Therapy For Triple-negative Breast Cancer Research Articles

Targeting Receptor Tyrosine Kinases as a Novel Strategy for the Treatment of Triple-Negative Breast Cancer.

Triple-negative breast cancer (TNBC) comprises a group of aggressive and heterogeneous breast carcinoma. Chemotherapy is the mainstay for the treatment of triple-negative tumors. Nevertheless, the success of chemotherapeutic treatments is limited by their toxicity and development of acquired resistance leading to therapeutic failure and tumor relapse. Hence, there is an urgent need to explore novel targeted therapies for TNBC. Receptor tyrosine kinases (RTKs) are a family of transmembrane receptors that are key regulators of intracellular signaling pathways controlling cell proliferation, differentiation, survival, and motility. Aberrant activity and/or expression of several types of RTKs have been strongly connected to tumorigenesis. RTKs are frequently overexpressed and/or deregulated in triple-negative breast tumors and are further associated with tumor progression and reduced survival in patients. Therefore, targeting RTKs could be an appealing therapeutic strategy for the treatment of TNBC. This review summarizes the current evidence regarding the antitumor activity of RTK inhibitors in preclinical models of TNBC. The review also provides insights into the clinical trials evaluating the use of RTK inhibitors for the treatment of patients with TNBC.

Exploring the biological behavior and underlying mechanism of KITLG in triple-negative breast cancer.

The tyrosine-kinase receptor that is specified by the KIT locus is demarcated by KITLG. This multifaceted factor is instrumental during in-utero germ and neural cell maturation and hematopoiesis, ostensibly reflecting its role in facilitating cell migration. Concurrently, KITLG is prone to a mutation in germ cell tumors, entailing a presumed connection to tumorigenesis. Despite this, the intricacies of its function in breast cancer and the relevant mechanisms remain elusive. Multiple independent databases depict a consistently low expression of KITLG within tissues affected by triple-negative breast cancers (TNBC), a trend strongly coupled with reduced survival rates. Interestingly, non-triple-negative breast cancers exhibit a markedly high expression of KITLG compared to the norm. An initial analysis of the GEO database speculates that KITLG may serve as an oncogene suppressor in TNBC, hinting at varied roles for KITLG isoforms within this disease context. In conclusion, our preliminary analysis offers valuable insights into the role and expression pattern of KITLG in TNBC. We provide evidence supporting its consideration as a promising new prognostic marker, thereby potentially enriching therapeutic strategies for TNBC. Indeed, given the limited advances in molecularly targeted therapy for TNBC, a significant need exists for a more precise therapeutic approach and a comprehensive understanding of its inherent mechanisms of action.

Dual-targeting of tumor cells and subcellular endoplasmic reticulum via AgPPIX-based Janus nanoparticles for photodynamic/immunotherapy against TNBC.

Triple-negative breast cancer (TNBC) is known for its strong invasiveness, high recurrence rates, and poor prognosis. Heme oxygenase-1 (HO-1) is closely related to tumor invasion, metastasis, recurrence and formation of tumor immunosuppression. The expression of HO-1 is high in TNBC and low in normal tissues. In this study, AgPPIX was synthesized as a heme oxygenase-1 (HO-1) inhibitor and a photosensitizer for TNBC therapy. PDA nanoparticles were synthesized and modified with anti-CD24 and p-toluenesulfonamide (PTSC) on their both sides to obtain PTSC@AgPPIX/PDA@anti-CD24 Janus nanoparticles (PAPC) for AgPPIX-targeted delivery. Anti-CD24 is targeted to CD24 on tumor cells and the PTSC moiety is targeted to endoplasmic reticulum (ER), where HO-1 is located. The results indicated that PAPC Janus nanoparticles exhibited higher cytotoxicity in 4T1 cells than that of the mono-modified nanoparticles. PAPC not only inhibited the expression of HO-1 and VEGF but also reduced TrxR activity significantly. Furthermore, PAPC not only promoted intracellular ROS production under laser irradiation for tumor photodynamic therapy (PDT) but also polarized TAMs from M2-type to M1 for tumor immunotherapy. In vivo experiments confirmed that PAPC could remodel the tumor immune microenvironment and almost completely inhibit the tumor growth in mouse models. Therefore, PAPC Janus nanoparticles are a promising nanoplatform with a dual-targeting capacity for TNBC immune/PDT synergistic therapy.

Gradient Rotating Magnetic Fields Impairing F-Actin-Related Gene CCDC150 to Inhibit Triple-Negative Breast Cancer Metastasis by Inactivating TGF-β1/SMAD3 Signaling Pathway.

Triple-negative breast cancer (TNBC) is the most aggressive and lethal malignancy in women, with a lack of effective targeted drugs and treatment techniques. Gradient rotating magnetic field (RMF) is a new technology used in oncology physiotherapy, showing promising clinical applications due to its satisfactory biosafety and the abundant mechanical force stimuli it provides. However, its antitumor effects and underlying molecular mechanisms are not yet clear. We designed two sets of gradient RMF devices for cell culture and animal handling. Gradient RMF exposure had a notable impact on the F-actin arrangement of MDA-MB-231, BT-549, and MDA-MB-468 cells, inhibiting cell migration and invasion. A potential cytoskeleton F-actin-associated gene, CCDC150, was found to be enriched in clinical TNBC tumors and cells. CCDC150 negatively correlated with the overall survival rate of TNBC patients. CCDC150 promoted TNBC migration and invasion via activation of the transforming growth factor β1 (TGF-β1)/SMAD3 signaling pathway invitro and invivo. CCDC150 was also identified as a magnetic field response gene, and it was marked down-regulated after gradient RMF exposure. CCDC150 silencing and gradient RMF exposure both suppressed TNBC tumor growth and liver metastasis. Therefore, gradient RMF exposure may be an effective TNBC treatment, and CCDC150 may emerge as a potential target for TNBC therapy.

Chitotriose Enhanced Antitumor Activity of Doxorubicin through Egr1 Upregulation in MDA-MB-231 Cells.

Dietary supplementation is proposed as a strategy to reduce the side effects of conventional chemotherapy for triple-negative breast cancer (TNBC). Chitosan oligosaccharides (COS), a functional carbohydrate, have been identified to potentially inhibit cancer cell proliferation. However, a detailed investigation is required to fully understand its exact influence, particularly in terms of COS composition. The antitumor activities of COS oligomers and its monomer of glucosamine, when combined with doxorubicin separately, were evaluated in MDA-MB-231 cells. Chitotriose was identified to have the most significant synergistic effect. Preincubation with chitotriose was observed to promote the entry of doxorubicin into the cell nuclei and induce morphological changes in the cells. Mechanism analysis at the transcriptional level revealed that the early growth response 1 (Egr1) gene was a key regulator in enhancing the suppressive effect. This gene was found to modulate the activity of its downstream gene, growth arrest, and DNA damage-inducible alpha (Gadd45a). The role of Egr1 was confirmed through a small interfering RNA test and function assay. These findings provide insight into the effect and underlying mechanism of chitotriose supplementation for TNBC therapy.

Targeting Metabolic Pathways Improves TNBC Therapy

Breast cancer (BC) accounts for a significant proportion of female tumor cases globally. Triple-negative breast cancer (TNBC) is its most difficult variant, which is defined by the absence of the estrogen receptor, progesterone receptor, and HER2 expression. Aerobic glycolysis (Warburg effect) plays a pivotal role in TNBC, influencing both tumor microenvironment and immune responses. TNBC cells undergo metabolic reprogramming, favoring glycolysis over oxidative phosphorylation for energy production, leading to lactate accumulation and extracellular acidification in the tumor milieu, which exacerbates tumor proliferation, metastasis, and immunosuppression. This review delves into key glycolytic enzymes and regulators, including hexokinase, phosphofructokinase, pyruvate kinase M2, lactate dehydrogenase, and monocarboxylate transporters, as potential therapeutic targets. Highlighting promising preclinical evidence and clinical studies utilizing glycolytic pathway modulators, the review underscores their potential to reduce TNBC cell viability, curb growth, inhibit metastasis, and enhance chemosensitivity. Chemotherapy is still the most commonly used systemic treatment for TNBC, although immunotherapy, especially employing PD-1 and PD-L1 inhibitors, has advanced despite obstacles in the metastatic setting due to TNBC heterogeneity and changed immunogenicity. This review underscores the urgent need for tailored, effective therapies for TNBC patients, especially those with metastatic disease, shedding light on strategies to harness glycolysis for improving treatment outcomes.

Ferroptosis Inducers Upregulate PD-L1 in Recurrent Triple-Negative Breast Cancer.

(1) Background: Triple-negative breast cancer (TNBC) is a distinct subgroup of breast cancer presenting a high level of recurrence, and neo-adjuvant chemotherapy is beneficial in its therapy management. Anti-PD-L1 immunotherapy improves the effect of neo-adjuvant therapy in TNBC. (2) Methods: Immune-modulation and ferroptosis-related R-packages were developed for integrative omics analyses under ferroptosis-inducer treatments: TNBC cells stimulated with ferroptosis inducers (GSE173905, GSE154425), single cell data (GSE191246) and mass spectrometry on breast cancer stem cells. Clinical association analyses were carried out with breast tumors (TCGA and METABRIC cohorts). Protein-level validation was investigated through protein atlas proteome experiments. (3) Results: Erastin/RSL3 ferroptosis inducers upregulate CD274 in TNBC cells (MDA-MB-231 and HCC38). In breast cancer, CD274 expression is associated with overall survival. Breast tumors presenting high expression of CD274 upregulated some ferroptosis drivers associated with prognosis: IDO1, IFNG and TNFAIP3. At the protein level, the induction of Cd274 and Tnfaip3 was confirmed in breast cancer stem cells under salinomycin treatment. In a 4T1 tumor treated with cyclophosphamide, the single cell expression of Cd274 was found to increase both in myeloid- and lymphoid-infiltrated cells, independently of its receptor Pdcd1. The CD274 ferroptosis-driver score computed on a breast tumor transcriptome stratified patients on their prognosis: low score was observed in the basal subgroup, with a higher level of recurrent risk scores (oncotypeDx, ggi and gene70 scores). In the METABRIC cohort, CD274, IDO1, IFNG and TNFAIP3 were found to be overexpressed in the TNBC subgroup. The CD274 ferroptosis-driver score was found to be associated with overall survival, independently of TNM classification and age diagnosis. The tumor expression of CD274, TNFAIP3, IFNG and IDO1, in a biopsy of breast ductal carcinoma, was confirmed at the protein level (4) Conclusions: Ferroptosis inducers upregulate PD-L1 in TNBC cells, known to be an effective target of immunotherapy in high-risk early TNBC patients who received neo-adjuvant therapy. Basal and TNBC tumors highly expressed CD274 and ferroptosis drivers: IFNG, TNFAIP3 and IDO1. The CD274 ferroptosis-driver score is associated with prognosis and to the risk of recurrence in breast cancer. A potential synergy of ferroptosis inducers with anti-PD-L1 immunotherapy is suggested for recurrent TNBC.

Self‐Promoted Targeting Delivery of Nanodrug Through Chemotherapeutic Upregulation of CD47 for Triple Negative Breast Cancer Therapy

AbstractThe high heterogeneity of receptor expression and varied chemotherapeutic sensitivity seriously compromise the therapeutic outcome of triple‐negative breast cancer (TNBC)‐targeting nanodrugs. In this work, a TNBC‐targeting nanodrug (designated as CPU) equipped with self‐promoted targeting property through chemotherapeutic upregulation of CD47 is constructed, enabling synergistic chemo/photodynamic therapy. Specifically, the hydrophobic docetaxel (DOC), which can upregulate the expression of CD47 in TNBC cells, is loaded in the nanomicelles (designated as P‐Pep) assembled from a protoporphyrin IX (PPIX)‐labeled amphiphilic chimeric peptide of Fmoc‐K(PPIX)‐AWSATWSNYWRH, obtaining the ca. 196 nm CPU. Aided by the enhanced permeability and retention effect and guidance of CD47‐binding peptide sequence, CPU is verified to prefer to accumulate in CD47 overexpressed TNBC cells, which can recruit more CPU by upregulating CD47 expression post‐treatment of DOC. Both in vitro and in vivo results demonstrate the superior tumor targeting ability, which can extensively amplify chemotherapeutic and photodynamic therapeutic effects while evading obvious adverse effects. The self‐promoted targeting strategy will inspire the design of nanodrugs for the personalized therapy of tumors with high heterogeneity and resistance.

Phytochemical Small Molecules as Potential Anti-angiogenesis Targeted Therapy for Triple-Negative Breast Cancer

Phytochemical Small Molecules as Potential Anti-angiogenesis Targeted Therapy for Triple-Negative Breast Cancer

Estrogen receptor beta suppresses the androgen receptor oncogenic effects in triple-negative breast cancer.

Triple-negative breast cancer (TNBC) is an aggressive type of breast cancer associated with poor prognosis and limited treatment options. The androgen receptor (AR) has emerged as a potential therapeutic target for luminal androgen receptor (LAR) TNBC. However, multiple studies have claimed that anti-androgen therapy for AR-positive TNBC only has limited clinical benefits. This study aimed to investigate the role of AR in TNBC and its detailed mechanism. Immunohistochemistry and TNBC tissue sections were applied to investigate AR and nectin cell adhesion molecule 4 (NECTIN4) expression in TNBC tissues. Then, in vitro and in vivo assays were used to explore the function of AR and estrogen receptor beta (ERβ) in TNBC. Chromatin immunoprecipitation sequencing (ChIP-seq), co-immunoprecipitation (co-IP), molecular docking method, and luciferase reporter assay were performed to identify key molecules that affect the function of AR. Based on the TNBC tissue array analysis, we revealed that ERβ and AR were positive in 21.92% (32/146) and 24.66% (36/146) of 146 TNBC samples, respectively, and about 13.70% (20/146) of TNBC patients were ERβ positive and AR positive. We further demonstrated the pro-tumoral effects of AR on TNBC cells, however, the oncogenic biology was significantly suppressed when ERβ transfection in LAR TNBC cell lines but not in AR-negative TNBC. Mechanistically, we identified that NECTIN4 promoter -42bp to -28bp was an AR response element, and that ERβ interacted with AR thus impeding the AR-mediated NECTIN4 transcription which promoted epithelial-mesenchymal transition in tumor progression. This study suggests that ERβ functions as a suppressor mediating the effect of AR in TNBC prognosis and cell proliferation. Therefore, our current research facilitates a better understanding of the role and mechanisms of AR in TNBC carcinogenesis.

TRPML1 as a potential therapeutic target for triple-negative breast cancer: a review.

Triple-negative breast cancer (TNBC) is the most refractory subtype of breast cancer, and effective treatments are urgently needed owing to its poor prognosis. Surgery, radiotherapy, and chemotherapy, alone or in combination, are the leading choices for TNBC therapy. Although promising approaches and procedures have emerged, several challenges, such as off-target effects, drug resistance, and severe side effects, remain to be addressed. Recently, transient receptor potential channel mucolipin 1 (TRPML1) has attracted the attention of researchers because its expression has been implicated in numerous diseases, including cancer. TRPML1 regulates biological events and signaling pathways, including autophagic flux, exocytosis, ionic homeostasis, and lysosomal biogenesis, all contributing to tumorigenesis and cancer progression. TRPML1 also functions as a building block for cancer cell growth, mitogenic signaling, priming tissues for metastasis, and activation of transcriptional programs, processes involved in several malignant tumors. This review provides an overview of breast cancer epidemiology and diagnostic techniques and then discusses the existing therapeutics. Additionally, we elaborate on the development of, and associated challenges to, TNBC diagnostics and treatment and the feasibility of TRPML1 as a therapeutic target for TNBC.

Modulation of glucose metabolism through macrophage-membrane-coated metal-organic framework nanoparticles for triple-negative breast cancer therapy

The clinical presentation of triple-negative breast cancer signifies a pathophysiological trajectory characterized by an aggressive nature. To satisfy the rapid tumor cell proliferation, glycolysis emerges as the primary modality for energy production, consequently engendering the copious generation of lactic acid. This, in turn, fosters an acidic microenvironment within the tumor milieu, which facilitates angiogenesis, tumor metastasis, extracellular matrix remodeling, and immune evasion. If the glycolytic flux was attenuated, a heightened influx of glucose-6-phosphate (G6P) towards the pentose phosphate pathway (PPP) ensues, promoting the synthesis of nicotinamide adenine dinucleotide phosphate (NADPH) and reduced glutathione (GSH). This orchestrated metabolic cascade gives rise to reductive equivalents and biosynthetic substrates, emblematic of a salient hallmark in the landscape of cancer cell metabolism. To surmount the quandary presented by aberrant tumor metabolism, we developed macrophage-membrane-coated metal–organic framework nanoparticles (AP@ZIF-Mem) to deliver atorvastatin (an inhibitor of MCT4, a lactic acid transporter within glycolysis) and polydatin (an inhibitor of G6PD, the rate-limiting enzyme of PPP) to interfere the glucose metabolism for sensitizing triple-negative breast cancer treatment. After i.v. injection, AP@ZIF-Mem could be accumulated into the tumor site via macrophage-biomimetic behavior. Through orchestrated intervention, these nanoparticles could provoke the accumulation of lactic acid within tumor cells, thereby precipitating a pronounced intratumoral acidosis; In parallel, the abrogation of G6PD function occasioned a surge in intracellular reactive oxygen species (ROS), consequentially culminating in diminished ribulose-5-phosphate and NADPH production. This dual-pronged intervention not only disrupted the tumor's energy provisioning framework but also perturbed the aberrant redox state of the tumor milieu, thereby sensitizing tumor treatment and impeding the metastatic trajectory. This study provided a paradigm of treatment/adjuvant treatment via the manipulation of glucose metabolism for triple-negative breast cancer.

Disclosing a metabolic signature of cisplatin resistance in MDA-MB-231 triple-negative breast cancer cells by NMR metabolomics

This work compared the metabolic profile of a parental MDA-MB-231 cisplatin-sensitive triple negative breast cancer (TNBC) cell line with that of a derived cisplatin-resistant line, to characterize inherent metabolic adaptations to resistance, as a means for marker and new TNBC therapies discovery. Supported by cytotoxic, microscopic and biochemical characterization of both lines, Nuclear Magnetic Resonance (NMR) metabolomics was employed to characterize cell polar extracts for the two cell lines, as a function of time (0, 24 and 48 h), and identify statistically relevant differences both between sensitive and resistant cells and their time course behavior. Biochemical results revealed a slight increase in activation of the NF-κB pathway and a marked decrease of the ERK signaling pathway in resistant cells. This was accompanied by lower glycolytic and glutaminolytic activities, possibly linked to glutamine being required to increase stemness capacity and, hence, higher survival to cisplatin. The TCA cycle dynamics seemed to be time-dependent, with an apparent activation at 48 h preferentially supported by anaplerotic aromatic amino acids, leucine and lysine. A distinct behavior of leucine, compared to the other branched-chain-amino-acids, suggested the importance of the recognized relationship between leucine and in mTOR-mediated autophagy to increase resistance. Suggested markers of MDA-MB-231 TNBC cisplatin-resistance included higher phosphocreatine/creatine ratios, hypotaurine/taurine–mediated antioxidant protective mechanisms, a generalized marked depletion in nucleotides/nucleosides, and a distinctive pattern of choline compounds. Although the putative hypotheses generated here require biological demonstration, they pave the way to the use of metabolites as markers of cisplatin-resistance in TNBC and as guidance to develop therapies.

Identifying candidate drugs based on transcriptional landscape associated with triple-negative breast cancer

Triple-negative breast cancer (TNBC) is a special type of breast cancer in which ER, PR and HER2 are all negative, characterized by high malignancy, strong invasiveness, and high recurrence rate. It is critical to develop novel drugs for improved therapies for triple-negative breast cancers. Here, we unveiled the transcriptional landscape associated with triple-negative breast cancer and identified candidate drugs using a comprehensive connectivity map. The candidate components could induce reverse expressions of the TNBC gene expression signature and trigger transcriptional reprogramming with a positive impact on modulating chemoresistance and the survival probability of breast cancer patients. Our study also provided an example of drug discovery using in silico drug screening followed by further validations, illustrating an effective computational drug discovery strategy.

EE210 Cost-Effectiveness Analysis of Pembrolizumab Plus Chemotherapy as Neoadjuvant Therapy and Continued as a Single Agent as Adjuvant Therapy for High-Risk Early-Stage Triple-Negative Breast Cancer in Greece

EE210 Cost-Effectiveness Analysis of Pembrolizumab Plus Chemotherapy as Neoadjuvant Therapy and Continued as a Single Agent as Adjuvant Therapy for High-Risk Early-Stage Triple-Negative Breast Cancer in Greece

Abstract C146: VIC-1911, a selective Aurora kinase A inhibitor, synergizes with sacituzumab govitecan in triple-negative breast cancer

Abstract BACKGROUND: Triple-negative breast cancer (TNBC) accounts for 15-20% of breast cancer cases and 30-40% of U.S. breast cancer deaths. Although current precision treatments improve TNBC patient outcomes, TNBC heterogeneity has led to therapeutic targeting challenges. Also, the resistance of TNBC to conventional treatment remains a significant clinical problem. Therefore, informed evaluation of new targets can improve the treatment of TNBC, representing an unmet need. Dysregulation of the cell cycle is a hallmark of cancer for unlimited proliferation. Abnormal mitosis and cell-cycle checkpoints are crucial in leading to aneuploidy and genetic instability. Aurora kinase A (AURKA), a serine/threonine kinase, regulates mitosis in the early stages (G2/M phase) by regulating centrosome maturation and disjunction, thereby establishing a bipolar mitotic spindle. VIC-1911 (previously known as TAS-119), a novel, orally active, highly selective inhibitor of AURKA with a low toxicity profile, suppresses the growth of various cancer cell lines in vitro and in vivo. As AURKA can modulate DNA damage response, we hypothesized that VIC-1911 combined with sacituzumab govitecan (SG), which has a topoisomerase 1 inhibitor as a payload, has a synergistic antitumor effect on TNBC. MATERIALS AND METHODS: To evaluate the short-term in vitro efficacy of VIC-1911 alone and combination with SG, a sulforhodamine B cell proliferation assay was performed using 10 TNBC cell lines. For long-term treatment conditions, a colony formation assay was conducted. Western blot and immunofluorescent analyses were conducted to confirm treatment-mediated DNA damage and apoptosis. Human TNBC cell line–derived mammary fat pad xenograft models were used to evaluate the antitumor effect of VIC-1911 and SG. RESULTS: In vitro proliferation, data demonstrated that single-agent VIC-1911 had a nanomolar to micromolar range of half-maximal inhibitory concentrations (2.69 nM to 10.6 mM) in the tested TNBC cell lines. The half-maximal inhibitory concentration was correlated with c-Myc expression (R2=0.4876, p=0.0247). Exposure to the combination of VIC-1911 and SG led to significant death of VIC-1911–sensitive TNBC cell lines (p<0.05). Western blot and immunofluorescent analysis revealed that VIC-1911 and SG combination caused TNBC cell death by inducing expression of phosphorylated histone H2AX (DNA damage marker) and cleaved poly (ADP-ribose) polymerase (apoptosis marker). Furthermore, the combination of VIC-1911 and SG had significantly greater antitumor efficacy than did either agent alone in SUM149 TNBC xenograft models (tumor growth inhibition rate (TGI): VIC-1911, 61.4%; SG, 68.3%; combination, 82.9%; p<0.01) and HCC1806 TNBC xenograft models (TGI: VIC-1911, 49.3%; SG, 66.3%; combination, 85.9%; p<0.01). CONCLUSION: The AURKA inhibitor VIC-1911 has a synergistic antitumor effect with SG by inducing DNA damage in TNBC cells. PDX and additional mechanistic studies are planned to further evaluate VIC-1911 and SG as novel combination therapy for TNBC. Citation Format: Jangsoon Lee, YoungJin Gi, Thomas Myers, Linda Paradiso, Debu Tripathy, Naoto T. Ueno. VIC-1911, a selective Aurora kinase A inhibitor, synergizes with sacituzumab govitecan in triple-negative breast cancer [abstract]. In: Proceedings of the AACR-NCI-EORTC Virtual International Conference on Molecular Targets and Cancer Therapeutics; 2023 Oct 11-15; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2023;22(12 Suppl):Abstract nr C146.

Abstract B005: In-silico identification of oxa/thiazole carboxamides as potential breast cancer therapeutic agents with vascular endothelial growth factor receptor-2 (VEGFR-2) inhibitory effect

Abstract Vascular Endothelial Growth Factor Receptor (VEGFR-2) is a tyrosine kinase receptor mainly known to be expressed in vascular endothelial cells. Overexpression of VEGFER-2 has been linked to tumor angiogenesis, necessitating the need for VEGFER-2 inhibitors. In-silico screening of oxa/thiazole carboxamide scaffold-bearing compounds retrieved from the ZINC database was conducted to identify potential anticancer agents with VEGFR-2 inhibitory effect. The interaction of VEGFR2 with tivozanib was used to generate a six-point pharmacophore model for screening ZINC chemical database. The virtual screening for potential VEGFR2 inhibitors generated 48 hits. The hits were filtered and ranked using molecular docking, drug-likeness, and absorption, distribution, metabolism, and excretion (ADME) protocols. The molecular docking results displayed ten compounds that adapted a similar binding mode and orientation within the active site of the VEGFR2 receptor. The molecular dynamic (MD) simulation analysis of the best hit, 3C, was carried out to validate the docking data. The RMSD and RMSF analysis was used to explain the stability of the VEGFR2 and 3c during the 50 ns simulation trajectory. The MD output revealed that the complex maintained conformational stability and consistent flexibility throughout the run. The results of the docking and simulation techniques supported each other. Thus, 3c emerged as a promising oxa/thiazole carboxamide-carrying lead molecule in our search for potential triple-negative breast cancer therapy. Citation Format: Steven M. Ewell, Getinet Mequanint, Donald Sikazwe, Kinfe Redda, Bereket Mochona. In-silico identification of oxa/thiazole carboxamides as potential breast cancer therapeutic agents with vascular endothelial growth factor receptor-2 (VEGFR-2) inhibitory effect [abstract]. In: Proceedings of the 16th AACR Conference on the Science of Cancer Health Disparities in Racial/Ethnic Minorities and the Medically Underserved; 2023 Sep 29-Oct 2;Orlando, FL. Philadelphia (PA): AACR; Cancer Epidemiol Biomarkers Prev 2023;32(12 Suppl):Abstract nr B005.

Multifunctional nanoparticles inhibit tumor and tumor-associated macrophages for triple-negative breast cancer therapy

HypothesisTumor-associated macrophages (TAM) are the mainstay of immunosuppressive cells in the tumor microenvironment, and elimination of M2-type macrophages (M2-TAM) is considered as a potential immunotherapy. However, the interaction of breast cancer cells with macrophages hinders the effectiveness of immunotherapy. In order to improve the efficacy of triple-negative breast cancer (TNBC) therapy, strategies that simultaneously target the elimination of M2-TAM and breast cancer cells may be able to achieve a better therapy. ExperimentsLyP-SA/AgNP@Dox multifunctional nanoparticles were synthesized by electrostatic adsorption. They were characterized by particle size, potential and spectroscopy. And the efficacy of multifunctional nanoparticles was evaluated in 4 T1 cell lines and M2 macrophages, including their cell uptake intracellular reactive oxygen species (ROS) production and the therapeutic effect. Furthermore, based on the orthotopic xenotransplantation model of triple negative breast cancer, the biological distribution, fluorescence imaging, biosafety evaluation and combined efficacy evaluation of the nanoplatform were performed. FindingsWe have successfully prepared LyP-SA/AgNP@Dox and characterized. Administering the nanosystem to 4 T1 tumor cells or M2 macrophages in culture induced accumulation of reactive oxygen species, destruction of mitochondria and apoptosis, and inhibited replication and transcription. Animal experiments demonstrated the nanoparticle had favorable targeting and antitumor activity. Our nanosystem may be useful for simultaneously inhibiting tumor and tumor-associated macrophages in breast cancer and, potentially, other malignancies.

Selective inhibition of CDK9 in triple negative breast cancer

Targeted therapy for triple-negative breast cancers (TNBC) remains a clinical challenge due to tumour heterogeneity. Since TNBC have key features of transcriptionally addicted cancers, targeting transcription via regulators such as cyclin-dependent kinase 9 (CDK9) has potential as a therapeutic strategy. Herein, we preclinically tested a new selective CDK9 inhibitor (CDDD11-8) in TNBC using cell line, patient-derived organoid, and patient-derived explant models. In vitro, CDDD11-8 dose-dependently inhibited proliferation (IC50 range: 281–734 nM), induced cell cycle arrest, and increased apoptosis of cell lines, which encompassed the three major molecular subtypes of TNBC. On target inhibition of CDK9 activity was demonstrated by reduced RNAPII phosphorylation at a CDK9 target peptide and down-regulation of the MYC and MCL1 oncogenes at the mRNA and protein levels in all cell line models. Drug induced RNAPII pausing was evident at gene promoters, with strongest pausing at MYC target genes. Growth of five distinct patient-derived organoid models was dose-dependently inhibited by CDDD11-8 (IC50 range: 272–771 nM), including three derived from MYC amplified, chemo-resistant TNBC metastatic lesions. Orally administered CDDD11-8 also inhibited growth of mammary intraductal TNBC xenograft tumours with no overt toxicity in vivo (mice) or ex vivo (human breast tissues). In conclusion, our studies indicate that CDK9 is a viable therapeutic target in TNBC and that CDDD11-8, a novel selective CDK9 inhibitor, has efficacy in TNBC without apparent toxicity to normal tissues.

Core Needle Biopsies as an Alternative Source for Ex Vivo Expanded TIL for Adoptive Cell Therapy in Triple-Negative Breast Cancer.

Adoptive transfer of ex vivo expanded tumor-infiltrating lymphocytes (TILs) have produced long-term response in metastatic cancers. TILs have traditionally been expanded from surgically resected specimens. Ultrasound-guided core needle biopsy (CNB) is an alternative method that avoids the morbidity of surgery and have added benefits which may include patients not amenable to surgery as well as the potential to produce TILs from multiple lesions in the same patient. We assessed the ability to produce and expand TILs from primary triple-negative breast cancer tumors from CNB (n=7) and demonstrate comparable expansion, phenotype and cytokine secretion after phorbol myristate acetate-ionomycin stimulation to TILs expanded from surgery (n=6). T cell Receptor clonality and diversity were also comparable between the two cohorts throughout the TIL culture. CNB is a safe and feasible method to obtain tumor tissue for TIL generation in patients with triple-negative breast cancer.