Pharmacoepigenomics and Pharmacovigilance in Gynecological Cancers

Abstract

Aberrant epigenetic changes have been reported in gynecological cancers and contribute to the tumorigenesis. Patients with the same type of cancer may carry different epigenetic defects. In fact, each tumor harbors a different set of epigenetic changes, demonstrating a heteroepigeneity among the tumors. The patients may respond differently to the same treatment due to the differences in epigenetic alterations they're harboring. Epigenetic changes are associated with loss of drug sensitivity and contribute to drug-resistance development. Pharmacoepigenomics include two aspects. One that has been emphasized previously is the interindividual differences at epigenome level that lead to different responses to the same drug. Another aspect that should not be overlooked is the effect of a treatment on the epigenome of patients. The emerging epigenetic therapies alone or in combination with chemotherapy or radiotherapy change the epigenome of patients, which in turn change the response of the patients to the drugs. Although currently most of the studies use loci-specific biomarkers to reflect epigenome changes, the advancement of next-generation sequencing will make more and more studies directly demonstrate the changes at the epigenome level. It is worth to notice that epigenetic therapy is still at its infancy. Lacking of specific targeting to reverse the epigenetic changes raise concerns of pharmacovigilance or drug safety. In this chapter, I focus on ovarian cancer, cervical cancer, and uterine cancer to discuss the pharmacoepigenomics and pharmacovigilance. For ovarian cancer, I emphasize that epigenetic alterations in patients cause chemoresistance acquisition and cancer recurrence, however, epigenetic therapies change the epigenome of cancer cells to resensitize them to chemotherapy. As for cervical cancer, the combination epigenetic therapies using both DNA methyltransferase (DNMT) inhibitors (DNMTIs) and histone deacetylase (HDAC) inhibitors (HDACIs) are emphasized. Regarding uterine cancer, application of epigenetic therapy to revive the hormonal therapy is discussed.