View The Document

Accession Number:

AD1135267

Title:

Development of New Agents for Treating Endocrine-Resistant Breast Cancer

Author(s):

Author Organization(s):

Report Date:

2021-01-01

Abstract:

Estrogen receptor alpha (ERa) is expressed in ~70% of all human breast cancers and, therefore, is a major therapeutic target for endocrinetherapy. The lack of response to anti-estrogens is a hallmark of resistance to endocrine therapies, yet the mechanisms are not completelyunderstood. One emerging mechanism is the development of mutations in ESR1, the gene encoding ERa. These mutant ERa proteinsconfer 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 ERalevels. We determined that Dip G functions via Hsp90 /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 ER mutant cell lines, with the levels of degradation of ERa, inhibition ofERa target genes and inhibition of cell proliferation all being concordant. Moreover, we have shown that Dip G can effectively inhibit thegrowth of human tumors in mice models without causing detectable tissue damages. Thus, Dip G may have minimum adverse side effectson normal tissues at the therapeutically effective doses. This application will test the hypothesis that Dip G alone or Dip G in combinationwith SERDs are effective to treat hormone-resistant breast cancers, including those harboring the ESR1 mutations.

Pages:

13

File Size:

1.26MB

Descriptors:

Identifiers:

SubjectCategory:

Distribution Statement:

Approved For Public Release

View The Document