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Title of Poster: Preclinical Development of a Second Generation of Selective Estrogen
Receptor Downregulators to Manage Estrogen Receptor-Positive Breast Cancers
Presenter: Brandon Bert
Division: Hematology-Oncology
☐ Faculty ☐ Fellow ☐ Resident ☐ Post-doc Research Fellow ☐ Graduate Student ☐ Medical Student ☒Other
Principal Investigator/Mentor: Richard J. Pietras Co-Investigators: Michael E. Jung, Diana C. Márquez-Garbán,
Gang Deng, Emelyne Diers, Nalo Hamilton, David Elashoff
Thematic Poster Category: Development, Morphogenesis, Cell Growth and Differentiation, Apoptosis, Stem Cell
Biology, Carcinogenesis and Cancer Biology
Brandon Bert1,4, Diana C. Márquez-Garbán1,4, Gang Deng2,4, Emelyne Diers2,4, Michael E. Jung2,4, Nalo
Hamilton3,4 and Richard J. Pietras1,4.
1Division of Hematology-Oncology, Department of Medicine, David Geffen School of Medicine,
2Department of Chemistry and Biological Chemistry, 3UCLA School of Nursing and 4Jonsson
Comprehensive Cancer Center.
Breast cancers (BC) with expression of estrogen receptor-alpha (ERα) occur in more than 70% of
newly-diagnosed patients in the U.S. Targeted therapy with selective estrogen receptor modulators
(SERMs), such as tamoxifen (antagonist in BC; partial agonist in uterus) and aromatase inhibitors
(block estrogen synthesis) are commonly used to treat ERα-positive tumors. However, a significant
proportion of ERα-positive BCs exhibit de novo or acquired resistance to current endocrine therapies
due to ligand-dependent or –independent mechanisms. Another class of ERα antagonist- termed
selective estrogen receptor downregulators (SERDs)- is represented by fulvestrant, a drug whose
mechanism of action differs from that of SERMs. Treatment with fulvestrant causes ERα downregulation, an event that helps overcome several resistance mechanisms. However, this firstgeneration SERD drug is poorly bioavailable, requires intramuscular dosing and may not have optimal
antitumor activity in clinic. To address this problem, we designed and tested a new generation of
SERD compounds. Using ERα-positive BC cells in vitro, we find that these steroidal derivatives
suppress ERα protein levels with efficacy similar to fulvestrant. Moreover, these new SERDs markedly
inhibit ERα-positive BC cell proliferation in vitro even in the presence of estradiol-17β, suggesting that
these SERDs may be active in both pre- and post-menopausal women. In addition, combination of
newly-designed SERDs with CDK4/6 inhibitors was significantly more effective in suppressing tumor
proliferation. It is urgent to find new drugs to overcome endocrine resistance in BC to improve patient
survival. Hence, these new ERα antagonists that also bind and induce down-regulation and
degradation of the receptor may potentially benefit patients who progress on current endocrine
therapies. [Funded by Tower Cancer Research Foundation-Jessica M. Berman Fund and NCI U54 CA14393].