Could new epigenetic cancer treatments be impacting the future offspring?

New advances in epigenetic drugs are allowing new options for the treatment of cancer and other diseases--but could these new treatments possibly have long-term effects that impact the fertility of both female patients and their future offspring? A recently published study in Clinical Epigenetics suggests that this is something that should be more closely examined in clinical drug trials given the results in their recent study examining the drug Tazemetostat and its impact on oocytes and germline genomes in female mice.

Advances in diagnostics and therapeutics in cancer research have allowed doctors to catch and treat cancer earlier, thus resulting in better prognoses in many cases. However, this also means that a larger number of women are being treated for cancer during what would be traditionally viewed as key reproductive years. While clinical trials of drugs examine the side effects on the patient, they do not often take into consideration the impact on that patient’s future offspring. With the evolution of genetically-based approaches to cancer treatments, and specifically epigenetically-based therapeutics, changes being introduced into a patient’s epigenome by the targeted treatment drugs could have lasting impacts on the germline genome that is passed to the patient’s offspring, with potentially unintentional, negative effects. Given that female mammals are born with a set number of eggs (oocytes) and more females of reproductive age are being treated for cancers, there is clearly a need to more fully understand the possible ramifications of these new therapies for women who might wish to have children post-treatment.

In a study published recently in Clinical Epigenetics, researchers examined the effects of the newly developed epigenetic drug Tazemetostat (currently in clinical trials; it works by inhibiting the target enzyme Enhancer of Zeste 2 (EZH2)) on mice of reproductive age. Because EZH1 and EZH2 are implicated in gain of function mutations and overexpression in a range of tumors, it was selected as target for epigenetic therapy: i.e., inhibit expression of this enzyme, inhibit expression of the gene that might lead to mutation or proliferation of cancer cells in tumors. However, while the inhibition of EZH1/2 might be a targeted treatment for cancer and other diseases, in this study the inhibition of EZH1/2 was shown to severely deplete H3K27me3, which is necessary for growing oocytes in female mice. As a result, both oocyte growth and fetal oocyte development were both negatively impacted in female mice treated with Tazemetostat.

Image of oocyte under control (sham) and treatment conditions show how treatment results in depletion of H3K27me3 (in red) and interferes with oocyte development.

More alarmingly, the researchers found that once the H3K27me3 was depleted, it did not recover even after treatment was terminated.  The damage caused by the depletion was lasting, resulting in the loss of the H3K27me3 protein in both the mother’s genome and that of their oocytes (clearly impacting the germline). While this research was carried out in lab mice, the researchers strongly advocated that these same effects could be seen in human women, and called for more extensive research to be carried out during clinical trials to examine these other possible ramifications.

Given the results of this study, it is clear that there needs to be more research which examines the potential impact on fertility and future offspring when developing and testing epigenetically-based drugs that may fundamentally change the functioning of a gene known to be involved in fertility and reproductive success. The study by Prokopuk, Hogg, and Western serves as a cautionary tale reminding us that there can sometimes be an unforeseen price to be paid in the war against cancer—but knowing what we know now about genetics and epigenetics, and all that we continue to learn—researchers can forearm themselves with knowledge about all the potential side effects of a given therapy to further refine it for certain populations of patients and even specific patients: true precision medicine.

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