Five Questions for Anna Mandinova and Sam Lee
In a paper published January 5, 2011 in Science Translational Medicine, Anna Mandinova and Sam Lee, both researchers at Massachusetts General Hospital and associate members of the Broad, describe the obstacles and promise of developing small compounds that target the p53 pathway, the most common pathway involved in cancer. I asked them both to discuss the challenges of finding p53-targeted molecules and the approaches they are currently working on.
Q1. Why does p53 have such a foundational role in cancer disease pathways?
SL: P53 is known as a guardian of the genome. In 1993, Science magazine named it as the molecule of the year. The human genome is constantly under assault by carcinogens and other stressors. Over time, a cell’s DNA can become mutated. P53 is on the front lines protecting the genome from further mishap by essentially directing a damaged cell to take one for the team and die, a process called apoptosis. Hence, its nom de guerre as guardian of our genomes.
P53 is an oncogene discovered in 1979. Originally not known as a tumor suppressor gene, p53 researchers eventually learned that it is a transcription factor that is involved with turning on many downstream pathways in cancer. In normal, so-called wild type cells, p53 acts as a gatekeeper by turning on important downstream genes that suppress cancer growth.
However, more than 50% of cancer tumors have a mutated copy of the p53 gene. The result is that it cannot turn on those downstream genes that are involved in tumor suppression. We know part of the reason cancer cells do not die is because they have a mutant p53 which would otherwise direct it to self-destruct.
No other pathway discovered to date appears to have such a major role in cancer.
Q2. In your paper, you describe the dark side of p53. Why is it a double-edged sword?
AM: Restoring p53’s activity remains an important, but frustratingly elusive, goal for developing new cancer treatments. The reason is that p53 has a dark side. Half of tumor cells still retain non-mutated p53. Increasing data show that cancer cells take advantage of this normal p53, which actually helps them survive.
Q3. What are the challenges in finding ways to maintain or activate p53?
AM: P53 is a classical undruggable target. Drugs work by finding a way to bind to certain molecules – proteins, lipids, etc. – to change their function. P53 has a fairly flat surface. For drugs like today’s small molecules to specifically attach well to a flat surface is nearly impossible.
But with increasing investigation, researchers are starting to find previously unknown pockets in p53’s structure where small molecules may possibly attach.
Q4. What are some of the chemical biology strategies to restore normal p53 tumor suppression activity?
SL: To avoid excessive cell death, normal cells do not want excess p53 in their vicinity. In a normal process, p53 is degraded by another protein, MDM2. In cancers with normal type p53, researchers are looking for ways to stop p53 degradation with MDM2 inhibitors, thereby overloading the cells with p53’s apoptosis message.
AM: Researchers have found a very specific surface on a p53 pocket where MDM2 binds. Using a type of small molecule called Nutlins, this binding can be prevented allowing the p53 to escape degradation. In clinical practice, however, Nutlins have not been successful. Still, the MDM2/p53 interaction remains a significant area of interest for finding new cancer therapies.
Q5. What strategies are you taking to develop new small molecules that act on p53?
"Our labs, together with Stuart Schreiber's laboratory at the Broad, are working to find small molecules that restore the normal function of mutant p53 proteins, which are routinely found in high concentrations in cancer cells" explains Anna. These small molecules would target and bind only to mutant p53 in cancer cells, restoring normal activity thereby killing the cell. In theory, neighboring normal cells should remain unaffected. Adds Sam, "This approach would allow p53 to return to its regular function as the guardian of the genome."