Courtesy of Karissa Van Tassel (left) and Yale Office of Communications (right)

Two Yale researchers have developed a new way to harness the body’s protein degradation system to target prostate cancer.

Professors Craig Crews and Daniel Petrylak at the Yale School of Medicine, have collaborated to develop a new drug that treats cancer by tagging specific problem cells for destruction. Proteolysis-targeting chimaera, or PROTACs, are now showing promise in clinical trials. 

“Every cell in your body has a system, a machinery that recycles proteins,” Crews said. “It takes old proteins — damaged proteins — and tags them for destruction.”

Crews is the John C. Malone Professor of molecular, cellular and developmental biology and a professor of chemistry, and Petrylak is a professor of medical oncology and urology.

PROTACs were born out of a cross-department collaboration initiative. According to Petrylak, he met Crews at a Chemistry Department conference. There oncologists were invited to present the most important clinical issues related to their type of tumor expertise with the goal of harnessing the knowledge of both the chemistry and oncology departments to develop a new drug.

Prostate cancer is stimulated by testosterone, so one way to treat prostate cancer is to deprive the cancer cells of this male sex hormone. For example, doctors can use drugs that target the pituitary gland to shut off signals that trigger production of testosterone, thereby reducing the level of the hormone within the body. 

However, in the 1960s, researchers noticed that the body could build a resistance to the treatment. Men who had received testosterone-inhibiting treatments still had elevated testosterone levels in their tissue samples, according to Petrylak. 

Petrylak explained that this resistance could stem from various mechanisms within the body. For example, target receptors — to which testosterone binds — could mutate and regain activity. Therefore, initial hormone therapy drugs are not a cure; They simply control testosterone levels for a set amount of time before the body starts to develop resistance. 

The body has a natural system for disposing of degraded proteins. This mechanism is necessary for the body to turn over and renew its proteins, disposing of older proteins while replacing them with new proteins. 

“One of the ways in which we dispose of old proteins is the ubiquitin proteasome system,” Petrylak said. “It tags proteins that are destined to be destroyed.” 

The ubiquitin proteasome system, which is responsible for disposing of old or degraded proteins, is at the center of PROTAC treatments. Both Crews and Petrylak explained that the modus operandi of PROTAC treatments is to tag the defective proteins within the specifically targeted cancer cells so that this naturally occurring disposal mechanism knows to dispose of that protein. 

“PROTAC binds to the protein and makes it so that it is better recognized by the proteasome degradation system,” Petrylak said. “It’s like putting a flag on the protein so that the enzyme E3 ubiquitin ligase can degrade it.”

PROTACs are a “two-headed” drug, meaning one end binds to the target protein and the other end binds to the quality control machinery in the cell that is responsible for getting rid of the problematic proteins. In the end, PROTACs essentially drag the problem protein to the disposal machinery, according to Crews.

Crews added that PROTACs are unique because they do not bind and inhibit protein function. Instead, they simply tag and move on to the next molecule. 

“ARV-110 is a pioneer since it was the first-ever PROTAC degrader to enter human clinical trials,” Taavi Neklesa, a former postdoctoral student in Crew’s lab who helped develop ARV-110, the PROTAC drug currently undergoing clinical trials, wrote to the News. “Since Androgen Receptor remains the driver of prostate cancer and the cancer cells keep making more of it as the disease worsens, the hope is that ARV-110 can completely wipe out Androgen Receptor and help patients with this type of cancer.”

Androgen receptors are receptors responsible for regulating the body’s response to hormones, such as testosterone. In prostate cancer, increased levels of androgen receptors and testosterone drive the progression of the disease. 

Traditional drugs need to bind to target proteins in order to inhibit their function. To ensure all of the target proteins are inhibited correctly, doctors have to administer high levels of the inhibitor drugs. PROTACs offer the promise of using lower doses of drugs. 

In addition, since PROTACs are not inhibitors, they can be used to target other proteins like scaffold proteins whose only function is to act as a physical piece of the cell. This opens up new possibilities for targeting other diseases such as Alzheimer’s, according to Petrylak. 

Over the past two years, the PROTAC drugs developed for prostate cancer have been undergoing clinical trials. 

“Along the way, there were many scientific challenges and we had to convince many people to appreciate the new modality and its clinical utility,” Neklesa wrote. “For instance, it took us 3 years to optimize AR PROTACs to achieve compounds that can be taken as an oral pill. All told, many thousands of molecules were synthesized to finally discover ARV-110.”

The data from the Phase I trials suggested that certain patients with a specific mutation in the androgen receptor benefit from treatment with the newly developed PROTAC drug, according to Petrylak. 

Crews said that he first published the technology in 2001. In 2013, Crews started a New Haven-based company, Arvinas, which now has three PROTACs in clinical trials for prostate and breast cancer.

Currently, the drug is moving into Phase III clinical trials, and Petrylak and Crews said their eventual goal is to obtain FDA approval for use in patients with prostate cancer. 

Crew joined Yale faculty in 1995, and Petrylak joined Yale faculty in 2012. 

Selin Nalbantoglu | selin.nalbantoglu@yale.edu