The selective estrogen receptor downregulator GDC-0810 is efficacious in diverse models of ER+ breast cancer
James D Joseph1, Beatrice Darimont1, Wei Zhou2
1Department of Biology, Seragon Pharmaceuticals, San Diego, United States.
Abstract:
ER-targeted therapeutics provide valuable treatment options for patients with ER+ breast cancer, however, current relapse and mortality rates emphasize the need for improved therapeutic strategies. The recent discovery of prevalent ESR1 mutations in relapsed tumors underscores a sustained reliance of advanced tumors on ERα signaling, and provides a strong rationale for continued targeting of ERα. Here we describe GDC-0810, a novel, non-steroidal, orally bioavailable selective ER downregulator (SERD), which was identified by prospectively optimizing ERα degradation, antagonism and pharmacokinetic properties. GDC-0810 induces a distinct ERα conformation, relative to that induced by currently approved therapeutics, suggesting a unique mechanism of action. GDC-0810 has robust in vitro and in vivo activity against a variety of human breast cancer cell lines and patient derived xenografts, including a tamoxifen-resistant model and those that harbor ERα mutations. GDC-0810 is currently being evaluated in Phase II clinical studies in women with ER+ breast cancer.
Insights
A new drug, GDC-0810, shows promise for treating estrogen receptor-positive (ER+) breast cancer by effectively targeting ERα signaling, even in resistant tumors. This oral medication is currently in Phase II clinical trials.
Area of Science:
- Oncology
- Pharmacology
- Molecular Biology
Background:
- Estrogen receptor-positive (ER+) breast cancer remains a significant health concern, with high relapse and mortality rates necessitating improved treatments.
- The discovery of ESR1 mutations in relapsed tumors highlights the continued importance of targeting ERα signaling in advanced disease.
Purpose of the Study:
- To develop and characterize GDC-0810, a novel oral selective estrogen receptor downregulator (SERD).
- To evaluate the efficacy of GDC-0810 against various ER+ breast cancer models, including those with tamoxifen resistance and ESR1 mutations.
Main Methods:
- GDC-0810 was designed by optimizing ERα degradation, antagonism, and pharmacokinetic profiles.
- In vitro and in vivo studies were conducted using human breast cancer cell lines and patient-derived xenografts.
- The drug's mechanism of action was assessed by analyzing the ERα conformation it induces.
Main Results:
- GDC-0810 demonstrated robust anti-cancer activity in preclinical models.
- The compound showed efficacy against tamoxifen-resistant models and those harboring ESR1 mutations.
- GDC-0810 induces a unique ERα conformation, suggesting a distinct mechanism of action compared to existing therapies.
Conclusions:
- GDC-0810 represents a promising novel SERD for ER+ breast cancer treatment.
- Its unique mechanism and demonstrated efficacy in resistant models warrant further clinical investigation.
- Phase II clinical studies are ongoing to assess GDC-0810 in patients with ER+ breast cancer.
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