Estrogen receptor coregulator binding modulators (ERXs) effectively target estrogen receptor positive human breast cancers
Abstract
The majority of human breast cancer is estrogen receptor alpha (ER) positive. While anti-estrogens/aromatase inhibitors are initially effective, resistance to these drugs commonly develops. Therapy-resistant tumors often retain ER signaling, via interaction with critical oncogenic coregulator proteins. To address these mechanisms of resistance, we have developed a novel ER coregulator binding modulator, ERX-11. ERX-11 interacts directly with ER and blocks the interaction between a subset of coregulators with both native and mutant forms of ER. ERX-11 effectively blocks ER-mediated oncogenic signaling and has potent anti-proliferative activity against therapy-sensitive and therapy-resistant human breast cancer cells. ERX-11 is orally bioavailable, with no overt signs of toxicity and potent activity in both murine xenograft and patient-derived breast tumor explant models. This first-in-class agent, with its novel mechanism of action of disrupting critical protein-protein interactions, overcomes the limitations of current therapies and may be clinically translatable for patients with therapy-sensitive and therapy-resistant breast cancers.
Document Details
- Document Type
- Pub Defense Publication
- Publication Date
- Aug 08, 2017
- Source ID
- 10.7554/elife.26857
Entities
People
- Bikash Manandhar
- Chien-cheng Chen
- Douglas W. Strand
- Ganesh V Raj
- Gangadhara Reddy Sareddy
- Jung-Mo Ahn
- Monica Mann
- Rajeshwar Rao Tekmal
- Ratna K Vadlamudi
- Rui Li
- Samaya Rajeshwari Krishnan
- Shihong Ma
- Shino Murakami
- Suryavathi Viswanadhapalli
- Tae-kyung Lee
- Vijay K Gonugunta
- Wan-ru Lee
- Xihui Liu
Organizations
- Cancer Prevention and Research Institute of Texas
- Congressionally Directed Medical Research Programs
- National Institutes of Health
- Robert A. Welch Foundation
- University of Texas Health Science Center at San Antonio
- University of Texas Southwestern Medical Center
- University of Texas at Austin
- University of Texas at Dallas