Development of New Agents for Treating Endocrine-Resistant Breast Cancer
Abstract
Breast cancer is a hormone-dependent disease. Female hormone estrogen is known to promote initiation and progression via its binding to estrogen receptor alpha (ERalpha). Because ERalpha-positive breast cancer constitutes ~70% of all breast cancers, endocrine therapy is applied to all stages of the disease in both pre- and post-menopausal women. Tamoxifen (Tam), a compound blocking ERalpha activity, and aromatase inhibitors (AIs), drugs to block estrogen production, are mainstays of drug in the treatment of ERalpha-positive breast cancers. Although many patients benefit from Tam and AIs treatment, approximately 50% of responsive tumors eventually relapse due to the development of resistance. Recent studies reveal an important mechanism of resistance being drug-induced mutations in ERalpha. ERalpha mutations occur in 10%-20% of endocrine therapy-resistant disease and could reach up to 50% at the metastatic sites. These mutations make ERalpha to be constitutively active; thus, tumors become resistant to endocrine therapies. One proposed method to overcome this resistance is to use a different kind of drug to decrease ERalpha protein. However, the clinically available drug faslodex can only degrade ERalpha mutants at non-therapeutic doses. AZD9496 and GDC-0810, two newly developed, orally bioavailable selective estrogen receptor degraders (SERDs), are in clinical trials. However, both displayed mild estrogen activity in endometrial cells and increased uteri weight in rat models, raising the concern that the mixed agonist/antagonist activity may increase risk of endometrial cancer. The clinical trial for GDC-0810 has been suspended. Thus, there is a pressing need to identify a new class of ERalpha-targeting compound for the treatment of recurrent ERalpha-expressing breast cancer. We recently identified a natural plant product, Diptoindonesin G (Dip G), that significantly decreases ERalpha protein levels and inhibits ERalpha cancer-promoting activity in breast cancer cells. Dip G can be either naturally isolated from the stem bark of several tropical plant species or chemically synthesized. We found that ERalpha-positive breast cancer cells are more sensitive to Dip G than ERalpha-negative cells, and cytotoxicity is the lowest with non-tumorigenic mammary epithelial cells, indicating low cytotoxicity and side effects of Dip G in vivo. Moreover, we have shown that Dip G can effectively inhibit the growth of human tumors in mice models without causing detectable tissue damages. So Dip G may have minimum adverse side effects on normal tissues at the therapeutically effective doses. Importantly, Dip G acts via a mechanism distinct from all known endocrine-therapy agents. Dip G does not bind to the same site on ERalpha as other SERDs; rather, it glues ERalpha with Hsp90 and CHIP, two proteins that are crucial for controlling the stability of ERalpha. Thus, we predict that Dip G can degrade ERalpha mutants and may replace faslodex for treating women developing secondary mutations in ERalpha. Dr. Xu has filed a US patent for using Dip G and a derivative compound for treatment of ER-positive breast cancer. Thus, we hypothesize that Dip G alone or Dip G in combination with SERDs will be effective to treat hormone-resistant breast cancers, including those harboring the ERalpha mutations. Dr. Li’s lab has established various mouse models bearing human tumors harboring ER mutations as those found in the metastatic breast cancer patients. Dr. Xu has cultured human tumors in dishes that enable multiplex testing of drug combination that work the best for individual human tumors. These models meet the goal of personalized treatment and have been validated for testing drug response in individual patients. The two Principal Investigators will compare the anti-cancer efficacy of the Dip G alone, SERDs alone, or Dip G in combination with faslodex or other Food and Drug Administration (FDA)-approved drugs using aforementi
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Mar 10, 2021
- Source ID
- W81XWH2010022
Entities
People
- Wei Xu
Organizations
- United States Army
- University of Wisconsin–Madison