly improved survival rates, resistance to these therapies remains a major challenge. This new discovery could help overcome this resistance and improve treatment options for men with advanced prostate cancer.

Targeted drug Combination Slows Prostate Cancer Progression, Heralding a New Era of Personalized Treatment

A large-scale international study led by researchers at UCL recently found that combining two cancer drugs could significantly slow the progression of a severe and often fatal form of prostate cancer in men with certain genetic mutations. The phase III AMPLITUDE study, published in Nature Medicine, investigated whether the addition of niraparib, a targeted cancer therapy known as a PARP inhibitor, could improve the effectiveness of the current standard treatment with abiraterone acetate and prednisone (AAP).

The study focused on men with advanced prostate cancer that had spread to other parts of the body and who were starting treatment for the first time. All participants had mutations in genes involved in homologous recombination repair (HRR), an important system that helps repair damaged DNA. When these DNA repair genes do not function properly, cancer cells can multiply and spread more quickly. About one in four men with advanced prostate cancer at this stage have mutations in HRR-related genes, including BRCA1, BRCA2, CHEK2, and PALB2.

The Study and its Findings

Currently, the standard treatment for advanced prostate cancer is AAP (or similar drugs). About one in five patients also receives chemotherapy with docetaxel. However, patients with HRR gene mutations typically experience faster disease progression and shorter survival times under standard treatment. The AMPLITUDE study, led by Professor Gerhardt Attard of the UCL Cancer Institute, involved 696 men from 32 countries with an average age of 68. Half received the combination of niraparib and AAP, while the other half received standard AAP treatment with a placebo. More than half of the participants (55.6%) had mutations in BRCA1 or BRCA2. The study was double-blind, meaning that neither the patients nor their doctors knew who was receiving the active treatment. After a median follow-up period of just over two and a half years (30.8 months), the researchers observed remarkable benefits from the combination of drugs:

• • Lower risk of progression: Niraparib reduced the risk of cancer growth by 37% in all participants and by 48% in those with BRCA1 or BRCA2 mutations.
  • Slower progression of symptoms: The time to symptom progression was approximately twice as long in those receiving niraparib. Only 16% of these patients showed significant symptom progression, compared with 34% in the placebo group.
  • Potential survival benefit: There was a trend toward improved overall survival in the niraparib group, but longer follow-up is needed to confirm whether life expectancy is prolonged.

Expert Opinion

Professor Attard said: “Although current standard treatments are very effective for the majority of patients with advanced prostate cancer, a small but very significant proportion of patients derive only limited benefit from them. We now know that prostate cancer with alterations in HRR genes represents a significant group of patients in whom the disease recurs rapidly and takes an aggressive course. By combining it with niraparib, we can delay the recurrence of cancer and hopefully significantly extend life expectancy. These results are remarkable because they support comprehensive genomic testing at diagnosis and the use of targeted treatment for patients who can benefit most from it. For cancers with a mutation in one of the eligible HRR genes for which niraparib is approved, a doctor should weigh the risks of side effects against the clear benefits of delaying disease growth and worsening symptoms.”

The treatment was generally well tolerated, but side effects occurred more frequently in the niraparib group. Significantly more cases of anemia and high blood pressure were reported with niraparib, and 25% of patients required blood transfusions. Treatment-related deaths were also higher in the niraparib group (14 versus 7), although the overall discontinuation rate remained low. The study authors note that while the results are promising, further research is needed to confirm the long-term survival benefits and to investigate the impact of newer imaging techniques and more comprehensive genetic testing.