title: Reactivation of p53 by MDM2 Inhibitor MI-77301 for the Treatment of Endocrine-Resistant Breast Cancer.
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. ©2016 AACR.
authors.affiliation: Department of Internal Medicine, University of Michigan Comprehensive Cancer Center, University of Michigan, Ann Arbor, Michigan.
authors.forename: Jianfeng
authors.initials: J
authors.lastname: Lu
authors.affiliation: Department of Internal Medicine, University of Michigan Comprehensive Cancer Center, University of Michigan, Ann Arbor, Michigan.
authors.forename: Donna
authors.initials: D
authors.lastname: McEachern
authors.affiliation: Section of Breast Oncology, Division of Oncology, Department of Internal Medicine, Washington University in St. Louis, St. Louis, Missouri.
authors.forename: Shunqiang
authors.initials: S
authors.lastname: Li
authors.affiliation: Lester and Sue Smith Breast Center, Baylor College of Medicine, Houston, Texas.
authors.forename: Matthew J
authors.initials: MJ
authors.lastname: Ellis
authors.affiliation: Department of Internal Medicine, University of Michigan Comprehensive Cancer Center, University of Michigan, Ann Arbor, Michigan. shaomeng@umich.edu.|Department of Pharmacology, University of Michigan Comprehensive Cancer Center, University of Michigan, Ann Arbor, Michigan.|Department of Medicinal Chemistry, University of Michigan Comprehensive Cancer Center, University of Michigan, Ann Arbor, Michigan.
authors.forename: Shaomeng
authors.initials: S
authors.lastname: Wang
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D018931:Antineoplastic Agents, Hormonal / Q000494:pharmacology; D001943:Breast Neoplasms / Q000188:drug therapy / Q000235:genetics* / Q000378:metabolism* / Q000473:pathology; D059447:Cell Cycle Checkpoints / Q000187:drug effects; D045744:Cell Line, Tumor; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D019008:Drug Resistance, Neoplasm; D005260:Female; D006801:Humans; D007211:Indoles / Q000494:pharmacology*; D051736:Proto-Oncogene Proteins c-mdm2 / Q000037:antagonists & inhibitors*; D020845:Selective Estrogen Receptor Modulators / Q000494:pharmacology; D013141:Spiro Compounds / Q000494:pharmacology*; D015533:Transcriptional Activation / Q000187:drug effects*; D016159:Tumor Suppressor Protein p53 / Q000235:genetics* / Q000378:metabolism; D023041:Xenograft Model Antitumor Assays
chemical_list: D000970:Antineoplastic Agents; D018931:Antineoplastic Agents, Hormonal; D007211:Indoles; D020845:Selective Estrogen Receptor Modulators; D013141:Spiro Compounds; D016159:Tumor Suppressor Protein p53; C000593797:SAR405838; D051736:Proto-Oncogene Proteins c-mdm2