acolbifene / Endoceutics - LARVOL DELTA

Different expression of CDK4 and CDK6 among B-cell non-Hodgkin lymphomas as a marker of sensitivity to CDK4/6 inhibitors (EORTC-NCI-AACR 2024) - "Inhibition of CDK4 and CDK6 kinases has radically changed the clinical perception of the treatment of advanced hormone receptor-positive breast cancer with four FDA-approved CDK4/6 inhibitors, palbociclib, ribociclib and abemaciclib. The obtained results demonstrated that low CDK6 expression may predict sensitivity to ribociclib and thus may serve as a useful biomarker to stratify patient response to CDK4/6i therapy. Additionally, retinoblastoma protein deficiency was confirmed as the next determinant of intrinsic resistance to CDK4/6 inhibition. In addition, for those types of lymphomas with poor outcomes with CDK4/6i treatment, we proposed novel treatment settings represented by combined therapy with PI3K inhibitors such as idelalisib and alpelisib, or with ERβ modulators, tamoxifen and acolbifene, providing promising results for the future improvement in lymphoma therapy.The study was supported by The National Institute for Cancer Research (EXCELES,LX22NPO5102)."

Breast Cancer • Burkitt Lymphoma • Diffuse Large B Cell Lymphoma • Eye Cancer • Hematological Malignancies • Hormone Receptor Breast Cancer • Hormone Receptor Positive Breast Cancer • Lymphoma • Mantle Cell Lymphoma • Non-Hodgkin’s Lymphoma • Oncology • Solid Tumor

Acolbifene Versus Low Dose Tamoxifen for the Prevention of Breast Cancer in Premenopausal Women at High Risk for Development of Breast Cancer (clinicaltrials.gov) - P2 | N=80 | Recruiting | Sponsor: National Cancer Institute (NCI) | Not yet recruiting ➔ Recruiting | Trial primary completion date: Sep 2026 ➔ Aug 2027

Enrollment open • Trial primary completion date • Breast Cancer • Oncology • Ovarian Cancer • Solid Tumor • AGR2 • ATM • BARD1 • BRIP1 • CDH1 • CHEK2 • MSH6 • NBN • NF1 • PTEN • RAD51C • RAD51D • TP53

Acolbifene Versus Low Dose Tamoxifen for the Prevention of Breast Cancer in Premenopausal Women at High Risk for Development of Breast Cancer (clinicaltrials.gov) - P2 | N=80 | Not yet recruiting | Sponsor: National Cancer Institute (NCI) | Phase classification: P2a ➔ P2 | Initiation date: Mar 2024 ➔ Oct 2024

Phase classification • Trial initiation date • Breast Cancer • Oncology • Ovarian Cancer • Solid Tumor • AGR2 • ATM • BARD1 • BRIP1 • CDH1 • CHEK2 • MSH6 • NBN • NF1 • PTEN • RAD51C • RAD51D • TP53

Acolbifene Versus Low Dose Tamoxifen for the Prevention of Breast Cancer in Premenopausal Women at High Risk for Development of Breast Cancer (clinicaltrials.gov) - P2a | N=80 | Not yet recruiting | Sponsor: National Cancer Institute (NCI) | Trial completion date: May 2026 ➔ Sep 2028 | Initiation date: Oct 2023 ➔ Mar 2024 | Trial primary completion date: May 2026 ➔ Sep 2026

Trial completion date • Trial initiation date • Trial primary completion date • Breast Cancer • Oncology • Ovarian Cancer • Solid Tumor • AGR2 • ATM • BARD1 • BRIP1 • CDH1 • CHEK2 • ER • MSH6 • NBN • NF1 • PGR • PTEN • RAD51C • RAD51D • TFF1 • TP53

Acolbifene Versus Low Dose Tamoxifen for the Prevention of Breast Cancer in Premenopausal Women at High Risk for Development of Breast Cancer (clinicaltrials.gov) - P2a | N=80 | Not yet recruiting | Sponsor: National Cancer Institute (NCI)

New P2a trial • Breast Cancer • Oncology • Ovarian Cancer • Solid Tumor • AGR2 • ATM • BARD1 • BRIP1 • CDH1 • CHEK2 • ER • MSH6 • NBN • NF1 • PGR • PTEN • RAD51C • RAD51D • TFF1 • TP53

Identification of Candidate Genes in Breast Cancer Induced by Estrogen Plus Progestogens Using Bioinformatic Analysis. (PubMed, Int J Mol Sci) - "Importantly, CNNE2 protein level could be upregulated with EPT and attenuated by estrogen receptor antagonist, acolbifene and had interactions with cancer driver genes (AKT1 and KRAS) and high mutation frequency gene (TP53 and PTEN) in breast cancer patients. In conclusion, the current study showed that CCNE2, CDCA5, RAD51, TCF19, KNTC1, MCM10, and NEIL3 might contribute to EPT-related tumorigenesis in breast cancer, with CCNE2 might be a sensitive risk indicator of breast cancer risk in women using MHT."

Journal • Breast Cancer • Estrogen Receptor Positive Breast Cancer • Hormone Receptor Breast Cancer • Hormone Receptor Positive Breast Cancer • Oncology • Solid Tumor • AKT1 • KRAS • MCM10 • NEIL3 • PTEN • RAD51 • TCF19 • TP53

Estradiol inhibits differentiation of mouse macrophage into a pro-inflammatory phenotype by upregulating the IRE1α-XBP1 signaling axis (PubMed, Nan Fang Yi Ke Da Xue Xue Bao) - "Estrogen can inhibit the differentiation of murine macrophages into a pro-inflammatory phenotype by up-regulating the IRE1α-XBP-1 signaling axis, thereby producing an inhibitory effect on inflammatory response."

Journal • Preclinical • Inflammation • ATF6 • IFNG • IL10 • IL6 • TGFB1 • TNFA • XBP1

AGR2 , an estrogen response gene associated with tamoxifen resistance, is modulated by acolbifene in premenopausal women at high risk for development of breast cancer (SABCS 2021) - "ERGI and AGR2 change indicate favorable modulation by acolbifene and appear to provide independent information. Conclusions These results suggest that change in expression of benign breast AGR2 might be a useful addition to change in expression of other classic estrogen response genes in evaluating the potential of novel SERMs such as acolbifene compared to standard SERMs like tamoxifen in early phase prevention trials."

Clinical • Breast Cancer • Hormone Receptor Breast Cancer • Oncology • Solid Tumor • AGR2 • FOXA1 • HSP90AA1 • KIT • TFF1

In Vitro and In Silico Analyses of the Inhibition of Human Aldehyde Oxidase by Bazedoxifene, Lasofoxifene, and Structural Analogues. (PubMed, J Pharmacol Exp Ther) - "Tamoxifen, raloxifene, and nafoxidine are selective estrogen receptor modulators (SERMs) reported to inhibit the catalytic activity of human aldehyde oxidase 1 (AOX1). Structural features of bazedoxifene and lasofoxifene contribute to AOX1 inhibition, whereas those of acolbifene render it considerably less susceptible to AOX1 inhibition. Our novel biochemical findings, together with molecular docking analyses, provide new insights into the differential inhibitory effect of SERMs on the catalytic activity of human AOX1, how SERMs bind to AOX1, and increase our understanding of the AOX1 pharmacophore in the inhibition of AOX1 by drugs and other chemicals."

Journal • Preclinical

Acolbifene in Preventing Cancer in Premenopausal Women at High Risk of Breast Cancer (clinicaltrials.gov) - P2; N=25; Completed; Sponsor: Carol Fabian, MD; N=44 ➔ 25; Trial primary completion date: Aug 2010 ➔ Dec 2010

Clinical • Enrollment change • IO Biomarker • Trial primary completion date

Inhibition of Human SULT2A1-Catalyzed Sulfonation of Lithocholic Acid, Glycolithocholic Acid, and Taurolithocholic Acid by Selective Estrogen Receptor Modulators and Various Analogues and Metabolites. (PubMed, J Pharmacol Exp Ther) - "The present study was done to characterize the sulfonation of LCA, GLCA, and TLCA and to investigate whether triphenylethylene (clomifene, tamoxifen, toremifene, ospemifene, droloxifene), benzothiophene (raloxifene, arzoxifene), tetrahydronaphthalene (lasofoxifene, nafoxidine), indole (bazedoxifene), and benzopyran (acolbifene) classes of selective estrogen receptor modulator (SERM) inhibit LCA, GLCA, and TLCA sulfonation. The findings provide an insight into the structural features of specific SERMs that contribute to their inhibition of SULT2A1-catalyzed LCA sulfonation. Inhibition of LCA, GLCA, and TLCA detoxification by a SERM may provide a biochemical basis for adverse effects associated with a SERM."

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