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Mol Cancer Ther. 2016 Dec;15(12):2887-2893. Epub 2016 Oct 7.

Reactivation of p53 by MDM2 Inhibitor MI-77301 for the Treatment of Endocrine-Resistant Breast Cancer.

Author information

1
Department of Internal Medicine, University of Michigan Comprehensive Cancer Center, University of Michigan, Ann Arbor, Michigan.
2
Section of Breast Oncology, Division of Oncology, Department of Internal Medicine, Washington University in St. Louis, St. Louis, Missouri.
3
Lester and Sue Smith Breast Center, Baylor College of Medicine, Houston, Texas.
4
Department of Internal Medicine, University of Michigan Comprehensive Cancer Center, University of Michigan, Ann Arbor, Michigan. shaomeng@umich.edu.
5
Department of Pharmacology, University of Michigan Comprehensive Cancer Center, University of Michigan, Ann Arbor, Michigan.
6
Department of Medicinal Chemistry, University of Michigan Comprehensive Cancer Center, University of Michigan, Ann Arbor, Michigan.

Abstract

Endocrine therapy has been highly effective for the treatment of estrogen receptor-positive breast cancer, but endocrine resistance develops in a significant proportion of patients. In an effort to develop novel therapeutic strategies for the treatment of endocrine-resistant breast cancer, we have evaluated a potent and specific MDM2-p53 interaction inhibitor, MI-77301, which has been advanced into clinical development, for its therapeutic potential and mechanism of action in vitro and in vivo in WHIM9 and WHIM18 patient-derived xenograft (PDX) models. Both WHIM9 and WHIM18 PDX models exhibit estradiol-independent tumor growth and are resistant to fulvestrant, a highly effective and selective estrogen receptor degrader (SERD). MI-77301 activates wild-type p53 in WHIM9 and WHIM18 cells in vitro and in xenograft tumor tissues in vivo, and it effectively induces upregulation of p21 and cell-cycle arrest in vitro in both models. Although fulvestrant fails to inhibit tumor growth in either of the xenograft models, MI-77301 is highly effective in inhibition of tumor growth at a well-tolerated dose schedule. This study provides a preclinical rationale for evaluation of MI-77301 or other MDM2 inhibitors as a new therapeutic strategy for the treatment of endocrine-resistant breast cancer retaining wild-type p53. Mol Cancer Ther; 15(12); 2887-93.

PMID:
27765850
PMCID:
PMC5367629
DOI:
10.1158/1535-7163.MCT-16-0028
[Indexed for MEDLINE]
Free PMC Article

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