Palazestrant (OP-1250), A Complete Estrogen Receptor Antagonist, Inhibits Wild-type and Mutant ER-positive Breast Cancer Models as Monotherapy and in Combination.

The estrogen receptor (ER) is a well-established target for the treatment of breast cancer, with the majority of patients presenting as ER-positive (ER+). Endocrine therapy is a mainstay of breast cancer treatment but the development of resistance mutations in response to aromatase inhibitors, poor pharmacokinetic properties of fulvestrant, agonist activity of tamoxifen, and limited benefit for elacestrant leave unmet needs for patients with or without resistance mutations in ESR1, the gene that encodes the ER protein. Here we describe palazestrant (OP-1250), a novel, orally bioavailable complete ER antagonist and selective ER degrader. OP-1250, like fulvestrant, has no agonist activity on the ER and completely blocks estrogen-induced transcriptional activity. In addition, OP-1250 demonstrates favorable biochemical binding affinity, ER degradation, and antiproliferative activity in ER+ breast cancer models that is comparable or superior to other agents of interest. OP-1250 has superior pharmacokinetic properties relative to fulvestrant, including oral bioavailability and brain penetrance, as well as superior performance in wild-type and ESR1-mutant breast cancer xenograft studies. OP-1250 combines well with cyclin-dependent kinase 4 and 6 inhibitors in xenograft studies of ER+ breast cancer models and effectively shrinks intracranially implanted tumors, resulting in prolonged animal survival. With demonstrated preclinical efficacy exceeding fulvestrant in wild-type models, elacestrant in ESR1-mutant models, and tamoxifen in intracranial xenografts, OP-1250 has the potential to benefit patients with ER+ breast cancer.

Estrogen receptor beta increases the efficacy of antiestrogens by effects on apoptosis and cell cycling in breast cancer cells.

Clinical evidence indicates that higher levels of estrogen receptor beta (ERbeta) predicts improved disease-free and overall survival in patients treated with adjuvant tamoxifen therapy. To better understand the mechanisms in which ERbeta can modulate breast cancer therapies, we introduced ERbeta under an inducible promoter into MCF-7 breast cancer cells. In these cells, induction of ERbeta expression led to a shift in the potency and an increase in the efficacy of tamoxifen to inhibit proliferation. A similar effect on breast cancer cells was observed for two other antiestrogens, raloxifene, and fulvestrant. Induced expression of ERbeta did not enhance the antiproliferative effects of small molecule inhibitors that target the epidermal growth factor receptor, insulin growth factor receptor-1 and histone deacetylase, indicating ERbeta specifically cooperates with antiestrogens. The combination of ERbeta expression, which arrests cells in G2, and tamoxifen, which arrests cells in G1, led to a potent blockade of the cell cycle. ERbeta also increased tamoxifen-induced cell death and cooperated with tamoxifen to induce expression of the pro-apoptotic gene bik. In summary, our data indicates that ERbeta increases the efficacy of antiestrogens by effects on apoptosis and on cell cycling and, together with clinical observations, suggests ERbeta could be a valuable prognostic marker and potential therapeutic target.

Inhibition of histone deacetylase enhances the anti-proliferative action of antiestrogens on breast cancer cells and blocks tamoxifen-induced proliferation of uterine cells.

Here we report a novel potential therapeutic strategy using histone deacetylase (HDAC) inhibitors to enhance the action of hormonal therapy agents in estrogen receptor alpha (ER alpha)-positive breast cancer. HDAC inhibitors [trichostatin A (TSA), suberoylanilide hydroxamic acid (SAHA) and valproic acid (VPA)], inhibited proliferation of MCF-7 breast cancer cells and, in combination with tamoxifen inhibited proliferation better than with either agent alone. VPA, an anti-convulsant drug with HDAC inhibitory activity, enhanced tamoxifen action at doses within the concentration range used for anti-convulsive therapy. VPA cooperated with tamoxifen in a variety of ER alpha-positive cell lines and was also effective when combined with other antiestrogens, and with aromatase inhibition. VPA enhanced antiestrogen action by promoting cell death via apoptosis without affecting cell cycling. Some of this action may be due to VPA's ability to induce the pro-apoptotic gene Bik, which is also induced by antiestrogens. Remarkably, VPA blocked the undesirable pro-proliferative action of tamoxifen on uterine endometrial cells. Our in vitro results suggest that VPA and other HDAC inhibitors have the potential to enhance hormonal therapy for ER alpha-positive breast cancer and simultaneously reverse the adverse effects of antiestrogens in the uterus.