The destructive power of PROTACs could tackle prostate cancer

Craig Crews talks to postdoc Momar Toure in a laboratory
Craig Crews talks to postdoc Momar Toure in a laboratory

Craig Crews (right), a biochemist at Yale University in New Haven, Connecticut, speaks with a postdoctoral chemist.Credit: Michael Marsland, Yale Univ.

The prognosis for prostate cancer today is bright — provided it is caught before it has spread. Once it has metastasized, the five-year survival rate plummets from almost 100% to around 30%.

In 1941, physiologist Charles Huggins demonstrated that prostate cancer is driven by androgens1, a class of hormones of which testosterone is the most common. Androgen-deprivation therapy, which uses surgical or chemical castration to lower androgen levels, has been the gold standard for metastatic prostate cancer ever since. If metastatic spread is minimal, the treatment can allow some people to stay in remission for the rest of their lives. Unfortunately, many tumours adapt to low androgen levels — a condition known as castration-resistant prostate cancer (CRPC).

When this happens, clinicians can turn to several drugs that shut down androgen signalling more completely. Enzalutamide, for example, binds to androgen receptors and blocks them from being activated. This can extend survival by a few months, but the cancer will again develop resistance; people invariably relapse. “Resistance ultimately is what’s killing patients,” says Gerhardt Attard, an oncologist at the University College London Cancer Institute. Developing treatments that tackle drug resistance is therefore a primary goal.

Enter a new contender: proteolysis-targeting chimaeras, or PROTACs. They are not just a new cancer treatment, but a new kind of drug. Most drugs have to remain bound to their target in order to maintain their effect, which means large doses are required to keep enough targets blocked, increasing the likelihood of side effects. “Twenty-one years ago, I set out to develop a different paradigm,” says Craig Crews, a biochemist at Yale University in New Haven, Connecticut: one in which drugs do not have to stay bound, and can instead leave their mark on a target and move on.

Overcoming resistance

The PROTACs that Crews and his colleagues have developed are designed to co-opt cells’ natural quality-control machinery — the proteasome. The PROTAC molecules mark proteins for degradation by joining a molecule that binds to a target protein, such as an androgen receptor, to another that binds to a protein called a ubiquitin ligase2. The ligase recruits an enzyme that helps to transfer ubiquitin onto the target protein — a signal to the proteasome to degrade the target. This tagging requires only a brief interaction, leaving the PROTAC free to find more targets. “One molecule of PROTAC can take out as many as 400 androgen-receptor molecules,” says Daniel Petrylak, a urologist at Yale University. “It’s a pretty potent drug.”

3D PROTAC model

Arvinas’s PROTAC protein degrader.Credit: Courtesy of Arvinas Operations

As well as reducing the potential for side effects, cell studies have shown that PROTACs can combat many of the mechanisms that underpin resistance in prostate tumours. The most common is amplification, in which cancer cells greatly increase androgen-receptor expression. “The tumour says: ‘If you’re going to starve me of testosterone, I’ll just make more receptors to scavenge what little is still there,” says Crews. “That’s a very successful resistance mechanism.” Combating this with a drug such as enzalutamide would require a larger dose than the body could handle, and “therefore the tumour wins simply by overexpressing the target”, explains Crews. “PROTACs can address that, as they can degrade as many receptors as the cancer produces.”

Another common resistance mechanism is the mutation of androgen receptors, which can cause them to become less selective and respond to other hormones, or even be activated by molecules that are normally inhibitory. In 2018, Crews and his team found that ARCC-4 — a PROTAC that uses enzalutamide to bind to its target — degraded several mutant receptors associated with drug resistance3.

In 2013, Crews founded a company called Arvinas, based in New Haven, which has now created an orally administered PROTAC called ARV-110. Data from a phase I clinical trial4, led by Petrylak, suggest that the drug is safe and reduces levels of prostate-specific antigen (PSA), a common prostate cancer biomarker, in some people with metastatic CRPC. “It was wonderful to be able to take an idea from my laboratory all the way through to first in-human validation,” says Crews.

Hot pursuit

The researchers hope that careful patient selection will bring greater success. Some androgen-receptor mutations might be more responsive to treatment with PROTACs than others, Petrylak suggests. Indeed, preliminary data from a phase II trial found that PSA levels at least halved in 46% of people who had two specific androgen-receptor mutations5.

Other groups are also pursuing the technology. In 2019, biochemist Shaomeng Wang and his group at the University of Michigan in Ann Arbor showed that another PROTAC, ARD-61, has anticancer effects in prostate cancer cells with a number of different androgen-receptor mutations6. Following this work, pharmaceutical company Bristol Myers Squibb in New York City is now conducting a phase I trial of a PROTAC for CRPC.

The applications of this technology go beyond prostate cancer, or even cancer more broadly. PROTACs can attach anywhere on a protein, which means that they can target proteins that lack active binding sites. This opens up a huge range of drug targets that were previously considered impossible to work with, and could lead to treatments for numerous conditions, including neurodegenerative diseases. “This offers an immense opportunity to change how we’re doing drug development today,” says Crews. “It’s getting a lot of people excited.”

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