New drug targets ER+ cells

An experimental drug called BHPI is especially effective in targeting ER+ cells that are resistant to Tamoxifen and other anti-cancer drugs. It's still in early phases of research, but has shown promise in the University of Illinois at Urbana-Champaign lab, found here.

News about this can be read here, here, and here.

Estrogen receptor α inhibitor activates the unfolded protein response, blocks protein synthesis, and induces tumor regression.
Authors: Neal Andruska , Xiaobin Zheng, X. Yang, Chengjian Mao, Mathew M. Cherian, Lily Mahapatra, William J. Helferich and David J.Shapiro.
2015 March 30

Significance: Late-stage estrogen receptor α (ERα)-positive breast and ovarian cancers exhibit many regulatory alterations and therefore resist therapy. Our novel ERα inhibitor, BHPI, stops growth and often kills drug-resistant ERα+ cancer cells and induces rapid and substantial tumor regression in a mouse model of human breast cancer. BHPI distorts a normally protective estrogen–ERα-mediated activation of the unfolded protein response (UPR) and elicits sustained UPR activation. The UPR cannot be deactivated because BHPI, acting at a second site, inhibits production of proteins that normally help turn it off. This persistent activation converts the UPR from protective to lethal. Targeting therapy-resistant ERα- positive cancer cells by converting the UPR from cytoprotective to cytotoxic may hold significant therapeutic promise.

Abstract: Recurrent estrogen receptor α (ERα)-positive breast and ovarian cancers are often therapy resistant. Using screening and functional validation, we identified BHPI, a potent noncompetitive small molecule ERα biomodulator that selectively blocks proliferation of drug-resistant ERα-positive breast and ovarian cancer cells. In a mouse xenograft model of breast cancer, BHPI induced rapid and substantial tumor regression. Whereas BHPI potently inhibits nuclear estrogen-ERα-regulated gene expression, BHPI is effective because it elicits sustained ERα-dependent activation of the endoplasmic reticulum (EnR) stress sensor, the unfolded protein response (UPR), and persistent inhibition of protein synthesis. BHPI distorts a newly described action of estrogen-ERα: mild and transient UPR activation. In contrast, BHPI elicits massive and sustained UPR activation, converting the UPR from protective to toxic. In ERα+ cancer cells, BHPI rapidly hyperactivates plasma membrane PLCγ, generating inositol 1,4,5-triphosphate (IP3), which opens EnR IP3R calcium channels, rapidly depleting EnR Ca2+ stores. This leads to activation of all three arms of the UPR. Activation of the PERK arm stimulates phosphorylation of eukaryotic initiation factor 2α (eIF2α), resulting in rapid inhibition of protein synthesis. The cell attempts to restore EnR Ca2+ levels, but the open EnR IP3R calcium channel leads to an ATP-depleting futile cycle, resulting in activation of the energy sensor AMP-activated protein kinase and phosphorylation of eukaryotic elongation factor 2 (eEF2). eEF2 phosphorylation inhibits protein synthesis at a second site. BHPI's novel mode of action, high potency, and effectiveness in therapy-resistant tumor cells make it an exceptional candidate for further mechanistic and therapeutic exploration.

Inquiries can be made to: Diana Yates, Public Affairs / Life Sciences Editor at UIUC
Email: diya AT illinois DOT edu