TY - JOUR
T1 - Targeted Maytansinoid Conjugate Improves Therapeutic Index for Metastatic Breast Cancer Cells
AU - Jiang, Zhengyang
AU - Yang, Zhen
AU - Li, Feng
AU - Li, Zheng
AU - Fishkin, Nathan
AU - Burgess, Kevin
N1 - Funding Information:
Financial support for this project was provided by the National Science Foundation (M1603497), The Robert A. Welch Foundation (A-1121), DoD BCRP Breakthrough Award (BC141561), CPRIT (RP150559 and RP170144), and George and Angelina Kostas Fund at Houston Methodist Research Institute. NMR instrumentation at Texas A&M University was supported by a grant from the National Science Foundation (DBI-9970232) and the Texas A&M University System. DM4 was supplied by ImmunoGen (Waltham, MA).
Publisher Copyright:
© 2018 American Chemical Society.
PY - 2018/9/19
Y1 - 2018/9/19
N2 - This study was undertaken to target cell surface receptors other than the ones typically associated with breast cancer {estrogen receptor (ER), progesterone receptor (PR), and human epidermal growth factor receptor 2 (HER2)}. It was also launched to use small molecules other than those most widely used for active targeting in general (e.g. folate and carbonic anhydrase IX ligands). Specifically, the focus of this study was on unique small molecules that bind the TrkC receptor, which is overexpressed in metastatic breast cancer. A conjugate (1) of a TrkC-targeting small molecule and the highly cytotoxic warhead, DM4 (a maytansinoid), was prepared. Cellular studies featuring TrkC+ and TrkC- human breast cells indicated this conjugate might have a better therapeutic effect than DM4 alone. It emerged that the conjugate 1 was very efficacious in vivo, completely ablating orthotopic 4T1 breast tumor in one case and dramatically reducing the tumor size in four other mice. Throughout, no significant weight loss or obvious neurotoxic effects were observed in the animals tested.
AB - This study was undertaken to target cell surface receptors other than the ones typically associated with breast cancer {estrogen receptor (ER), progesterone receptor (PR), and human epidermal growth factor receptor 2 (HER2)}. It was also launched to use small molecules other than those most widely used for active targeting in general (e.g. folate and carbonic anhydrase IX ligands). Specifically, the focus of this study was on unique small molecules that bind the TrkC receptor, which is overexpressed in metastatic breast cancer. A conjugate (1) of a TrkC-targeting small molecule and the highly cytotoxic warhead, DM4 (a maytansinoid), was prepared. Cellular studies featuring TrkC+ and TrkC- human breast cells indicated this conjugate might have a better therapeutic effect than DM4 alone. It emerged that the conjugate 1 was very efficacious in vivo, completely ablating orthotopic 4T1 breast tumor in one case and dramatically reducing the tumor size in four other mice. Throughout, no significant weight loss or obvious neurotoxic effects were observed in the animals tested.
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U2 - 10.1021/acs.bioconjchem.8b00340
DO - 10.1021/acs.bioconjchem.8b00340
M3 - Article
C2 - 30102524
AN - SCOPUS:85053708101
SN - 1043-1802
VL - 29
SP - 2920
EP - 2926
JO - Bioconjugate chemistry
JF - Bioconjugate chemistry
IS - 9
ER -