Treating gynecologic malignancies with selective estrogen receptor downregulators (SERDs): promise and challenges.
Endometrial and ovarian cancers are estrogen-dependent gynecologic malignancies. Although many are estrogen receptor (ER) positive, treatment with the selective estrogen receptor modulator (SERM) tamoxifen, a tissue selective partial-agonist, has demonstrated only modest clinical benefit. Selective estrogen receptor downregulators (SERDs) are pure ER antagonists showing a benefit for advanced ER positive breast cancer, which has bolstered their potential use for ER positive gynecologic malignancies. We summarize these preclinical and clinical data, suggesting that a subpopulation of patients with endometrial or ovarian cancer exists in which treatment with SERDs results in improved outcome. However, the full potential of SERDs for a gynecologic malignancies will be realized only when the appropriate predictive biomarkers are identified. Additionally, a further understanding ER signaling in the context of ovarian and endometrial tissues that appear to involve c-Src and other kinase pathways is needed to successfully address the emergence of resistance with rationally designed combination therapies.
Division of Gynecologic Oncology, Magee-Womens Hospital of the University of Pittsburgh Medical Center, Pittsburgh, PA, USA. Electronic address: boockmeiermm@upmc.edu.
Michelle M
MM
Boisen
Department of Pharmacology and Chemical Biology, University of Pittsburgh School of Medicine Molecular Pharmacology Training Program, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA.
Courtney L
CL
Andersen
Women's Cancer Research Center, Department of Pharmacology and Chemical Biology, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA.
Sreeja
S
Sreekumar
University of Pittsburgh Drug Discovery Institute and the Department of Computational and Systems Biology, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA.
Andrew M
AM
Stern
University of Pittsburgh Cancer Institute, Department of Pharmacology and Chemical Biology, Women's Cancer Research Center, Magee-Womens Research Institute, Pittsburgh, PA, USA.
Steffi
S
Oesterreich
D002986:Clinical Trials as Topic; D019008:Drug Resistance, Neoplasm; D016889:Endometrial Neoplasms / Q000188:drug therapy* / Q000378:metabolism; D005260:Female; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D006801:Humans; D010051:Ovarian Neoplasms / Q000188:drug therapy* / Q000378:metabolism; D020845:Selective Estrogen Receptor Modulators / Q000494:pharmacology / Q000627:therapeutic use*; D015398:Signal Transduction / Q000187:drug effects; D016896:Treatment Outcome
D020845:Selective Estrogen Receptor Modulators
Endometrial carcinoma; Estrogen receptor; Ovarian carcinoma; Selective estrogen receptor downregulators (SERDs)