Harnessing the Power of p53 to Treat Cancer
PMV Pharma is pioneering the discovery and development of p53 targeted small molecule drugs for the treatment of cancer. p53’s importance in human biology is profound: it is the most commonly mutated protein in human cancers, with more than half of all tumors containing mutant p53.
Discovered in 1979 by one of PMV’s founders, p53 is a potent transcription factor that plays a pivotal role in the body’s natural defense mechanism against cancer. Situated at the nexus of multiple regulatory pathways, p53 is activated following diverse forms of cellular stress and directly regulates transcription of multiple downstream genes involved in apoptosis, cell cycle regulation, and senescence. In responding to DNA damage, activated p53 induces transcription of the cyclin-dependent kinase inhibitor p21, which leads to cell cycle arrest. This activity of p53 provides a critical check on cancer development by helping the DNA repair machinery to complete its function before cellular replication. If the damage is too severe, then the same activated p53 molecule induces a highly organized program of cellular death, or apoptosis, to prevent the proliferation of potentially cancerous cells. Thus, p53 is a critical tumor suppressor and has been referred to as the “guardian of the genome”.
It has been estimated that more than 27 million people are living with a tumor in which p53 or an element of its regulatory pathway has been mutated. Most tumor suppressor genes are inactivated by mutation, and most tumor-associated p53 mutations are missense mutations, clustered within the DNA binding domain of the protein. One of the consequences of many of these mutations is a dramatic increase in the half-life of mutant p53, and many of the mutants are dominant negative proteins that block the activity of the protein encoded by the remaining wild-type p53 allele. Ultimately, the tumor undergoes loss of heterozygosity, arguing that loss of the wild-type allele selects for a more robust tumor.
The level and activity of wild-type p53 in the cell is controlled by its negative regulator, MDM2. MDM2 binds to the transactivation domain of p53 and inhibits its transcriptional activity. MDM2 is also an E3 ubiquitin ligase that targets p53 for degradation in the proteasome. The expression of MDM2 protein is in turn up-regulated by p53, creating a negative feedback loop controlling the amount of p53 protein that accumulates in normal cells. Many cancers containing wild-type p53 break this feedback loop by over-expression of MDM2, and consequently target wild-type p53 for chronic degradation, leading to loss of p53-mediated tumor suppression.