Prostate tumour growth driven by onecut2

[Wendy_Winnall]

Some prostate cancers are more aggressive than others. They grow quickly, spread and become resistant to drugs. Developing better treatments for aggressive prostate cancers is a major research priority. Results have been published from a new study indicating an alternative to hormone signalling may be driving the growth of some aggressive prostate cancers. This study has uncovered a new way to target prostate cancer, aside from drugs that suppress testosterone.

Aggressive prostate cancers don’t usually stay localised for long. They spread and rapidly become resistant to drugs such as hormone therapy (androgen deprivation therapy). Researchers are trying to understand what makes aggressive prostate cancers different to non-aggressive ones. They also want to know what is driving the growth of these tumours. This information uncovers weaknesses that can be exploited by new drugs and treatments.

How do prostate cancers grow without hormones?

Interesting research has shown that testosterone and its receptor are not always necessary for prostate cancer growth. This is particularly so for metastatic castration resistant prostate cancer (mCRPC). Production of the testosterone receptor (androgen receptor) is switched off in some mCRPC tumour cells. These cells are resistant to drugs that target testosterone signalling, as they no longer need testosterone to grow. Alternative cellular processes must exist that drive the growth of these tumours.

What are these processes and how can we target them? This question was the subject of a research project conducted by scientists from the US. The team was led by Prof Michael Freeman from Cedars-Sinai Medical Center in Los Angeles. Results are published in the journal Nature Medicine.

To start this project, the researchers used a technique called computational biology. They used algorithms to analyse data derived from a previous experiment. The dataset included information about gene usage from 2,115 prostate cancer tumours, including 260 mCRPC tumours. This data was used to find out which genes are being used by the different tumours.

The researchers used this information to identify proteins that turn on (or off) specific genes used by mCRPC tumours. These gene regulators are proteins called transcription factors. They are the first step in switching on or off the production of proteins from specific genes. Some of these gene regulators are very specific, only affecting one or a few genes. Others are master-regulators, that can affect many hundreds of genes. These master regulators are often very influential; they can change the actions of a cell. Master regulators of gene use can affect processes such as growing and dividing, moving to another location, or performing a specific function.

The computational approach uncovered a number of possible master regulators in mCRPC cells. Some were identified that we already knew about. The exciting news is that a new one was identified, called onecut2.

Discovery of onecut2 in prostate cancer cells

Onecut2 was not previously known to be a master regulator for prostate cancer. The predicted activity of Onecut2 was greater than the testosterone receptor. Therefore, onecut2 seemed to be working very hard inside the cells to control genes that combine to drive tumour growth.

The next step was to confirm the presence and role of onecut2 in prostate cancer cells. To do this, the researchers conducted experiments using cells grown in the laboratory and using mice. This is known as basic research. Research in laboratory and mouse experiments are where most discoveries happen. These experiments are necessary, before new drugs and treatments can be developed for humans.

Results from laboratory and mouse experiments showed:

- Onecut2 was working when the testosterone receptor was switched off. Onecut2 was more active when the testosterone receptor was less active.

- Onecut2 negatively regulated testosterone receptor activity. When onecut2 is active in a cell, it’s actually switching off the all genes needed for the testosterone receptor to promote tumour growth in response to testosterone.

- Relatively high amounts of onecut2 were found in neuroendocrine prostate cancer cells. Onecut2 was shown to turn on genes associated with switching from the typical adenocarcinoma form to a neuroendocrine form of prostate cancer. This is an aggressive type of prostate cancer. Switching to a neuroendocrine form is an event that happens in some men’s tumours at the mCRPC stage, which is associated with poor outcomes.

Onecut2 in humans

The researchers then looked at data from human studies where gene usage was analysed. High onecut2 levels were associated with rising PSA levels after prostate cancer treatment. They used samples from a study that were taken before and after treatment of localised prostate cancer. These showed that onecut2 was already high prior to treatment, in some patients. The researchers were fascinated to find that where the testosterone receptor use was low, onecut2 was high, and vice-versa. Onecut2 was also high in high-risk patients before treatment. It was highest in patients whose prostate tumours had early neuroendocrine features and tumours that were a mix of adenocarcinoma and neuroendocrine cells.

The researchers believe that many lethal prostate tumours identified as adenocarcinomas actually consist of cells that are in the process of switching towards a neuroendocrine form. The results of their study support this possibility.

Targeting onecut2 with drugs

The US researchers believe that onecut2 may be a useful target for new drugs to treat metastatic prostate cancer. They believe that up to a third of men with mCRPC could benefit from drugs that inhibit onecut2.

As part of this project, they aimed for “proof of concept” that targeting onecut2 could slow prostate cancer growth. They screened a chemical library of 500,000 compounds, finding one compound that bound to the active regions of the onecut2 protein. It appeared biologically active in their assays.

Inhibiting onecut2 in lab-grown cells and mice with prostate tumours reduced prostate cancer cell growth. The treated mice had reduced tumour burden and weight, and reduced amount of metastatic tumour growth. The treatment wasn’t perfect. It didn’t cure the mice, it just reduced the size of the tumours.

These exciting results indicate that a drug that inhibits onecut2 could be an effective treatment for aggressive prostate cancers.

Drug development is a long process. These initial results indicate that targeting onecut2 is feasible. But the first compound found is unlikely to be the best for use in humans. The next steps are to modify this drug and try numerous similar drugs to find one that works best and is non-toxic.

Just this week another study has been published that supports the conclusions of the US study. This new Canadian study showed that onecut2 is a driver of neuroendocrine prostate cancer. The Canadian researchers developed another drug that potently reduced the neuroendocrine tumour growth.