New Estrogen Receptor Downregulators for Breast Cancer
Creators: name: University Of California Office Of The President
Publisher: name: University of California Office of the President
publisherIdentifier: https://ror.org/00dmfq477
publisherIdentifierScheme: ROR
Year: 2024

description: At diagnosis of breast cancer, 70% of tumors express estrogen receptors (ER) and depend, in part, on estrogen (E2) to grow. Estrogens bind ERs that act, in turn, at the level of tumor cell DNA gene regulation to stimulate cell division and tumor progression. Although anti-estrogens (disrupt E2 binding to ER) and aromatase inhibitors (AI’s; block E2 production) improve the survival of patients with ER+ tumors, only about half of advanced breast cancers that express hormone receptors respond to endocrine therapy. Further, as treatment progresses, all tumors develop resistance to hormonal therapy, leading to treatment failure. It is urgent to find new ways to improve patient survival.
 
 
 
 
 
 
 
 We predict that a new class of endocrine agents may reverse tumor resistance. ER controls tumor growth by two different pathways: a) the “classical pathway” involves direct binding of E2-bound ER to tumor DNA; and b) an alternate “non-classical pathway” involves indirect control of tumor DNA by ER interaction with other signaling complexes in the tumor cell by protein-protein connections. For example, tumors that overexpress growth factor receptors (such as HER-2) are resistant to endocrine therapy because the growth factor receptors (even in the absence of estrogens) activate ER and stimulate non-classical signaling pathways. A search for better, Selective ER Modulators (termed SERMs) is ongoing, and a lead therapeutic, fulvestrant (marketed by AstraZeneca with the brand name Faslodex), elicits a unique loss (down-regulation) of tumor ER, thereby markedly blocking non-classical ER signals and tumor growth. Due to poor bioavailability of fulvestrant (requires intramuscular injections of high doses), new and improved agents are needed in the clinic. 
 
 
 
 
 
 
 
 Thus, we plan to design, synthesize and test a new class of SERM compounds designed to deplete tumor ER and stop cancer growth driven by non-classical ER pathways. This project is a collaborative, interactive effort of chemistry and oncology researchers. A new class of small organic compounds will be synthesized as SERMs designed to specifically bind ER, but include unique chemical groups to disrupt and destabilize ER, leading to ER loss in tumors and blockade of growth-promoting pathways. These candidate SERMs will then be screened in the laboratory using endocrine-sensitive and -resistant human breast tumor cells to discover agents that best block growth (driven by non-classical ER pathways) and increase tumor cell death. In preliminary work, we have identified a lead compound. After further assessment and refinement of this compound and related chemicals in the chemistry laboratory, a promising SERM will be selected and evaluated for anti-tumor activity using human breast tumor models growing in vivo (using immunodeficient mice). SERM activity will be tested in endocrine-sensitive cells and in endocrine-resistant cells that are HER2-positive (active in non-classical ER signaling). Potential synergy of a SERM with the HER2 inhibitor trastuzumab (Herceptin) will be tested as a dual treatment strategy.
 
 
 
 
 
 
 
 Our goal is to develop SERMs with the proper biologic/pharmacologic/anti-tumor profile to be ultimately used as therapeutics for ER-positive cancers in the clinic. Given the high incidence of endocrine resistance, the impact on breast cancer may be significant.