tamoxifen

We proved that this strategy is capable of targeting ERα for degradation through ubiquitination, leading to the inhibition of proliferation in ERα+ breast cancer cells and tamoxifen-resistant breast cancer cells. Furthermore, we investigated the mechanisms involved in overcoming resistance. By circumventing drug resistance associated with LBD mutations in ERα, our approach provides a promising avenue for the discovery of new therapeutic agents.

Moreover, these findings further validated the ability of prolactin as a persuader of a more differentiated and less aggressive breast cancer phenotype. Hence, it suggested a potential implication of prolactin as a therapeutic candidate.

To determine the optimal concentrations of G1 and 4-hydroxytamoxifen (TAM), GPER expression and ERK1/2 phosphorylation were analyzed using qRT-PCR and western blotting, respectively...The distinct unfolded protein response observed in MDA-MB231 cells may stem from the unique characteristics of these cells, which lack receptors for estrogen, progesterone, and HER2/neu hormones, possessing only the GPER receptor (ER-/PR-/HER2-/GPER+). This study introduced a new pathway in TNBC cells, indicating that targeting GPER could be crucial in comprehensive therapeutic strategies in TNBC cells.

Preliminary testing showed increased dedifferentiation after tamoxifen (TAM) stimulation, making TAM-dependent lineage-tracing models unsuitable for quantification of naturally occurring DFAT cells. The regulatory role of ATMs in adipocyte dedifferentiation was shown through macrophage depletion using Plexxicon 5622 or clodronate liposomes, which significantly increased DFAT cell levels...Our findings suggest a regulatory role of resident ATMs in maintaining the mature adipocyte phenotype and preventing excessive adipocyte dedifferentiation. The specific regulatory pathways as well as the impact that DFAT cells might have on ATMs, and vice versa, are subject to further investigation.

Importantly, we found ER target gene transcription and promoter cofactor recruitment by tamoxifen can be reversed by induced miR205 expression. Altogether, miR-205 functions as a negative regulator of MED1 and HER3, affecting the regulation of the HER3-PI3K/Akt-MED1 axis in anti-estrogen resistance, and could serve as a potential therapeutic regime to overcome treatment resistance.

P3, N=812, Recruiting, Hoffmann-La Roche | Trial completion date: Sep 2032 --> Dec 2030 | Trial primary completion date: Aug 2026 --> Mar 2027

Our study suggests differential tamoxifen benefit by menopausal status. Improved long-term endocrine therapy prediction in premenopausal patients is needed and could involve molecular markers because standard tumor characteristics cannot predict benefit beyond 10 years.

P=N/A, N=329, Completed, Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins | Active, not recruiting --> Completed

P2, N=200, Recruiting, Oana Danciu | Trial completion date: Dec 2027 --> Aug 2029 | Trial primary completion date: Dec 2024 --> Aug 2028

PIK3CA overexpression partially reversed these reductions. In conclusion, our study demonstrates that miR-592 attenuates TAM resistance by inhibiting the PIK3CA-driven PI3K/AKT/mTOR signaling pathway, representing a promising strategy to address chemoresistance in BC.

P3, N=7154, Completed, Queen Mary University of London | Active, not recruiting --> Completed

P=N/A, N=290, Recruiting, M.D. Anderson Cancer Center | Trial completion date: Oct 2024 --> Oct 2026 | Trial primary completion date: Oct 2024 --> Oct 2026

The most potent compound in the series outperformed tamoxifen and 5-fluorouracil, with selectivity indices (SI) of 1.60 and 1.99 against MDA-MB-468 and MDA-MB-231 cancer cells, respectively. The Caspase 3/7 7-AAD assay showed live cell populations of 72.10% and 49.20% after 24 and 48 hours, respectively, indicating that the cytotoxic effect is mediated through the caspase apoptotic pathway. Molecular docking studies further suggested the compound's potential as an EGFR inhibitor, highlighting its promise as a therapeutic agent.

To address the need for clinically relevant models, we generated tamoxifen-inducible, epithelial cell specific Kras G12D/+ ( G12D ) mice...Tumor-released factors promote adipocyte lipolysis, a driver of adipose wasting in human CC, and adipose tissue wasting was inversely related to tumor burden. Thus, G12D mice model key features of human lung CC and suggest a novel role for early adipose tissue wasting in CC.

All hybrid ligands are antagonists of estrogen receptor alpha and agonists of the melatonin MT1 receptor with variable potencies. Several drug conjugates including the (CH2)4-linked analogues 4a and 16a and the (CH2)6-linked compound 16c showed higher potency to inhibit cell viability than the combination of melatonin and tamoxifen on at least one cancer cell line including MCF-7, MDA-MB-231, and HT-1080.

Interactive drugs were identified, including amoxicillin, atenolol, infliximab, colchicine, propionyl-L-carnitine, BMN-111, and tamoxifen, which were known to have a positive effect on height. Our results suggest that many genes have causal effects on height. By interrogating drug-gene interactions, interactive drugs have been identified as having both positive and negative effects on growth, which would help make clinical decisions.

Notably, the combined approach of ET and CDK4/6 inhibitor represents a novel intervention in managing DCBM in patients with LBC.

Hormonal or endocrine therapy includes selective estrogen receptor modulators (SERMs) such as raloxifene, tamoxifen and toremifene, selective estrogen-receptor degraders (SERDs) including elacestrant and fulvestrant, and aromatase inhibitors such as anastrozole, letrozole, and exemestane...These agents include taxanes (docetaxel, nab-paclitaxel, and paclitaxel), anthracyclines (doxorubicin, epirubicin), anti-metabolites (capecitabine, gemcitabine, fluorouracil, methotrexate), alkylating agents (carboplatin, cisplatin, and cyclophosphamide), and drugs that target microtubules (eribulin, ixabepilone, ado-trastuzumab emtansine). Patients with ER-positive tumors are treated with 5-10 years of endocrine therapy and chemotherapy. For patients with metastatic breast cancer, standard first-line and follow-up therapy options include targeted approaches such as CDK4/6 inhibitors, PI3K inhibitors, PARP inhibitors, and anti-PDL1 immunotherapy, depending on the tumor type and molecular profile.

P1, N=12, Recruiting, University of Wisconsin, Madison | Trial completion date: Dec 2025 --> Dec 2026 | Trial primary completion date: Dec 2024 --> Dec 2025

Previously, we identified that resistance to tamoxifen and rapamycin is associated with the suppression of DNMT3A. The coordinated suppression of NR6A1 and DNMT3A may contribute to sustaining the resistant phenotype in breast cancer cells. This pathway could serve as a predictive marker, helping guide the selection of optimal therapeutic strategies for breast cancer treatment in the future.

Mechanistically, increased p110α levels result from inhibited degradation by E3 ubiquitin ligase NEDD4L. These findings suggest N6AMT1 as a potential luminal breast cancer biomarker and highlight the N6AMT1-p110α pathway as a therapeutic target to sensitize cells to tamoxifen.

Further, IGFBP-3 expression was increased by treatment with the GPER1 agonist G-1 and attenuated upon treatment with P17, a YAP/TAZ inhibitor. These data suggest that IGFBP-3 modulates breast cancer cells and is a mediator of breast cancer cell response to fulvestrant and tamoxifen.

on key kinase signaling pathways was further studied in the ER+ breast cancer (MCF-7) and bcr-abl+ leukemic (AR-230) in vitro tumor models in a comparative manner to the reference drugs tamoxifen and imatinib, respectively. Inhibition of the JAK/STAT signaling pathway was outlined as a prominent mechanism in the antileukemic activity against the Ph+ AR-230 in vitro model, whereas recruitment and activation of the extrinsic apoptotic pathway was established in the MCF-7 cells.

Here, we report a new class of SERDs by pharmacological evolution of a selective estrogen receptor modulator, lasofoxifene. 51 exhibited favorable pharmacokinetic properties and good brain penetration, with a brain/plasma ratio of 3.05, and significantly suppressed the growth of tumor in a tamoxifen-resistant MCF-7 Tam1 xenograft model. Overall, the study demonstrates 51 as a highly potent, oral, and brain penetrant ER degrader and pure antagonist, showing a good potential in overcoming endocrine resistance.

Secondary prophylaxis reduces CBC and improves OS in BRCA1/2 carriers, with variations by genetic and physiological factors. These findings underscore the need for personalized strategies, considering menopausal status and treatment duration.

P3, N=456, Not yet recruiting, Sun Yat-Sen Memorial Hospital of Sun Yat-Sen University | Trial completion date: May 2029 --> May 2030 | Initiation date: May 2024 --> Jan 2025 | Trial primary completion date: May 2028 --> Jan 2029

P3, N=230, Recruiting, Hoffmann-La Roche | Trial completion date: Oct 2028 --> Jan 2028 | Trial primary completion date: Oct 2028 --> Oct 2026

Based on real-world data analysis, in ER-positive, HER2-negative post-menopausal women with early breast cancer in Taiwan, the use of tamoxifen compared to AIs is associated with a lower risk of recurrence. Improved adherence to medication can break the cycle of recurrence and improve health outcomes.

Using proximity ligation assays, we showed that VPC-260724 disrupts the interaction between ER-AF2 and the coactivator SRC-3 and reduces the expression of ER target genes in various breast cancer models including the tamoxifen resistant cell line TamR3. In conclusion, we developed a novel ER-AF2 binder, VPC-260724, which shows antiproliferative activity in ER-positive breast cancer models. The use of an ER-AF2 inhibitor in combination with current treatments may provide a novel complementary therapeutic approach to target treatment resistance in ER-positive breast cancer.

Interpretations of EC FAK-null phenotypes are complicated by related PYK2 (protein tyrosine kinase 2) expression, and to test this, we created PYK2 -/- FAK fl/fl mice with tamoxifen-inducible EC-specific Cre recombinase expression...Together, these results underscore the linkage between PYK2 and FAK loss with p53 activation impacting tumor growth. PYK2-null combined with endothelial cell-specific FAK transgenic mouse models show that loss of FAK activity limits tumor spread and that genetic or chemical degradation preventing combined FAK-PYK2 expression may be an approach to induce a p53-associated anti-tumor response.

Tamoxifen (1-[4-(2-dimethylaminoethoxy)-phenyl]-1,2- diphenylbut-1(Z)-ene) is a nonsteroidal antiestrogen prodrug which formed pharmacologically active metabolite, 4-hydroxytamoxifen, largely used for endocrine therapy in pre and postmenopausal women with ER-positive breast cancer...Hence, can serve as potential lead against alpha Estrogen receptor (ER-α). The online version contains supplementary material available at 10.1007/s40203-024-00282-5.

MitoTam, a mitochondria-targeted tamoxifen, emerges as a potent CBS-targeting TRAP1 inhibitor. Our findings highlight the potential of Rho6TPP as a crucial tool for advancing the development of CBS-targeting TRAP1 inhibitors.

After receiving capecitabine, lapatinib, gonadotropin-releasing hormone (GnRH) agonist, and tamoxifen, multiple new lesions appeared in the brain after 14 months. The patient then received capecitabine, neratinib, GnRH agonist, and letrozole; however, her brain metastases still progressed after 7 months...Now aged 30, the patient is continuing to receive T-DXd treatment to prevent recurrence. We conclude that T-DXd was effective for the treatment of brain metastases in this young patient with triple-positive metastatic breast cancer who had multiple risk factors and had received several anti-HER2 therapies prior to T-DXd.

P3, N=3832, Not yet recruiting, Region Örebro County | Initiation date: May 2024 --> Jan 2025

Additionally, SOX9-AS1 knockdown facilitated tamoxifen-induced cellular senescence and the transcription of senescence-associated secretory phenotype (SASP) factors (IL-1α, IL-1β, IL-6 and IL-8) mechanistically by resisting senescence-induced Wnt signal (GSK-3β/β-catenin) activation...In conclusion, SOX9-AS1 resists TNBC senescence via regulating the Wnt signalling pathway and inhibits immune infiltration. Targeted inhibition of SOX9-AS1 enhances SASP and thus mobilises immune infiltration to adjunct TIS strategy.

These findings suggest Ptf1a haploinsufficiency in Ptf1acreERT mouse models promotes KRASG12D priming of genes for promotion of PDAC.

There were two clinical correlational studies: tamoxifen adverse effects and CYP2D6 variants and FTO gene rs9939609 variants and weight gain caused by second-generation antipsychotics. Eight descriptive studies evaluated prevalence of CYP2D6 variants, HLA-B*15:02 allele, KRAS gene mutations and variants related to statin, warfarin and anticancer drug metabolism. Additionally, nine studies developed, validated and tested novel assays for detecting key pharmacogenomically important variants. While pharmacogenomics research in Sri Lanka has made strides, more clinical studies and broader genomic research are needed. Overcoming challenges related to funding, public awareness and regional collaboration is essential to advance personalized medicine and improve therapeutic outcomes in Sri Lanka and South Asia.

Tamoxifen is the drug of choice in ER-positive breast cancer, and several studies have shown better disease-free survival in these patients...In addition, a computational approach involving molecular modeling and simulation of phosphorylated and unphosphorylated forms of PAK1 was used to elucidate the dynamics of nuclear localization. Thus, PAK1 phosphorylation by JAK2 is a prerequisite for its nuclear localization and its tumorigenic effects on endometrial cancer cells.

P2, N=90, Active, not recruiting, Dana-Farber Cancer Institute | Recruiting --> Active, not recruiting | Trial primary completion date: Jan 2026 --> Jun 2025

We generated tamoxifen inducible Dab2 conditional knockout system for our study...In patients, TCGA data analysis of skin cancer melanoma (SKCM) showed a trend where high levels of Dab2 correlated with poor overall survival. The present study shows that Dab2 promotes tumour progression in skin SCC.

P3, N=1156, Not yet recruiting, Alliance for Clinical Trials in Oncology

"The first 120 postmenopausal participants (60 with invasive ductal carcinoma [IDC] and 60 with invasive lobular carcinoma [ILC]) were randomized to letrozole versus tamoxifen for a 2-week window phase; all patients were then randomized 2:1 to a 24-week treatment phase of NET +/- Palbociclib (Palbo). Among patients treated with NET +/- Palbo, 43.6% of whom had ILC, 57.8% exhibited CCA. Most patients with available PAM50 results had luminal B subtype (61.3%). Cell cycle arrest after NET and baseline intrinsic subtype did not correlate with ypN status among patients treated with NET +/- Palbo."