A Yale chemist and an oncologist worked together to develop a new treatment for prostate cancer that would tag specific proteins in the cancer cells and make it easier for the body’s natural mechanisms to identify and destroy them.
Courtesy of Karissa Van Tassel (left) and Yale Office of Communications (right)
Two Yale researchers have developed a new way to use the body’s protein breakdown system to fight prostate cancer.
Yale School of Medicine professors Craig Crews and Daniel Petrylak have worked together to develop a new drug that treats cancer by targeting specific problem cells for destruction. Proteolysis-targeted chimeras, 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 marks them for destruction.”
Crews is the John C. Malone Professor of Molecular, Cellular, and Developmental Biology and Professor of Chemistry, and Petrylak is Professor of Medical Oncology and Urology.
PROTACs emerged from a cross-departmental collaborative initiative. According to Petrylak, he met Crews at a chemistry department conference. There, oncologists were invited to present the most important clinical questions related to their type of tumor expertise, with the aim of making the knowledge of both the chemistry and oncology departments usable for the development of a new drug.
Prostate cancer is stimulated by testosterone, so one way to treat prostate cancer is to deprive cancer cells of this male sex hormone. For example, doctors can use drugs that target the pituitary gland to turn off signals that trigger the production of testosterone, thereby lowering hormone levels in the body.
However, in the 1960s, researchers noticed that the body could build resistance to the treatment. Men who had received testosterone-inhibiting treatments still had elevated levels of testosterone in their tissue samples, Petrylak said.
Petrylak explained that this resistance could come from different mechanisms in 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 period of time before the body begins to develop resistance.
The body has a natural system for disposing of broken down proteins. This mechanism is necessary for the body to transform and renew its proteins by discarding older proteins and replacing them with new proteins.
“One of the ways we dispose of old proteins is through the ubiquitin-proteasome system,” Petrylak said. “It marks proteins that are destined to be destroyed.”
At the heart of PROTAC treatments is the ubiquitin-proteasome system, which is responsible for the disposal of old or degraded proteins. Both Crews and Petrylak explained that the modus operandi of PROTAC treatments is to tag the defective proteins in the specifically targeted cancer cells, allowing this naturally occurring disposal mechanism to dispose of that protein.
“PROTAC binds to the protein and ensures that it is better recognized by the proteasome degradation system,” says Petrylak. “It’s like putting a flag on the protein so that the enzyme E3 ubiquitin ligase can break it down.”
PROTACs are a “two-headed” drug, meaning one end attaches to the target protein and the other end attaches to the quality control machinery in the cell responsible for getting rid of the offending proteins. In the end, PROTACs essentially pull the problem protein into the disposal machinery, according to crews.
The crews added that PROTACs are unique because they don’t bind to proteins and inhibit their function. Instead, they just tag and move on to the next molecule.
“ARV-110 is a pioneer in that it was the first-ever PROTAC metabolite to enter human clinical trials,” wrote Taavi Neklesa, a former postdoctoral researcher in Crew’s lab who helped develop ARV-110, the PROTAC metabolite. Drug, which is currently in clinical trials, was involved in the news. “Since the androgen receptor remains the driver of prostate cancer, and cancer cells produce more and more of it as the disease worsens, there is hope that ARV-110 may completely wipe out the androgen receptor and help patients with this type of cancer.”
are androgen receptors Receptors responsible for regulating the body’s response to hormones such as testosterone. In prostate cancer, elevated levels of androgen receptors and testosterone drive disease progression.
Conventional drugs need to bind to target proteins to inhibit their function. To ensure all target proteins are inhibited correctly, physicians must administer high concentrations of the inhibitors. PROTACs offer the promise of using lower drug doses.
Additionally, since PROTACs are not inhibitors, they can be used to target other proteins, such as scaffold proteins, whose sole function is to function as a physical part of the cell. According to Petrylak, this opens up new possibilities for specifically tackling other diseases such as Alzheimer’s.
In the last two years, the PROTAC drugs developed for prostate cancer have been tested in clinical trials.
“There were many scientific challenges along the way and we had to convince many people to appreciate the new modality and its clinical utility,” Neklesa wrote. “For example, it took us 3 years to optimize AR PROTACs to get compounds that can be taken as an oral pill. All in all, many thousands of molecules were synthesized to eventually discover ARV-110.”
According to Petrylak, the data from the phase I studies indicated that certain patients with a specific mutation in the androgen receptor benefit from treatment with the newly developed drug PROTAC.
“It’s a technology that I first published in 2001,” Crews said. “In 2013 I founded New Haven-based Arvins and we now have two PROTACs in clinical trials for prostate and breast cancer.”
Currently, the drug is in Phase III clinical trials, and Petrylak and Crews said their ultimate goal is to get FDA approval for use in patients with prostate cancer.
Crew joined the Yale faculty in 1995 and Petrylak joined the Yale faculty in 2012.
Selin Nabantoglu | [email protected]