Molecular docking, MMGBSA, and ADMET studies of phytoconstituents of Ocimum gratissimum on multiple breast cancer targets.

O. gratissimum is one of the most common medicinal plants in every community in Nigeria. This plant has been presumed to be useful in the management of diseases including breast cancer, which is one the commonest cancers affecting women globally. Hence, this study aimed to computationally investigate the phytochemicals present in O. gratissimum by elucidate their binding dynamics against five selected molecular targets of breast cancer and predict their pharmacokinetics properties. Molecular docking, MMGBSA calculation and ADMET prediction were used. The results showed that isovitexin has the highest binding affinity of -9.11 kcal/mol and -9.80 kcal/mol for Human Epidermal Growth Factor Receptor 2 (HER2) and Epidermal Growth Factor Receptor (EGFR) respectively. Rosmarinic acid has the highest binding affinity of -12.15 kcal/mol for Phosphatidylinositol 3-kinase (PI3K), Nepetoidin A has the highest binding affinity of -9.14 kcal/mol for oestrogen receptor (ER), and Vitexin has the highest binding affinity of -12.90 kcal/mol for Progesterone receptor (PR). MMGBSA provided total binding energy that confirmed the stability of the complexes under physiological conditions. The ADMET profiles showed that O. gratissimum top phytochemicals identified would be safe for oral administration with no hepatoxicity. Overall, this study identified isovitexin, vitexin, rosmarinic acid, nepetoidin A and luteolin among others, as compounds that exhibit strong anti-cancer properties against breast cancer cells.

Universal CAR T cells targeted to HER2 with a biotin-trastuzumab soluble linker penetrate spheroids and large tumor xenografts that are inherently resistant to trastuzumab mediated ADCC.

CAR T cell therapies face challenges in combating solid tumors due to their single-target approach, which becomes ineffective if the targeted antigen is absent or lost. Universal CAR T cells (UniCAR Ts) provide a promising solution by utilizing molecular tags (linkers), such as biotin conjugated to monoclonal antibodies, enabling them to target a variety of tumor antigens. Recently, we showed that conventional CAR T cells could penetrate the extracellular matrix (ECM) of ADCC-resistant tumors, which forms a barrier to therapeutic antibodies. This finding led us to investigate whether UniCAR T cells, targeted by soluble antibody-derived linkers, could similarly tackle ADCC-resistant tumors where ECM restricts antibody penetration. We engineered UniCAR T cells by incorporating a biotin-binding monomeric streptavidin 2 (mSA2) domain for targeting HER2 via biotinylated trastuzumab (BT). The activation and cytotoxicity of UniCAR T cells in the presence or absence of BT were evaluated in conventional immunoassays. A 3D spheroid coculture was set up to test the capability of UniCAR Ts to access ECM-masked HER2+ cells. For in vivo analysis, we utilized a HER2+ xenograft model in which intravenously administered UniCAR T cells were supplemented with intraperitoneal BT treatments. In vitro, BT-guided UniCAR T cells showed effective activation and distinct anti-tumor response. Upon target recognition, IFNγ secretion correlated with BT concentration. In the presence of BT, UniCAR T cells effectively penetrated HER2+ spheroids and induced cell death in their core regions. In vivo, upon intravenous administration of UniCAR Ts, circulating BT linkers immediately engaged the mSA2 domain and directed effector cells to the HER2+ tumors. However, these co-treated mice died early, possibly due to the lung infiltration of UniCAR T cells that could recognize both native biotin and HER2. Our results suggest that UniCAR T cells guided with soluble linkers present a viable alternative to conventional CAR T cells, especially for patients resistant to antibody therapy and those with solid tumors exhibiting high antigenic variability. Critical to their success, however, is the choice of an appropriate binding domain for the CAR and the corresponding soluble linker, ensuring both efficacy and safety in therapeutic applications.

Artemisia argyi extracts overcome lapatinib resistance via enhancing TMPRSS2 activation in HER2-positive breast cancer.

Breast cancer stands as the predominant malignancy and primary cause of cancer-related mortality among females globally. Approximately 25% of breast cancers exhibit HER2 overexpression, imparting a more aggressive tumor phenotype and correlating with poor prognoses. Patients with metastatic breast cancer receiving HER2 tyrosine kinase inhibitors (HER2 TKIs), such as Lapatinib, develop acquired resistance within a year, posing a critical challenge in managing this disease. Here, we explore the potential of Artemisia argyi, a Chinese herbal medicine known for its anti-cancer properties, in mitigating HER2 TKI resistance in breast cancer. Analysis of the Cancer Genome Atlas (TCGA) revealed diminished expression of transmembrane serine protease 2 (TMPRSS2), a subfamily of membrane proteolytic enzymes, in breast cancer patients, correlating with unfavorable outcomes. Intriguingly, lapatinib-responsive patients exhibited higher TMPRSS2 expression. Our study unveiled that the compounds from Artemisia argyi, eriodictyol, and umbelliferone could inhibit the growth of lapatinib-resistant HER2-positive breast cancer cells. Mechanistically, they suppressed HER2 kinase activation by enhancing TMPRSS2 activity. Our findings propose TMPRSS2 as a critical determinant in lapatinib sensitivity, and Artemisia argyi emerges as a potential agent to overcome lapatinib via activating TMPRSS2 in HER2-positive breast cancer. This study not only unravels the molecular mechanisms driving cell death in HER2-positive breast cancer cells induced by Artemisia argyi but also lays the groundwork for developing novel inhibitors to enhance therapy outcomes.

Rhodomyrtus tomentosa as a new anticancer molecular strategy in breast histology via Her2, IL33, EGFR, and MUC1.

The prevalence of breast cancer among patients in Indonesia is significant. Indonesian individuals maintain the belief that cancer cannot be cured alone by pharmaceuticals and treatment; herbal remedies must be used in conjunction. Rhodomyrtus tomentosa, also known as Haramonting, is an indigenous Indonesian medicinal plant renowned for its copious antioxidant properties. The objective of study was to assess the impact of haramonting on breast cancer by examining the expression of various biomarker proteins associated with breast cancer. Haramonting was administered to breast cancer model mice at different doses over a period of 30 days. Subsequently, blood and breast samples were obtained for immunohistochemistry and enzyme-linked immunosorbent assays (ELISA). Authors have discovered that there has been a notable rise in the proliferation of epithelial cells in the duct lobes, resulting in the formation of ducts and lobules. Additionally, the researchers discovered that the breasts exhibited distinct clinical and histological alterations. Haramonting possesses the capacity to restore the concentrations of malondialdehyde (MDA) and superoxide dismutase (SOD) to normal levels in the blood serum of rats afflicted with cancer. The histopathological analysis of the breast tissue revealed elevated levels of Her2, IL33, EGFR, and MUC1. The authors also discovered a notable increase in the growth of epithelial cells, with two or more layers of cells reaching towards the centre of the duct. The size of the epithelial cells exhibits variability; however, this state ameliorates with the administration of a dosage of 300 mg/kgBW of this botanical specimen. This study proposes that Haramonting may be effective in treating breast cancer.

A Multifunctional Bimetallic Nanoplatform for Synergic Local Hyperthermia and Chemotherapy Targeting HER2-Positive Breast Cancer.

Anti-HER2 (human epidermal growth factor receptor 2) therapies significantly increase the overall survival of patients with HER2-positive breast cancer. Unfortunately, a large fraction of patients may develop primary or acquired resistance. Further, a multidrug combination used to prevent this in the clinic places a significant burden on patients. To address this issue, this work develops a nanotherapeutic platform that incorporates bimetallic gold-silver hollow nanoshells (AuAg HNSs) with exceptional near-infrared (NIR) absorption capability, the small-molecule tyrosine kinase inhibitor pyrotinib (PYR), and Herceptin (HCT). This platform realizes targeted delivery of multiple therapeutic effects, including chemo-and photothermal activities, oxidative stress, and immune response. In vitro assays reveal that the HCT-modified nanoparticles exhibit specific recognition ability and effective internalization by cells. The released PYR inhibit cell proliferation by downregulating HER2 and its associated pathways. NIR laser application induces a photothermal effect and tumor cell apoptosis, whereas an intracellular reactive oxygen species burst amplifies oxidative stress and triggers cancer cell ferroptosis. Importantly, this multimodal therapy also promotes the upregulation of genes related to TNF and NF-κB signaling pathways, enhancing immune activation and immunogenic cell death. In vivo studies confirm a significant reduction in tumor volume after treatment, substantiating the potential effectiveness of these nanocarriers.

A historical controlled study of domestic trastuzumab and pertuzumab in combination with docetaxel for the neoadjuvant treatment of early HER2-positive breast cancer.

Background: HER2-positive molecular breast cancer subtypes are characterized by high aggressiveness and malignancy, and their metastasis and mortality rates are among the highest of all types of breast cancer. The use of anti-HER2-targeted agents in neoadjuvant therapy has significantly improved the prognosis of patients with HER2-positive breast cancer. In this study, we investigated the efficacy and safety of a neoadjuvant Chinese THP regimen (docetaxel, trastuzumab biosimilar TQB211 plus the pertuzumab biosimilar TQB2440 or pertuzumab) for ER/PR-negative and HER2-positive breast cancer in China. Method: All enrolled patients received the THP regimen (T: docetaxel 75 mg/m2 per cycle; H: trastuzumab biosimilar TQB211 8 mg/kg in the first cycle and 6 mg/kg maintenance dose in cycles 2 to 4; P: pertuzumab biosimilar TQB2440 or pertuzumab 840 mg in the first cycle, maintenance dose 420 mg in cycles 2 to 4) every 3 weeks for 4 cycles. The biosimilar TQB2440 pertuzumab and pertuzumab were randomly assigned to patients. Docetaxel, TQB211, and TQB2440 were all developed by Chiatai Tianqing. The primary endpoint was the complete pathological response (pCR) in the breast, and the secondary endpoint was cardiac safety. Results: Of the 28 eligible patients, 19 (67.9%) achieved tpCR. The tpCR rate was higher than in the NeoSphere trial (pCR63.2%) and the PEONY study (tpCR52.5%). The adverse events that occurred most frequently were leukopenia and neutropenia, with incidence rates of 82.1% and 75.0%, respectively. Of these, grade 3 leukopenia and neutropenia occupied 46.4% and 35.7%. Other grade 3 or higher adverse events were bone marrow suppression (7.1%), lymphopenia (3.6%), and anemia (3.6%). There were no events of heart failure in patients and no patient died during the neoadjuvant phase. Conclusion: Domestic dual-target HP has a more satisfactory efficacy and safety in the neoadjuvant phase of treatment. Clinical trial registration: https://clinicaltrials.gov/study/NCT05985187, NCT05985187.

Cost-effectiveness analysis of add-on pertuzumab to trastuzumab biosimilar and chemotherapy as neoadjuvant treatment for human epidermal growth receptor 2-positive early breast cancer patients in Singapore.

OBJECTIVES: The Asian PEONY trial showed that add-on pertuzumab to trastuzumab and chemotherapy significantly improved pathological complete response in the neoadjuvant treatment of patients with human epidermal growth factor receptor 2-positive (HER2+) early breast cancer (EBC). This study evaluated the cost-effectiveness of pertuzumab as an add-on therapy to trastuzumab and chemotherapy for neoadjuvant treatment of patients with HER2+ EBC in Singapore. METHODS: A six-state Markov model was developed from the Singapore healthcare system perspective, with a lifetime time horizon. Model outputs were: costs; life-years (LYs); quality-adjusted LYs (QALYs); incremental cost-effectiveness ratios (ICERs). Sensitivity/scenario analyses explored model uncertainties. RESULTS: The base case projected the addition of pertuzumab to be associated with improved outcomes by 0.277 LYs and 0.271 QALYs, increased costs by S$1,387, and an ICER of S$5,121/QALY. The ICER was most sensitive to the pCR rate, and the probabilistic sensitivity analysis showed that add-on pertuzumab had an 81.3% probability of being cost-effective at a willingness-to-pay threshold of S$45,000/QALY gained. CONCLUSIONS: This model demonstrated that the long-term clinical impact of early pertuzumab use, particularly the avoidance of metastatic disease and thus avoidance of higher costs and mortality rates, make neoadjuvant pertuzumab a cost-effective option in the management of patients with HER2+ breast cancer in Singapore.

Quantitative parameters of dual-layer spectral detector computed tomography for evaluating Ki-67 and human epidermal growth factor receptor 2 expression in colorectal adenocarcinoma.

Background: Ki-67 and human epidermal growth factor receptor 2 (HER2) are key biomarkers in evaluating the prognosis of colorectal adenocarcinoma (CRAC). The purpose of this study was to investigate the value of quantitative parameters in dual-layer spectral detector computed tomography (SDCT) for evaluating the expression of Ki-67 and HER2 in CRAC. Methods: In this retrospective, cross-sectional study, 88 eligible patients with pathologically confirmed CRAC were selected from Taicang Hospital of Traditional Chinese Medicine between May 2021 and April 2023. The study participants underwent enhanced SDCT of the whole abdomen within 2 weeks before to surgery, did not receive antitumor therapy, and had complete immunohistochemical (IHC) indexes. Patients with nonadenocarcinoma pathologic types, poor quality of spectral CT images, or no complete immunohistochemistry results were excluded. Spectral parameters including CT values at 40 and 100 keV, effective atomic number, iodine concentration (IC), the slope of the spectral Hounsfield unit (HU) curve (λHU), and normalized iodine concentration (NIC) in the arterial phase (AP) and venous phase (VP) were analyzed for their value in distinguishing between the high and low expression of Ki-67 and HER2-positive and -negative status in CRAC. The statistical significance of the SDCT parameters between the different groups of Ki-67 expression and those of HER2 status was assessed with the Mann-Whitney test. Spearman correlation analysis was used to analyze the correlation between the SDCT parameters and the extent of Ki-67 expression and HER2 expression status. The receiver operating characteristic (ROC) curve was used, and the area under the curve (AUC) was calculated. Results: The SDCT parameters of CT values at 40 keV, effective atomic number, IC, and the λHU in the VP showed significant differences between the Ki-67 high- and low-expression groups in CRAC (P=0.035, P=0.041, P=0.036, and P=0.044, respectively), with AUCs of 0.639 [95% confidence interval (CI): 0.512-0.766], 0.634 (95% CI: 0.508-0.761), 0.638 (95% CI: 0.510-0.766), and 0.633 (95% CI: 0.504-0.762), respectively. The expression of CRAC Ki-67 was positively correlated with CT values at 40 keV (r=0.227; P=0.034), effective atomic number (r=0.219; P=0.040), IC (r=0.225; P=0.035), and the λHU in VP (r=0.216; P=0.043). SDCT parameter values showed no statistical difference between negative and positive expression in HER2 (all P values >0.05). There was no significant correlation between SDCT parameters and the expression of HER2 in CRAC (all P values >0.05). Conclusions: The quantitative parameters of SDCT in the VP provide valuable information for distinguishing between the low expression and high expression of Ki-67 in CRAC.

The FJQR Has Synergistic Effect with Fluoropyrimidine in the Maintenance Treatment for HER-2 Negative Gastric Cancer.

INTRODUCTION: Maintenance therapy aimed to strengthen the first-line chemotherapy and improve quality of life is needed for gastric cancer (GC). Currently, many clinical studies have confirmed the important role of fluoropyrimidine in the maintenance stage. Our team has created patented prescriptions "Fuzheng jiedu Quyu Method" recipe (FJQR), which was considered as an adjuvant therapeutic scheme (reduce toxicity and increase the efficacy of chemotherapy). This study aimed to evaluate the efficacy and safety of FJQR combined with fluoropyrimidine as a maintenance treatment in HER-2 negative GC patients. METHODS: We performed the analysis of 129 patients with HER-2 negative GC who entered the maintenance stage in our hospital and Tianjin Cancer Hospital between January 2018 and December 2020. Out of the 129 eligible patients, 64 were categorized into the maintenance treatment group with FJQR+fluoropyrimidine, and 65 patients were assigned to the control group if they received fluoropyrimidine alone. Capecitabine was orally 1000mg/m2, Qd, half an hour after meals, and FGQR was 15g Bid after capecitabine. The primary endpoint was progression-free survival (PFS). The secondary endpoints were overall survival (OS), overall remission rate (ORR), quality of Life (QOL), TCM syndrome and safety. RESULTS: The mPFS in the treatment group was significantly prolonged compared with the control group (6.3 vs. 5.0 months, p = 0.03), while the mOS was not substantially improved (11.4 vs. 10.5 months, p = 0.38). Gastrointestinal symptoms and pain became better in the treatment group. The number of distant metastatic organs, first-line chemotherapy cycles, and lymph node metastasis were independent risk predictors for PFS. Blood stasis syndrome may be the protective factor. In terms of safety, treatment-related adverse events (AEs) in the treatment group were relatively lighter, and the incidence of grade III-IV AEs could be significantly reduced. CONCLUSION: FJQR and fluoropyrimidine have synergistic effects as maintenance treatment in HER-2 negative GC, with good efficacy and safety.

Protopanaxatriol activates EGFR and HER2 to strengthen the molecules of skin protection in human keratinocytes.

BACKGROUND: Protopanaxatriol (PPT) is an important ginsenoside produced by ginseng, a tonic plant used in many areas. PPT has beneficial effects against many disease states including inflammation, diabetes, and cancer. However, PPT's protective effects on skin integrity have been rarely studied. Previously, we reported that PPT can maintain skin moisture through activation of nuclear factor kappa B (NF-κB) and mitogen-activated protein kinases (MAPKs) pathways. However, the cellular targets for enhancing skin moisturizing effects via PPT are still unknown. PURPOSE: We wanted to identify the upstream targets of PPT on upregulating moisturizing factor (HAS-2) expression. STUDY DESIGN: We investigated which upstream proteins can be directly stimulated by PPT to modulate NF-κB, MAPKs and other signaling cascades. Then, the targeted proteins were overexpressed to check the relationship with HAS-2. Next, the cellular thermal shift assay (CETSA) was conducted to check the relationship between targeted proteins and PPT. METHODS: A human keratinocyte HaCaT were employed to measure the levels of moisturizing factors and the signaling proteins activated by PPT. Transfection conditions were established with DNA constructs expressing epidermal growth factor receptor (EGFR) and human epidermal growth factor receptor 2 (HER2) and their mutants prepared by site-directed mutagenesis. Further investigation on molecular mechanisms was conducted by RT-PCR, luciferase reporter gene assay, CETSA, or Western blot. RESULTS: We found that PPT can activate the phosphorylation of EGFR and HER2. These stimulations caused Src phosphorylation, which resulted in the activation of phosphoinositide 3-kinases (PI3K)/pyruvate dehydrogenase kinase 1 (PDK1)/protein kinase B (AKT)/NF-κB and MAPKs signaling cascades. Additionally, EGFR and HER2 activation resulted in phosphorylation of signal transducer and activator of transcription 3 (STAT3) and calcium/calmodulin-dependent protein kinase II (CaMKII). This induced the AMP-activated protein kinase alpha (AMPKα) signaling pathway. Additionally, PPT blocked peroxisome proliferator activated receptor gamma (PPARγ), which also contributed to the phosphorylation of Src. CONCLUSION: Overall, we first found that PPT offers excellent protection of the skin barrier and hydrogen supply in keratinocytes. Moreover, growth factor receptors such as EGFR and HER2 were revealed to be central enzymes to be directly targeted by PPT. These results suggest a potentially valuable role as a cosmetic ingredient.

Targosomes: Anti-HER2 PLGA nanocarriers for bioimaging, chemotherapy and local photothermal treatment of tumors and remote metastases.

Developing combined cancer therapy strategies is of utmost importance as it can enhance treatment efficacy, overcome drug resistance, and ultimately improve patient outcomes by targeting multiple pathways and mechanisms involved in cancer growth and progression. Specifically, the potential of developing a combination chemo&photothermal therapy using targeted polymer nanoparticles as nanocarriers offers a promising approach for synergistic cancer treatment by combining the benefits of both therapies, such as targeted drug delivery and localized hyperthermia. Here, we report the first targeted anti-HER2 PLGA nanocarriers, called targosomes, that simultaneously possess photothermal, chemotherapeutic and diagnostic properties using only molecular payloads. Biocompatible poly(lactic-co-glycolic acid), PLGA, nanoparticles were loaded with photosensitizer phthalocyanine, diagnostic dye Nile Blue, and chemotherapeutic drug irinotecan, which was chosen as a result of screening a panel of theragnostic nanoparticles. The targeted delivery to cell surface oncomarker HER2 was ensured by nanoparticle modification with the anti-HER2 monoclonal antibody, trastuzumab, using the one-pot synthesis method without chemical conjugation. The irradiation tests revealed prominent photothermal properties of nanoparticles, namely heating by 35 °C in 10 min. Nanoparticles exhibited a 7-fold increase in binding and nearly an 18-fold increase in cytotoxicity for HER2-overexpressing cells compared to cells lacking HER2 expression. This enhancement of cytotoxicity was further amplified by >20-fold under NIR light irradiation. In vivo studies proved the efficacy of nanoparticles for bioimaging of primary tumor and metastasis sites and demonstrated 93% tumor growth inhibition, making these nanoparticles excellent candidates for translation into theragnostic applications.

Current Management and Future Perspectives of Hormone Receptor-Positive HER2-Negative Advanced Breast Cancer.

OBJECTIVES: An overview of the best therapeutic approaches for the management of hormone receptor-positive, human epidermal growth factor receptor 2 (HER2)-negative advanced breast cancer is provided, and emerging treatment advances are discussed. Key nursing considerations and the role of the nurse in the provision of optimal care are explored. DATA SOURCES: Data sources include peer-reviewed articles sourced in electronic databases. CONCLUSION: With a multitude of current and emerging treatments for the management of hormone receptor-positive, HER2-negative advanced breast cancer, patients with this subtype have improved overall survival. It is essential that specialist nurses holistically support patients; this will ensure treatment adherence, leading to enhanced longevity and quality of life. IMPLICATIONS FOR NURSING PRACTICE: Nurses play an important role in patient education and the early identification and management of treatment toxicities. Nurses also need to monitor and facilitate adherence by identifying barriers and implementing strategies to overcome them, ultimately improving patient outcomes.

Sphingomyelin Metabolism Modifies Luminal A Breast Cancer Cell Line under a High Dose of Vitamin C.

The role of sphingomyelin metabolism and vitamin C in cancer has been widely described with conflicting results ranging from a total absence of effect to possible preventive and/or protective effects. The aim of this study was to establish the possible involvement of sphingomyelin metabolism in the changes induced by vitamin C in breast cancer cells. The MCF7 cell line reproducing luminal A breast cancer and the MDA-MB-231 cell line reproducing triple-negative breast cancer were used. Cell phenotype was tested by estrogen receptor, progesterone receptor, human epidermal growth factor receptor 2 expression, and proliferation index percentage. Sphingomyelin was localized by an EGFP-NT-Lys fluorescent probe. Sphingomyelin metabolism was analyzed by RT-PCR, Western blotting and UFLC-MS/MS. The results showed that a high dose of vitamin C produced reduced cell viability, modulated cell cycle related genes, and changed the cell phenotype with estrogen receptor downregulation in MCF7 cell. In these cells, the catabolism of sphingomyelin was promoted with a large increase in ceramide content. No changes in viability and molecular expression were observed in MB231 cells. In conclusion, a high dose of vitamin C induces changes in the luminal A cell line involving sphingomyelin metabolism.

Enhanced therapeutic action of Trastuzumab loaded ZnxMn1-xFe2O4 nanoparticles using a pre-treatment step for hyperthermia treatment of HER2+ breast cancer.

In this study, Ferrites (Fe3O4, MnFe2O4, ZnFe2O4) and different stoichiometric ratios of ZnxMn1-xFe2O4 (x = 0.2, 0.4, 0.6, and 0.8) nanoparticles (<15 nm) were synthesized by microwave-assisted method and optimised for hyperthermia studies. The selection of the optimised variant of ferrite i.e. Zn0.4Mn0.6Fe2O4 was found to be the best variant based on VSM (38.14 emu g-1) hyperthermia-based temperature rise (maximum ΔT of 38 °C), SAR and ILP values. Trastuzumab, which is known to bind with HER2 receptors of breast cancer was chemically tethered onto Zn0.4Mn0.6Fe2O4 nanoparticles through EDC/NHS coupling with a loading efficiency of 80%. The attached Trastuzumab aided during the pre-treatment step by aiding in the internalisation of Zn0.4Mn0.6Fe2O4 nanoparticles, with cellular uptake of 11% in SK-BR-3 (cancerous HER2+) cells compared to ∼5% for MDA-MB-231 (cancerous HER2-) and RPE-1 (non-cancerous) cells. In the presence of a hyperthermia trigger for 15 mins, ZnxMn1-xFe2O4 -Trastuzumab formulation had a maximum therapeutic effect by reducing the SK-BR-3 cell viability to 14% without adversely affecting the RPE-1 cells. The mechanism of ZnxMn1-xFe2O4-Trastuzumab combination was examined using an internalisation study, MTT-based viability, proliferation study, and ROS generation assay. By utilizing both Trastuzumab and hyperthermia, we achieve their synergistic anticancer properties while minimizing the drug requirement and reducing any effect on non-cancerous cells.

Elacestrant for ER-Positive HER2-Negative Advanced Breast Cancer.

OBJECTIVE: This article aims to discuss elacestrant, an oral selective estrogen receptor downregulator approved by the Food and Drug Administration (FDA) in January 2023 for the treatment of hormone receptor positive (HR+) human epidermal growth factor receptor 2 negative (HER2-) advanced breast cancer. DATA SOURCES: PubMed, Embase, Medline, Clinicaltrials.gov, and the National Comprehensive Cancer Network (NCCN) were searched from inception to August 31, 2023. STUDY SELECTION AND DATA EXTRACTION: Clinical trials published in English were included and relevant information regarding methodology and results were extracted. DATA SYNTHESIS: Phase 1 and 3 trials showed elacestrant was safe and improved progression-free survival in patients with endocrine receptor 1 (ESR1) mutations who failed cyclin-dependent kinase 4/6 inhibitor (CDK 4/6i) plus 1 prior endocrine therapy compared with standard of care (SOC) (fulvestrant, anastrozole, letrozole, or exemestane monotherapy). RELEVANCE TO PATIENT CARE AND CLINICAL PRACTICE IN COMPARISON TO EXISTING DRUGS: Elacestrant maintains a comparable adverse event profile with other endocrine therapies and offers an alternative to typical sequential therapy which can delay the use of or be used after traditional chemotherapy. Elacestrant is currently being studied in CDK 4/6 inhibitor naïve patients and as a component of combination therapy for first-line use which could lead to future indications. CONCLUSIONS: Elacestrant gained FDA approval in January 2023 and can be considered in patients with HR+ HER2- advanced breast cancer and ESR1 mutations who have progressed despite therapy with either CDK 4/6i plus aromatase inhibitors (AI) or fulvestrant or chemotherapy.

Design, synthesis and evaluation of 177Lu-labeled inverso and retro-inverso A9 peptide variants targeting HER2-overexpression.

Several HER2-specific peptides are being continuously explored to find a candidate with suitable pharmacokinetic properties for development of effective radiopharmaceutical that can find applications for clinical screening of breast cancer patients. In the present work with an aim of preparing a radiopeptide with improved metabolic stability and in vivo pharmacokinetic performance we modified our previously reported [177Lu]DOTA-L-A9 peptide. Here we designed an 'inverso' peptide with all d-amino acids and a 'retro-inverso' peptide where sequence of d-amino acids was reversed. Higher secondary structure stabilization of retro- inverso A9 variant compared to inverso A9 peptide was evident by circular dichroism studies. The two radiopeptides [177Lu]DOTA-D-A9 and [177Lu]DOTA-rD-A9 exhibited significantly improved in vivo metabolic stability over the original l-peptide. The retro-inverso variant, [177Lu]DOTA-rD-A9 demonstrated better pharmacokinetic behavior with significantly higher tumor uptake than the inverso peptide, [177Lu]DOTA-D-A9 and the original peptide, [177Lu]DOTA-L-A9. In the present case of A9 peptide, reversal of the peptide sequence of d-amino acids boosted the uptake and retention of radioactivity in HER2-positive tumor. The present study can thus guide the design and development of newer and improved versions of peptides.

An ultrasensitive ratiometric electrochemical aptasensor based on metal-organic frameworks and nanoflower-like Bi2CuO4 for human epidermal growth factor receptor 2 detection.

An ultra-sensitive ratiometric electrochemical aptasensor was constructed based on metal-organic frameworks (MOFs) and bimetallic oxides for the detection of the human epidermal growth factor receptor 2 (HER2), a breast cancer marker. The aluminum metal-organic framework (Al-MOF) and cerium-metal-organic framework (Ce-MOF) have higher specific surface area, which is conducive to load more aptamers or complementary DNA (cDNA), and realize the amplification of internal reference signal Fc. Furthermore, nanoflower-like bismuth copper oxide (Bi2CuO4) with abundant active sites was introduced to modify more aptamers on its surface, which were then fixed to the glassy carbon electrode (GCE) to amplify the detection signal. The quantitative detection of HER2 was achieved by differential pulse voltammetry (DPV), cyclic voltammetry (CV) and electrochemical impedance spectroscopy (EIS). The materials were characterized by scanning electron microscope, transmission electron microscope, Zeta potential analyzer, X-ray diffraction and X-ray photoelectron spectroscopy. The ratiometric electrochemical aptasensor based on nanomaterial and chain displacement signal amplification technology could discern HER2 in a very wide range (0.001-20.0 ng/mL) with an extremely low detection limit (0.049 pg/mL) and has demonstrated good performance in clinical serum analysis. This strategy also provides a feasible idea for sensitive analysis of other clinical tumor markers.

Neratinib + fulvestrant + trastuzumab for HR-positive, HER2-negative, HER2-mutant metastatic breast cancer: outcomes and biomarker analysis from the SUMMIT trial.

BACKGROUND: HER2 mutations are targetable alterations in patients with hormone receptor-positive (HR+) metastatic breast cancer (MBC). In the SUMMIT basket study, patients with HER2-mutant MBC received neratinib monotherapy, neratinib + fulvestrant, or neratinib + fulvestrant + trastuzumab (N + F + T). We report results from 71 patients with HR+, HER2-mutant MBC, including 21 (seven in each arm) from a randomized substudy of fulvestrant versus fulvestrant + trastuzumab (F + T) versus N + F + T. PATIENTS AND METHODS: Patients with HR+ HER2-negative MBC with activating HER2 mutation(s) and prior cyclin-dependent kinase 4/6 inhibitor (CDK4/6i) therapy received N + F + T (oral neratinib 240 mg/day with loperamide prophylaxis, intramuscular fulvestrant 500 mg on days 1, 15, and 29 of cycle 1 then q4w, intravenous trastuzumab 8 mg/kg then 6 mg/kg q3w) or F + T or fulvestrant alone. Those whose disease progressed on F + T or fulvestrant could cross-over to N + F + T. Efficacy endpoints included investigator-assessed objective response rate (ORR), clinical benefit rate (RECIST v1.1), duration of response, and progression-free survival (PFS). Plasma and/or formalin-fixed paraffin-embedded tissue samples were collected at baseline; plasma was collected during and at end of treatment. Extracted DNA was analyzed by next-generation sequencing. RESULTS: ORR for 57 N + F + T-treated patients was 39% [95% confidence interval (CI) 26% to 52%); median PFS was 8.3 months (95% CI 6.0-15.1 months). No responses occurred in fulvestrant- or F + T-treated patients; responses in patients crossing over to N + F + T supported the requirement for neratinib in the triplet. Responses were observed in patients with ductal and lobular histology, 1 or ≥1 HER2 mutations, and co-occurring HER3 mutations. Longitudinal circulating tumor DNA sequencing revealed acquisition of additional HER2 alterations, and mutations in genes including PIK3CA, enabling further precision targeting and possible re-response. CONCLUSIONS: The benefit of N + F + T for HR+ HER2-mutant MBC after progression on CDK4/6is is clinically meaningful and, based on this study, N + F + T has been included in the National Comprehensive Cancer Network treatment guidelines. SUMMIT has improved our understanding of the translational implications of targeting HER2 mutations with neratinib-based therapy.

Inhibiting HER3 Hyperphosphorylation in HER2-Overexpressing Breast Cancer through Multimodal Therapy with Branched Gold Nanoshells.

Treatment failure in breast cancers overexpressing human epidermal growth factor receptor 2 (HER2) is associated mainly to the upregulation of human epidermal growth factor receptor 3 (HER3) oncoprotein linked to chemoresitence. Therefore, to increase patient survival, here a multimodal theranostic nanoplatform targeting both HER2 and HER3 is developed. This consists of doxorubicin-loaded branched gold nanoshells functionalized with the near-infrared (NIR) fluorescent dye indocyanine green, a small interfering RNA (siRNA) against HER3, and the HER2-specific antibody Transtuzumab, able to provide a combined therapeutic outcome (chemo- and photothermal activities, RNA silencing, and immune response). In vitro assays in HER2+ /HER3+ SKBR-3 breast cancer cells have shown an effective silencing of HER3 by the released siRNA and an inhibition of HER2 oncoproteins provided by Trastuzumab, along with a decrease of the serine/threonine protein kinase Akt (p-AKT) typically associated with cell survival and proliferation, which helps to overcome doxorubicin chemoresistance. Conversely, adding the NIR light therapy, an increment in p-AKT concentration is observed, although HER2/HER3 inhibitions are maintained for 72 h. Finally, in vivo studies in a tumor-bearing mice model display a significant progressively decrease of the tumor volume after nanoparticle administration and subsequent NIR light irradiation, confirming the potential efficacy of the hybrid nanocarrier.

Extensive review on breast cancer its etiology, progression, prognostic markers, and treatment.

As the most frequent and vulnerable malignancy among women, breast cancer universally manifests a formidable healthcare challenge. From a biological and molecular perspective, it is a heterogenous disease and is stratified based on the etiological factors driving breast carcinogenesis. Notably, genetic predispositions and epigenetic impacts often constitute the heterogeneity of this disease. Typically, breast cancer is classified intrinsically into histological subtypes in clinical landscapes. These stratifications empower physicians to tailor precise treatments among the spectrum of breast cancer therapeutics. In this pursuit, numerous prognostic algorithms are extensively characterized, drastically changing how breast cancer is portrayed. Therefore, it is a basic requisite to comprehend the multidisciplinary rationales of breast cancer to assist the evolution of novel therapeutic strategies. This review aims at highlighting the molecular and genetic grounds of cancer additionally with therapeutic and phytotherapeutic context. Substantially, it also renders researchers with an insight into the breast cancer cell lines as a model paradigm for breast cancer research interventions.