TY - JOUR
T1 - Antitumor activity of Z-endoxifen in aromatase inhibitor-sensitive and aromatase inhibitor-resistant estrogen receptor-positive breast cancer
AU - Jayaraman, Swaathi
AU - Hou, Xiaonan
AU - Kuffel, Mary J.
AU - Suman, Vera J.
AU - Hoskin, Tanya L.
AU - Reinicke, Kathryn E.
AU - Monroe, David G.
AU - Kalari, Krishna R.
AU - Tang, Xiaojia
AU - Zeldenrust, Megan A.
AU - Cheng, Jingfei
AU - Bruinsma, Elizabeth S.
AU - Buhrow, Sarah A.
AU - McGovern, Renee M.
AU - Safgren, Stephanie L.
AU - Walden, Chad A.
AU - Carter, Jodi M.
AU - Reid, Joel M.
AU - Ingle, James N.
AU - Ames, Matthew M.
AU - Hawse, John R.
AU - Goetz, Matthew P.
N1 - Publisher Copyright:
© 2020 The Author(s).
PY - 2020/5/19
Y1 - 2020/5/19
N2 - Background: The tamoxifen metabolite, Z-endoxifen, demonstrated promising antitumor activity in endocrine-resistant estrogen receptor-positive (ER+) breast cancer. We compared the antitumor activity of Z-endoxifen with tamoxifen and letrozole in the letrozole-sensitive MCF7 aromatase expressing model (MCF7AC1), as well as with tamoxifen, fulvestrant, exemestane, and exemestane plus everolimus in a letrozole-resistant MCF7 model (MCF7LR). Methods: MCF7AC1 tumor-bearing mice were randomized to control (no drug), letrozole (10 μg/day), tamoxifen (500 μg/day), or Z-endoxifen (25 and 75 mg/kg). Treatment in the letrozole arm was continued until resistance developed. MCF7LR tumor-bearing mice were then randomized to Z-endoxifen (50 mg/kg) or tamoxifen for 4 weeks and tumors harvested for microarray and immunohistochemistry analysis. The antitumor activity of Z-endoxifen in the MCF7LR tumors was further compared in a second in vivo study with exemestane, exemestane plus everolimus, and fulvestrant. Results: In the MCF7AC1 tumors, both Z-endoxifen doses were significantly superior to control and tamoxifen in reducing tumor volumes at 4 weeks. Additionally, the 75 mg/kg Z-endoxifen dose was additionally superior to letrozole. Prolonged letrozole exposure resulted in resistance at 25 weeks. In MCF7LR tumor-bearing mice, Z-endoxifen significantly reduced tumor volumes compared to tamoxifen, letrozole, and exemestane, with no significant differences compared to exemestane plus everolimus and fulvestrant. Additionally, compared to tamoxifen, Z-endoxifen markedly inhibited ERα target genes, Ki67 and Akt expression in vivo. Conclusion: In endocrine-sensitive and letrozole-resistant breast tumors, Z-endoxifen results in robust antitumor and antiestrogenic activity compared to tamoxifen and aromatase inhibitor monotherapy. These data support the ongoing development of Z-endoxifen.
AB - Background: The tamoxifen metabolite, Z-endoxifen, demonstrated promising antitumor activity in endocrine-resistant estrogen receptor-positive (ER+) breast cancer. We compared the antitumor activity of Z-endoxifen with tamoxifen and letrozole in the letrozole-sensitive MCF7 aromatase expressing model (MCF7AC1), as well as with tamoxifen, fulvestrant, exemestane, and exemestane plus everolimus in a letrozole-resistant MCF7 model (MCF7LR). Methods: MCF7AC1 tumor-bearing mice were randomized to control (no drug), letrozole (10 μg/day), tamoxifen (500 μg/day), or Z-endoxifen (25 and 75 mg/kg). Treatment in the letrozole arm was continued until resistance developed. MCF7LR tumor-bearing mice were then randomized to Z-endoxifen (50 mg/kg) or tamoxifen for 4 weeks and tumors harvested for microarray and immunohistochemistry analysis. The antitumor activity of Z-endoxifen in the MCF7LR tumors was further compared in a second in vivo study with exemestane, exemestane plus everolimus, and fulvestrant. Results: In the MCF7AC1 tumors, both Z-endoxifen doses were significantly superior to control and tamoxifen in reducing tumor volumes at 4 weeks. Additionally, the 75 mg/kg Z-endoxifen dose was additionally superior to letrozole. Prolonged letrozole exposure resulted in resistance at 25 weeks. In MCF7LR tumor-bearing mice, Z-endoxifen significantly reduced tumor volumes compared to tamoxifen, letrozole, and exemestane, with no significant differences compared to exemestane plus everolimus and fulvestrant. Additionally, compared to tamoxifen, Z-endoxifen markedly inhibited ERα target genes, Ki67 and Akt expression in vivo. Conclusion: In endocrine-sensitive and letrozole-resistant breast tumors, Z-endoxifen results in robust antitumor and antiestrogenic activity compared to tamoxifen and aromatase inhibitor monotherapy. These data support the ongoing development of Z-endoxifen.
KW - AI-resistant and AI-sensitive ER+ breast cancer
KW - Estrogen-regulated genes
KW - Signaling kinase
KW - Tamoxifen
KW - Tumor growth in vivo
KW - Z-endoxifen
UR - http://www.scopus.com/inward/record.url?scp=85084961919&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85084961919&partnerID=8YFLogxK
U2 - 10.1186/s13058-020-01286-7
DO - 10.1186/s13058-020-01286-7
M3 - Article
C2 - 32430040
AN - SCOPUS:85084961919
SN - 1465-5411
VL - 22
JO - Breast Cancer Research
JF - Breast Cancer Research
IS - 1
M1 - 51
ER -