brilanestrant (GDC-0810)

This study systematically reveals that EDCs promote HCC initiation and progression by perturbing cell cycle, metabolic, and immune homeostasis through multi-target, multi-pathway mechanisms. The nine-gene risk model demonstrates superior performance in HCC diagnosis and prognosis and shows potential clinical translational value in drug-sensitivity prediction and pan-cancer analyses. This work provides a new perspective at the intersection of environmental toxicology and precision oncology and informs individualized therapeutic strategies.

Our investigations validate a DRLR-based risk scoring model as an effective prognostic tool for Asian HCC. This model not only enhances understanding of disulfidptosis's role in HCC but also facilitates personalised treatment strategies, potentially improving patient outcomes.

A signature was constructed on the basis of three DRLRs, providing novel insights for personalized precision therapy in R0 HCC patients.

M2 could be the first discrete diglucuronide that was formed from both acyl- and N-glucuronidation on a molecule identified in human plasma. Significance Statement A discrete diglucuronidation metabolite of GDC-0810, a breast cancer drug candidate, was characterized as a unique circulating metabolite in humans that was not observed in rats or little formed human in vitro system.

GDC-0810 was safe and tolerable with preliminary anti-tumor activity in heavily pretreated patients with ER + advanced/MBC, with/without ESR1 mutations, highlighting the potential for oral SERDs. Clinical Trial and registration date April 4, 2013. NCT01823835 .

P1a/1b; N=152; Terminated; Sponsor: Genentech, Inc.; Active, not recruiting --> Terminated; The Sponsor decided to halt the development of GDC-0810, but not due to any safety concerns.

P2, N=71, Terminated, Genentech, Inc. | Active, not recruiting --> Terminated; The Sponsor decided to halt the development of GDC-0810, but not due to any safety concerns.

P1a/1b, N=152, Active, not recruiting, Genentech, Inc. | Trial completion date: Mar 2019 --> Mar 2020 | Trial primary completion date: Mar 2019 --> Mar 2020

P2, N=71, Active, not recruiting, Genentech, Inc. | Trial completion date: Mar 2019 --> Mar 2020 | Trial primary completion date: Mar 2019 --> Mar 2020

GDC-0810-resistant clones were cross-resistant to other endocrine agents, including SERMs (tamoxifen) and SERDs (fulvestrant), consistent with general loss of dependency on ER. Surprisingly, the cells also lost sensitivity to palbociclib, the latter likely linked to their loss of one copy of the retinoblastoma (Rb) tumor suppressor gene...Our work provides novel insights into mechanisms and biomarkers of acquired resistant to estrogen therapies in ER+ breast cancer and reveals the acquisition of actionable dependencies that may potentially be exploited in resistant tumors. Furthermore, our studies provide rationale for testing specific chemotherapy regimens upon endocrine resistance accompanied by cell cycle and DNA repair checkpoint dysfunction in ER+ breast cancer.