PMID- 26162914
OWN - NLM
STAT- MEDLINE
DCOM- 20160524
LR  - 20191210
IS  - 1479-6821 (Electronic)
IS  - 1351-0088 (Print)
IS  - 1351-0088 (Linking)
VI  - 22
IP  - 5
DP  - 2015 Oct
TI  - Evaluation of the pharmacological activities of RAD1901, a selective estrogen 
      receptor degrader.
PG  - 713-24
LID - 10.1530/ERC-15-0287 [doi]
AB  - Endocrine therapy, using tamoxifen or an aromatase inhibitor, remains a 
      first-line treatment for estrogen receptor 1 (ESR1) positive breast cancer. 
      However, tumor resistance limits the duration of response. The clinical efficacy 
      of fulvestrant, a selective ER degrader (SERD) that triggers receptor 
      degradation, has confirmed that ESR1 often remains engaged in endocrine therapy 
      resistant cancers. Recently developed, selective ER modulators (SERMs)/SERD 
      hybrids (SSHs) that facilitate ESR1 degradation in breast cancer cells and 
      reproductive tissues have been advanced as an alternative treatment for advanced 
      breast cancer, particularly in the metastatic setting. RAD1901 is one SSH 
      currently being evaluated clinically that is unique among ESR1 modulators in that 
      it readily enters the brain, a common site of breast cancer metastasis. In this 
      study, RAD1901 inhibited estrogen activation of ESR1 in vitro and in vivo, 
      inhibited estrogen-dependent breast cancer cell proliferation and xenograft tumor 
      growth, and mediated dose-dependent downregulation of ESR1 protein. However, 
      doses of RAD1901 insufficient to induce ESR1 degradation were shown to result in 
      the activation of ESR1 target genes and in the stimulation of xenograft tumor 
      growth. RAD1901 is an SSH that exhibits complex pharmacology in breast cancer 
      models, having dose-dependent agonist/antagonist activity displayed in a 
      tissue-selective manner. It remains unclear how this unique pharmacology will 
      impact the utility of RAD1901 for breast cancer treatment. However, being the 
      only SERD currently known to access the brain, RAD1901 merits evaluation as a 
      targeted therapy for the treatment of breast cancer brain metastases.
CI  - (c) 2015 Society for Endocrinology.
FAU - Wardell, Suzanne E
AU  - Wardell SE
AD  - Department of Pharmacology and Cancer Biology Duke University School of Medicine, 
      Box 3813, Durham, North Carolina 27710, USA.
FAU - Nelson, Erik R
AU  - Nelson ER
AD  - Department of Pharmacology and Cancer Biology Duke University School of Medicine, 
      Box 3813, Durham, North Carolina 27710, USA.
FAU - Chao, Christina A
AU  - Chao CA
AD  - Department of Pharmacology and Cancer Biology Duke University School of Medicine, 
      Box 3813, Durham, North Carolina 27710, USA.
FAU - Alley, Holly M
AU  - Alley HM
AD  - Department of Pharmacology and Cancer Biology Duke University School of Medicine, 
      Box 3813, Durham, North Carolina 27710, USA.
FAU - McDonnell, Donald P
AU  - McDonnell DP
AD  - Department of Pharmacology and Cancer Biology Duke University School of Medicine, 
      Box 3813, Durham, North Carolina 27710, USA donald.mcdonnell@duke.edu.
LA  - eng
GR  - R01 DK048807/DK/NIDDK NIH HHS/United States
GR  - R37 DK048807/DK/NIDDK NIH HHS/United States
GR  - R37DK048807/DK/NIDDK NIH HHS/United States
PT  - Evaluation Study
PT  - Journal Article
PT  - Research Support, N.I.H., Extramural
PT  - Research Support, Non-U.S. Gov't
DEP - 20150710
PL  - England
TA  - Endocr Relat Cancer
JT  - Endocrine-related cancer
JID - 9436481
RN  - 0 (Estrogen Receptor alpha)
RN  - 0 (RNA, Messenger)
RN  - 0 (Selective Estrogen Receptor Modulators)
SB  - IM
MH  - Animals
MH  - Apoptosis/drug effects
MH  - Blotting, Western
MH  - Cell Proliferation/drug effects
MH  - Estrogen Receptor alpha/genetics/*metabolism
MH  - Female
MH  - Humans
MH  - Immunoenzyme Techniques
MH  - Mice
MH  - Mice, Inbred C57BL
MH  - RNA, Messenger/genetics
MH  - Real-Time Polymerase Chain Reaction
MH  - Reverse Transcriptase Polymerase Chain Reaction
MH  - Selective Estrogen Receptor Modulators/*pharmacology
MH  - Tumor Cells, Cultured
MH  - Uterine Cervical Neoplasms/*drug therapy/metabolism/*pathology
MH  - Xenograft Model Antitumor Assays
PMC - PMC4545300
MID - NIHMS708740
OTO - NOTNLM
OT  - RAD1901
OT  - SERM
OT  - endocrine-resistant breast cancer
OT  - selective estrogen receptor degrader
COIS- Declaration of interest D.P.M. has previously served as a scientific advisory 
      board member for Radius Pharmaceuticals, Inc. D.P.M., S.E.W., and E.R.N. have 
      applied for a patent for the use of RAD1901 for the treatment of breast cancer 
      brain metastases.
EDAT- 2015/07/15 06:00
MHDA- 2016/05/25 06:00
PMCR- 2016/08/01
CRDT- 2015/07/12 06:00
PHST- 2015/07/08 00:00 [accepted]
PHST- 2015/07/12 06:00 [entrez]
PHST- 2015/07/15 06:00 [pubmed]
PHST- 2016/05/25 06:00 [medline]
PHST- 2016/08/01 00:00 [pmc-release]
AID - ERC-15-0287 [pii]
AID - 10.1530/ERC-15-0287 [doi]
PST - ppublish
SO  - Endocr Relat Cancer. 2015 Oct;22(5):713-24. doi: 10.1530/ERC-15-0287. Epub 2015 
      Jul 10.