Experimental drug targets prostate cancer’s chief weakness

The National Cancer Institute (NCI) estimate that 164,690 people will be diagnosed with prostate cancer in 2018.

They suggest that more than 11 percent of men will receive this diagnosis at some point during their lifetime.

Treatments for prostate cancer can include radiation therapy, hormone therapy, and chemotherapy.

But unfortunately, in many cases, tumors that recur after the initial treatment become largely unresponsive to therapy.

In a landmark study, scientists from the University of California, San Francisco (UCSF) have not only pinpointed the factors that render some prostate cancers so resilient, but they have also identified an experimental drug that can neutralize these defenses and eliminate the tumors.

“We have learned,” says senior study author Davide Ruggero, “that cancer cells become ‘addicted’ to protein synthesis to fuel their need for high-speed growth, but this dependence is also a liability: too much protein synthesis can become toxic.”

“We have discovered the molecular restraints that let cancer cells keep their addiction under control and showed that if we remove these restraints they quickly burn out under the pressure of their own greed for protein.”

The researchers’ findings were published in the journal Science Translational Medicine.

Aggressive forms control protein synthesis

Previous research led by Ruggero and other researchers revealed that numerous types of cancers are “hooked” on proteins — they contain genetic mutations that encourage a high rate of protein synthesis. This excess, the scientist explains, could in fact set off the process of cell death.

This is part of the cellular stress response, which encompasses any changes that occur in a cell as a result of exposure to stressors in its immediate environment.

However, the same does not appear to hold true in the case resilient prostate cancer cells. These, Ruggero and team explain, often contain not one, but several genetic mutations that drive a heightened protein production.

Yet, contrary to all expectations, this does not trigger cell death in prostate cancer tumors. So the scientists asked: how do these cancers protect their own integrity, and how can we disrupt that defense mechanism?

In order to answer this question, the researchers worked with mice that had been genetically engineered to develop prostate cancer — specifically, tumors presenting a pair of genetic mutations found in almost half of all individuals with treatment-resistant prostate cancer.

These mutations promote the overexpression of the MYC oncogene (which promotes the growth of cancer) and inhibit the expression of the gene PTEN (which has been linked to tumor suppression).

But, to the team’s surprise, prostate cancers presenting these mutations also had lower levels of protein synthesis — unlike less aggressive types of cancer, which presented only one mutation.

“I spent 6 months trying to understand if this was actually occurring, because it’s not at all what we expected,” confesses study co-author Crystal Conn.

Experimental brain drug proves effective

What Conn eventually understood was that the pairs of mutations that controlled the expression of MYC and PTEN, when put together, also activated something called “the unfolded protein response” at cellular level.

This response allows the cancer cells to become resistant to cellular stress by lowering the levels protein synthesis. It does that by turning a protein called eIF2a, which helps to facilitate protein production, into a different kind of protein called P-eIF2a. This has the opposite effect: to downregulate synthesis.

Further analyses conducted on human prostate cancer tumors revealed that high levels of P-eIF2a were a strong predictor of negative health outcomes in patients with resilient forms of cancer.

So, the researchers decided to go ahead and test if blocking P-eIF2a production would change the cancer cells’ response to cellular stress and render them vulnerable to cell death.

They collaborated with Peter Walter, also from the UCSF, whose own team of researchers found that a molecule referred to as the integrated stress response inhibitor (ISRIB) can reverse the effects of P-eIF2a.

ISRIB had not previously been considered as a useful tool in cancer treatment. Instead, Walter and his laboratory used it as a drug that could reverse the impact of severe brain damage in rodents.

The mechanism by which it does this, however, is probably by upregulating protein synthesis in affected neurons.

‘Beautiful scientific work’

In the new study, Conn and her team administered ISRIB to mice with prostate cancer. They also tested it on human prostate cancer cell lines in vitro.

The results were promising; the molecule restored a high rate of protein synthesis in aggressive cancer with combined genetic mutations, thus exposing them to sustained cellular stress and triggering apoptosis, or cell death.

Also, the researchers saw that ISRIB did not affect healthy cells surrounding the cancerous tissue.

The team then conducted some experiments on mice that received transplants of human prostate cancer tissue — a process known as “patient-derived xenografts.”

They found that the animals who received samples of aggressive tumors — with the MYC/PTEN mutations — responded very well to ISRIB, and their tumors shrank drastically.

Mice that received less aggressive prostate cancer tumor grafts only experienced a temporary slowing of tumor growth.

“Together these experiments show that blocking P-eIF2a signaling with ISRIB both slows down tumor progression and also kills off the cells that have already progressed or metastasized to become more aggressive,” Conn explains.

And co-author Peter Carroll adds, “This is beautiful scientific work that could lead to urgently needed novel treatment strategies for men with very advanced prostate cancer.”

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