Development of New Agents for Treating Endocrine-Resistant Breast Cancer
Abstract
Estrogen receptor alpha (ERa) is expressed in ~70% of all human breast cancers and, therefore, is a major therapeutic target for endocrine therapy. The lack of response to anti-estrogens is a hallmark of resistance to endocrine therapies, yet the mechanisms are not completely understood. One emerging mechanism is the development of mutations in ESR1, the gene encoding ERa. These mutant ERa proteins confer significantly higher ERa activity than the wild-type receptor and are resistant to degradation by selective estrogen receptor degraders (SERDs) such as faslodex. Our laboratory discovered a natural plant product, Diptoindonesin G (Dip G), that significantly decreases ERa levels. We determined that Dip G functions via Hsp90a /CHIP, yet the mechanism is different from that of the Hsp90a ATPase inhibitor 17-AAG. Dip G is more effective than faslodex in inhibiting growth of ERa mutant cell lines, with the levels of degradation of ERa, inhibition of ERa target genes and inhibition of cell proliferation all being concordant. Moreover, we have shown that Dip G can effectively inhibit the growth of human tumors in mice models without causing detectable tissue damages. Thus, Dip G may have minimum adverse side effects on normal tissues at the therapeutically effective doses. This application will test the hypothesis that Dip G alone or Dip G in combination with SERDs are effective to treat hormone-resistant breast cancers, including those harboring the ESR1 mutations.
Document Details
- Document Type
- Technical Report
- Publication Date
- Jan 01, 2021
- Accession Number
- AD1135309
Entities
People
- Wei Xu
Organizations
- University of Wisconsin–Madison