Elephants rarely get cancer, which is puzzling because their massive size and long lifespans should make them prime candidates for runaway cell growth. The reason why might lie in a tumor-suppressing protein called p53.
The animals have 20 copies of the gene that makes p53, which patrols the body for damaged cells and can then pull off several anti-cancer tricks: stopping them from dividing, repairing damage or triggering them to self-destruct if they show hints of becoming cancerous.
But the power of this mechanism may be muted by the fact that humans only have one p53-producing gene: TP53. Mutations in the TP53 gene that affect p53 production are among the most common drivers of cancer in humans. People with Li-Fraumeni syndrome, who inherit a faulty gene, have a 90% chance of developing cancer by the time they turn 60, half of them before age 40.
Given its widespread impact in cancer, the prospect of harnessing this mechanism has made p53 a big-game target. It’s also vexed scientists for years.
“Unlike many oncology targets, where candidates are designed to selectively inhibit the activity of an oncogenic driver, drugging p53 poses the opposite challenge: the need to restore the function of an impaired tumor suppressor protein,” said Jonathan Bennett, vice president of discovery chemistry at Merck & Co., in a written statement.
Adding to the complexity is the fact that p53 mutations are highly variable.
“This remains a significant challenge in drug discovery and development,” Bennett said.
But because the gene is implicated in so many types of cancer, the payoff in drug development could be significant.
An undruggable target
For many years, p53 was considered ‘undruggable’ and a series of failures did little to raise confidence that it’s not. One of the most recent setbacks was Boehringer Ingelheim’s MDM2-targeting p53 drug, brigimadlin, which was scrapped after it failed in a phase 2/3 trial as a first-line option for a rare cancer that originates in fat cells called liposarcoma.
A number of companies, including Roche, Novartis and Sanofi, have also tried and failed to regulate p53 by targeting MDM2, a protein that degrades p53. By blocking MDM2, researchers hoped to boost p53 function.
Despite the setbacks, a few companies are still in the running, including Merck, which announced a p53 collaboration with Astex Pharmaceuticals in 2023. Among the furthest along is Kartos Therapeutics, which has an MDM2 candidate, navtemadlin in testing both as an add-on to ruxolitinib and as a standalone treatment in two phase 3 trials for myelofibrosis.
Ascentage Pharma is in phase 2 with its MDM2-p53 inhibitor, alrizomadlin, in combination with the PD-1drug toripalimab for advanced adenoid cystic carcinoma, a cancer that arises in secretory glands as well as in other solid tumors. The company released phase 2 results at ASCO in June, showing that the drug had an objective response rate of 16.7% and a 100% disease control rate. Lamassu also has an early-stage option, SA53, targeting the same mechanism.
After years of false starts and a graveyard of failed drugs, these glimmers of success offer hope that a new generation of p53 drugs is finally making progress.
