Possibly the human body's most infamous protein, P53 is mutated in 50% of all cancers. That's right, TP53 (the gene that encodes P53 protein) is cancer's most mutated gene!
P53 is a tumor suppressor, meaning it protects cells from becoming cancerous. In times of genotoxic and cellular stress, P53 activates cellular pathways that promote DNA repair, cell-cycle arrest, and cell death (killing off dangerous and damaged cells). If P53 is defective, the opposite occurs. Cells don't repair DNA appropriately, causing genetic mutations. Cells don't undergo cell death, allowing malfunctioning cells to survive and propagate. And cells don't stop dividing, enabling uncontrolled cellular growth that contributes to tumor formation.
In a nutshell, P53 is a good guy; he's the guardian of the genome. But if he becomes mutated, P53's hero status gets demoted. Mutant P53 presents quite the challenge for cancer biologists. Can P53's hero status be medicinally reinstated? Well — yes! We can reactivate P53 to guard the genome again. Two strategies to bolster P53's hero status have been quite successful in recent years and are setting the stage for a new class of chemotherapies:
1. Inhibiting MDM2, P53's sworn enemy
The P53 protein can be tagged with a small protein called ubiquitin, signaling P53 for degradation. P53 ubiquitination is a healthy, normal event in our cells to sustain P53 at an appropriate level (too much of a good thing can be a bad thing). However, if P53 is deficient, we don't need P53 to be ubiquitinated as frequently. So, scientists have developed inhibitors for MDM2, the protein responsible for P53 ubiquitination and destruction. By blocking MDM2, P53 is not ubiquitinated, and P53 levels in the cell rise, allowing deficient P53 the extra help to do its job.
Seven MDM2 inhibitors are currently in clinical trials for various cancers, and a few have even progressed to phase III trials!
Note: MDM2 isn't the only protein that regulates P53 levels in the cell. Other proteins for this pathway are also chemotherapeutic targets.
2. A direct approach: P53 activators
Most P53 mutants are deficient in the DNA binding domain. If the DNA binding domain is unstable, the protein can't bind DNA and jumpstart the cellular pathways needed for cell death, DNA repair, and cell division arrest.
Scientists have designed small molecule activators that bind P53 and restore the structure of the DNA binding domain, allowing P53 to bind DNA and initiate gene expression. Two small-molecule activators are now in clinical trials and seem promising thus far. COTI-2 is undergoing stage II clinical trials for various cancers, while APR-246 has made it to stage three for blood cancers!
P53 activators aren't approved yet, nor is their approval for clinical use guaranteed. But the fact that P53 activators are in clinical trials, especially stage three, is a remarkable accomplishment by the scientific community! P53 is the holy grail of chemotherapeutic targets. With so many cancers harboring P53 mutations the therapeutic reach of these activators is substantial. There was a time when P53 was considered undruggable, an impossible chemotheraputic target.
P53 activation is no longer a fantasy. Unlike Marvel movies and comic books, P53 reactivation is a reality.