Several biopharma companies are working on compounds to inhibit AKT, a protein kinase that has been implicated in many cancers. Researchers at Mount Sinai Hospital in New York are pursuing a different tact against the oncogenic protein, seeking to degrade it rather than just blocking it.
Now they have early evidence that a drug they developed to do just that could become a new weapon against some forms of breast cancer, prostate cancer and other tumor types. The drug, called MS21, inhibited the growth of some cancer cells with mutations in the PI3K/PTEN pathway and slowed tumor growth in mouse models of breast and prostate cancer, they reported in the journal Cancer Discovery.
MS21 binds to AKT much like drugs that have been designed to inhibit the protein do, but it has been engineered to bind to a second protein called VHL E3 ligase, also known as the von Hippel–Lindau E3 ubiquitin ligase. VHL E3 is well known for its ability to suppress tumors by degrading toxic proteins.
The drug, “simply by bringing VHL in close proximity to AKT, allows the targeting of the ubiquitin ligase to AKT,” resulting in its degradation, said Ramon Parsons, M.D., Ph.D., director of the Tisch Cancer Institute at Mount Sinai’s Icahn School of Medicine, in an interview.
The researchers tested MS21 in mice with active prostate and breast tumors, comparing them to mice that were either untreated or that received capivasertib (AZD5363), an experimental AKT inhibitor from AstraZeneca.
Administering MS21 once daily for 21 days resulted in 90% inhibition of tumor growth in the prostate cancer models and 80% in the breast cancer models as compared to untreated mice. A low dose of capivasertib, by contrast, inhibited tumor growth by 50% in both models, the researchers reported.
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Why shoot for degradation of AKT rather than settling for inhibition? Oncology researchers haven’t yet answered that question definitively, Parsons said, but preclinical research suggests there are benefits to wiping out the protein.
“When you inhibit AKT kinase, you really only inhibit it temporarily,” he said. “The cell has a way to bypass the inhibition. So it only lasts for a matter of hours. When you degrade it, there’s nothing there. So we see the inhibition of AKT’s ability to function lasts for days, and we think that’s a real benefit.”
AstraZeneca is testing AKT inhibitor capivasertib in breast and prostate cancer, setting up a potential showdown with Roche, which is also in phase 3 with its own AKT blocker, ipatasertib. But the true efficacy of these compounds remains controversial.
Last September, Roche said that in a trial of ipatasertib with Zytiga in a subset of patients with PTEN-loss prostate tumors, the combination improved progression-free survival by only two months over Zytiga alone. Another study revealed that adding ipatasertib to paclitaxel in a subset of breast cancer patients had no effect—a result that analysts at Jefferies called “disappointing.”
The Mount Sinai team suspected that MS21 might also work well as part of combination therapies, so they combined it with a MEK inhibitor in cancer cells with BRAF and KRAS mutations. The combination inhibited the growth of cells more effectively than either drug alone did, they reported.
The researchers are planning additional animal trials to further assess the toxicology and ideal dosing profile for MS21, Parsons said. Mount Sinai is in discussions with several companies, in the hopes of finding a partner to take the drug into clinical trials, he added.