brilanestrant (GDC-0810) / Roche - LARVOL DELTA

Integrated multi-Omics and network toxicology elucidate the multi-target mechanisms of environmental hormones in driving hepatocellular carcinoma. (PubMed, Ecotoxicol Environ Saf) - "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."

Journal • Tumor mutational burden • Hepatocellular Cancer • Oncology • Solid Tumor • CCNB1 • CCNB2 • CD74 • TMB • TP53

Tuning Bottlebrush Polymer Architecture and Composition of Poly(acrylic acid) Improves GDC-0810 Drug Solubility Maintenance. (PubMed, Biomacromolecules) - "The ASDs containing 40 wt % GDC-0810 exhibited a linear performance trend, correlating improved performance to increased carboxylic acid content in bottlebrush polymers, indicating the importance of electrostatic repulsions with the weak acid API on dissolution efficacy. This work demonstrates the importance of architecture, placement, and amount of carboxylate groups in excipient performance."

Journal • Breast Cancer • Oncology • Solid Tumor

ATP6V0A4 as a novel prognostic biomarker and potential therapeutic target in oral squamous cell carcinoma. (PubMed, BMC Oral Health) - "ATP6V0A4 may serve as a novel prognostic biomarker and potential therapeutic target in oral squamous cell carcinoma."

Biomarker • IO biomarker • Journal • Oncology • Oral Cancer • Squamous Cell Carcinoma • ATP6V0A4

Based on disulfidptosis, unveiling the prognostic and immunological signatures of Asian hepatocellular carcinoma and identifying the potential therapeutic target ZNF337-AS1. (PubMed, Discov Oncol) - "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."

Journal • Tumor mutational burden • Hepatocellular Cancer • Immune Modulation • Immunology • Oncology • Solid Tumor • TMB

Integrated multi-omics analysis and machine learning refine molecular subtypes and clinical outcome for hepatocellular carcinoma. (PubMed, Hereditas) - "Encouragingly, we observed that the high-CMLBS patients may exhibit increased sensitivity to Alpelisib, AZD7762, BMS-536,924, Carmustine, and GDC0810, whereas they may demonstrate reduced sensitivity to Axitinib, AZD6482, AZD8055, Entospletinib, GSK269962A, GSK1904529A, and GSK2606414, suggesting that CMLBS may contribute to the selection of chemotherapeutic agents for HCC patients. Therefore, in-depth examination of data from multi-omics data can provide valuable insights and contribute to the refinement of the molecular classification of HCC. In addition, the CMLBS model demonstrates potential as a screening tool for identifying HCC patients who may derive benefit from immunotherapy, and it possesses practical utility in the clinical management of HCC."

Clinical data • Journal • Hepatocellular Cancer • Oncology • Solid Tumor

Overexpression pattern, function, and clinical value of proteasome 26S subunit non-ATPase 6 in hepatocellular carcinoma. (PubMed, World J Clin Oncol) - "This study was the first to discover that PSMD6 was overexpressed in HCC tissues. PSMD6 is essential for the growth of HCC cells and may be involved in ribosome biogenesis and RNA splicing."

Journal • Hepatocellular Cancer • Oncology • Solid Tumor

Construction of a prognostic model for disulfidptosis-related long noncoding RNAs in R0 resected hepatocellular carcinoma and analysis of their impact on malignant behavior. (PubMed, BMC Cancer) - "A signature was constructed on the basis of three DRLRs, providing novel insights for personalized precision therapy in R0 HCC patients."

Biomarker • Journal • Tumor mutational burden • Gastrointestinal Cancer • Hepatocellular Cancer • Oncology • Solid Tumor • CD4 • TMB • TMCC1 • TMCC1-DT

Bottlebrush polymers improve binding, solubility, and delivery of small and macromolecular therapeutics (ACS-Fall 2024) - "This is likely due to strong polymer−drug noncovalent interactions and compaction of GDC-0810 along the PVPVA bottlebrush backbone. Overall, it was observed that the most effective formulations had a hydrodynamic radius less than 25 nm with tightly compacted nanodroplet morphologies."

Breast Cancer • Oncology • Solid Tumor

Unlocking the future of hepatocellular carcinoma treatment: A comprehensive analysis of disulfidptosis-related lncRNAs for prognosis and drug screening. (PubMed, Open Med (Wars)) - "We also discovered differences in the response to immune targets and anticancer drugs between the two groups of patients, with GDC0810, Osimertinib, Paclitaxel, and YK-4-279 being more effective for patients in the high-risk group. In conclusion, we have developed a risk model that can guide future efforts to diagnose and treat HCC."

Journal • Gastrointestinal Cancer • Hepatocellular Cancer • Oncology • Solid Tumor

Drug-Polymer Nanodroplet Formation and Morphology Drive Solubility Enhancement of GDC-0810. (PubMed, Bioconjug Chem) - "This is likely due to strong polymer-drug noncovalent interactions and the compaction of GDC-0810 along the PVPVA bottlebrush backbone. Overall, it was observed that the most effective formulations had a hydrodynamic radius less than 25 nm with tightly compacted nanodroplet morphologies."

Journal • Breast Cancer • Oncology • Solid Tumor

Utilizing Molecular Simulations to Examine Nanosuspension Stability. (PubMed, Pharmaceutics) - "To test these ideas prospectively, we applied our model to an uncharacterized drug compound, GDC-0810...To avoid computationally expensive simulations in the future, we extended our model by showing that simple, two-dimensional properties of single drug molecules can be used to rationalize nanosuspension designs without simulations. In all, our work demonstrates how computational tools can provide molecular insight into drug-excipient interactions and aid in rational formulation design."

Journal

Identification of a Discrete Diglucuronide of GDC-0810 in Human Plasma after Oral Administration. (PubMed, Drug Metab Dispos) - "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."

Journal • Breast Cancer • Oncology • Solid Tumor • UGT1A4 • UGT1A8

Development of an assay pipeline for the discovery of novel small molecule inhibitors of human glutathione peroxidases GPX1 and GPX4. (PubMed, Redox Biol) - "Additionally, every GPX1 inhibitor identified (including omapatrilat, tenatoprazole, cefoxitin and ceftibuten) showed similar inhibitory activity against GPX2...Compounds only inhibiting GPX4 included pranlukast sodium hydrate, lusutrombopag, brilanestrant, simeprevir, grazoprevir (MK-5172), paritaprevir, navitoclax, venetoclax and VU0661013. Two compounds (metamizole sodium and isoniazid sodium methanesulfate) inhibited all three GPXs but not TXNRD1, while 2,3-dimercaptopropanesulfonate, PI4KIII beta inhibitor 3, SCE-2174 and cefotetan sodium inhibited all tested selenoproteins (but not GR)...With this approach, we could indeed identify novel GPX1/GPX2- or GPX4-specific inhibitors, thus presenting a validated pipeline for future identification of specific selenoprotein-targeting agents. Our study also identified GPX1/GPX2, GPX4 and/or TXNRD1 as targets for several previously developed pharmacologically active compounds."

Journal • Oncology • GPX1 • GPX2 • GPX4

Glycochenodeoxycholate and glycodeoxycholate 3-O-glucuronides, but not hexadecanedioate and tetradecanedioate, detected weak inhibition of OATP1B caused by GDC-0810 in humans. (PubMed, Br J Clin Pharmacol) - "Endogenous biomarkers of drug transporters are promising tools to evaluate in vivo transporter function and potential alterations in the pharmacokinetics of their substrates. Among bile acids and their conjugates, glycochenodeoxycholate and glycodeoxycholate 3-O-glucuronides (GCDCA-3G and GDCA-3G) showed increases with Cmax geometric mean ratio (95% CI) of 1.58 (1.13-2.22) and 1.49 (1.21-1.83), consistent with previous reports from low dose rifampin co-administration and pharmacogenetic studies. These results suggest that GCDCA-3G and GDCA-3G are two more promising biomarkers that may capture weak OATP1B inhibition in addition to coproporphyrin I/III."

Journal

The oral selective estrogen receptor degrader GDC-0810 (ARN-810) in postmenopausal women with hormone receptor-positive HER2-negative (HR + /HER2 -) advanced/metastatic breast cancer. (PubMed, Breast Cancer Res Treat) - P1a/1b | "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 ."

Journal • Breast Cancer • Constipation • Fatigue • Gastroenterology • Gastrointestinal Disorder • HER2 Breast Cancer • HER2 Negative Breast Cancer • Hormone Receptor Breast Cancer • Hormone Receptor Positive Breast Cancer • Oncology • Solid Tumor • ER • HER-2

Assessing the Interrelationship of Microstructure, Properties, Drug Release Performance, and Preparation Process for Amorphous Solid Dispersions Via Noninvasive Imaging Analytics and Material Characterization. (PubMed, Pharm Res) - "Strong interrelationship of microstructure, physical properties, and dissolution performance was observed for GDC-0810 ASDs. XRM image-based analysis is a powerful tool to assess the contribution of microstructure to the characteristics of ASDs and provide mechanistic understanding of the interrelationship."

Journal

End-Group Modified Bottlebrush Copolymers to Deliver Active Pharmaceutical Ingredients (ACS-Sp 2022) - "Therefore, we thoroughly characterized the phenotype of amorphous nanostructures formed in solution during ASD dissolution between an orally administered breast cancer therapeutic, GDC-0810, and a library of commercial linear polymer and end-group modified bottlebrush copolymer excipients. The resulting insight was then used to interpret the differences in bioavailability observed through in vivo pharmacokinetic studies and in vitro permeation assays as a function of nanostructure formation."

Breast Cancer • CNS Disorders • Epilepsy • Oncology • Solid Tumor

Biomarker-informed model-based risk assessment of organic anion transporting polypeptide 1B mediated drug-drug interactions. (PubMed, Clin Pharmacol Ther) - "For several inhibitors (cyclosporine, diltiazem, fenebrutinib, GDC-0810, itraconazole, probenecid, and rifampicin at 3 different doses), PBPK models were developed and verified against available CP-I plasma exposure data to obtain in vivo OATP1B inhibition potency-which tend to be lower than the experimentally measured in vitro IC by about 2-fold (probenecid, rifampicin) to 37-fold (GDC-0810). Models verified with CP-I data are subsequently used to predict DDIs with OATP1B probe drugs, rosuvastatin and pitavastatin. The predicted and observed area under the plasma concentration-time curve ratios are within 20% error in 55% cases, and within 30% error in 89% cases. Collectively, this comprehensive study illustrates the adequacy and utility of endogenous biomarker-informed PBPK modeling in mechanistic understanding and quantitative predictions of OATP1B-mediated DDIs in drug development."

Biomarker • Journal

[VIRTUAL] Targeting ESR1 in breast cancer treatment: Repurposing of statins (ESMO 2021) - "A systematic in silico study was carried out to find out some potential statin drug candidates that may be used in breast cancer treatment. Molecular docking of statins and the reference drug (brilanestrant) with ESR1, superimposition of selected drugs with ESR1-reference, comparison of interactions of reference and candidate drugs with the protein (ESR1) and pharmacokinetic properties of the chosen drugs were evaluated to come up with the most promising statin drug candidate for breast cancer treatment...Among them, pitavastatin, rosuvastatin and simvastatin had four common amino acids with the ESR1-reference interactions... The study indicates that the drugs, simvastatin, lovastatin and mevastatin could be effective drugs in breast cancer treatment. However, further studies including in vitro and in vivo tests will be required to investigate their safety, efficacy and dosing profiles."

Breast Cancer • Hormone Receptor Breast Cancer • Lung Cancer • Oncology • Solid Tumor • ER

GDC-9545: A novel ER antagonist and clinical candidate that combines desirable mechanistic and pre-clinical DMPK attributes (SABCS 2018) - P1a/1b; "However, we find that therapeutic candidates that have recently emerged from prospective optimization of ER degradation, including GDC-0810 and GDC-0927, are not mechanistically equivalent. The highly potent in vivo efficacy of GDC-9545 likely arises due to the particular combination of high binding potency, full suppression of ER signaling, and an improved DMPK profile when compared to GDC-0927 and fulvestrant. GDC-9545 is currently being evaluated in Phase 1 clinical trials (ClinicalTrials.gov Identifier: NCT03332797). "

Breast Cancer • Hormone Receptor Breast Cancer • Oncology • Solid Tumor

[VIRTUAL] Bottlebrush polymer excipients to improve the solubility and delivery of an orally administered breast cancer therapeutic (ACS-Fall 2021) - "In this talk, we will elucidate the performance of bottlebrush polymer excipients compared to common linear polymer excipients (hydroxypropyl methylcellulose acetate succinate, polyvinylpyrrolidone vinyl acetate, and linear PND) with an orally administered selective estrogen receptor degrader, GDC-0810, with proven efficacy against tamoxifen resistant, estrogen receptor positive breast cancers. Beyond solubility enhancement, by synthetically controlling the surface functionality of unimolecular drug-loaded micelle-like nanoparticles, we investigated how mucoadhesive versus non-mucoadhesive end-groups affected the delivery of GDC-0810 with in vivo studies. A thorough understanding of excipient-drug interactions in vitro and in vivo will be key to optimize the sequestration, solubilization, and delivery of future impactful active payloads."

Breast Cancer • Estrogen Receptor Positive Breast Cancer • Hormone Receptor Breast Cancer • Hormone Receptor Positive Breast Cancer • Oncology • Solid Tumor • ER

Pharmacologic and PK/PD study of D-0502: An orally bioavailable SERD with potent antitumor activity in ER-positive breast cancer cell lines and xenograft models (AACR 2018) - "...Endocrine therapy such as selective estrogen receptor degrader (SERD) fulvestrant has been used effectively to extend the life of ER+ breast cancer patients, either alone or in combination with CDK4/6 inhibitor (palbociclib or abemaciclib)...In addition, patients relapsed after prolonged endocrine therapy with aromatase inhibitors such as letrozole and anastrozole due to emergence of ER mutations...Comparison of various SERD molecules showed our candidate has more potent antitumor activity in MCF-7 xenograft model than GDC-0810, AZD9496 and fulvestrant. More importantly, drug metabolism and pharmacokinetic (PK) studies both in vitro and in vivo demonstrated that our SERD molecule D-0502 exhibits superior PK profiles suitable for clinical development."

Preclinical • Hormone Receptor Breast Cancer

Endocrine resistance in metastatic breast cancer: Mechanisms and new therapeutic strategies (AACR 2018) - "...Most of the ESR1 mutations confer constitutive ligand-independent ER activity, causing resistance to estrogen deprivation (i.e., aromatase inhibitors) and reduced sensitivity to the selective ER modulator (SERM) tamoxifen and the selective ER downregulator (SERD) fulvestrant...While the therapeutic value of newly developed orally bioavailable SERMs/SERDs such as GDC-0810 and GDC-0927 for patients with tumors harboring ESR1 mutations is yet to be clinically proven, we anticipate that ongoing studies will address this open question. Additionally, the recent clinically potent CDK4/6 inhibitor palbociclib, in combination with fulvestrant, has shown promising therapeutic efficacy against tumors harboring ESR1 mutations...In addition, a more complete suppression of the levels and activity of ER, its co-activators, and alternative survival pathways may prove to be a better therapeutic strategy in effectively combating endocrine resistance. Effective therapeutic strategies may...&quo

HER2 Breast Cancer • Hormone Receptor Breast Cancer • Renal Cell Carcinoma

Not all SERDs are equal: Context-independent ER degradation and full ER antagonism define the next generation of ER therapeutics (AACR 2018) - "...Though the clinical activity of fulvestrant is believed to be limited by its poor drug-like properties, a recent study demonstrated superiority of fulvestrant over the aromatase inhibitor, anastrozole...GDC-0927 is in Phase I clinical studies, and like GDC-0810 and AZD9496 was optimized for ER degradation in MCF7 cells...Specifically, FRAP (fluorescence recovery after photobleaching) demonstrated that while partial agonists 4OH-tamoxifen and GNE-274 maintain high mobility of ER, the full antagonists fulvestrant and GDC-0927 profoundly decrease ER mobility, suggesting that the immobilization of ER is likely a general property of full antagonists...The observation that full ER antagonism invariably associates with ER degradation could be interpreted as degradation driving full antagonism. However, we have discovered that full antagonists can be distinguished from partial agonists prior to the loss of ER protein, suggesting that ER degradation may

IO Biomarker • Hormone Receptor Breast Cancer

Discovery and evolution of orally bioavailable selective estrogen receptor degraders for ER+ breast cancer: From GDC-0810 to GDC-0927 (AACR 2018) - "Endocrine resistant tumors often remain dependent on ER for growth and survival, as evidenced by their sensitivity to the selective estrogen receptor degrader (SERD), fulvestrant. Co-crystal structures of both GDC-0810 and GDC-0927 with ER will be shared. Subsequent optimization of GDC-0927 resulting in improved pharmacokinetic properties will also be highlighted."

Hormone Receptor Breast Cancer