Metastatic castration-resistant prostate cancer is the most dangerous form of this disease. Although there are some treatments, these cancers inevitably becomes resistant to the latest drugs and resume growth. Significant progress in finding new drugs for this stage of prostate cancer has been made by Australian researchers. They have developed a method to test new drugs on tumours grown in the laboratory, and their early results show that inhibiting protein production can slow tumour growth.
What is metastatic castration-resistant prostate cancer?
While most men have localised prostate cancer, which can be effectively treated, unfortunately some suffer from stage 4, metastatic prostate cancer. This dangerous form of prostate cancer has tumours spread to distant sites, such as the lymph nodes, bones and lungs. Treatments for metastatic prostate cancer involve chemotherapy, androgen deprivation therapy (ADT; also called hormonal therapy) and drugs such as Enzalutamide (Xtandi) and Abiraterone (Zytiga).
Most of the drugs for metastatic prostate cancer aim to reduce the effects of testosterone. Prostate cancer cells usually rely on testosterone to grow. Testosterone enters the cancer cell and sticks to androgen receptor molecules. The combined testosterone/androgen receptor unit moves into the cell nucleus and changes the use of DNA, leading to cell division and tumour growth. So reducing the amount of testosterone in the body can slow or stop the tumours growing. But eventually this treatment stops working; the tumours become resistant to the treatment and grow, even when very little testosterone is being made by the testicles. This is known as metastatic castration-resistant prostate cancer.
How does prostate cancer become resistant to drugs that inhibit testosterone?
Metastatic castration-resistant prostate cancer can arise for numerous possible reasons, such as:
- The cancer cells start producing their own testosterone
- Many more androgen receptors are made, making the cancer more sensitive to low levels of testosterone
- The androgen receptor and associated proteins change, making them able to promote tumour growth even when testosterone is absent
- Other hormones and their receptors start promoting tumour growth
Second line hormonal treatments can temporarily stop tumour growth at this stage. Enzalutamide stops hormones from sticking to the androgen receptor and stops the androgen receptor from moving into the cell nucleus. Abiraterone acts to stop testosterone production, including the testosterone produced by tumour cells.
But metastatic castration-resistant prostate cancer inevitably becomes resistant to these second line drugs. Some of these treatment-resistant tumours take on a new form, called neuroendocrine prostate cancer. Other types seem to be able to grow even without the use of the androgen receptor. The wide variety of changes to the tumours, between different patients and within one patient, makes development of new treatments quite challenging.
New method to study resistant tumours
Australian researchers have developed a new method to grow and study tumours from men with metastatic castration-resistant prostate cancer. These results come from a large collaboration of researchers and clinicians, led by Prof Gail Risbridger from Biomedicine Discovery Institute at Monash University and the Peter MacCallum Cancer Centre in Melbourne. Their recent paper was published in the prestigious journal European Urology. The first authors were Drs Mitchell Lawrence, Daisuke Obinata, Shahneen Shandhu, Luke Selth and Stephen Wong from Monash University, the Peter MacCallum Cancer Centre and University of Adelaide.
The Australian team developed a method to grow and study human prostate tumours in the laboratory. Surprisingly, prostate cancer is one of the most difficult types of cancer to keep alive in the laboratory. Nevertheless, the researchers have developed techniques for keeping patient tumours growing long-term. The researchers collected 109 tumour samples from 29 patients, which yielded 10 new long-term growing tumours. They showed that the genetic nature of these tumour cells remained quite similar for hundreds of days. This allows the study of specific tumour types in detail, over multiple experiments.
Changes in resistant tumour cells
Tumour cells resistant to treatment with Enzalutamide and Abiraterone were studied. Genomic analysis was used to show that these tumour cells were acting as if they had testosterone to help them grow. Changes to the androgen receptor gene were shown to have occurred that might allow it to work even in the absence of testosterone.
One of the tumours lacked androgen receptors and did not have a typical neuroendocrine form. When studied in detail, these cells had some characteristics of neuroendocrine prostate cancer. This unique form could not easily be classified, showing how complex and diverse the tumours become at this late stage of prostate cancer.
Testing new drugs on human tumours
To test a range of drugs for their ability to stop tumour growth, the researchers concentrated on four of the tumours. These four tumour types had a variety of different changes that made them resistant to Enzalutamide or Abiraterone. Samples were grown in the laboratory and treated with a range of drugs proposed to stop their growth. Despite the wide variety of mechanisms leading to treatment resistance, all four tumour types responded to a combination of drugs that target a complex unit of molecules called a ribosome.
"These lab-grown tumours have enabled us to rapidly compare different treatments and identify those that cause the most striking reduction in tumour growth," Dr Lawrence said.
"We developed a novel combination of two drugs that suppresses the growth of aggressive prostate cancer cells that do not respond to other treatments," he said.
This promising new treatment is a combination of two drugs that inhibits protein production by ribosomes. Ribosomes are an essential part of any cell; they make proteins using information from genes. Inside the nucleus, RNA copies are made from the DNA of some genes that the cell wants to turn on. The RNA copy is a message that moves out of the nucleus to the ribosomes. Ribosomes decode the message, producing proteins according to the RNA instructions from the gene. All of a cell's proteins are made by this method. Cancer cells typically divide and grow very quickly. They need ribosomes to be efficiently producing proteins at a high rate. The results from this study indicate that prostate cancer cells are sensitive to drugs that slow the actions of ribosomes.
These drugs are candidates for a new prostate cancer treatment, but there is a long way to go before this might become a reality. Fortunately, ribosome-targeting drugs are already being tested in clinical trials for blood and breast cancers. Reducing the capacity of the ribosomes to produce proteins could lead to unacceptable side effects. Clinical trials must first show that they are safe for use in humans before they can be tested in large trials as a cancer treatment.
This exciting Australian study has demonstrated a new technique to grow and analyse metastatic castration-resistant prostate cancer tumours in the laboratory. This method also allows testing of a range of potential drugs, showing a combination of ribosome-targeting drugs can slow tumour growth. The technique can be used in the future for drug discovery, and to better understand the nature of this stage of prostate cancer that is diverse and difficult to treat.
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