sar405838 and Breast-Neoplasms

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.

Topics: Animals; Antineoplastic Agents; Antineoplastic Agents, Hormonal; Breast Neoplasms; Cell Cycle Checkpoints; Cell Line, Tumor; Disease Models, Animal; Dose-Response Relationship, Drug; Drug Resistance, Neoplasm; Female; Humans; Indoles; Proto-Oncogene Proteins c-mdm2; Selective Estrogen Receptor Modulators; Spiro Compounds; Transcriptional Activation; Tumor Suppressor Protein p53; Xenograft Model Antitumor Assays