UPDATES ON p53

p53 in normal cells

• p53 (also called TP53) is a tumor suppressor gene, meaning that it normally acts to prevent cells from proliferating too much or surviving too long. When it is lost or mutated or shut off, those processes go awry, and cells grow too much, survive too long, and are more likely to form a tumor.
• Some people have referred to p53 as the “guardian of the genome”, because when there is damage to the DNA (e.g. from radiation), p53 gets activated and either kills cells or stops them from dividing until they can repair the damage

p53 in cancer

• p53 mutations are extremely common in cancer. It’s believed that >50% of cancers have p53 mutations, and that even in tumors where there aren’t obvious mutations, the function of p53 is probably lost (because if it were around, it would presumably exert its role of preventing growth and survival)

Targeting p53 with MDM-2 inhibitors

• A holy grail of cancer therapy is to re-activate p53, so that it can do its tumor suppressor thing, and stop the tumor from growing or kill it.
• One way to do this is by inhibiting the enzyme that breaks down p53, which is called MDM2 (or sometimes HDM2). There are experimental drugs that do this — the most commonly used one is Nutlin-3 (incidentally, named that because it was discovered at Roche Pharmaceuticals, which used to be in Nutley, NJ.)
• Nutlin-3 works in the lab, but is not really a drug that can be used in humans. However, there are a number of MDM-2 inhibitors in clinical trials:

• • Idasanutlin (RG7388) — there is a nice paper showing that this crosses the BBB. There is a trial in Germany (NCT03158389) in which it is supposed to be used (as one of several agents) for patients with glioblastoma (not medullo), but it hasn’t started recruiting yet
  • RO5045337 (RG7112) — supposed to cross the BBB, but all studies on ClinicalTrials.gov are listed as “completed”
  • RO6839921 — not clear if crosses BBB
  • AMG-232 — supposed to cross the BBB, being tested in glioma (NCT03107780)
  • DS-3032b — not clear if crosses BBB. Ongoing trial excludes patients with brain mets
  • ALRN-6924 — not clear if crosses BBB. Ongoing trial excludes patients with brain mets
• MDM-2 inhibitors are likely to work on tumors that do not have p53 mutations, because in those tumors if you simply prevent p53 from being degraded, it should be able to stop or kill cells. In tumors that have p53 mutations, the p53 protein is likely to be non-functional, so even if you prevent it from being degraded, it may not be able to exert its normal function.
• Even though MDM-2 inhibitors should be great cancer drugs, so far there is no clear evidence that they can inhibit tumor growth in people. But it’s early days: most of these drugs are still in Phase I trials, which are evaluating their safety.

p53 in medullobastoma

• In newly diagnosed medulloblastoma, p53 mutations are usually found in WNT and SHH tumors, and rarely in Group 3 and 4. But therapies, especially radiation, tend to cause p53 mutations, so at relapse (after therapy), a much larger percentage of patients have p53 mutations
•  Group 4 Medullos don’t usually have p53 mutations, and therefore might respond to MDM-2 inhibitors, that might be correct. But there’s no evidence (yet) that these tumors do respond to MDM-2 inhibitors, or that other subgroups do not respond, so I’m not sure I’d call it a specific target. Plus, Recurrent Group 4 medulloblastomas MAY have p53 mutations, in which case they wouldn’t be good targets for MDM-2 inhibitors.

Other drugs that activate p53

• In addition to MDM-2 inhibitors, there are some other strategies for activating p53, including a study on DHODH inhibitors. It’s a fascinating study, and suggests that these drugs may be useful for activating p53.  In this paper, they test the drug in vivo on a melanoma cell line growing in the leg of a mouse, and they see an effect when the drug is administered together with MDM-2 inhibitors, but not when it is administered on its own. We don’t know if the same would be true with medulloblastoma growing in the brain. And this is really the only paper that has shown an effect of these drugs. So I think more work needs to be done.