A recent provocative report by Lisa Abegglen and a team from the Huntsman Cancer Institute in Salt Lake City, Utah showed that elephants from the San Diego Zoo had 20 extra copies of the p53 gene. Since p53 is a tumor suppressor gene, the researchers linked this to the low occurrence of cancer in these elephants, even in old age. So, is this correlation correct? And what does this tell us about the development of human cancers such as myeloma?
Well, p53 is definitely a very important “anticancer” gene and has often been called the guardian of the genome (or DNA of the cell). When DNA is damaged, the p53 gene is turned on and a cascade of protective measures is activated. If there is major damage, the cell is triggered to die—apoptosis. If there is lesser damage, repair is activated. Many complex mechanisms are involved, and, although much more work needs to be done, it is very reasonable to propose that having extra p53 proteins would be extremely helpful in reducing the risk of cancer in elephants and maybe in humans.
So what is the status of p53 in myeloma? The p53 gene is located on the top part (“p arm”) of chromosome number 17. Loss of part or all of this p arm occurs in 10-30% of newly diagnosed myeloma patients. More detailed studies indicate that partial losses of p53 and/or mutations of the gene occur in a higher percentage of patients, especially over time. So, a type of high-risk myeloma is characterized by loss of the p arm: 17p- or 17p deletion with loss of one copy of the p53. Thus in myeloma there can be just one p53 gene, versus 20 copies in elephants. Healthy humans have two copies of the p53 gene, which should be enough under normal circumstances—but with the exposure to toxins in the modern environment, more could be helpful.
In addition, the function of that one remaining p53 gene can be blocked by several mechanisms, including molecules called microRNAs (miRNAs). These RNAs carry messages from other DNA molecules and recent studies have shown that toxic chemicals trigger the production of these dangerous miRNAs which block p53. The chemicals are ones I have discussed in the past: TCDD (a dioxin contaminant in Agent Orange) and benzo[a]pyrene (BaP) a PAH (polycyclic aromatic hydrocarbon molecule). BaP is an IARC (International Agency for Research on Cancer) category I cancer-causing chemical found originally in coal tar. Major current sources of BaP include fumes from incineration, automobile exhaust, cigarette smoking, and charbroiled food. BaP leads to “mutational hotspots” in the p53 gene. TCDD and BaP therefore both suppress and/or damage p53.
Bottom line: Reduced levels and function of p53 are definitely important as a causative factor for myeloma.
Bottom, bottom line: As suggested in a New York Times article about the elephant study, having more p53 could be really helpful. Is it possible to add more p53 genes or increase the amount of p53 activity? There are already several ideas about this.
Ø Selinexor is a new drug in clinical trials which retains p53 protein in the nucleus of myeloma cells: thus increasing the amount of p53 activity. Important efficacy in the ongoing STORM trial in which selinexor is combined with dexamethasone suggests this can be a valuable strategy by increasing availability of functional p53 protein. (I discussed selinexor in a recent episode of “Ask Dr. Durie.”)
Ø Green tea constituents EGCG (epigallo-catechin-3-gallate) and Polyphenon E have been shown to block the production of interfering miRNAs and improve p53 functioning in lab and animal studies in doses that would be well tolerated in human trials. These are potential options for myeloma treatment and for the prevention of transition from MGUS to active myeloma.
Quite a number of additional treatment options can be considered, including gene therapy, and I suspect we will now see increased interest in exploring these ideas.
Final comment: Elephants never forget, love to paint, and maybe are showing us the way forward in how to better target and improve myeloma therapies!
Dr. Brian G.M. Durie serves as Chairman of the International Myeloma Foundation and serves on its Scientific Advisory Board. Additionally, he is Chairman of the IMF's International Myeloma Working Group, a consortium of nearly 200 myeloma experts from around the world. Dr. Durie also leads the IMF’s Black Swan Research Initiative®.
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