Breast Cancer Therapy Research Articles

Adipocytes reprogram the proteome of breast cancer cells in organotypic three-dimensional cell cultures.

While epidemiological evidence has long linked obesity with an increased risk of breast cancer, the intricate interactions between adipocytes and cancer cells within the tumor microenvironment remain largely uncharted territory. The use of organotypic three-dimensional (3D) cell cultures that more accurately mimic the spatial architecture of tumors represents an innovative approach to this complex issue. In the present study, we investigated the effects of adipocytes on the proteome of Hs578t breast cancer cells cultured in a 3D microenvironment. Using different treatments, we rigorously optimized the experimental conditions to induce the optimal differentiation of 3T3-L1 fibroblasts into mature adipocytes. Then, we grow the Hs578t cells in a simulated microenvironment using an on-top model for organotypic 3D cultures. Our data showed that cancer cells formed 3D stellate-like architectures when grown over an extracellular matrix proteins-enriched scaffold for 48h. Proteomic profiling using LC-MS/MS mass spectrometry of Hs578t cells grown in 3D conditions with or without the adipocyte-enriched culture discovered 916 unique proteins. Of these, 605 showed no significant changes in abundance, whereas 87 proteins were significantly upregulated and 224 downregulated after interaction with fat cells (p < 0.05, FC > 2.0). Bioinformatic analysis of upregulated proteins indicated that the most enriched GO terms and molecular functions were related to lipids transport, cell differentiation, hypoxia response, and cell junctions. In addition, several modulated proteins have been previously associated with breast cancer progression. Interestingly, lipid transport proteins, including PITPNM2, ATP2C1, ABCA12, HDLBP, and APOB, showed perturbations in their expression, which were also associated with low overall survival in breast cancer patients. Functional studies showed that the knockdown of apolipoprotein B (APOB) expression in Hs578t cells reduced the size of 3D cellular structures. Moreover, APOB-knocked cells cocultured with adipocytes for 48h exhibited a significant decrease of intracellular lipids, whereas an increase in the adipocytes was found. Our results indicate that the 3D microenvironment and the adipocytes crosstalk reprogram the proteome of breast cancer cells. These data help us understand the environmental effects in gene expression and contribute to discovering novel tumor proteins with potential intervention in breast cancer therapy.

Nanoconjugate Carrying pH-Responsive Transferrin Receptor-Targeted Hesperetin Triggers Triple-Negative Breast Cancer Cell Death through Oxidative Attack and Assemblage of Pro-Apoptotic Proteins.

Triple-negative breast cancer (TNBC) is recognized as a major aggressive subtype of breast cancer due to its expeditious worsening growth, extensive metastatic capability, and recalcitrance to standard current treatments. Hesperetin (HSP), a natural bioflavonoid from citrus fruits, demonstrates pronounced anticancer efficacy, but its hydrophobicity limits its clinical development. The present study reports the fabrication of a biocompatible and pH-responsive transferrin (TF) receptor-targeted HSP-loaded poly(lactic-co-glycolic acid) (PLGA) nanobioconjugate (PLGA-HSP-TF NPs) and the exploration of its in vitro and in vivo antineoplastic potential. PLGA nanoparticles (NPs), PLGA-HSP NPs, and PLGA-HSP-TF NPs were synthesized and characterized by DLS, FTIR, FE-SEM, and 1H NMR spectroscopy. The stability and in vitro release profile of nanoparticles were inspected, and anticancer efficacy was scrutinized in terms of in vitro cytotoxicity, oxidative stress and apoptosis biomarkers, and cell cycle arrest. In vivo tumor regression and host survival studies were executed in Ehrlich ascites carcinoma (EAC) cell-bearing Swiss albino mice. The drug uptake of highly stable PLGA-HSP-TF NPs was accomplished effectively in MDA-MB-231 cells and showed the pH-dependent intracellular release of HSP, which generated excessive intracellular reactive oxygen species (ROS) that led to oxidative assault to the TNBC cells. This elevated ROS dropped the mitochondrial membrane potential and triggered apoptosis-mediated cell death by arresting the cell cycle at the G0/G1 phase. Furthermore, PLGA-HSP-TF NPs unveiled significant in vivo Ehrlich ascites carcinoma regression and host survival compared to free HSP with minimum toxicity at a minimum dose of 20 mg/kg body weight. The study divulges that PLGA-HSP-TF NPs may be an astounding anticancer nanocandidate for aggressive triple-negative breast cancer therapy.

Inhibition of GPX4 enhances CDK4/6 inhibitor and endocrine therapy activity in breast cancer.

CDK4/6 inhibition in combination with endocrine therapy is the standard of care for estrogen receptor (ER+) breast cancer, and although cytostasis is frequently observed, new treatment strategies that enhance efficacy are required. Here, we perform two independent genome-wide CRISPR screens to identify genetic determinants of CDK4/6 and endocrine therapy sensitivity. Genes involved in oxidative stress and ferroptosis modulate sensitivity, with GPX4 as the top sensitiser in both screens. Depletion or inhibition of GPX4 increases sensitivity to palbociclib and giredestrant, and their combination, in ER+ breast cancer models, with GPX4 null xenografts being highly sensitive to palbociclib. GPX4 perturbation additionally sensitises triple negative breast cancer (TNBC) models to palbociclib. Palbociclib and giredestrant induced oxidative stress and disordered lipid metabolism, leading to a ferroptosis-sensitive state. Lipid peroxidation is promoted by a peroxisome AGPAT3-dependent pathway in ER+ breast cancer models, rather than the classical ACSL4 pathway. Our data demonstrate that CDK4/6 and ER inhibition creates vulnerability to ferroptosis induction, that could be exploited through combination with GPX4 inhibitors, to enhance sensitivity to the current therapies in breast cancer.

Development and evaluation of folate-gelatin-poloxamer P407 copolymer nanogels for enhanced co-delivery of paclitaxel and curcumin in breast cancer therapy

Development and evaluation of folate-gelatin-poloxamer P407 copolymer nanogels for enhanced co-delivery of paclitaxel and curcumin in breast cancer therapy

Neoadjuvant chemotherapy in breast cancer: a retrospective pathway assessment in a regional cancer centre.

The optimal care pathway (OCP) for people with breast cancer provides a framework for investigation and management of patients with breast cancer, with delays previously identified regionally. With emphasis on the neoadjuvant pathway, the primary aim of this study was to assess the practicality of implementing the breast cancer OCP timeframes regionally in comparison to nationally referenced standards. A retrospective institutional audit was performed for patients undergoing neoadjuvant therapy for breast cancer. The time from referral to specialist review, completion of investigations, discussion at multidisciplinary team (MDT) meetings, initiation of neoadjuvant chemotherapy (NACT) and surgery were calculated and compared to OCP. Fifty-three patients were included, with 19 patients living rurally (36%). Twenty-four patients (45%) were seen by a specialist surgeon within 2 weeks of referral. Following surgical review, 44 patients (83%) completed investigations within 2 weeks, and 43 patient cases (81%) were discussed at MDT meetings within 2 weeks. Forty-eight patients (91%) were commenced on neoadjuvant treatment within 4 weeks of decision to treat, and 43 patients (81%) underwent surgery within 6 weeks of neoadjuvant treatment completion. Delays from initial referral to NACT were more frequent in rural patients compared to urban (79% vs 94%, P < 0.05). Adherence to OCP timeframes for patients undergoing neoadjuvant therapy in a regional centre was feasible and strategies are needed to bridge gaps identified for rural patients.

Preparation of transferrin-modified IR820-loaded liposomes and its effect on photodynamic therapy of breast cancer

ObjectiveTo prepare and characterize transferrin (Tf)-modified liposomes (Lipo) encapsulating the photosensitizing agent neoindocyanine green (IR820), and to investigate their effects on breast cancer 4T1 cells as well as in a breast cancer mouse model.MethodsPhotosensitive liposomes, IR820@Lipo and Tf-IR820@Lipo, were synthesized using thin film dispersion, with encapsulation efficiency assessed via UV detection. The physicochemical properties were analyzed using transmission electron microscopy (TEM) and particle size analysis. Uptake by breast cancer 4T1 cells was evaluated through confocal laser scanning microscopy and flow cytometry, while cell proliferation inhibition was measured using the CCK8 assay. Differences in intracellular fluorescence intensity were utilized to assess drug aggregation in vivo through small animal imaging techniques. The anticancer efficacy and potential side effects of the formulations were examined through pharmacodynamic studies conducted in vivo.ResultsThe mean particle sizes of IR820@Lipo and Tf-IR820@Lipo were found to be 84.30 ± 15.66 nm and 116.20 ± 14.68 nm respectively, with zeta potentials of −8.21 ± 2.06 mV for IR820@Lipo and −5.23 ± 1.19 mV for Tf-IR820@Lipo; TEM revealed that the liposomes exhibited a spheroid morphology with uniform distribution across samples; encapsulation efficiencies reached 86.38 ± 0.99% for IR820@Lipo and an impressive 93.81 ± 1.06% for Tf-IR820@Lipo; notably, Tf-IR820@Lipo significantly inhibited proliferation while promoting apoptosis of the 4T1 cells upon laser irradiation; reactive oxygen species (ROS) detection indicated enhanced fluorescence intensity within the treated cells under light exposure when utilizing both formulations; in vivo experiments demonstrated tumor accumulation of both IR820@Lipo and Tf-IR820@Lipo, indicating effective tumor targeting within a breast cancer mouse model; pharmacodynamic assessments revealed that Tf-IR820@Lipo exhibited superior inhibitory effects against breast cancer without causing liver or kidney dysfunctions in mice nor presenting significant toxic side effects overall.ConclusionGiven its high targeting capability, potent efficacy, and low toxicity profile, Tf-IR820@Lipo holds promise as a novel therapeutic agent for breast cancer treatment when combined with photodynamic therapy (PDT), potentially offering new avenues for patient management.

Real-world outcomes of pyrotinib-based therapy for HER2-positive breast cancer with brain metastases: A multicentre, retrospective analysis

Real-world outcomes of pyrotinib-based therapy for HER2-positive breast cancer with brain metastases: A multicentre, retrospective analysis

Camizestrant, a next-generation oral SERD, versus fulvestrant in post-menopausal women with oestrogen receptor-positive, HER2-negative advanced breast cancer (SERENA-2): a multi-dose, open-label, randomised, phase 2 trial

Resistance to endocrine therapies in hormone receptor-positive breast cancer is challenging. We aimed to assess the next-generation oral selective oestrogen receptor degrader (SERD) and complete oestrogen receptor antagonist, camizestrant, versus the first-approved SERD, fulvestrant, in post-menopausal women with oestrogen receptor-positive, HER2-negative, advanced breast cancer. SERENA-2 is an open-label, randomised, phase 2 trial that is being conducted at 74 study centres across Asia, Europe, the Middle East, and North America. Female patients aged 18 years or older who were post-menopausal with histologically or cytologically confirmed metastastic or locoregional oestrogen receptor-positive, HER2-negative breast cancer, an Eastern Cooperative Oncology Group or WHO performance status of 0 or 1, and disease recurrence or progression on at least one line of endocrine therapy, and no more than one previous endocrine therapy in the advanced setting. Patients were initially randomly assigned (1:1:1:1) to receive oral camizestrant once daily at 75 mg, 150 mg, or 300 mg (until the 300 mg group was closed), or fulvestrant intramuscularly at 500 mg (per label). Randomisation was managed through an interactive web-based system and stratified by previous treatment with CDK4/6 inhibitors and presence of liver and/or lung metastases. The primary objective was to determine clinical efficacy of camizestrant versus fulvestrant at each dose level using the primary endpoint of investigator-assessed progression-free survival, per Response Evaluation Criteria in Solid Tumours (version 1.1), assessed by intention to treat in all randomly assigned patients (full analysis set). No formal statistical comparison for the efficacy analysis of the camizestrant 300 mg dose versus fulvestrant was to be performed. Safety analyses included all randomly assigned patients who received at least one dose of study treatment. This study is registered with ClinicalTrials.gov, NCT04214288, and is ongoing. Between May 11, 2020, and Aug 10, 2021, 240 patients were randomly assigned to receive camizestrant 75 mg (n=74), 150 mg (n=73), 300 mg (n=20), or fulvestrant (n=73), and were included in the full analysis set. All patients received at least one dose of study drug. Median follow-up was 16·6 months (IQR 12·9-19·4) for the camizestrant 75 mg group, 16·3 months (12·9-18·3) for the camizestrant 150 mg group, and 14·7 months (12·7-20·1) for the fulvestrant 500 mg group. Median progression-free survival was 7·2 months (90% CI 3·7-10·9) with camizestrant 75 mg, 7·7 months (5·5-12·9) with camizestrant 150 mg, and 3·7 months (2·0-6·0) with fulvestrant. The hazard ratio for camizestrant 75 mg versus fulvestrant was 0·59 (90% CI 0·42-0·82; p=0·017), and the hazard ratio for camizestrant 150 mg versus fulvestrant was 0·64 (0·46-0·89; p=0·0090). Treatment-related adverse events occurred in 39 (53%) of 74 patients in the camizestrant 75 mg group, 49 (67%) of 73 patients in the camizestrant 150 mg group, 14 (70%) of 20 patients in the camizestrant 300 mg group, and 13 (18%) of 73 patients in the fulvestrant group. No single grade 3 or worse treatment-emergent adverse event occurred in more than two (3%) patients in any group. Serious treatment-emergent adverse events occurred in six (8%) patients in the camizestrant 75 mg group, seven (10%) patients in the camizestrant 150 mg group, two (10%) patients in the camizestrant 300 mg group, and four (5%) patients in the fulvestrant group. No treatment-related deaths occurred. Camizestrant at 75 and 150 mg showed a significant benefit in progression-free survival versus fulvestrant. These results support further development of camizestrant for the treatment of oestrogen receptor-positive, HER2-negative breast cancer. AstraZeneca.

Inavolisib-Based Therapy in PIK3CA-Mutated Advanced Breast Cancer

BackgroundInavolisib is a highly potent and selective inhibitor of the alpha isoform of the p110 catalytic subunit of the phosphatidylinositol 3-kinase complex (encoded by PIK3CA) that also promotes the degradation of mutated p110α. Inavolisib plus palbociclib–fulvestrant has shown synergistic activity in preclinical models and promising antitumor activity in early-phase trials.MethodsIn a phase 3, double-blind, randomized trial, we compared first-line inavolisib (at an oral dose of 9 mg once daily) plus palbociclib–fulvestrant (inavolisib group) with placebo plus palbociclib–fulvestrant (placebo group) in patients with PIK3CA-mutated, hormone receptor–positive, human epidermal growth factor receptor 2 (HER2)–negative locally advanced or metastatic breast cancer who had had relapse during or within 12 months after the completion of adjuvant endocrine therapy. The primary end point was progression-free survival as assessed by the investigator.ResultsA total of 161 patients were assigned to the inavolisib group and 164 to the placebo group; the median follow-up was 21.3 months and 21.5 months, respectively. The median progression-free survival was 15.0 months (95% confidence interval [CI], 11.3 to 20.5) in the inavolisib group and 7.3 months (95% CI, 5.6 to 9.3) in the placebo group (hazard ratio for disease progression or death, 0.43; 95% CI, 0.32 to 0.59; P<0.001). An objective response occurred in 58.4% of the patients in the inavolisib group and in 25.0% of those in the placebo group. The incidence of grade 3 or 4 neutropenia was 80.2% in the inavolisib group and 78.4% in the placebo group; grade 3 or 4 hyperglycemia, 5.6% and 0%, respectively; grade 3 or 4 stomatitis or mucosal inflammation, 5.6% and 0%; and grade 3 or 4 diarrhea, 3.7% and 0%. No grade 3 or 4 rash was observed. Discontinuation of any trial agent because of adverse events occurred in 6.8% of the patients in the inavolisib group and in 0.6% of those in the placebo group.ConclusionsIn patients with PIK3CA-mutated, hormone receptor–positive, HER2-negative locally advanced or metastatic breast cancer, inavolisib plus palbociclib–fulvestrant led to significantly longer progression-free survival than placebo plus palbociclib–fulvestrant, with a greater incidence of toxic effects. The percentage of patients who discontinued any trial agent because of adverse events was low. (Funded by F. Hoffmann–La Roche; INAVO120 ClinicalTrials.gov number, NCT04191499.)

Environment-friendly Synthesis of AgNPs from Fimbristylis miliacea Flower Extract: Characterization and its Applications as an Antioxidant Activity, Anticancerous Activity and in the Reduction of 4-Nitrophenol

Background: Silver metal is useful in a variety of fields. Different silver salts exhibit good application in the organic transformation. The use of a green methodology in AgNPs preparation has gained interest of young researchers. Plant systems are employed in the green approach of preparing AgNPs, serving as both a stabilizing and reducing agent. Silver nanoparticles (AgNPs) made from silver salts exhibit a variety of biological activities and may be useful in organic transformation. Method: AgNPs were synthesized with the use of flower extract from Fimbristylis miliacea, which acts as a stabilizing and reducing agent. Result: Fimbristylis miliacea flower extract is used as a reducing and stabilising agent for preparation of AgNPs. These synthesised AgNPs were characterised by using FTIR, XRD, FESEM/ EDS, HR-TEM, TGA, and ICP-AES. Fimbristylis milliciea flower extract was subjected to FTIR and HR-LCMS analysis in order to identify the phytoconstituents that are responsible for the reduction of AgNO3. The HR-TEM shows particle size between 8.98434+0.69669nm and 19.07464+1.4384nm. The size of AgNPs determined by using HR-TEM shows good agreement with XRD particle size. The synthesized AgNPs show excellent antioxidant properties with IC50=56.45 μg/mL. The present study confers significant cytotoxic activity against MDA-MB-231 human breast cancer cell line culture (IC50= 61.97 μg/ml). The AgNPs show a faster reduction of 4-nitrophenol. Conclusion: In conclusion, we have prepared AgNPs by using Fimbristylis miliacea flower extract. The study further concludes that green synthesis of AgNPs has many advantages as compared to chemical methods, such as cost-effectiveness, rapid, and environment-friendly methods. The results indicated that the biosynthesized AgNPs have significant cytotoxic activity against the MDA-MB-231 breast cancer cell line. Further, it indicates that biosynthesized AgNPs can be a potential alternative agent for human breast cancer therapy. The cytotoxic potential can be used for treatments and provides a new method to develop molecules for cancer therapy. The catalytic activity of AgNPs was examined by using the reduction of 4-nitrophenol. It shows that the reduction of 4-nitrophenol in 6 minutes is confirmed by using 1H NMR analysis.

Targeting PGK1: A New Frontier in Breast Cancer Therapy Under Hypoxic Conditions

Breast cancer represents one of the most prevalent malignant neoplasms affecting women, and its pathogenesis has garnered significant scholarly interest. Research indicates that the progression of breast cancer is intricately regulated by glucose metabolism. Under hypoxic conditions within the tumor microenvironment, breast cancer cells generate ATP and essential biosynthetic precursors for growth via the glycolytic pathway. Notably, phosphoglycerate kinase 1 (PGK1) is intimately associated with the regulation of hypoxia-inducible factors in breast cancer and plays a crucial role in modulating glycolytic processes. Further investigation into the role of PGK1 in breast cancer pathogenesis is anticipated to identify novel therapeutic targets and strategies. This review consolidates current research on the regulation of glucose metabolism and the function of PGK1 in breast cancer within hypoxic conditions. It aims to offer a significant theoretical foundation for elucidating the mechanisms underlying breast cancer progression and metastasis, thereby facilitating the development of innovative treatment approaches.

Reciprocal inhibition of NOTCH and SOX2 shapes tumor cell plasticity and therapeutic escape in triple-negative breast cancer.

Cancer cell plasticity contributes significantly to the failure of chemo- and targeted therapies in triple-negative breast cancer (TNBC). Molecular mechanisms of therapy-induced tumor cell plasticity and associated resistance are largely unknown. Using a genome-wide CRISPR-Cas9 screen, we investigated escape mechanisms of NOTCH-driven TNBC treated with a gamma-secretase inhibitor (GSI) and identified SOX2 as a target of resistance to Notch inhibition. We describe a novel reciprocal inhibitory feedback mechanism between Notch signaling and SOX2. Specifically, Notch signaling inhibits SOX2 expression through its target genes of the HEY family, and SOX2 inhibits Notch signaling through direct interaction with RBPJ. This mechanism shapes divergent cell states with NOTCH positive TNBC being more epithelial-like, while SOX2 expression correlates with epithelial-mesenchymal transition, induces cancer stem cell features and GSI resistance. To counteract monotherapy-induced tumor relapse, we assessed GSI-paclitaxel and dasatinib-paclitaxel combination treatments in NOTCH inhibitor-sensitive and -resistant TNBC xenotransplants, respectively. These distinct preventive combinations and second-line treatment option dependent on NOTCH1 and SOX2 expression in TNBC are able to induce tumor growth control and reduce metastatic burden.

Adding Metastasis-Directed Therapy to Standard-of-Care Systemic Therapy for Oligometastatic Breast Cancer (EXTEND): a Multicenter, Randomized Phase II Trial

PurposePrior evidence suggests a progression-free survival (PFS) benefit from adding metastasis-directed therapy (MDT) to standard-of-care (SOC) systemic therapy for patients with some oligometastatic solid tumors. Randomized trials testing this hypothesis in breast cancer have yet to be published. We sought to determine whether adding MDT to SOC systemic therapy improves PFS in oligometastatic breast cancer. MethodsEXTEND is a multicenter phase II randomized basket trial testing the addition of MDT to SOC systemic therapy in patients with ≤5 metastases (NCT03599765). Patients were randomized 1:1 to MDT (definitive local treatment to all sites of disease, plus SOC systemic therapy) or to SOC systemic therapy only. Primary endpoint was PFS, and secondary endpoints included overall survival (OS), time to subsequent line of systemic therapy, and time to the appearance of new metastases. Exploratory analyses included quality of life (QOL) and systemic immune response measures. ResultsFrom September 2018 through July 2022, 22 and 21 patients were randomized to the MDT and no-MDT arms, respectively. At a median follow-up of 24.8 months, PFS was not improved with the addition of MDT to SOC systemic therapy (median PFS 15.6 months MDT vs 24.9 months no-MDT [hazard ratio {HR} 0.91; 95% CI 0.34–2.48, p=0.86]). Similarly, MDT did not improve OS, time to subsequent line of systemic therapy, or time to the appearance of new metastases (all p>0.05). No significant differences were found in QOL measures, systemic T-cell activation, or T-cell stimulatory cytokine concentration. ConclusionAmong patients with oligometastatic breast cancer, the addition of MDT to SOC systemic therapy did not improve PFS. These findings suggest that MDT may have no systemic benefit in otherwise unselected oligometastatic breast cancer patients, although this trial was limited by a heterogenous and small sample size and overperformance of both treatment arms.

The Role of the Microbiome and of Radiotherapy-Derived Metabolites in Breast Cancer

The gut microbiome has emerged as a crucial player in modulating cancer therapies, including radiotherapy. In the case of breast cancer, the interplay between the microbiome and radiotherapy-derived metabolites may enhance therapeutic outcomes and minimize adverse effects. In this review, we explore the bidirectional relationship between the gut microbiome and breast cancer. We explain how gut microbiome composition influences cancer progression and treatment response, and how breast cancer and its treatments influence microbiome composition. A dual role for radiotherapy-derived metabolites is explored in this article, highlighting both their therapeutic benefits and potential hazards. By integrating genomics, metabolomics, and bioinformatics tools, we present a comprehensive overview of these interactions. The study provides real-world insight through case studies and clinical trials, while therapeutic innovations such as probiotics, and dietary interventions are examined for their potential to modulate the microbiome and enhance treatment effectiveness. Moreover, ethical considerations and patient perspectives are discussed, ensuring a comprehensive understanding of the subject. Towards revolutionizing treatment strategies and improving patient outcomes, the review concludes with future research directions. It also envisions integrating microbiome and metabolite research into personalized breast cancer therapy.

Evaluation of natural compounds as VEGFR-2 inhibitors for breast cancer therapy: insights from molecular docking and drug-likeness analysis

Breast cancer remains one of the most common cancers worldwide, with VEGFR-2 (KDR) playing a key role in tumor angiogenesis. Inhibiting VEGFR-2 is a promising therapeutic strategy. Natural compounds are increasingly studied for their potential to inhibit VEGFR-2. This study aims to assess the binding affinity of 11 natural compounds (andrographolide, alpha-mangostin, pinostrobin, pinocembrin, ethyl-p-methoxycinnamate (EPMS), xanthorrhizol, galangin, gamma-mangostin, curcumin, cinnamaldehyde, and alashanoid B) to the VEGFR-2 protein through molecular docking and Lipinski's rule analysis, identifying promising candidates for breast cancer treatment. Molecular docking simulations were performed for 11 compounds and sunitinib as a control, with binding energies and interactions analyzed. The compounds were also evaluated for drug-likeness using Lipinski’s rule of five. Curcumin showed the highest binding affinity to VEGFR-2 with a binding energy of -9.9 kcal/mol, surpassing sunitinib (-9.4 kcal/mol). Key interactions were observed with active site residues Cys919 and Asp1046. All tested compounds met the criteria for oral bioavailability per Lipinski’s rules. Curcumin demonstrates potential as a VEGFR-2 inhibitor due to its favorable binding affinity and drug-like properties. Enhancing curcumin’s bioavailability is recommended for effective therapeutic application.

Resveratrol‐Loaded Silver Nanoparticles as an Effective Strategy for Targeted Breast Cancer Therapy

AbstractThe AgNPs‐Rsvl complex was investigated for its anti‐cancer effects on human breast cancer cell lines. The UV–vis spectrophotometer was used to perform synthesized AgNPs‐Rsvl binding analyses. The size and morphology of the AgNPs were determined by field emission gun‐transmission electron microscopy (FEG‐TEM). The surface chemical signatures of AgNPs nanocomposites were assessed using FT‐IR spectroscopy, and the zeta potential (ζ potential) of various AgNPs colloids was measured using the Zetasizer Nano ZS analyzer. Cell proliferation was analyzed using the XTT method and cell apoptosis was analyzed using the AnnexinV‐fluorescein isothiocyanate (FITC)/PI method. The effects of resveratrol were evaluated on human breast cancer cell lines (MDA‐MB‐231 and MCF‐7). As a result of flow cytometry, a decrease in viability was observed in the MDA‐MB‐231 cells, and an increase in early apoptotic, late apoptotic, and necrotic values was observed. Resveratrol arrests the cell cycle in the G0/G1 phase but when used with AgNPs, the cell cycle arrests at the S phase. The combination of resveratrol and AgNPs exhibited a cytotoxic effect on cancer cells, with MDA‐MB‐231 breast cancer cells being the most sensitive to AgNPs‐Rsvl. Resveratrol and AgNPs arrested the cell cycle and increased apoptosis, indicating their potential use in breast cancer treatment.

Machine learning-guided synthesis of nanomaterials for breast cancer therapy

Breast cancer is a common malignant tumor, which mostly occurs in female population and is caused by excessive proliferation of breast epithelial cells. Breast cancer can cause nipple discharge, breast lumps and other symptoms, but these symptoms lack certain specificity and are easily confused with other diseases, thus affecting the early treatment of the disease. Once the tumor progresses to the advanced stage, distant metastasis can occur, leading to dysfunction of the affected organs, and even threatening the patients’ lives. In this study, we synthesized high drug-loading gel particles and applied them to control the release of insoluble drugs. This method is simple to prepare, cost-effective, and validates their potential in breast cancer therapy. We first characterized the morphology and physicochemical properties of gel loaded with newly synthesized compound 1 by scanning electron microscopy (SEM), Fourier-transform infrared spectroscopy (FT-IR), and thermal gravimetric analysis (TGA). Using newly synthesized insoluble compound 1 as a model drug, its efficacy in treating breast cancer was investigated. The results showed that hydrogel@compound 1 was able to significantly inhibit the proliferation, migration and invasion of breast cancer cells. Additionally, we utilized machine learning to screen three structurally similar compounds, which showed promising therapeutic effects, providing a new approach for the development of novel small-molecule drugs.

A Multicenter Physician Survey Evaluating the Use of Ki-67 in Breast Cancer Management in Canada

Background: Ki-67’s response to pre-operative endocrine therapy (ET) in early breast cancer is an evidence-based tool to guide adjuvant treatment decisions. Physicians across Canada were surveyed to explore current practice patterns and perceived barriers to the use of Ki-67 in practice. Methods: Physicians were invited to participate in an anonymous survey and were eligible if they prescribed systemic therapy for breast cancer in Canada. Respondents were asked to describe their usage of Ki-67, perceptions of the evidence surrounding Ki-67 ET response, and interest in future trials using this approach. Results: The survey received 48/163 responses (29.4%). The majority of respondents (97.6%) reported access to Ki-67 testing upon request. Treatment decisions for adjuvant Abemaciclib was the most common reason (97.6%), followed by adjuvant chemotherapy decisions (16.7%). Only 19.0% had used Ki-67’s response to pre-operative ET in practice. Common barriers to this approach that were identified included a lack of awareness from other providers (54.8%), an increased resource requirement (54.8%), and a lack of timely medical oncology consultation (52.4%). The majority of physicians (85.3%) reported that they would participate in future trials using the Ki-67 endocrine response, and that rate of treatment decision change (95.2%) and cost analysis (42.3%) were important endpoints. Conclusions: Despite the widespread availability of Ki-67 testing, few physicians in Canada currently use it to assess endocrine response, predominantly due to logistical and resource constraints. There is a high level of interest in participating in future trials using this strategy, which should focus on disease related outcomes, feasibility, and the financial impact on the public healthcare system.

Procedural findings and follow-up results of catheter ablation of atrial fibrillation in patients after radiation therapy for breast cancer

Abstract Backround Data on breast cancer radiation therapy (RT) associated atrial cardiomyopathy and its potential role in the pathophysiology of atrial fibrillation (AF) is very limited. Objectives To investigate the effect of breast cancer radiotherapy (RT) on atrial cardiomyopathy and its possible role in the pathophysiology of atrial fibrillation. What is the therapeutic success of antral pulmonary vein isolation (PVI) with possible substrate modifications (CFAE) in patients with breast cancer radiation therapy and paroxysmal or persistent atrial fibrillation. Methods We searched the institution’s data base for patients who received RT for breast cancer and underwent subsequently 3D mapping guided AF ablation. Intraprocedural mapping data and short- and long-term results of ablation were evaluated according to "no low voltage" and "low voltage" present. Low voltage amplitudes in bipolar electrograms were defined as &amp;lt;0.5 mV for endocardial maps created during SR and &amp;lt;0.3mV during AF. Ablation strategy comprised pulmonary vein isolation (PVI) ± additional substrate modification according to the mapping results. Follow Up (FU) was evaluated using repetitive 7-days Holter ECG and clinical visits. Results We included 45 patients (all female, 70.9±7.2 years) with paroxysmal or persistent AF (n=18 and n=27). In 3D mapping, 60% of the patients (27/45) showed left atrial low voltage (LV group) with the majority showing low voltage in the anterior wall of the left atrium (LA) in 18 of 45 patients (40%). PVI with ablation of complex fractionated signals (CFAE) was predominantly performed (18/27). After one ablation, 33.3% (9) of the patients in the LV group were recurrence-free and after an average of 1.9 ablations, freedom from recurrence was achieved in 21 patients with low voltage (77.8%). In 18 patients, no low voltage was detected (NLV group) and PVI only was performed in the majority (14/18). In this NLV group, 61.1% (11) of the patients were recurrence-free after one ablation and freedom from recurrence was achieved in 72.2% (13) after an average of 1.2 ablations. Conclusion Thoracic radiation therapy in patients with breast cancer can lead to low voltage in the LA with the predominant low voltage location being the anterior wall of the LA. An extended ablation strategy (PVI &amp; CFAE) can show good treatment options in these patients with atrial fibrillation, with high freedom from recurrence after a mean of two ablation procedures.Freedom from recurrence after ablationCharacteristics of left atrium (LA)

GD2 in Breast Cancer: A Potential Biomarker and Therapeutic Target.

Expression of disialoganglioside GD2 in normal tissues is primarily limited to the central nervous system, peripheral sensory nerve fibers, dermal melanocytes, lymphocytes, and mesenchymal stem cells. Its widespread overexpression in various cancer types allows it to be classified as a tumor-associated antigen with potential diagnostic and therapeutic implications. This article reviews the synthesis pathways of GD2 and its role in cancer cell adhesion, proliferation, and metastasis with a focus on breast cancer. GD2 appears to be overexpressed on the outer membrane of most breast cancer cells and breast cancer stem cells (BCSCs) and is closely linked to epithelial-mesenchymal transition (EMT). GD3 synthase (GD3S) is considered to be the rate-determining step in GD2 synthesis. Clinical studies indicate that GD2 expression is increased in 35-70% of breast cancer samples, with higher levels in triple-negative breast cancer (TNBC). This overexpression correlates with more aggressive tumor features and worse prognosis. Therapeutic targeting of GD2 with monoclonal antibodies (moABs) like dinutuximab and naxitamab has demonstrated anti-cancer activity in preclinical cancer models and human clinical trials against high-risk neuroblastoma reducing tumor growth and enhancing survival. GD2-specific chimeric antigen receptor (CAR) T-cell therapy and GD3S inhibition present other promising therapeutic strategies to improve clinical outcomes. Furthermore, GD2-targeted vaccines are currently being investigated in cancer therapy. This narrative review article underscores the critical role of GD2 in breast cancer pathogenesis and highlights the promising therapeutic opportunities it offers. It advocates for the initiation of clinical trials to further explore the potential of GD2-targeted treatment in combination with standard breast cancer therapies.