New Estrogen Receptor Downregulators for Breast Cancer

Institution: University of California, Los Angeles
Investigator(s): Richard Pietras, M.D., Ph.D. -
Award Cycle: 2010 (Cycle 16) Grant #: 16IB-0042 Award: $150,000
Award Type: IDEA
Research Priorities
Detection, Prognosis and Treatment>Innovative Treatment Modalities: search for a cure



Initial Award Abstract (2010)

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.




Final Report (2012)

Breast cancer is the most common cancer in women in the US. Of these cancers, 70% express estrogen receptors (ER) and depend, in part, on estrogen (E2) to grow. Estrogens bind ERs that act to stimulate cell division and tumor progression. Although anti-estrogens (disrupt E2 binding to ER) and aromatase inhibitors (AI’s; block E2 synthesis) improve survival of patients with ER-positive tumors, only half of advanced breast cancers that express ER respond to endocrine therapy. Further, as therapy progresses, all tumors develop resistance to hormonal therapy, leading to treatment failure. It is urgent to find new ways to improve survival.

We predict that a new class of endocrine agents may reverse tumor resistance. ER controls tumor growth by either the 'classical pathway' that involves direct binding of E2-bound ER to tumor DNA; or an alternate 'non-classical pathway' that involves indirect control of tumor DNA by ER interaction with other tumor signaling complexes by protein-protein connections. For example, tumors that overexpress growth factor receptors (such as HER-2-positive) are resistant to endocrine therapy because the growth factor receptors (even in the absence of E2) activate ER and stimulate non-classical signaling for growth. We expect that such non¬classical ER signaling, especially in endocrine-resistant tumors, is critical for tumor progression. Current endocrine therapies (tamoxifen, AI’s) effectively block classical ER pathways in tumors but also elicit detrimental effects in other tissues. A search for better, Selective ER Modulators (termed SERMs) is ongoing, and a lead therapeutic, fulvestrant, 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 injection of high doses), new and improved agents are needed in the clinic.

Over the past two years, we used the collaborative efforts of chemistry and oncology researchers to design, synthesize and test new classes of SERMs designed to deplete tumor ER and stop cancer growth driven by non-classical ER pathways. Candidate small organic compounds were designed to specifically bind and disrupt ER signaling, then screened in the laboratory using endocrine-sensitive and -resistant human tumor cells to find agents that best block growth and increase tumor cell death. In the discovery of 2 new SERMs that strongly block cancer growth and deplete tumor ER, we have successfully completed the primary aims of this project. These new agents were screened from more than 65 candidate compounds. We plan to carry this clinical- translational work forward to select the most promising SERM for antitumor activity using human breast tumor xenograft models growing in vivo in the coming months. Potential synergy of this SERM with the HER2 inhibitor trastuzumab and with the biguanide metformin, agents that may effectively synergize with SERM compounds, will be evaluated as a possible dual treatment strategy for ER-positive breast malignancies.

Publications:
Hijacking of Endocrine and Metabolic Regulation in Cancer and Diabetes
Biologic Roles of Estrogen Receptor-and Insulin-Like Growth Factor-2 in Triple-Negative Breast Cancer
Biologic Roles of Estrogen Receptor-beta and Insulin-Like Growth Factor-2 in Triple-Negative Breast Cancer



Biologic Roles of Estrogen Receptor-b and Insulin-Like Growth Factor-2 in Triple-Negative Breast Cancer doi:10.1155/2015/925703
Periodical:BioMed Research International
Index Medicus: BioMed Research International
Authors: Nalo Hamilton, Diana Márquez-Garbán, Vei Mah, Gowry Fernando, Yahya Elshimali, et al.
Yr: 2015 Vol: 2015 Nbr: 925703 Abs: Pg:15 pages