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Hermawan A, Hanif N, Putri DDP, Fatimah N, Prasetio HH. Citrus flavonoids for overcoming breast cancer resistance to methotrexate: identification of potential targets of nobiletin and sinensetin. Discov Oncol 2025; 16:365. [PMID: 40111633 PMCID: PMC11926326 DOI: 10.1007/s12672-025-02116-y] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/14/2024] [Accepted: 03/11/2025] [Indexed: 03/22/2025] Open
Abstract
Breast cancer is a potentially fatal illness that affects millions of women worldwide. Methotrexate (MTX) may be beneficial for treating breast cancer; however, high doses and prolonged use can cause drug resistance. Although certain citrus flavonoids-nobiletin, sinensetin, tangeretin, hesperidin, hesperetin, and naringenin-may overcome resistance to chemotherapy, no study has investigated MTX resistance. This study investigated the potential of natural chemicals, specifically nobiletin and sinensetin, to overcome MTX resistance in breast cancer cells using MTX-resistant MCF-7 (MCF-7/MTX) and MCF-7 cells. Protein targets of citrus flavonoids were identified from multiple databases and were collected using Venny 2.1. Microarray data of MCF-7 and MCF-7/MTX cells were acquired from the Gene Expression Omnibus. Subsequently, we constructed a protein-protein interaction network and selected the hub proteins. Gene ontology and Kyoto Encyclopedia of Genes and Genomes pathway enrichment analysis, drug- and disease-gene enrichment analyses, genetic alteration examination, receiver operating characteristic curve analysis, mRNA levels analysis, prognostic value analysis, and molecular docking analysis were performed along with in vitro experiments. Cytotoxicity of citrus flavonoids (individually and combined) was assessed in MCF-7/MTX cells. Nobiletin and sinensetin significantly enhanced the cytotoxicity of MTX in MCF-7/MTX cells. BCL2L1, CDK1, EGFR, PTGS2, PLK1, MMP2, ACHE, ABCG2, and KIT genes were enriched in cholinesterase activity, cell cycle regulation, and the PI3K/Akt signaling pathway. Nobiletin and sinensetin impeded PLK1, CDK1, and ACHE activities based on molecular docking. Nobiletin and sinensetin in combination with MTX may overcome breast cancer cell resistance to MTX.
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Affiliation(s)
- Adam Hermawan
- Laboratory of Macromolecular Engineering, Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Universitas Gadjah Mada, Yogyakarta, Indonesia.
- Laboratory of Advanced Pharmaceutical Sciences, Faculty of Pharmacy, Universitas Gadjah Mada, Yogyakarta, Indonesia.
| | - Naufa Hanif
- Doctoral Student, School of Pharmacy, Institut Teknologi Bandung, Bandung, Indonesia
| | - Dyaningtyas Dewi Pamungkas Putri
- Laboratory of Advanced Pharmaceutical Sciences, Faculty of Pharmacy, Universitas Gadjah Mada, Yogyakarta, Indonesia
- Laboratory of Pharmacology and Toxicology, Department of Pharmacology and Clinical Pharmacy, Faculty of Pharmacy, Universitas Gadjah Mada, Yogyakarta, Indonesia
| | - Nurul Fatimah
- Laboratory of Advanced Pharmaceutical Sciences, Faculty of Pharmacy, Universitas Gadjah Mada, Yogyakarta, Indonesia
| | - Heri Himawan Prasetio
- Laboratory of Macromolecular Engineering, Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Universitas Gadjah Mada, Yogyakarta, Indonesia
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Houcine Y, Ben Salem H, El Fekih S, Maaoui A, Driss M. Immunohistochemical expression of epidermal growth factor receptor: prognostic value in HER2 positive breast cancer. J Immunoassay Immunochem 2025; 46:262-273. [PMID: 40059383 DOI: 10.1080/15321819.2025.2475291] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 05/03/2025]
Abstract
INTRODUCTION Epidermal Growth Factor Receptor (EGFR) expression is not well-studied in Human Epidermal Growth Factor Receptor 2 (HER2) positive breast cancer. We aim to study the prevalence of EGFR immunohistochemical expression in HER2-positive breast carcinomas and to correlate this expression with different anatomo-clinical parameters. METHODS It was a retrospective study involving cases of HER2-positive breast carcinoma collected at the Immuno-Histo-Cytology Department of Salah Azaïez Institute of Tunis between 2018 and 2020. An immunohistochemical study using the anti-human EGFR monoclonal antibody was performed. Cases with an overall score ≥1+ were considered positive. RESULTS Fifty patients were included. EGFR expression in HER2-positive breast carcinomas was more likely to occur in patients under the age of 50 (p = 0.063). It was significantly associated with the absence of lymphovascular invasion (p = 0.047). In multivariate analysis, young age, absence of lympho-vascular invasion, and high Ki67 proliferation index (>60%) were independently associated with positive EGFR expression (p = 0.047, p = 0.040, and p = 0.050, respectively). CONCLUSION Through this first Tunisian study, our data revealed that the immunohistochemical expression of EGFR is associated with young age, absence of lymphovascular invasion, and a high mitotic index (Ki67), which may suggest a potential predictive value for chemotherapy response.
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Affiliation(s)
- Yoldez Houcine
- Immuno-histo-cytology department, Salah Azaiz Institute, Tunis, Tunisia
- Faculty of Medicine, El Manar University, Tunis, Tunisia
| | - Hend Ben Salem
- Faculty of Medicine, El Manar University, Tunis, Tunisia
| | - Sirine El Fekih
- Immuno-histo-cytology department, Salah Azaiz Institute, Tunis, Tunisia
| | - Amal Maaoui
- Immuno-histo-cytology department, Salah Azaiz Institute, Tunis, Tunisia
| | - Maha Driss
- Immuno-histo-cytology department, Salah Azaiz Institute, Tunis, Tunisia
- Faculty of Medicine, El Manar University, Tunis, Tunisia
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Mariana SM, Brenda RP, Heriberto PG, Cristina L, David B, Guadalupe ÁL. GPER1 activation by estrogenic compounds in the inflammatory profile of breast cancer cells. J Steroid Biochem Mol Biol 2025; 245:106639. [PMID: 39571822 DOI: 10.1016/j.jsbmb.2024.106639] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/08/2024] [Revised: 10/28/2024] [Accepted: 11/19/2024] [Indexed: 11/24/2024]
Abstract
Breast cancer (BC) is the most frequent female neoplasm worldwide. Its establishment and development have been related to inflammatory cytokine expression. Steroid hormones such as estradiol (E2) can regulate proinflammatory cytokine secretion through interaction with its nuclear receptors. However, little is known regarding the activation of its membrane estrogen receptor (GPER1) and the inflammatory cytokine environment in BC. We have studied the synthesis and biological effects of molecules analogs to E2 for hormone replacement therapy (HRT), such as pentolame. Nevertheless, its interaction with GPER1 and the modulation of inflammatory cytokines in different BC types has been barely studied and deserves deeper investigation. In this research, the role of GPER1 in the proliferation and modulation of inflammatory cytokines involved in carcinogenesis and metastatic processes in different BC cell lines was assessed by binding to various compounds. To achieve this goal, the presence of GPER1 was identified in different BC cell lines. Subsequently, cell proliferation after exposure to E2, pentolame and GPER1 agonist, G1, was subsequently determined alone or in combination with the GPER1 antagonist, G15. Finally, the pro-inflammatory cytokine secretion derived from the supernatants of BC cells exposed to the previous treatments was also assessed. Interestingly, GPER1 activation or inhibition has significant effects on the cytokine regulation associated with invasion in BC. Notably, pentolame did not induce cell proliferation or increase the proinflammatory cytokine expression compared to E2 in BC cell lines. In addition, pentolame did not induce the presence of the cell adhesion molecule PECAM-1. In contrast, E2 treatment weakly induced the expression of PECAM-1 in MCF-7 and HCC1937 cells, and G1 treatment showed this effect only in MCF-7 cells. The results suggest that GPER1 might be a significant inflammatory modulator with angiogenic-related effects in BC cells. In addition, pentolame might represent an HRT alternative in patients with BC predisposition.
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Affiliation(s)
- Segovia-Mendoza Mariana
- Departamento de Farmacología, Facultad de Medicina, Universidad Nacional Autónoma de México, Ciudad de México, Mexico.
| | - Reyes-Plata Brenda
- Facultad de Estudios Superiores Zaragoza. Universidad Nacional Autónoma de México,Ciudad de México, Mexico
| | - Prado-Garcia Heriberto
- Laboratorio de Onco-Inmunobiología, Departamento de Enfermedades Crónico-Degenerativas, Instituto Nacional de Enfermedades Respiratorias, "Ismael Cosio Villegas" Calzada de Tlalpan 4502, Col. Sección XVI, Ciudad de México 14080, Mexico
| | - Lemini Cristina
- Departamento de Farmacología, Facultad de Medicina, Universidad Nacional Autónoma de México, Ciudad de México, Mexico
| | - Barrera David
- Departamento de Biología de la Reproducción "Dr. Carlos Gual Castro", Instituto Nacional de Ciencias Médicas y Nutrición Salvador Zubirán, Av. Vasco de Quiroga No. 15, Col. Belisario Domínguez, Sección XVI, Ciudad de México 14080, Mexico
| | - Ángeles-López Guadalupe
- Departamento de Farmacología, Facultad de Medicina, Universidad Nacional Autónoma de México, Ciudad de México, Mexico.
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Makwana P, Modi U, Dhimmar B, Vasita R. Design and development of in-vitro co-culture device for studying cellular crosstalk in varied tissue microenvironment. BIOMATERIALS ADVANCES 2024; 163:213952. [PMID: 38991495 DOI: 10.1016/j.bioadv.2024.213952] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 03/26/2024] [Revised: 06/16/2024] [Accepted: 07/03/2024] [Indexed: 07/13/2024]
Abstract
Despite of being in different microenvironment, breast cancer cells influence the bone cells and persuade cancer metastasis from breast to bone. Multiple co-culture approaches have been explored to study paracrine signaling between these cells and to study the progression of cancer. However, lack of native tissue microenvironment remains a major bottleneck in existing co-culture technologies. Therefore, in the present study, a tumorigenic and an osteogenic microenvironment have been sutured together to create a multi-cellular environment and has been appraised to study cancer progression in bone tissue. The PCL-polystyrene and PCL-collagen fibrous scaffolds were characterized for tumorigenic and osteogenic potential induction on MDA-MB-231 and MC3T3-E1 cells respectively. Diffusion ability of crystal violet, glucose, and bovine serum albumin across the membrane were used to access the potential paracrine interaction facilitated by device. While in co-cultured condition, MDA-MB-231 cells showed EMT phenotype along with secretion of TNFα and PTHrP which lower down the expression of osteogenic markers including alkaline phosphatase, RUNX2, Osteocalcin and Osteoprotegerin. The cancer progression in bone microenvironment demonstrated the role and necessity of creating multiple tissue microenvironment and its contribution in studying multicellular disease progression and therapeutics.
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Affiliation(s)
- Pooja Makwana
- Biomaterial and Biomimetic Laboratory, School of Life Sciences, Central University of Gujarat, India
| | - Unnati Modi
- Biomaterial and Biomimetic Laboratory, School of Life Sciences, Central University of Gujarat, India
| | - Bindiya Dhimmar
- Biomaterial and Biomimetic Laboratory, School of Life Sciences, Central University of Gujarat, India
| | - Rajesh Vasita
- Biomaterial and Biomimetic Laboratory, School of Life Sciences, Central University of Gujarat, India; Terasaki Institute of Biomedical Innovation, Los Angeles, CA, USA.
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Torres Quintas S, Canha-Borges A, Oliveira MJ, Sarmento B, Castro F. Special Issue: Nanotherapeutics in Women's Health Emerging Nanotechnologies for Triple-Negative Breast Cancer Treatment. SMALL (WEINHEIM AN DER BERGSTRASSE, GERMANY) 2024; 20:e2300666. [PMID: 36978237 DOI: 10.1002/smll.202300666] [Citation(s) in RCA: 9] [Impact Index Per Article: 9.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 01/24/2023] [Revised: 03/03/2023] [Indexed: 06/18/2023]
Abstract
Breast cancer appears as the major cause of cancer-related deaths in women, with more than 2 260 000 cases reported worldwide in 2020, resulting in 684 996 deaths. Triple-negative breast cancer (TNBC), characterized by the absence of estrogen, progesterone, and human epidermal growth factor type 2 receptors, represents ≈20% of all breast cancers. TNBC has a highly aggressive clinical course and is more prevalent in younger women. The standard therapy for advanced TNBC is chemotherapy, but responses are often short-lived, with high rate of relapse. The lack of therapeutic targets and the limited therapeutic options confer to individuals suffering from TNBC the poorest prognosis among breast cancer patients, remaining a major clinical challenge. In recent years, advances in cancer nanomedicine provided innovative therapeutic options, as nanoformulations play an important role in overcoming the shortcomings left by conventional therapies: payload degradation and its low solubility, stability, and circulating half-life, and difficulties regarding biodistribution due to physiological and biological barriers. In this integrative review, the recent advances in the nanomedicine field for TNBC treatment, including the novel nanoparticle-, exosome-, and hybrid-based therapeutic formulations are summarized and their drawbacks and challenges are discussed for future clinical applications.
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Affiliation(s)
- Sofia Torres Quintas
- i3S - Instituto de Investigação e Inovação em Saúde, Universidade do Porto, Rua Alfredo Allen 208, Porto, 4200-135, Portugal
- INEB - Instituto de Engenharia Biomédica, Universidade do Porto, Rua Alfredo Allen 208, Porto, 4200-135, Portugal
- ICBAS - Instituto de Ciências Biomédicas Abel Salazar, Rua Jorge de Viterbo Ferreira 228, Porto, 4050-313, Portugal
| | - Ana Canha-Borges
- i3S - Instituto de Investigação e Inovação em Saúde, Universidade do Porto, Rua Alfredo Allen 208, Porto, 4200-135, Portugal
- INEB - Instituto de Engenharia Biomédica, Universidade do Porto, Rua Alfredo Allen 208, Porto, 4200-135, Portugal
- ICBAS - Instituto de Ciências Biomédicas Abel Salazar, Rua Jorge de Viterbo Ferreira 228, Porto, 4050-313, Portugal
| | - Maria José Oliveira
- i3S - Instituto de Investigação e Inovação em Saúde, Universidade do Porto, Rua Alfredo Allen 208, Porto, 4200-135, Portugal
- INEB - Instituto de Engenharia Biomédica, Universidade do Porto, Rua Alfredo Allen 208, Porto, 4200-135, Portugal
- ICBAS - Instituto de Ciências Biomédicas Abel Salazar, Rua Jorge de Viterbo Ferreira 228, Porto, 4050-313, Portugal
| | - Bruno Sarmento
- i3S - Instituto de Investigação e Inovação em Saúde, Universidade do Porto, Rua Alfredo Allen 208, Porto, 4200-135, Portugal
- INEB - Instituto de Engenharia Biomédica, Universidade do Porto, Rua Alfredo Allen 208, Porto, 4200-135, Portugal
- IUCS-CESPU - Instituto de Investigação e Formação Avançada em Ciências e Tecnologias da Saúde, Rua Central de Gandra 1317, 4585-116, Gandra, Portugal
| | - Flávia Castro
- i3S - Instituto de Investigação e Inovação em Saúde, Universidade do Porto, Rua Alfredo Allen 208, Porto, 4200-135, Portugal
- INEB - Instituto de Engenharia Biomédica, Universidade do Porto, Rua Alfredo Allen 208, Porto, 4200-135, Portugal
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Cheung A, Chenoweth AM, Johansson A, Laddach R, Guppy N, Trendell J, Esapa B, Mavousian A, Navarro-Llinas B, Haider S, Romero-Clavijo P, Hoffmann RM, Andriollo P, Rahman KM, Jackson P, Tsoka S, Irshad S, Roxanis I, Grigoriadis A, Thurston DE, Lord CJ, Tutt ANJ, Karagiannis SN. Anti-EGFR Antibody-Drug Conjugate Carrying an Inhibitor Targeting CDK Restricts Triple-Negative Breast Cancer Growth. Clin Cancer Res 2024; 30:3298-3315. [PMID: 38772416 PMCID: PMC11292198 DOI: 10.1158/1078-0432.ccr-23-3110] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/12/2023] [Revised: 03/06/2024] [Accepted: 05/15/2024] [Indexed: 05/23/2024]
Abstract
PURPOSE Anti-EGFR antibodies show limited response in breast cancer, partly due to activation of compensatory pathways. Furthermore, despite the clinical success of cyclin-dependent kinase (CDK) 4/6 inhibitors in hormone receptor-positive tumors, aggressive triple-negative breast cancers (TNBC) are largely resistant due to CDK2/cyclin E expression, whereas free CDK2 inhibitors display normal tissue toxicity, limiting their therapeutic application. A cetuximab-based antibody drug conjugate (ADC) carrying a CDK inhibitor selected based on oncogene dysregulation, alongside patient subgroup stratification, may provide EGFR-targeted delivery. EXPERIMENTAL DESIGN Expressions of G1/S-phase cell cycle regulators were evaluated alongside EGFR in breast cancer. We conjugated cetuximab with CDK inhibitor SNS-032, for specific delivery to EGFR-expressing cells. We assessed ADC internalization and its antitumor functions in vitro and in orthotopically grown basal-like/TNBC xenografts. RESULTS Transcriptomic (6,173 primary, 27 baseline, and matched post-chemotherapy residual tumors), single-cell RNA sequencing (150,290 cells, 27 treatment-naïve tumors), and spatial transcriptomic (43 tumor sections, 22 TNBCs) analyses confirmed expression of CDK2 and its cyclin partners in basal-like/TNBCs, associated with EGFR. Spatiotemporal live-cell imaging and super-resolution confocal microscopy demonstrated ADC colocalization with late lysosomal clusters. The ADC inhibited cell cycle progression, induced cytotoxicity against high EGFR-expressing tumor cells, and bystander killing of neighboring EGFR-low tumor cells, but minimal effects on immune cells. Despite carrying a small molar fraction (1.65%) of the SNS-032 inhibitor, the ADC restricted EGFR-expressing spheroid and cell line/patient-derived xenograft tumor growth. CONCLUSIONS Exploiting EGFR overexpression, and dysregulated cell cycle in aggressive and treatment-refractory tumors, a cetuximab-CDK inhibitor ADC may provide selective and efficacious delivery of cell cycle-targeted agents to basal-like/TNBCs, including chemotherapy-resistant residual disease.
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Affiliation(s)
- Anthony Cheung
- Breast Cancer Now Research Unit, School of Cancer and Pharmaceutical Sciences, King’s College London, Guy’s Cancer Centre, London, United Kingdom
- St. John’s Institute of Dermatology, School of Basic and Medical Biosciences & KHP Centre for Translational Medicine, King’s College London, Guy’s Hospital, London, United Kingdom
| | - Alicia M. Chenoweth
- Breast Cancer Now Research Unit, School of Cancer and Pharmaceutical Sciences, King’s College London, Guy’s Cancer Centre, London, United Kingdom
- St. John’s Institute of Dermatology, School of Basic and Medical Biosciences & KHP Centre for Translational Medicine, King’s College London, Guy’s Hospital, London, United Kingdom
| | - Annelie Johansson
- Breast Cancer Now Research Unit, School of Cancer and Pharmaceutical Sciences, King’s College London, Guy’s Cancer Centre, London, United Kingdom
- Cancer Bioinformatics, School of Cancer and Pharmaceutical Sciences, King’s College London, Guy’s Cancer Centre, London, United Kingdom
| | - Roman Laddach
- St. John’s Institute of Dermatology, School of Basic and Medical Biosciences & KHP Centre for Translational Medicine, King’s College London, Guy’s Hospital, London, United Kingdom
- Department of Informatics, Faculty of Natural, Mathematical and Engineering Sciences, King’s College London, London, United Kingdom
| | - Naomi Guppy
- The Breast Cancer Now Toby Robins Research Centre, The Institute of Cancer Research, London, United Kingdom
| | - Jennifer Trendell
- Breast Cancer Now Research Unit, School of Cancer and Pharmaceutical Sciences, King’s College London, Guy’s Cancer Centre, London, United Kingdom
| | - Benjamina Esapa
- St. John’s Institute of Dermatology, School of Basic and Medical Biosciences & KHP Centre for Translational Medicine, King’s College London, Guy’s Hospital, London, United Kingdom
| | - Antranik Mavousian
- The Breast Cancer Now Toby Robins Research Centre, The Institute of Cancer Research, London, United Kingdom
| | - Blanca Navarro-Llinas
- Breast Cancer Now Research Unit, School of Cancer and Pharmaceutical Sciences, King’s College London, Guy’s Cancer Centre, London, United Kingdom
| | - Syed Haider
- The Breast Cancer Now Toby Robins Research Centre, The Institute of Cancer Research, London, United Kingdom
| | - Pablo Romero-Clavijo
- St. John’s Institute of Dermatology, School of Basic and Medical Biosciences & KHP Centre for Translational Medicine, King’s College London, Guy’s Hospital, London, United Kingdom
| | - Ricarda M. Hoffmann
- St. John’s Institute of Dermatology, School of Basic and Medical Biosciences & KHP Centre for Translational Medicine, King’s College London, Guy’s Hospital, London, United Kingdom
- The Breast Cancer Now Toby Robins Research Centre, The Institute of Cancer Research, London, United Kingdom
| | - Paolo Andriollo
- Institute of Pharmaceutical Science, School of Cancer and Pharmaceutical Sciences, King’s College London, London, United Kingdom
| | - Khondaker M. Rahman
- Institute of Pharmaceutical Science, School of Cancer and Pharmaceutical Sciences, King’s College London, London, United Kingdom
| | - Paul Jackson
- Institute of Pharmaceutical Science, School of Cancer and Pharmaceutical Sciences, King’s College London, London, United Kingdom
| | - Sophia Tsoka
- Department of Informatics, Faculty of Natural, Mathematical and Engineering Sciences, King’s College London, London, United Kingdom
| | - Sheeba Irshad
- Breast Cancer Now Research Unit, School of Cancer and Pharmaceutical Sciences, King’s College London, Guy’s Cancer Centre, London, United Kingdom
| | - Ioannis Roxanis
- The Breast Cancer Now Toby Robins Research Centre, The Institute of Cancer Research, London, United Kingdom
| | - Anita Grigoriadis
- Breast Cancer Now Research Unit, School of Cancer and Pharmaceutical Sciences, King’s College London, Guy’s Cancer Centre, London, United Kingdom
- Cancer Bioinformatics, School of Cancer and Pharmaceutical Sciences, King’s College London, Guy’s Cancer Centre, London, United Kingdom
| | - David E. Thurston
- Institute of Pharmaceutical Science, School of Cancer and Pharmaceutical Sciences, King’s College London, London, United Kingdom
| | - Christopher J. Lord
- The Breast Cancer Now Toby Robins Research Centre, The Institute of Cancer Research, London, United Kingdom
| | - Andrew N. J. Tutt
- Breast Cancer Now Research Unit, School of Cancer and Pharmaceutical Sciences, King’s College London, Guy’s Cancer Centre, London, United Kingdom
- The Breast Cancer Now Toby Robins Research Centre, The Institute of Cancer Research, London, United Kingdom
| | - Sophia N. Karagiannis
- Breast Cancer Now Research Unit, School of Cancer and Pharmaceutical Sciences, King’s College London, Guy’s Cancer Centre, London, United Kingdom
- St. John’s Institute of Dermatology, School of Basic and Medical Biosciences & KHP Centre for Translational Medicine, King’s College London, Guy’s Hospital, London, United Kingdom
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Enan ET, El Hafez AA, Hussin E, El Din Ismail Hany HS. Immunohistochemical Expression of Caspase1 and Epidermal Growth Factor Receptor in Invasive Breast Carcinoma and Their Biological and Prognostic Associations. Asian Pac J Cancer Prev 2024; 25:2529-2537. [PMID: 39068588 PMCID: PMC11480596 DOI: 10.31557/apjcp.2024.25.7.2529] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/06/2024] [Indexed: 07/30/2024] Open
Abstract
BACKGROUND Despite advances in breast carcinoma therapies, drug resistance mechanisms as anti-apoptosis and anti-pyroptosis limit the application of these therapies. This work assesses the immunohistochemical (IHC) expression of Caspase1 and EGFR in breast carcinoma and analyzes their clinicopathological associations as prognostic markers and potential therapeutic targets. Caspase1/EGFR expression patterns are utilized to specify breast carcinoma patients who may benefit from these therapies. METHODS After reviewing the hematoxylin and eosin-stained slides and the routine breast carcinoma IHC stains (estrogen receptors, progesterone receptors, HER2/NEU, Ki-67) by two pathologists and preparation of tissue microarray blocks, anti-Caspase-1 and EGFR IHC staining was performed using Horseradish Peroxidase (HRP) technique. Intensity and percentage-based scoring was applied dividing the 153 included breast carcinomas into Caspase1-negative and positive expression groups; and EGFR low and overexpression groups. Groups were statistically analyzed in relation to age, tumor size, histological and molecular subtype, grade, nodal status, metastasis/recurrence, TNM stage and Ki-67 proliferation index. Kaplan-Meier's analysis was used to compare disease-free survival (DFS) and overall survival (OS). Combined patterns based on Caspase1 and EGFR expression status were created to stratify patients into prognostic groups. RESULTS Caspase1 was positive in 54.2% of breast carcinomas and its positivity was significantly associated with smaller tumor size, absence of metastasis/recurrence, luminal A and B molecular subtypes and longer OS (p<0.05). EGFR overexpression was detected in 32.7% of carcinomas and was significantly associated with larger tumor size, TNBLBC and a shorter OS (p<0.05). Caspase1-negative/EGFR-overexpression pattern comprised 14.4% of carcinomas and had the worst prognostic associations including larger tumor size, metastasis/recurrence, TNBLBC subtype and shortest OS (p=0.002, 0.002, 0.004 and ≤0.001 respectively). Conclusions: Combined Caspase1/EGFR IHC expression may provide a tool for selection of patients who benefit from combined EGFR-inhibitors with miR-155-5p down-regulators or photodynamic therapy via induction of apoptosis/pyroptosis in EGFR-overexpression carcinomas through enhanced Caspase1 signaling.
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Affiliation(s)
- Eman Tawfik Enan
- Anatomic Pathology Department, Faculty of Medicine, Mansoura University, Mansoura, Egypt.
| | - Amal Abd El Hafez
- Anatomic Pathology Department, Faculty of Medicine, Mansoura University, Mansoura, Egypt.
- Faculty of Medicine, Horus University-Egypt (HUE), New Damietta, Egypt.
| | - Emadeldeen Hussin
- Department of Human Anatomy and Embryology, Faculty of Medicine, Mansoura University, Mansoura, Egypt.
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Oopkaew L, Injongkol Y, Rimsueb N, Mahalapbutr P, Choowongkomon K, Hadsadee S, Rojanathanes R, Rungrotmongkol T. Targeted Therapy with Cisplatin-Loaded Calcium Citrate Nanoparticles Conjugated with Epidermal Growth Factor for Lung Cancer Treatment. ACS OMEGA 2024; 9:25668-25677. [PMID: 38911765 PMCID: PMC11191089 DOI: 10.1021/acsomega.3c08969] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 11/10/2023] [Revised: 05/19/2024] [Accepted: 05/24/2024] [Indexed: 06/25/2024]
Abstract
Lung cancer is the leading cause of cancer-related deaths worldwide with high incidence rates for new cases. Conventional cisplatin (CDDP) therapy has limitations due to severe side effects from nonspecific targeting. To address this challenge, nanomedicine offers targeted therapies. In this study, cisplatin-loaded calcium citrate nanoparticles conjugated with epidermal growth factor (CaCit@CDDP-EGF NPs) were synthesized. The resulting nanodrug had a size below 350 nm with a cation charge. Based on density functional theory (DFT), the CaCit@CDDP NP model containing two citrates substituted on two chlorides exhibited a favorable binding energy of -5.42 eV, and the calculated spectrum at 261 nm closely matched the experimental data. CaCit@CDDP-EGF NPs showed higher inhibition rates against EGFR-expressed and mutant carcinoma cells compared to those of cisplatin while displaying lower cytotoxicity to lung fibroblast cells. Integrating in vitro experiments with in silico studies, these nanoparticles hold promise as a novel nanomedicine for targeted therapy in clinical applications.
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Affiliation(s)
- Lipika Oopkaew
- Center
of Excellence in Biocatalyst and Sustainable Biotechnology, Department
of Biochemistry, Faculty of Science, Chulalongkorn
University, Bangkok 10330, Thailand
| | - Yuwanda Injongkol
- Center
of Excellence in Biocatalyst and Sustainable Biotechnology, Department
of Biochemistry, Faculty of Science, Chulalongkorn
University, Bangkok 10330, Thailand
| | - Natchanon Rimsueb
- National
Nanotechnology Center NANOTEC, National
Science and Technology Development Agency NSTDA, Pathum Thani 12120, Thailand
- Center
of Excellence in Nanomedicine, Department of Anatomy, Faculty of Medicine, Chulalongkorn University, Bangkok 10330, Thailand
| | - Panupong Mahalapbutr
- Department
of Biochemistry, Center for Translational Medicine, Faculty of Medicine, Khon Kaen University, Khon Kaen 40002, Thailand
| | - Kiattawee Choowongkomon
- Department
of Biochemistry, Faculty of Science, Kasetsart
University, Bangkok 10900, Thailand
| | - Sarinya Hadsadee
- Center
of Excellence in Biocatalyst and Sustainable Biotechnology, Department
of Biochemistry, Faculty of Science, Chulalongkorn
University, Bangkok 10330, Thailand
| | - Rojrit Rojanathanes
- Center of
Excellence in Biocatalyst and Sustainable Biotechnology, Department
of Chemistry, Faculty of Science, Chulalongkorn
University Bangkok, 10330, Thailand
| | - Thanyada Rungrotmongkol
- Center
of Excellence in Biocatalyst and Sustainable Biotechnology, Department
of Biochemistry, Faculty of Science, Chulalongkorn
University, Bangkok 10330, Thailand
- Program
in Bioinformatics and Computational Biology, Graduate School, Chulalongkorn University, Bangkok 10330, Thailand
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Satriyo PB, Mustofa M, Wahyuningsih TD, Damayanti E, Wiraswati HL, Satria D, Bashari MH, Sholikhah EN. N-phenyl pyrazoline derivative inhibits cell aggressiveness and enhances paclitaxel sensitivity of triple negative breast cancer cells. Sci Rep 2024; 14:13200. [PMID: 38851778 PMCID: PMC11162478 DOI: 10.1038/s41598-024-63778-2] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/10/2023] [Accepted: 06/02/2024] [Indexed: 06/10/2024] Open
Abstract
Protein kinase dysregulation induces cancer cell aggressiveness leading to rapid tumor progression and poor prognosis in TNBC patients. Many small-molecule kinase inhibitors have been tested in clinical trials to treat TNBC patients. In the previous study, we found that N-phenylpyrazoline small molecule acts as a protein kinase inhibitor in cervical cancer cells. However, there remains unknown about N-phenyl pyrazoline potency as a kinase inhibitor and its anti-cancer activity in TNBC cells. In this study, we investigated the activity of N-phenyl pyrazoline against TNBC cells via tyrosine kinase inhibition. Based on the MTT assay, the IC50 values for the N-phenyl pyrazoline 2, 5, A, B, C, and D against Hs578T were 12.63 µM, 3.95 µM, not available, 18.62 µM, 30.13 µM, and 26.79 µM, respectively. While only P5 exhibited the IC50 against MDA MB 231 (21.55 µM). Further, N-phenyl pyrazoline 5 treatment significantly inhibited the cell proliferation rate of Hs578T and MDA MB 231 cells. The migration assay showed that treatment with the compound N-phenyl pyrazoline 5 with 4 µM concentration significantly reduced cell migration of Hs578T cells. N-phenyl pyrazoline 5 treatment at 1 µM and 2 µM was able to reduce the tumorsphere size of Hs578t cells. A combination treatment of P5 and paclitaxel showed a synergistic effect with a combination index score > 1 in both TNBC cells. Further, the P5 predictively targeted the protein kinases that significantly correlated to breast cancer prognosis. The GSEA analysis result shows that receptor tyrosine kinase, Notch3, Notch4, and Ephrin signaling pathways were targeted by P5. The P5 treatment reduced the EGFR expression level and activation in TNBC cells.
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Affiliation(s)
- Pamungkas Bagus Satriyo
- Department of Pharmacology and Therapy, Faculty of Medicine Public Health and Nursing, Universitas Gadjah Mada, Yogyakarta, 55281, Indonesia
| | - Mustofa Mustofa
- Department of Pharmacology and Therapy, Faculty of Medicine Public Health and Nursing, Universitas Gadjah Mada, Yogyakarta, 55281, Indonesia
| | - Tutik Dwi Wahyuningsih
- Department of Chemistry, Faculty of Mathematics and Natural Sciences, Universitas Gadjah Mada, Yogyakarta, 55281, Indonesia
| | - Ema Damayanti
- Research Center for Food Technology and Processing, National Research and Innovation Agency, Gunungkidul, 55861, Indonesia
| | - Hesti Lina Wiraswati
- Department of Biomedical Sciences, Faculty of Medicine, Universitas Padjadjaran, Sumedang, Indonesia
- Oncology and Stem Cell Working Group, Faculty of Medicine, Universitas Padjadjaran, Bandung, Indonesia
| | - Denny Satria
- Department of Pharmaceutical Biology, Faculty of Pharmacy, Universitas Sumatera Utara, Medan, Indonesia
| | - M Hasan Bashari
- Department of Biomedical Sciences, Faculty of Medicine, Universitas Padjadjaran, Sumedang, Indonesia
- Oncology and Stem Cell Working Group, Faculty of Medicine, Universitas Padjadjaran, Bandung, Indonesia
| | - Eti Nurwening Sholikhah
- Department of Pharmacology and Therapy, Faculty of Medicine Public Health and Nursing, Universitas Gadjah Mada, Yogyakarta, 55281, Indonesia.
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10
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Iida M, Crossman BE, Kostecki KL, Glitchev CE, Kranjac CA, Crow MT, Adams JM, Liu P, Ong I, Yang DT, Kang I, Salgia R, Wheeler DL. MerTK Drives Proliferation and Metastatic Potential in Triple-Negative Breast Cancer. Int J Mol Sci 2024; 25:5109. [PMID: 38791148 PMCID: PMC11121248 DOI: 10.3390/ijms25105109] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/21/2024] [Revised: 04/29/2024] [Accepted: 05/02/2024] [Indexed: 05/26/2024] Open
Abstract
Triple-negative breast cancer (TNBC) is characterized by the absence of the estrogen receptor, progesterone receptor, and receptor tyrosine kinase HER2 expression. Due to the limited number of FDA-approved targeted therapies for TNBC, there is an ongoing need to understand the molecular underpinnings of TNBC for the development of novel combinatorial treatment strategies. This study evaluated the role of the MerTK receptor tyrosine kinase on proliferation and invasion/metastatic potential in TNBC. Immunohistochemical analysis demonstrated MerTK expression in 58% of patient-derived TNBC xenografts. The stable overexpression of MerTK in human TNBC cell lines induced an increase in proliferation rates, robust in vivo tumor growth, heightened migration/invasion potential, and enhanced lung metastases. NanoString nCounter analysis of MerTK-overexpressing SUM102 cells (SUM102-MerTK) revealed upregulation of several signaling pathways, which ultimately drive cell cycle progression, reduce apoptosis, and enhance cell survival. Proteomic profiling indicated increased endoglin (ENG) production in SUM102-MerTK clones, suggesting that MerTK creates a conducive environment for increased proliferative and metastatic activity via elevated ENG expression. To determine ENG's role in increasing proliferation and/or metastatic potential, we knocked out ENG in a SUM102-MerTK clone with CRISPR technology. Although this ENG knockout clone exhibited similar in vivo growth to the parental SUM102-MerTK clone, lung metastasis numbers were significantly decreased ~4-fold, indicating that MerTK enhances invasion and metastasis through ENG. Our data suggest that MerTK regulates a unique proliferative signature in TNBC, promoting robust tumor growth and increased metastatic potential through ENG upregulation. Targeting MerTK and ENG simultaneously may provide a novel therapeutic approach for TNBC patients.
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Affiliation(s)
- Mari Iida
- Department of Human Oncology, University of Wisconsin-Madison, Madison, WI 53705, USA; (M.I.); (B.E.C.); (K.L.K.); (C.E.G.); (C.A.K.); (M.T.C.); (J.M.A.)
| | - Bridget E. Crossman
- Department of Human Oncology, University of Wisconsin-Madison, Madison, WI 53705, USA; (M.I.); (B.E.C.); (K.L.K.); (C.E.G.); (C.A.K.); (M.T.C.); (J.M.A.)
| | - Kourtney L. Kostecki
- Department of Human Oncology, University of Wisconsin-Madison, Madison, WI 53705, USA; (M.I.); (B.E.C.); (K.L.K.); (C.E.G.); (C.A.K.); (M.T.C.); (J.M.A.)
| | - Christine E. Glitchev
- Department of Human Oncology, University of Wisconsin-Madison, Madison, WI 53705, USA; (M.I.); (B.E.C.); (K.L.K.); (C.E.G.); (C.A.K.); (M.T.C.); (J.M.A.)
| | - Carlene A. Kranjac
- Department of Human Oncology, University of Wisconsin-Madison, Madison, WI 53705, USA; (M.I.); (B.E.C.); (K.L.K.); (C.E.G.); (C.A.K.); (M.T.C.); (J.M.A.)
| | - Madisen T. Crow
- Department of Human Oncology, University of Wisconsin-Madison, Madison, WI 53705, USA; (M.I.); (B.E.C.); (K.L.K.); (C.E.G.); (C.A.K.); (M.T.C.); (J.M.A.)
| | - Jillian M. Adams
- Department of Human Oncology, University of Wisconsin-Madison, Madison, WI 53705, USA; (M.I.); (B.E.C.); (K.L.K.); (C.E.G.); (C.A.K.); (M.T.C.); (J.M.A.)
| | - Peng Liu
- Departments of Biostatistics and Medical Informatics, University of Wisconsin-Madison, Madison, WI 53726, USA; (P.L.); (I.O.)
- Carbone Cancer Center, University of Wisconsin-Madison, Madison, WI 53792, USA
| | - Irene Ong
- Departments of Biostatistics and Medical Informatics, University of Wisconsin-Madison, Madison, WI 53726, USA; (P.L.); (I.O.)
- Carbone Cancer Center, University of Wisconsin-Madison, Madison, WI 53792, USA
- Department of Obstetrics and Gynecology, University of Wisconsin-Madison, Madison, WI 53705, USA
| | - David T. Yang
- Department of Pathology and Laboratory Medicine, University of Wisconsin-Madison, Madison, WI 53705, USA;
| | - Irene Kang
- Department of Medical Oncology and Experimental Therapeutics, Comprehensive Cancer Center, City of Hope, Duarte, CA 91010, USA; (I.K.); (R.S.)
| | - Ravi Salgia
- Department of Medical Oncology and Experimental Therapeutics, Comprehensive Cancer Center, City of Hope, Duarte, CA 91010, USA; (I.K.); (R.S.)
| | - Deric L. Wheeler
- Department of Human Oncology, University of Wisconsin-Madison, Madison, WI 53705, USA; (M.I.); (B.E.C.); (K.L.K.); (C.E.G.); (C.A.K.); (M.T.C.); (J.M.A.)
- Carbone Cancer Center, University of Wisconsin-Madison, Madison, WI 53792, USA
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11
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Volonte D, Benson CJ, Daugherty SL, Beckel JM, Trebak M, Galbiati F. Purinergic signaling promotes premature senescence. J Biol Chem 2024; 300:107145. [PMID: 38460941 PMCID: PMC11002311 DOI: 10.1016/j.jbc.2024.107145] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/24/2024] [Revised: 02/26/2024] [Accepted: 02/28/2024] [Indexed: 03/11/2024] Open
Abstract
Extracellular ATP activates P2 purinergic receptors. Whether purinergic signaling is functionally coupled to cellular senescence is largely unknown. We find that oxidative stress induced release of ATP and caused senescence in human lung fibroblasts. Inhibition of P2 receptors limited oxidative stress-induced senescence, while stimulation with exogenous ATP promoted premature senescence. Pharmacological inhibition of P2Y11 receptor (P2Y11R) inhibited premature senescence induced by either oxidative stress or ATP, while stimulation with a P2Y11R agonist was sufficient to induce cellular senescence. Our data show that both extracellular ATP and a P2Y11R agonist induced calcium (Ca++) release from the endoplasmic reticulum (ER) and that either inhibition of phospholipase C or intracellular Ca++ chelation impaired ATP-induced senescence. We also find that Ca++ that was released from the ER, following ATP-mediated activation of phospholipase C, entered mitochondria in a manner dependent on P2Y11R activation. Once in mitochondria, excessive Ca++ promoted the production of reactive oxygen species in a P2Y11R-dependent fashion, which drove development of premature senescence of lung fibroblasts. Finally, we show that conditioned medium derived from senescent lung fibroblasts, which were induced to senesce through the activation of ATP/P2Y11R-mediated signaling, promoted the proliferation of triple-negative breast cancer cells and their tumorigenic potential by secreting amphiregulin. Our study identifies the existence of a novel purinergic signaling pathway that links extracellular ATP to the development of a protumorigenic premature senescent phenotype in lung fibroblasts that is dependent on P2Y11R activation and ER-to-mitochondria calcium signaling.
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Affiliation(s)
- Daniela Volonte
- Department of Pharmacology & Chemical Biology, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania, USA
| | - Cory J Benson
- Department of Pharmacology & Chemical Biology, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania, USA; Vascular Medicine Institute, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania, USA
| | - Stephanie L Daugherty
- Department of Pharmacology & Chemical Biology, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania, USA
| | - Jonathan M Beckel
- Department of Pharmacology & Chemical Biology, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania, USA
| | - Mohamed Trebak
- Department of Pharmacology & Chemical Biology, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania, USA; Vascular Medicine Institute, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania, USA
| | - Ferruccio Galbiati
- Department of Pharmacology & Chemical Biology, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania, USA.
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12
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Lusby R, Zhang Z, Mahesh A, Tiwari VK. Decoding gene regulatory circuitry underlying TNBC chemoresistance reveals biomarkers for therapy response and therapeutic targets. NPJ Precis Oncol 2024; 8:64. [PMID: 38472332 DOI: 10.1038/s41698-024-00529-6] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/22/2023] [Accepted: 01/30/2024] [Indexed: 03/14/2024] Open
Abstract
Triple-negative breast cancer (TNBC) is the most aggressive breast cancer subtype characterised by extensive intratumoral heterogeneity, high rates of metastasis and chemoresistance, leading to poor clinical outcomes. Despite progress, the mechanistic basis of chemotherapy resistance in TNBC patients remains poorly understood. Here, leveraging single-cell transcriptome datasets of matched longitudinal TNBC chemoresponsive and chemoresistant patient cohorts, we unravel distinct cell subpopulations intricately associated with chemoresistance and the signature genes defining these populations. Notably, using genome-wide mapping of the H3K27ac mark, we show that the expression of these chemoresistance genes is driven via a set of TNBC super-enhancers and associated transcription factor networks across TNBC subtypes. Furthermore, genetic screens reveal that a subset of these transcription factors is essential for the survival of TNBC cells, and their loss increases sensitivity to chemotherapeutic agents. Overall, our study has revealed epigenetic and transcription factor networks underlying chemoresistance and suggests novel avenues to stratify and improve the treatment of patients with a high risk of developing resistance.
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Affiliation(s)
- Ryan Lusby
- Wellcome-Wolfson Institute for Experimental Medicine, School of Medicine, Dentistry & Biomedical Science, Queens University, Belfast, BT9 7BL, UK
| | - Ziyi Zhang
- Wellcome-Wolfson Institute for Experimental Medicine, School of Medicine, Dentistry & Biomedical Science, Queens University, Belfast, BT9 7BL, UK
| | - Arun Mahesh
- Wellcome-Wolfson Institute for Experimental Medicine, School of Medicine, Dentistry & Biomedical Science, Queens University, Belfast, BT9 7BL, UK
- Institute of Molecular Medicine, University of Southern Denmark, Odense M, Denmark
| | - Vijay K Tiwari
- Wellcome-Wolfson Institute for Experimental Medicine, School of Medicine, Dentistry & Biomedical Science, Queens University, Belfast, BT9 7BL, UK.
- Institute of Molecular Medicine, University of Southern Denmark, Odense M, Denmark.
- Patrick G. Johnston Centre for Cancer Research, Queen's University, Belfast, BT9 7AE, UK.
- Danish Institute for Advanced Study (DIAS), Odense M, Denmark.
- Department of Clinical Genetics, Odense University Hospital, Odense C, Denmark.
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13
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Sinha S, Farfel A, Luker KE, Parker BA, Yeung KT, Luker GD, Ghosh P. Growth signaling autonomy in circulating tumor cells aids metastatic seeding. PNAS NEXUS 2024; 3:pgae014. [PMID: 38312224 PMCID: PMC10833458 DOI: 10.1093/pnasnexus/pgae014] [Citation(s) in RCA: 1] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Subscribe] [Scholar Register] [Received: 06/20/2023] [Accepted: 01/03/2024] [Indexed: 02/06/2024]
Abstract
Self-sufficiency (autonomy) in growth signaling, the earliest recognized hallmark of cancer, is fueled by the tumor cell's ability to "secrete-and-sense" growth factors (GFs); this translates into cell survival and proliferation that is self-sustained by autocrine/paracrine secretion. A Golgi-localized circuitry comprised of two GTPase switches has recently been implicated in the orchestration of growth signaling autonomy. Using breast cancer cells that are either endowed or impaired (by gene editing) in their ability to assemble the circuitry for growth signaling autonomy, here we define the transcriptome, proteome, and phenome of such an autonomous state, and unravel its role during cancer progression. We show that autonomy is associated with enhanced molecular programs for stemness, proliferation, and epithelial-mesenchymal plasticity. Autonomy is both necessary and sufficient for anchorage-independent GF-restricted proliferation and resistance to anticancer drugs and is required for metastatic progression. Transcriptomic and proteomic studies show that autonomy is associated, with a surprising degree of specificity, with self-sustained epidermal growth factor receptor (EGFR)/ErbB signaling. Derivation of a gene expression signature for autonomy revealed that growth signaling autonomy is uniquely induced in circulating tumor cells (CTCs), the harshest phase in the life of tumor cells when it is deprived of biologically available epidermal growth factor (EGF). We also show that autonomy in CTCs tracks therapeutic response and prognosticates outcome. These data support a role for growth signaling autonomy in multiple processes essential for the blood-borne dissemination of human breast cancer.
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Affiliation(s)
- Saptarshi Sinha
- Department of Cellular and Molecular Medicine, School of Medicine, University of California San Diego, La Jolla, CA 92093, USA
| | - Alex Farfel
- Biointerfaces Institute, University of Michigan, Ann Arbor, MI 48109-2200, USA
| | - Kathryn E Luker
- Biointerfaces Institute, University of Michigan, Ann Arbor, MI 48109-2200, USA
| | - Barbara A Parker
- Moores Cancer Center, University of California San Diego, La Jolla, CA 92093, USA
- Department of Medicine, School of Medicine, University of California San Diego, La Jolla, CA 92093, USA
| | - Kay T Yeung
- Moores Cancer Center, University of California San Diego, La Jolla, CA 92093, USA
- Department of Medicine, School of Medicine, University of California San Diego, La Jolla, CA 92093, USA
| | - Gary D Luker
- Department of Biomedical Engineering, University of Michigan, Ann Arbor, MI 48109-2200, USA
- Department of Microbiology and Immunology, University of Michigan, Ann Arbor, MI 48109-2200, USA
- Center for Molecular Imaging, Department of Radiology, University of Michigan, Ann Arbor, MI 48109-2200, USA
| | - Pradipta Ghosh
- Department of Cellular and Molecular Medicine, School of Medicine, University of California San Diego, La Jolla, CA 92093, USA
- Department of Medicine, School of Medicine, University of California San Diego, La Jolla, CA 92093, USA
- Veterans Affairs Medical Center, 3350 La Jolla Village Drive, San Diego, CA 92161, USA
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14
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Piedra-Delgado L, Chambergo-Michilot D, Morante Z, Fairen C, Jerves-Coello F, Luque-Benavides R, Casas F, Bustamante E, Razuri-Bustamante C, Torres-Roman JS, Fuentes H, Gomez H, Narvaez-Rojas A, De la Cruz-Ku G, Araujo J. Survival according to the site of metastasis in triple-negative breast cancer patients: The Peruvian experience. PLoS One 2024; 19:e0293833. [PMID: 38300959 PMCID: PMC10833533 DOI: 10.1371/journal.pone.0293833] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/15/2023] [Accepted: 10/19/2023] [Indexed: 02/03/2024] Open
Abstract
BACKGROUND Evidence regarding differences in survival associated with the site of metastasis in triple-negative breast cancer (TNBC) remains limited. Our aim was to analyze the overall survival (OS), distant relapse free survival (DRFS), and survival since the diagnosis of the relapse (MS), according to the side of metastasis. METHODS This was a retrospective study of TNBC patients with distant metastases at the Instituto Nacional de Enfermedades Neoplasicas (Lima, Peru) from 2000 to 2014. Prognostic factors were determined by multivariate Cox regression analysis. RESULTS In total, 309 patients were included. Regarding the type of metastasis, visceral metastasis accounted for 41% and the lung was the most frequent first site of metastasis (33.3%). With a median follow-up of 10.2 years, the 5-year DRFS and OS were 10% and 26%, respectively. N staging (N2-N3 vs. N0, HR = 1.49, 95%CI: 1.04-2.14), metastasis in visceral sites (vs. bone; HR = 1.55, 95%CI: 0.94-2.56), the central nervous system (vs. bone; HR = 1.88, 95% CI: 1.10-3.22), and multiple sites (vs. bone; HR = 2.55, 95%CI:1.53-4.25) were prognostic factors of OS whereas multiple metastasis (HR = 2.30, 95% CI: 1.42-3.72) was a predictor of MS. In terms of DRFS, there were no differences according to metastasis type or solid organ. CONCLUSION TNBC patients with multiple metastasis and CNS metastasis have an increased risk of death compared to those with bone metastasis in terms of OS and MS.
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Affiliation(s)
| | | | - Zaida Morante
- Departamento de Oncología Médica, Instituto Nacional de Enfermedades Neoplásicas, Lima, Perú
| | - Carlos Fairen
- Boston Medical Center, Boston, Massachusetts, United States of America
| | | | | | - Fresia Casas
- Universidad Peruana Cayetano Heredia, Lima, Peru
| | | | | | | | - Hugo Fuentes
- Departamento de Oncología Médica, Instituto Nacional de Enfermedades Neoplásicas, Lima, Perú
| | - Henry Gomez
- Departamento de Oncología Médica, Instituto Nacional de Enfermedades Neoplásicas, Lima, Perú
| | - Alexis Narvaez-Rojas
- Department of Surgical Oncology, Miller School of Medicine, University Of Miami, Miami, Florida, United States of America
| | | | - Jhajaira Araujo
- Escuela Profesional de Medicina Humana, Universidad Privada San Juan Bautista, Chorrillos, Lima, Peru
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15
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Facca VJ, Cai Z, Ku A, Georgiou CJ, Reilly RM. Adjuvant Auger Electron-Emitting Radioimmunotherapy with [ 111In]In-DOTA-Panitumumab in a Mouse Model of Local Recurrence and Metastatic Progression of Human Triple-Negative Breast Cancer. Mol Pharm 2023; 20:6407-6419. [PMID: 37983089 DOI: 10.1021/acs.molpharmaceut.3c00780] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/21/2023]
Abstract
Triple-negative breast cancer (TNBC) has a high risk for recurrence and metastasis. We studied the effectiveness of Auger electron (AE) radioimmunotherapy (RIT) with antiepidermal growth factor receptor (EGFR) panitumumab conjugated with DOTA complexed to 111In ([111In]In-DOTA-panitumumab) for preventing metastatic progression after local treatment of 231/LM2-4 Luc+ human TNBC tumors in the mammary fat pad of NRG mice. Prior to RIT, the primary tumor was resected, and tumor margins were treated with X-irradiation (XRT; 5 days × 6 Gy/d). RIT was administered 1 day post-XRT by intravenous injection of 26 MBq (15 μg) or 2 × 10 MBq (15 μg each) separated by 7 d. These treatments were compared to tumor resection with or without XRT combined with DOTA-panitumumab (15 μg) or irrelevant [111In]In-DOTA-IgG2 (24 MBq; 15 μg), and efficacy was evaluated by Kaplan-Meier survival curves. The effect of [111In]In-DOTA-panitumumab (23 MBq; 15 μg) after tumor resection without local XRT was also studied. Tumor resection followed by XRT and RIT with 26 MBq [111In]In-DOTA-panitumumab significantly increased the median survival to 35 d compared to tumor resection with or without XRT (23-24 d; P < 0.0001). Local treatment with tumor resection and XRT followed by 2 × 10 MBq of [111In]In-DOTA-panitumumab, DOTA-panitumumab, or [111In]In-DOTA-IgG2 did not significantly improve median survival (26 days for all treatments). RIT alone with [111In]In-DOTA-panitumumab postresection of the tumor without XRT increased median survival to 29 days, though this was not significant. Despite significantly improved survival in mice treated with tumor resection, XRT, and RIT with [111In]In-DOTA-panitumumab, all mice eventually succumbed to advanced metastatic disease by 45 d post-tumor resection. SPECT/CT with [111In]In-DOTA-panitumumab, PET/MRI with [64Cu]Cu-DOTA-panitumumab F(ab')2, and PET/CT with [18F]FDG were used to detect recurrent and metastatic disease. Uptake of [111In]In-DOTA-panitumumab at 4 d p.i. in the MFP tumor was 26.8 ± 9.7% ID/g and in metastatic lymph nodes (LN), lungs, and liver was 34.2 ± 26.9% ID/g, 17.5 ± 6.0% ID/g, and 9.4 ± 2.4%ID/g, respectively, while uptake in the lungs (6.0 ± 0.9% ID/g) and liver (5.2 ± 2.9% ID/g) of non-tumor-bearing NRG was significantly lower (P < 0.05). Radiation-absorbed doses in metastatic LN, lungs, and liver were 9.7 ± 6.1, 6.4 ± 2.1, and 10.9 ± 2.7 Gy, respectively. In conclusion, we demonstrated that RIT with [111In]In-DOTA-panitumumab combined with tumor resection and XRT significantly improved the survival of mice with recurrent TNBC. However, the aggressive nature of 231/LM2-4 Luc+ tumors in NRG mice may have contributed to the tumor recurrence and progression observed.
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Affiliation(s)
- Valerie J Facca
- Department of Pharmaceutical Sciences, Leslie Dan Faculty of Pharmacy, University of Toronto, 144 College St., Toronto, Ontario M5S 3M2, Canada
| | - Zhongli Cai
- Department of Pharmaceutical Sciences, Leslie Dan Faculty of Pharmacy, University of Toronto, 144 College St., Toronto, Ontario M5S 3M2, Canada
| | - Anthony Ku
- Department of Pharmaceutical Sciences, Leslie Dan Faculty of Pharmacy, University of Toronto, 144 College St., Toronto, Ontario M5S 3M2, Canada
| | - Constantine J Georgiou
- Department of Pharmaceutical Sciences, Leslie Dan Faculty of Pharmacy, University of Toronto, 144 College St., Toronto, Ontario M5S 3M2, Canada
| | - Raymond M Reilly
- Department of Pharmaceutical Sciences, Leslie Dan Faculty of Pharmacy, University of Toronto, 144 College St., Toronto, Ontario M5S 3M2, Canada
- Department of Medical Imaging, Temerty Faculty of Medicine, University of Toronto, Toronto, Ontario M5S 1A8, Canada
- Joint Department of Medical Imaging and Princess Margaret Cancer Centre, University Health Network, Toronto, Ontario M5G 2C1, Canada
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16
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A SERS/fluorescence dual-mode immuno-nanoprobe for investigating two anti-diabetic drugs on EGFR expressions. Mikrochim Acta 2023; 190:124. [PMID: 36894729 DOI: 10.1007/s00604-023-05705-2] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/18/2022] [Accepted: 02/11/2023] [Indexed: 03/11/2023]
Abstract
A surface-enhanced Raman scattering (SERS)/fluorescence dual-mode nanoprobe was proposed to assess anti-diabetic drug actions from the expression level of the epidermal growth factor receptor (EGFR), which is a significant biomarker of breast cancers. The nanoprobe has a raspberry shape, prepared by coating a dye-doped silica nanosphere with a mass of SERS tags, which gives high gains in fluorescence imaging and SERS measurement. The in situ detection of EGFR on the cell membrane surfaces after drug actions was achieved by using this nanoprobe, and the detection results agree with the enzyme-linked immunosorbent assay (ELISA) kit. Our study suggests that rosiglitazone hydrochloride (RH) may be a potential drug for diabetic patients with breast cancer, while the anti-cancer effect of metformin hydrochloride (MH) is debatable since MH slightly promotes the EGFR expression of MCF-7 cells in this study. This sensing platform endows more feasibility for highly sensitive and accurate feedback of pesticide effects at the membrane protein level.
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17
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Son S, Kim H, Lim H, Lee JH, Lee KM, Shin I. CCN3/NOV promotes metastasis and tumor progression via GPNMB-induced EGFR activation in triple-negative breast cancer. Cell Death Dis 2023; 14:81. [PMID: 36737605 PMCID: PMC9898537 DOI: 10.1038/s41419-023-05608-3] [Citation(s) in RCA: 14] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/27/2022] [Revised: 01/19/2023] [Accepted: 01/20/2023] [Indexed: 02/05/2023]
Abstract
Triple-negative breast cancer (TNBC) is the most aggressive subtype of breast cancer. TNBC patients typically exhibit unfavorable outcomes due to its rapid growth and metastatic potential. Here, we found overexpression of CCN3 in TNBC patients. We identified that CCN3 knockdown diminished cancer stem cell formation, metastasis, and tumor growth in vitro and in vivo. Mechanistically, ablation of CCN3 reduced activity of the EGFR/MAPK pathway. Transcriptome profiling revealed that CCN3 induces glycoprotein nonmetastatic melanoma protein B (GPNMB) expression, which in turn activates the EGFR pathway. An interrogation of the TCGA dataset further supported the transcriptional regulation of GPNMB by CCN3. Finally, we showed that CCN3 activates Wnt signaling through a ligand-dependent or -independent mechanism, which increases microphthalmia-associated transcription factor (MITF) protein, a transcription factor inducing GPNMB expression. Together, our findings demonstrate the oncogenic role of CCN3 in TNBC, and we propose CCN3 as a putative therapeutic target for TNBC.
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Affiliation(s)
- Seogho Son
- Department of Life Science, Hanyang University, Seoul, 04763, Korea
| | - Hyungjoo Kim
- Department of Life Science, Hanyang University, Seoul, 04763, Korea
| | - Hogeun Lim
- Department of Life Science, Hanyang University, Seoul, 04763, Korea
| | - Joo-Hyung Lee
- Department of Life Science, Hanyang University, Seoul, 04763, Korea
| | - Kyung-Min Lee
- Department of Life Science, Hanyang University, Seoul, 04763, Korea
- Natural Science Institute, Hanyang University, Seoul, 04763, Korea
- Hanyang Institute of Bioscience and Biotechnology, Hanyang University, Seoul, 04763, Korea
| | - Incheol Shin
- Department of Life Science, Hanyang University, Seoul, 04763, Korea.
- Natural Science Institute, Hanyang University, Seoul, 04763, Korea.
- Hanyang Institute of Bioscience and Biotechnology, Hanyang University, Seoul, 04763, Korea.
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18
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Ho ECH, Qiu R, Miller E, Bilotta MT, FitzGerald D, Antignani A. Antibody drug conjugates, targeting cancer-expressed EGFR, exhibit potent and specific antitumor activity. Biomed Pharmacother 2023; 157:114047. [PMID: 36459711 PMCID: PMC9840435 DOI: 10.1016/j.biopha.2022.114047] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/19/2022] [Revised: 11/18/2022] [Accepted: 11/25/2022] [Indexed: 11/30/2022] Open
Abstract
The monoclonal antibody '40H3' binds to EGFRvIII and to full-length EGFR when it is overexpressed on cancer cells. To generate candidate cytotoxic antibody-drug conjugates (ADCs), 40H3 was modified by the addition of small molecular weight payloads that included two tubulin-modifying agents, two topoisomerase inhibitors and a pyrrolobenzodiazepine (PBD) dimer. Conjugates retained antigen binding activity comparable to the unmodified 40H3 antibody. The cytotoxicity of five distinct ADCs was evaluated on a variety of EGFR-expressing cells including three triple negative breast cancer (TNBC) lines. Generally, the 40H3 conjugate with the PBD dimer (40H3-Tesirine) was the most active killing agent. The killing of EGFR-positive cells by 40H3-Tesirine correlated with the number of surface binding sites for 40H3. However, bystander killing was also evident in experiments with antigen-negative cells. In vivo tumor xenograft experiments were conducted on two TNBC tumor lines. Three treatments with the 40H3-Tesirine ADC at 1 mg/kg were sufficient to achieve complete remissions without evidence of mouse toxicity. Data support the development of ADCs derived from the 40H3 antibody for the treatment of cancers that express EGFRvIII or high levels of EGFR.
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Affiliation(s)
- Eric Chun Hei Ho
- Laboratory of Molecular Biology, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892-4264, United States
| | - Rong Qiu
- Laboratory of Molecular Biology, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892-4264, United States
| | - Ellis Miller
- Laboratory of Molecular Biology, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892-4264, United States
| | - Maria Teresa Bilotta
- Laboratory of Molecular Biology, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892-4264, United States
| | - David FitzGerald
- Laboratory of Molecular Biology, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892-4264, United States.
| | - Antonella Antignani
- Laboratory of Molecular Biology, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892-4264, United States.
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19
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Mechanisms and Strategies to Overcome PD-1/PD-L1 Blockade Resistance in Triple-Negative Breast Cancer. Cancers (Basel) 2022; 15:cancers15010104. [PMID: 36612100 PMCID: PMC9817764 DOI: 10.3390/cancers15010104] [Citation(s) in RCA: 21] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/29/2022] [Revised: 12/20/2022] [Accepted: 12/21/2022] [Indexed: 12/28/2022] Open
Abstract
Triple-negative breast cancer (TNBC) is characterized by a high rate of systemic metastasis, insensitivity to conventional treatment and susceptibility to drug resistance, resulting in a poor patient prognosis. The immune checkpoint inhibitors (ICIs) represented by antibodies of programmed death receptor 1 (PD-1) and programmed death receptor ligand 1 (PD-L1) have provided new therapeutic options for TNBC. However, the efficacy of PD-1/PD-L1 blockade monotherapy is suboptimal immune response, which may be caused by reduced antigen presentation, immunosuppressive tumor microenvironment, interplay with other immune checkpoints and aberrant activation of oncological signaling in tumor cells. Therefore, to improve the sensitivity of TNBC to ICIs, suitable patients are selected based on reliable predictive markers and treated with a combination of ICIs with other therapies such as chemotherapy, radiotherapy, targeted therapy, oncologic virus and neoantigen-based therapies. This review discusses the current mechanisms underlying the resistance of TNBC to PD-1/PD-L1 inhibitors, the potential biomarkers for predicting the efficacy of anti-PD-1/PD-L1 immunotherapy and recent advances in the combination therapies to increase response rates, the depth of remission and the durability of the benefit of TNBC to ICIs.
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20
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Facca VJ, Cai Z, Gopal NEK, Reilly RM. Panitumumab-DOTA- 111In: An Epidermal Growth Factor Receptor Targeted Theranostic for SPECT/CT Imaging and Meitner-Auger Electron Radioimmunotherapy of Triple-Negative Breast Cancer. Mol Pharm 2022; 19:3652-3663. [PMID: 35926098 DOI: 10.1021/acs.molpharmaceut.2c00457] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/29/2022]
Abstract
Epidermal growth factor receptors (EGFR) are overexpressed in triple-negative breast cancer (TNBC) and are an attractive target for the development of theranostic radiopharmaceuticals. We studied anti-EGFR panitumumab labeled with 111In (panitumumab-DOTA-111In) for SPECT/CT imaging and Meitner-Auger electron (MAE) radioimmunotherapy (RIT) of TNBC. Panitumumab-DOTA-111In was bound, internalized, and routed to the nucleus in MCF7, MDA-MB-231/Luc, and MDA-MB-468 human breast cancer (BC) cells dependent on the EGFR expression level (1.5 × 104, 1.7 × 105, or 1.3 × 106 EGFR/cell, respectively). The absorbed dose in the nuclei of MCF7, MDA-MB-231/Luc, and MDA-MB-468 cells incubated with 4.4 MBq of panitumumab-DOTA-111In (20 nM) was 1.20 ± 0.02, 2.2 ± 0.1, and 25 ± 2 Gy, respectively. The surviving fraction (SF) of MDA-MB-231/Luc cells treated with panitumumab-DOTA-111In (10-300 nM; 1.5 MBq/μg) was reduced as the absorbed dose in the cell increased, with clonogenic survival reduced to an SF = 0.12 ± 0.05 at 300 nM corresponding to 12.7 Gy. The SFs of MDA-MB-468, MDA-MB-231/Luc, and MCF7 cells treated with panitumumab-DOTA-111In (20 nM; 1.7 MBq/μg) were <0.01, 0.56 ± 0.05, and 0.67 ± 0.04, respectively. Unlabeled panitumumab had no effect on SF, and irrelevant IgG-DOTA-111In only modestly reduced the SF of MDA-MB-231/Luc cells but not MCF7 or MDA-MB-468 cells. The cytotoxicity of panitumumab-DOTA-111In was mediated by increased DNA double-strand breaks (DSB), cell cycle arrest at G2/M-phase and apoptosis measured by immunofluorescence detection by flow cytometry. MDA-MB-231/Luc tumors in the mammary fat pad (MFP) of NRG mice were clearly imaged with panitumumab-DOTA-111In by microSPECT/CT at 4 days postinjection (p.i.), and biodistribution studies revealed high tumor uptake [18 ± 2% injected dose/g (% ID/g] and lower normal tissue uptake (<10% ID/g). Administration of up to 24 MBq (15 μg) of panitumumab-DOTA-111In to healthy NRG mice caused no major hematological, renal, or hepatic toxicity with no decrease in body weight. Treatment of NOD SCID mice with MDA-MB-231 tumors with panitumumab-DOTA-111In (22 MBq; 15 μg) slowed tumor growth. The mean time for tumors to reach a volume of ≥500 mm3 was 61 ± 5 days for RIT with panitumumab-DOTA-111In compared to 42 ± 6 days for mice treated with irrelevant IgG2-DOTA-111In (P < 0.0001) and 35 ± 3 days for mice receiving 0.9% NaCl (P < 0.0001). However, tumors regrew at later time points. The median survival of mice treated with panitumumab-DOTA-111In was 70 days versus 46 days for IgG2-DOTA-111In (P < 0.0001) or 40 days for 0.9% NaCl (P < 0.0001). We conclude that panitumumab-DOTA-111In is a promising theranostic agent for TNBC. Increasing the administered amount of panitumumab-DOTA-111In and/or combination with radiosensitizing PARP inhibitors used for treatment of patients with TNBC may provide a more durable response to RIT.
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Affiliation(s)
- Valerie J Facca
- Department of Pharmaceutical Sciences, Leslie Dan Faculty of Pharmacy, University of Toronto, 144 College Street, Toronto, Ontario M5S 3M2, Canada
| | - Zhongli Cai
- Department of Pharmaceutical Sciences, Leslie Dan Faculty of Pharmacy, University of Toronto, 144 College Street, Toronto, Ontario M5S 3M2, Canada
| | - Nakita E K Gopal
- Faculty of Arts and Sciences, University of Toronto, Toronto, Ontario M5S 3G3, Canada
| | - Raymond M Reilly
- Department of Pharmaceutical Sciences, Leslie Dan Faculty of Pharmacy, University of Toronto, 144 College Street, Toronto, Ontario M5S 3M2, Canada.,Department of Medical Imaging, Temerty Faculty of Medicine, University of Toronto, Toronto, Ontario M5S 1A8, Canada.,Joint Department of Medical Imaging and Princess Margaret Cancer Centre, University Health Network, Toronto, Ontario M5G 2C1, Canada
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21
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Dewi C, Fristiohady A, Amalia R, Khairul Ikram NK, Ibrahim S, Muchtaridi M. Signaling Pathways and Natural Compounds in Triple-Negative Breast Cancer Cell Line. MOLECULES (BASEL, SWITZERLAND) 2022; 27:molecules27123661. [PMID: 35744786 PMCID: PMC9227697 DOI: 10.3390/molecules27123661] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 03/24/2022] [Revised: 05/25/2022] [Accepted: 05/30/2022] [Indexed: 11/16/2022]
Abstract
Triple-negative breast cancer (TNBC) is the most aggressive subtype of breast cancer, having a poor prognosis and rapid metastases. TNBC is characterized by the absence of estrogen, progesterone, and human epidermal growth receptor-2 (HER2) expressions and has a five-year survival rate. Compared to other breast cancer subtypes, TNBC patients only respond to conventional chemotherapies, and even then, with limited success. Shortages of chemotherapeutic medication can lead to resistance, pressured index therapy, non-selectivity, and severe adverse effects. Finding targeted treatments for TNBC is difficult owing to the various features of cancer. Hence, identifying the most effective molecular targets in TNBC pathogenesis is essential for predicting response to targeted therapies and preventing TNBC cell metastases. Nowadays, natural compounds have gained attention as TNBC treatments, and have offered new strategies for solving drug resistance. Here, we report a systematic review using the database from Pubmed, Science Direct, MDPI, BioScince, Springer, and Nature for articles screening from 2003 to 2022. This review analyzes relevant signaling pathways and the prospect of utilizing natural compounds as a therapeutic agent to improve TNBC treatments in the future.
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Affiliation(s)
- Citra Dewi
- Department of Pharmaceutical Analysis and Medicinal Chemistry, Faculty of Pharmacy, Universitas Padjadjaran, Sumedang 45363, Indonesia;
- Pharmacy Department, Faculty of Science and Technology, Mandala Waluya University, Kendari 93561, Indonesia
| | - Adryan Fristiohady
- Faculty of Pharmacy, Halu Oleo University, Kampus Hijau Bumi Tridharma, Kendari 93232, Indonesia;
| | - Riezki Amalia
- Department of Pharmacology and Clinical Pharmacy, Faculty of Pharmacy, Universitas Padjadjaran, Sumedang 45363, Indonesia;
| | - Nur Kusaira Khairul Ikram
- Institute of Biological Sciences, Faculty of Science, Universiti Malaya, Kuala Lumpur 50603, Malaysia;
| | - Sugeng Ibrahim
- Department of Molecular Biology, Faculty of Medicine, Universitas Katolik Soegijapranata, Semarang 50234, Indonesia;
| | - Muchtaridi Muchtaridi
- Department of Pharmaceutical Analysis and Medicinal Chemistry, Faculty of Pharmacy, Universitas Padjadjaran, Sumedang 45363, Indonesia;
- Correspondence:
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22
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Xie X, Lee J, Fuson JA, Liu H, Iwase T, Yun K, Margain C, Tripathy D, Ueno NT. Emerging drug targets for triple-negative breast cancer: a guided tour of the preclinical landscape. Expert Opin Ther Targets 2022; 26:405-425. [PMID: 35574694 PMCID: PMC11972560 DOI: 10.1080/14728222.2022.2077188] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/04/2021] [Accepted: 05/10/2022] [Indexed: 02/06/2023]
Abstract
INTRODUCTION Triple-negative breast cancer (TNBC) is the most fatal molecular subtype of breast cancer because of its aggressiveness and resistance to chemotherapy. FDA-approved therapies for TNBC are limited to poly(ADP-ribose) polymerase inhibitors, immune checkpoint inhibitors, and trophoblast cell surface antigen 2-targeted antibody-drug conjugate. Therefore, developing a novel effective targeted therapy for TNBC is an urgent unmet need. AREAS COVERED In this narrative review, we discuss emerging targets for TNBC treatment discovered in early translational studies. We focus on cancer cell membrane molecules, hyperactive intracellular signaling pathways, and the tumor microenvironment (TME) based on their druggability, therapeutic potency, specificity to TNBC, and application in immunotherapy. EXPERT OPINION The significant challenges in the identification and validation of TNBC-associated targets are 1) application of appropriate genetic, molecular, and immunological approaches for modulating the target, 2) establishment of a proper mouse model that accurately represents the human immune TME, 3) TNBC molecular heterogeneity, and 4) failure translation of preclinical findings to clinical practice. To overcome those difficulties, future research needs to apply novel technology, such as single-cell RNA sequencing, thermostable group II intron reverse transcriptase sequencing, and humanized mouse models. Further, combination treatment targeting multiple pathways in both the TNBC tumor and its TME is essential for effective disease control.
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Affiliation(s)
- Xuemei Xie
- Section of Translational Breast Cancer Research, Department of Breast Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA
| | - Jangsoon Lee
- Section of Translational Breast Cancer Research, Department of Breast Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA
| | - Jon A. Fuson
- Section of Translational Breast Cancer Research, Department of Breast Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA
| | - Huey Liu
- Section of Translational Breast Cancer Research, Department of Breast Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA
| | - Toshiaki Iwase
- Section of Translational Breast Cancer Research, Department of Breast Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA
| | - Kyuson Yun
- Research Institute at Houston Methodist, Weill Cornell Medical College, Houston, TX 77030, USA
| | | | - Debu Tripathy
- Section of Translational Breast Cancer Research, Department of Breast Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA
| | - Naoto T. Ueno
- Section of Translational Breast Cancer Research, Department of Breast Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA
- Cancer Biology and Therapeutics, University of Hawai’i Cancer Center, Honolulu, HI 96813, USA
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23
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Chaudhuri A, Kumar DN, Dehari D, Singh S, Kumar P, Bolla PK, Kumar D, Agrawal AK. Emergence of Nanotechnology as a Powerful Cavalry against Triple-Negative Breast Cancer (TNBC). Pharmaceuticals (Basel) 2022; 15:542. [PMID: 35631368 PMCID: PMC9143332 DOI: 10.3390/ph15050542] [Citation(s) in RCA: 21] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/12/2022] [Revised: 04/26/2022] [Accepted: 04/26/2022] [Indexed: 12/11/2022] Open
Abstract
Triple-negative breast cancer (TNBC) is considered one of the un-manageable types of breast cancer, involving devoid of estrogen, progesterone, and human epidermal growth factor receptor 2 (HER 2) receptors. Due to their ability of recurrence and metastasis, the management of TNBC remains a mainstay challenge, despite the advancements in cancer therapies. Conventional chemotherapy remains the only treatment regimen against TNBC and suffers several limitations such as low bioavailability, systemic toxicity, less targetability, and multi-drug resistance. Although various targeted therapies have been introduced to manage the hardship of TNBC, they still experience certain limitations associated with the survival benefits. The current research thus aimed at developing and improving the strategies for effective therapy against TNBC. Such strategies involved the emergence of nanoparticles. Nanoparticles are designated as nanocavalries, loaded with various agents (drugs, genes, etc.) to battle the progression and metastasis of TNBC along with overcoming the limitations experienced by conventional chemotherapy and targeted therapy. This article documents the treatment regimens of TNBC along with their efficacy towards different subtypes of TNBC, and the various nanotechnologies employed to increase the therapeutic outcome of FDA-approved drug regimens.
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Affiliation(s)
- Aiswarya Chaudhuri
- Department of Pharmaceutical Engineering & Technology, Indian Institute of Technology (BHU), Varanasi 221005, India; (A.C.); (D.N.K.); (D.D.); (S.S.); (D.K.)
| | - Dulla Naveen Kumar
- Department of Pharmaceutical Engineering & Technology, Indian Institute of Technology (BHU), Varanasi 221005, India; (A.C.); (D.N.K.); (D.D.); (S.S.); (D.K.)
| | - Deepa Dehari
- Department of Pharmaceutical Engineering & Technology, Indian Institute of Technology (BHU), Varanasi 221005, India; (A.C.); (D.N.K.); (D.D.); (S.S.); (D.K.)
| | - Sanjay Singh
- Department of Pharmaceutical Engineering & Technology, Indian Institute of Technology (BHU), Varanasi 221005, India; (A.C.); (D.N.K.); (D.D.); (S.S.); (D.K.)
- Babasaheb Bhimrao Ambedkar University, Lucknow 226025, India
| | - Pradeep Kumar
- Department of Pharmacy and Pharmacology, School of Therapeutic Sciences, Faculty of Health Sciences, University of the Witwatersrand, Johannesburg 2193, South Africa;
| | - Pradeep Kumar Bolla
- Department of Biomedical Engineering, College of Engineering, The University of Texas at El Paso, 500 W. University Ave, El Paso, TX 79968, USA;
| | - Dinesh Kumar
- Department of Pharmaceutical Engineering & Technology, Indian Institute of Technology (BHU), Varanasi 221005, India; (A.C.); (D.N.K.); (D.D.); (S.S.); (D.K.)
| | - Ashish Kumar Agrawal
- Department of Pharmaceutical Engineering & Technology, Indian Institute of Technology (BHU), Varanasi 221005, India; (A.C.); (D.N.K.); (D.D.); (S.S.); (D.K.)
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24
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Abdelmalek CM, Hu Z, Kronenberger T, Küblbeck J, Kinnen FJM, Hesse SS, Malik A, Kudolo M, Niess R, Gehringer M, Zender L, Witt-Enderby PA, Zlotos DP, Laufer SA. Gefitinib-Tamoxifen Hybrid Ligands as Potent Agents against Triple-Negative Breast Cancer. J Med Chem 2022; 65:4616-4632. [PMID: 35286086 DOI: 10.1021/acs.jmedchem.1c01646] [Citation(s) in RCA: 21] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/20/2022]
Abstract
Anticancer drug conjugates may benefit from simultaneous action at two targets potentially overcoming the drawbacks of current cancer treatment, such as insufficient efficacy, high toxicity, and development of resistance. Compared to a combination of two single-target drugs, they may offer an advantage of pharmacokinetic simplicity and fewer drug-drug interactions. Here, we report a series of compounds connecting tamoxifen or endoxifen with the EGFR-inhibitor gefitinib via a covalent linkage. These hybrid ligands retain both ER antagonist activity and EGFR inhibition. The most potent analogues exhibited single-digit nanomolar activities at both targets. The amide-linked endoxifen-gefitinib drug conjugates 17b and 17c demonstrated the most favorable anti-cancer profile in cellular viability assays on MCF7, MDA-MB-231, MDA-MB-468, and BT-549 breast cancer cells. Most importantly, in TNBC cells 17b and 17c displayed nanomolar IC50-values (380 nM - 970 nM) and were superior in their anti-cancer activity compared to their control compounds and combinations thereof.
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Affiliation(s)
- Carine M Abdelmalek
- Department of Pharmaceutical Chemistry, Faculty of Pharmacy and Biotechnology, The German University in Cairo, 11835 New Cairo City, Cairo, Egypt.,Department of Pharmaceutical/Medicinal Chemistry, Eberhard Karls University Tübingen, Auf der Morgenstelle 8, 72076 Tübingen, Germany
| | - Zexi Hu
- Department of Medical Oncology and Pneumology (Internal Medicine VIII), University Hospital of Tübingen, 72076 Tübingen, Germany.,Cluster of Excellence iFIT (EXC 2180) 'Image-Guided & Functionally Instructed Tumor Therapies', University of Tübingen, 72076 Tübingen, Germany
| | - Thales Kronenberger
- Department of Pharmaceutical/Medicinal Chemistry, Eberhard Karls University Tübingen, Auf der Morgenstelle 8, 72076 Tübingen, Germany.,Department of Medical Oncology and Pneumology (Internal Medicine VIII), University Hospital of Tübingen, 72076 Tübingen, Germany.,Cluster of Excellence iFIT (EXC 2180) 'Image-Guided & Functionally Instructed Tumor Therapies', University of Tübingen, 72076 Tübingen, Germany
| | - Jenni Küblbeck
- A.I. Virtanen Institute for Molecular Sciences, University of Eastern Finland, P.O. Box 1627, FI-70210 Kuopio, Finland.,School of Pharmacy, University of Eastern Finland, P.O. Box 1627, FI-70210 Kuopio, Finland
| | - Franziska J M Kinnen
- Department of Pharmaceutical/Medicinal Chemistry, Eberhard Karls University Tübingen, Auf der Morgenstelle 8, 72076 Tübingen, Germany
| | - Salma S Hesse
- Department of Pharmaceutical Chemistry, Faculty of Pharmacy and Biotechnology, The German University in Cairo, 11835 New Cairo City, Cairo, Egypt
| | - Afsin Malik
- School of Pharmacy, Division of Pharmaceutical, Administrative and Social Sciences, Duquesne University, Pittsburgh, Pennsylvania 15282, United States
| | - Mark Kudolo
- Department of Pharmaceutical/Medicinal Chemistry, Eberhard Karls University Tübingen, Auf der Morgenstelle 8, 72076 Tübingen, Germany
| | - Raimund Niess
- Department of Pharmaceutical/Medicinal Chemistry, Eberhard Karls University Tübingen, Auf der Morgenstelle 8, 72076 Tübingen, Germany
| | - Matthias Gehringer
- Department of Pharmaceutical/Medicinal Chemistry, Eberhard Karls University Tübingen, Auf der Morgenstelle 8, 72076 Tübingen, Germany.,Cluster of Excellence iFIT (EXC 2180) 'Image-Guided & Functionally Instructed Tumor Therapies', University of Tübingen, 72076 Tübingen, Germany
| | - Lars Zender
- Department of Medical Oncology and Pneumology (Internal Medicine VIII), University Hospital of Tübingen, 72076 Tübingen, Germany.,Cluster of Excellence iFIT (EXC 2180) 'Image-Guided & Functionally Instructed Tumor Therapies', University of Tübingen, 72076 Tübingen, Germany
| | - Paula A Witt-Enderby
- School of Pharmacy, Division of Pharmaceutical, Administrative and Social Sciences, Duquesne University, Pittsburgh, Pennsylvania 15282, United States
| | - Darius P Zlotos
- Department of Pharmaceutical Chemistry, Faculty of Pharmacy and Biotechnology, The German University in Cairo, 11835 New Cairo City, Cairo, Egypt
| | - Stefan A Laufer
- Department of Pharmaceutical/Medicinal Chemistry, Eberhard Karls University Tübingen, Auf der Morgenstelle 8, 72076 Tübingen, Germany.,Cluster of Excellence iFIT (EXC 2180) 'Image-Guided & Functionally Instructed Tumor Therapies', University of Tübingen, 72076 Tübingen, Germany.,Tübingen Center for Academic Drug Discovery, Auf der Morgenstelle 8, 72076 Tübingen, Germany
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25
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Chimplee S, Roytrakul S, Sukrong S, Srisawat T, Graidist P, Kanokwiroon K. Anticancer Effects and Molecular Action of 7-α-Hydroxyfrullanolide in G2/M-Phase Arrest and Apoptosis in Triple Negative Breast Cancer Cells. Molecules 2022; 27:407. [PMID: 35056723 PMCID: PMC8779136 DOI: 10.3390/molecules27020407] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/30/2021] [Revised: 12/29/2021] [Accepted: 01/06/2022] [Indexed: 02/07/2023] Open
Abstract
Triple negative breast cancer (TNBC) is a breast cancer subtype characterized by the absence of estrogen receptor, progesterone receptor and human epidermal growth factor receptor 2 expression. TNBC cells respond poorly to targeted chemotherapies currently in use and the mortality rate of TNBC remains high. Therefore, it is necessary to identify new chemotherapeutic agents for TNBC. In this study, the anti-cancer effects of 7-α-hydroxyfrullanolide (7HF), derived from Grangea maderaspatana, on MCF-7, MDA-MB-231 and MDA-MB-468 breast cancer cells were assessed using MTT assay. The mode of action of 7HF in TNBC cells treated with 6, 12 and 24 µM of 7HF was determined by flow cytometry and propidium iodide (PI) staining for cell cycle analysis and annexin V/fluorescein isothiocyanate + PI staining for detecting apoptosis. The molecular mechanism of action of 7HF in TNBC cells was investigated by evaluating protein expression using proteomic techniques and western blotting. Subsequently, 7HF exhibited the strongest anti-TNBC activity toward MDA-MB-468 cells and a concomitantly weak toxicity toward normal breast cells. The molecular mechanism of action of low-dose 7HF in TNBC cells primarily involved G2/M-phase arrest through upregulation of the expression of Bub3, cyclin B1, phosphorylated Cdk1 (Tyr 15) and p53-independent p21. Contrastingly, the upregulation of PP2A-A subunit expression may have modulated the suppression of various cell survival proteins such as p-Akt (Ser 473), FoxO3a and β-catenin. The concurrent apoptotic effect of 7HF on the treated cells was mediated via both intrinsic and extrinsic modes through the upregulation of Bax and active cleaved caspase-7-9 expression and downregulation of Bcl-2 and full-length caspase-7-9 expression. Notably, the proteomic approach revealed the upregulation of the expression of pivotal protein clusters associated with G1/S-phase arrest, G2/M-phase transition and apoptosis. Thus, 7HF exhibits promising anti-TNBC activity and at a low dose, it modulates signal transduction associated with G2/M-phase arrest and apoptosis.
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Affiliation(s)
- Siriphorn Chimplee
- Department of Biomedical Sciences and Biomedical Engineering, Faculty of Medicine, Prince of Songkla University, Hat Yai, Songkhla 90110, Thailand; (S.C.); (P.G.)
| | - Sittiruk Roytrakul
- Functional Ingredients and Food Innovation Research Group, National Center for Genetic Engineering and Biotechnology (BIOTEC), National Science and Technology Development Agency (NSTDA), Pathum Thani 12120, Thailand;
| | - Suchada Sukrong
- Research Unit of DNA Barcoding of Thai Medicinal Plants, Department of Pharmacognosy and Pharmaceutical Botany, Faculty of Pharmaceutical Sciences, Chulalongkorn University, Bangkok 10330, Thailand;
| | - Theera Srisawat
- Faculty of Science and Industrial Technology, Surat Thani Campus, Prince of Songkla University, Surat Thani 84000, Thailand;
- Faculty of Innovative Agriculture and Fisheries, Surat Thani Campus, Prince of Songkla University, Surat Thani 84000, Thailand
| | - Potchanapond Graidist
- Department of Biomedical Sciences and Biomedical Engineering, Faculty of Medicine, Prince of Songkla University, Hat Yai, Songkhla 90110, Thailand; (S.C.); (P.G.)
| | - Kanyanatt Kanokwiroon
- Department of Biomedical Sciences and Biomedical Engineering, Faculty of Medicine, Prince of Songkla University, Hat Yai, Songkhla 90110, Thailand; (S.C.); (P.G.)
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26
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Lipovka Y, Alday E, Hernandez J, Velazquez C. Molecular Mechanisms of Biologically Active Compounds from Propolis in Breast Cancer: State of the Art and Future Directions. FOOD REVIEWS INTERNATIONAL 2021. [DOI: 10.1080/87559129.2021.2003380] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 10/25/2022]
Affiliation(s)
- Yulia Lipovka
- Department of Chemistry-Biology, University of Sonora, Hermosillo, Mexico
| | - Efrain Alday
- Department of Chemistry-Biology, University of Sonora, Hermosillo, Mexico
| | - Javier Hernandez
- Unidad de Servicios de Apoyo en Resolución Analítica, Universidad Veracruzana, Xalapa, Mexico
| | - Carlos Velazquez
- Department of Chemistry-Biology, University of Sonora, Hermosillo, Mexico
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Sepahdar Z, Miroliaei M, Bouzari S, Khalaj V, Salimi M. Surface Engineering of Escherichia coli-Derived OMVs as Promising Nano-Carriers to Target EGFR-Overexpressing Breast Cancer Cells. Front Pharmacol 2021; 12:719289. [PMID: 34867325 PMCID: PMC8638777 DOI: 10.3389/fphar.2021.719289] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/02/2021] [Accepted: 09/15/2021] [Indexed: 11/13/2022] Open
Abstract
Bacterial outer membrane vesicles (OMVs) have recently drawn a great deal of attention due to their therapeutic efficiency and ability to target specific cells. In the present study, we sought to probe engineered OMVs as novel and promising carriers to target breast cancer cells. Following the fusion of the affiEGFR-GALA structure to the C-terminal of ClyA as an anchor protein, the ClyA-affiEGFR-GALA construct was successfully expressed on the surface of ∆msbB/∆pagP E. coli W3110-derived OMVs. Morphological features of the engineered and wild-type OMVs were identical. The engineered OMVs induced no endotoxicity, cytotoxicity, or immunogenicity, indicating the safety of their application. These OMVs could specifically bind to EGF receptors of MDA-MB-468 cells expressing high levels of EGFR and not to those with low levels of EGFR (HEK293T cells). Interestingly, despite a lower binding affinity of the engineered OMVs relative to the positive control Cetuximab, it was strong enough to identify these cells. Moreover, confocal microscopy revealed no uptake of the modified OMVs by the EGFR-overexpressing cells in the presence of EGFR competitors. These results suggest that OMVs might internalize into the cells with EGF receptors, as no OMVs entered the cells with any EGFR expression or those pretreated with EGF or Cetuximab. Regarding the EGFR-binding affinity of the engineered OMVs and their cellular uptake, they are presented here as a potential carrier for cell-specific drug delivery to treat a wide variety of cancer cells. Interestingly, the engineered OMVs are capable of reaching the cytoplasm while escaping the endosome due to the incorporation of a fusogenic GALA peptide in the construct.
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Affiliation(s)
- Zahra Sepahdar
- Department of Cell and Molecular Biology and Microbiology, Faculty of Biological Science and Technology, University of Isfahan, Isfahan, Iran
| | - Mehran Miroliaei
- Department of Cell and Molecular Biology and Microbiology, Faculty of Biological Science and Technology, University of Isfahan, Isfahan, Iran
| | - Saeid Bouzari
- Department of Molecular Biology, Pasteur Institute of Iran, Tehran, Iran
| | - Vahid Khalaj
- Medical Biotechnology Department, Biotechnology Research Center, Pasteur Institute of Iran, Tehran, Iran
| | - Mona Salimi
- Physiology and Pharmacology Department, Pasteur Institute of Iran, Tehran, Iran
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Schwartz MR, Debski AC, Price RJ. Ultrasound-targeted nucleic acid delivery for solid tumor therapy. J Control Release 2021; 339:531-546. [PMID: 34655678 PMCID: PMC8599656 DOI: 10.1016/j.jconrel.2021.10.010] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/08/2021] [Revised: 10/07/2021] [Accepted: 10/08/2021] [Indexed: 12/16/2022]
Abstract
Depending upon multiple factors, malignant solid tumors are conventionally treated by some combination of surgical resection, radiation, chemotherapy, and immunotherapy. Despite decades of research, therapeutic responses remain poor for many cancer indications. Further, many current therapies in our armamentarium are either invasive or accompanied by toxic side effects. In lieu of traditional pharmaceutics and invasive therapeutic interventions, gene therapies offer more flexible and potentially more durable approaches for new anti-cancer therapies. Nonetheless, many current gene delivery approaches suffer from low transfection efficiency due to physiological barriers limiting extravasation and uptake of genetic material. Additionally, systemically administered gene therapies may lack target-specificity, which can lead to off-target effects. To overcome these challenges, many preclinical studies have shown the utility of focused ultrasound (FUS) to increase macromolecule uptake in cells and tissue under image guidance, demonstrating promise for improved delivery of therapeutics to solid tumors. As FUS-based drug delivery is now being tested in several clinical trials around the world, FUS-targeted gene therapy for solid tumor therapy may not be far behind. In this review, we comprehensively cover the literature pertaining to preclinical attempts to more efficiently deliver therapeutic genetic material with FUS and offer perspectives for future studies and clinical translation.
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Affiliation(s)
- Mark R Schwartz
- Department of Biomedical Engineering, University of Virginia, Charlottesville, VA, USA
| | - Anna C Debski
- Department of Biomedical Engineering, University of Virginia, Charlottesville, VA, USA
| | - Richard J Price
- Department of Biomedical Engineering, University of Virginia, Charlottesville, VA, USA; Department of Radiology and Medical Imaging, University of Virginia, Charlottesville, VA, USA.
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Wakiyama H, Kato T, Furusawa A, Choyke PL, Kobayashi H. Near infrared photoimmunotherapy of cancer; possible clinical applications. NANOPHOTONICS 2021; 10:3135-3151. [PMID: 36405499 PMCID: PMC9646249 DOI: 10.1515/nanoph-2021-0119] [Citation(s) in RCA: 16] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 03/20/2021] [Accepted: 04/15/2021] [Indexed: 05/07/2023]
Abstract
Near-infrared photoimmunotherapy (NIR-PIT) is a new cancer treatment that uses an antibody-photo-absorber conjugate (APC) composed of a targeting monoclonal antibody conjugated with a photoactivatable phthalocyanine-derivative dye, IRDye700DX (IR700). APCs injected into the body can bind to cancer cells where they are activated by local exposure to NIR light typically delivered by a NIR laser. NIR light alters the APC chemical conformation inducing damage to cancer cell membranes, resulting in necrotic cell death within minutes of light exposure. NIR-PIT selectivity kills cancer cells by immunogenic cell death (ICD) with minimal damage to adjacent normal cells thus, leading to rapid recovery by the patient. Moreover, since NIR-PIT induces ICD only on cancer cells, NIR-PIT initiates and activates antitumor host immunity that could be further enhanced when combined with immune checkpoint inhibition. NIR-PIT induces dramatic changes in the tumor vascularity causing the super-enhanced permeability and retention (SUPR) effect that dramatically enhances nanodrug delivery to the tumor bed. Currently, a worldwide Phase 3 study of NIR-PIT for recurrent or inoperable head and neck cancer patients is underway. In September 2020, the first APC and accompanying laser system were conditionally approved for clinical use in Japan. In this review, we introduce NIR-PIT and the SUPR effect and summarize possible applications of NIR-PIT in a variety of cancers.
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Affiliation(s)
- Hiroaki Wakiyama
- Molecular Imaging Branch, Center for Cancer Research, National Cancer Institute, NIH, Bethesda, MD, 20892, USA
| | - Takuya Kato
- Molecular Imaging Branch, Center for Cancer Research, National Cancer Institute, NIH, Bethesda, MD, 20892, USA
| | - Aki Furusawa
- Molecular Imaging Branch, Center for Cancer Research, National Cancer Institute, NIH, Bethesda, MD, 20892, USA
| | - Peter L. Choyke
- Molecular Imaging Branch, Center for Cancer Research, National Cancer Institute, NIH, Bethesda, MD, 20892, USA
| | - Hisataka Kobayashi
- Molecular Imaging Branch, Center for Cancer Research, National Cancer Institute, NIH, Bethesda, MD, 20892, USA
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Human Papillomavirus in Breast Carcinogenesis: A Passenger, a Cofactor, or a Causal Agent? BIOLOGY 2021; 10:biology10080804. [PMID: 34440036 PMCID: PMC8389583 DOI: 10.3390/biology10080804] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 06/12/2021] [Revised: 08/05/2021] [Accepted: 08/06/2021] [Indexed: 12/16/2022]
Abstract
Simple Summary Breast cancer (BC) is the most frequent tumor in women worldwide. A minority of BC patients have a family history of the disease, suggesting the importance of environmental and lifestyle factors. Human papillomavirus (HPV) infection has been detected in a subset of tumors, suggesting a potential role in BC. In this review, we summarized relevant information in respect to this topic and we propose a model of HPV-mediated breast carcinogenesis. Evidence suggests that breast tissue is accessible to HPV, which may be a causal agent of BC in a subset of cases. Abstract Breast cancer (BC) is the most commonly diagnosed malignancy in women worldwide as well as the leading cause of cancer-related death in this gender. Studies have identified that human papillomavirus (HPV) is a potential risk factor for BC development. While vaccines that protect against oncogenic HPVs infection have been commercially available, global disparities persist due to their high cost. Interestingly, numerous authors have detected an increased high risk (HR)-HPV infection in BC specimens when compared with non-tumor tissues. Therefore, it was suggested that HR-HPV infection could play a role in breast carcinogenesis in a subset of cases. Additional epidemiological and experimental evidence is still needed regarding the role of HR-HPV infection in the development and progression of BC.
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Mir MA, Qayoom H, Mehraj U, Nisar S, Bhat B, Wani NA. Targeting Different Pathways Using Novel Combination Therapy in Triple Negative Breast Cancer. Curr Cancer Drug Targets 2021; 20:586-602. [PMID: 32418525 DOI: 10.2174/1570163817666200518081955] [Citation(s) in RCA: 30] [Impact Index Per Article: 7.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/07/2020] [Revised: 03/22/2020] [Accepted: 03/24/2020] [Indexed: 02/07/2023]
Abstract
Triple negative breast cancer (TNBC) is one of the most aggressive subtypes of breast cancer accounting for 15-20% of cases and is defined by the lack of hormonal receptors viz., estrogen receptor (ER), progesterone receptor (PR) and expression of human epidermal growth receptor 2 (HER2). Treatment of TNBC is more challenging than other subtypes of breast cancer due to the lack of markers for the molecularly targeted therapies (ER, PR, and HER-2/ Neu), the conventional chemotherapeutic agents are still the mainstay of the therapeutic protocols of its patients. Despite, TNBC being more chemo-responsive than other subtypes, unfortunately, the initial good response to the chemotherapy eventually turns into a refractory drug-resistance. Using a monotherapy for the treatment of cancer, especially high-grade tumors like TNBC, is mostly worthless due to the inherent genetic instability of tumor cells to develop intrinsic and acquired resistance. Thus, a cocktail of two or more drugs with different mechanisms of action is more effective and could successfully control the disease. Furthermore, combination therapy reveals more, or at least the same, effectiveness with lower doses of every single agent and decreases the likelihood of chemoresistance. Herein, we shed light on the novel combinatorial approaches targeting PARP, EGFR, PI3K pathway, AR, and wnt signaling, HDAC, MEK pathway for efficient treatment of high-grade tumors like TNBC and decreasing the onset of resistance.
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Affiliation(s)
- Manzoor A Mir
- Department of Bioresources, School of Biological Sciences, University of Kashmir, Srinagar, India
| | - Hina Qayoom
- Department of Bioresources, School of Biological Sciences, University of Kashmir, Srinagar, India
| | - Umar Mehraj
- Department of Bioresources, School of Biological Sciences, University of Kashmir, Srinagar, India
| | - Safura Nisar
- Department of Bioresources, School of Biological Sciences, University of Kashmir, Srinagar, India
| | - Basharat Bhat
- Department of Bioresources, School of Biological Sciences, University of Kashmir, Srinagar, India
| | - Nissar A Wani
- Department of Bioresources, School of Biological Sciences, University of Kashmir, Srinagar, India
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Si Y, Zhang Y, Ngo HG, Guan JS, Chen K, Wang Q, Singh AP, Xu Y, Zhou L, Yang ES, Liu X(M. Targeted Liposomal Chemotherapies to Treat Triple-Negative Breast Cancer. Cancers (Basel) 2021; 13:cancers13153749. [PMID: 34359650 PMCID: PMC8345094 DOI: 10.3390/cancers13153749] [Citation(s) in RCA: 14] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/30/2021] [Revised: 07/23/2021] [Accepted: 07/24/2021] [Indexed: 02/08/2023] Open
Abstract
Simple Summary Triple-negative breast cancers (TNBCs) are mainly treated with standard chemotherapies. Combined therapies have been demonstrated as a promising treatment strategy in clinics. The aim of this study was to develop a new formulation of combined chemotherapies facilitated with a targeted delivery vehicle. We found that the mertansine and gemcitabine with different anti-cancer mechanisms resulted in high cytotoxicity in TNBC cells. The in vivo evaluations using two TNBC xenograft models confirmed the anti-tumor efficacy, i.e., significantly reduced tumor growth rate. Furthermore, the antibody-tagged liposomes effectively delivered the therapeutic drugs to TNBC tumor, which could reduce the side effects. This study is highly translational and the targeted liposomal drug formulation can be further investigated in future clinical trials for TNBC treatment. Abstract Triple-negative breast cancers (TNBCs) are highly aggressive and recurrent. Standard cytotoxic chemotherapies are currently the main treatment options, but their clinical efficacies are limited and patients usually suffer from severe side effects. The goal of this study was to develop and evaluate targeted liposomes-delivered combined chemotherapies to treat TNBCs. Specifically, the IC50 values of the microtubule polymerization inhibitor mertansine (DM1), mitotic spindle assembly defecting taxane (paclitaxel, PTX), DNA synthesis inhibitor gemcitabine (GC), and DNA damage inducer doxorubicin (AC) were tested in both TNBC MDA-MB-231 and MDA-MB-468 cells. Then we constructed the anti-epidermal growth factor receptor (EGFR) monoclonal antibody (mAb) tagged liposomes and confirmed its TNBC cell surface binding using flow cytometry, internalization with confocal laser scanning microscopy, and TNBC xenograft targeting in NSG female mice using In Vivo Imaging System. The safe dosage of anti-EGFR liposomal chemotherapies, i.e., <20% body weight change, was identified. Finally, the in vivo anti-tumor efficacy studies in TNBC cell line-derived xenograft and patient-derived xenograft models revealed that the targeted delivery of chemotherapies (mertansine and gemcitabine) can effectively inhibit tumor growth. This study demonstrated that the targeted liposomes enable the new formulations of combined therapies that improve anti-TNBC efficacy.
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Affiliation(s)
- Yingnan Si
- Department of Biomedical Engineering, University of Alabama at Birmingham, 1825 University Blvd, Birmingham, AL 35294, USA; (Y.S.); (Y.Z.); (H.G.N.); (K.C.); (Q.W.); (A.P.S.); (L.Z.)
| | - Ya Zhang
- Department of Biomedical Engineering, University of Alabama at Birmingham, 1825 University Blvd, Birmingham, AL 35294, USA; (Y.S.); (Y.Z.); (H.G.N.); (K.C.); (Q.W.); (A.P.S.); (L.Z.)
| | - Hanh Giai Ngo
- Department of Biomedical Engineering, University of Alabama at Birmingham, 1825 University Blvd, Birmingham, AL 35294, USA; (Y.S.); (Y.Z.); (H.G.N.); (K.C.); (Q.W.); (A.P.S.); (L.Z.)
| | - Jia-Shiung Guan
- Department of Medicine, University of Alabama at Birmingham, 703 19th Street South, Birmingham, AL 35294, USA; (J.-S.G.); (Y.X.)
| | - Kai Chen
- Department of Biomedical Engineering, University of Alabama at Birmingham, 1825 University Blvd, Birmingham, AL 35294, USA; (Y.S.); (Y.Z.); (H.G.N.); (K.C.); (Q.W.); (A.P.S.); (L.Z.)
| | - Qing Wang
- Department of Biomedical Engineering, University of Alabama at Birmingham, 1825 University Blvd, Birmingham, AL 35294, USA; (Y.S.); (Y.Z.); (H.G.N.); (K.C.); (Q.W.); (A.P.S.); (L.Z.)
| | - Ajeet Pal Singh
- Department of Biomedical Engineering, University of Alabama at Birmingham, 1825 University Blvd, Birmingham, AL 35294, USA; (Y.S.); (Y.Z.); (H.G.N.); (K.C.); (Q.W.); (A.P.S.); (L.Z.)
| | - Yuanxin Xu
- Department of Medicine, University of Alabama at Birmingham, 703 19th Street South, Birmingham, AL 35294, USA; (J.-S.G.); (Y.X.)
| | - Lufang Zhou
- Department of Biomedical Engineering, University of Alabama at Birmingham, 1825 University Blvd, Birmingham, AL 35294, USA; (Y.S.); (Y.Z.); (H.G.N.); (K.C.); (Q.W.); (A.P.S.); (L.Z.)
- Department of Medicine, University of Alabama at Birmingham, 703 19th Street South, Birmingham, AL 35294, USA; (J.-S.G.); (Y.X.)
| | - Eddy S. Yang
- Department of Radiation Oncology, University of Alabama at Birmingham, 1808 7th Avenue South, Birmingham, AL 35294, USA;
| | - Xiaoguang (Margaret) Liu
- Department of Biomedical Engineering, University of Alabama at Birmingham, 1825 University Blvd, Birmingham, AL 35294, USA; (Y.S.); (Y.Z.); (H.G.N.); (K.C.); (Q.W.); (A.P.S.); (L.Z.)
- Correspondence:
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Nanomedicines functionalized with anti-EGFR ligands for active targeting in cancer therapy: Biological strategy, design and quality control. Int J Pharm 2021; 605:120795. [PMID: 34119579 DOI: 10.1016/j.ijpharm.2021.120795] [Citation(s) in RCA: 26] [Impact Index Per Article: 6.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/22/2021] [Revised: 05/28/2021] [Accepted: 06/07/2021] [Indexed: 02/06/2023]
Abstract
Recently, active targeting using nanocarriers with biological ligands has emerged as a novel strategy for improving the delivery of therapeutic and/or imaging agents to tumor cells. The presence of active targeting moieties on the surface of nanomedicines has been shown to play an important role in enhancing their accumulation in tumoral cells and tissues versus healthy ones. This property not only helps to increase the therapeutic index but also to minimize possible side effects of the designed nanocarriers. Since the overexpression of epidermal growth factor receptors (EGFR) is a common occurrence linked to the progression of a broad variety of cancers, the potential application of anti-EGFR immunotherapy and EGFR-targeting ligands in active targeting nanomedicines is getting increasing attention. Henceforth, the EGFR-targeted nanomedicines were extensively studied in vitro and in vivo but exhibited both satisfactory and disappointing results, depending on used protocols. This review is designed to give an overview of a variety of EGFR-targeting ligands available for nanomedicines, how to conjugate them onto the surface of nanoparticles, and the main analytical methods to confirm this successful conjugation.
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Kato T, Wakiyama H, Furusawa A, Choyke PL, Kobayashi H. Near Infrared Photoimmunotherapy; A Review of Targets for Cancer Therapy. Cancers (Basel) 2021; 13:cancers13112535. [PMID: 34064074 PMCID: PMC8196790 DOI: 10.3390/cancers13112535] [Citation(s) in RCA: 43] [Impact Index Per Article: 10.8] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/16/2021] [Revised: 05/12/2021] [Accepted: 05/18/2021] [Indexed: 12/15/2022] Open
Abstract
Simple Summary Near-infrared photoimmunotherapy (NIR-PIT) is a newly developed cancer treatment that uses an antibody-photoabsorber (IRDye700DX) conjugate (APC) that is activated by NIR light irradiation. A major benefit of NIR-PIT is that only APC-bound cancer cells that are exposed to NIR light are killed by NIR-PIT; thus, minimal damage occurs in adjacent normal cells. NIR-PIT has now been applied to many cancers expressing various cell-surface target proteins using monoclonal antibodies designed to bind to them. Moreover, NIR-PIT is not limited to tumor antigens but can also be used to kill specific host cells that create immune-permissive environments in which tumors grow. Moreover, multiple targets can be treated simultaneously with NIR-PIT using a cocktail of APCs. NIR-PIT has great potential to treat a wide variety of cancers by targeting appropriate tumor cells, immune cells, or both, and can be augmented by other immunotherapies. Abstract Near-infrared photoimmunotherapy (NIR-PIT) is a newly developed cancer treatment that uses an antibody-photoabsorber (IRDye700DX) conjugate (APC) that is activated by NIR light irradiation. In September 2020, the first APC and laser system were conditionally approved for clinical use in Japan. A major benefit of NIR-PIT is that only APC-bound cancer cells that are exposed to NIR light are killed by NIR-PIT; thus, minimal damage occurs in adjacent normal cells. These early trials have demonstrated that in addition to direct cell killing, there is a significant therapeutic host immune response that greatly contributes to the success of the therapy. Although the first clinical use of NIR-PIT targeted epidermal growth factor receptor (EGFR), many other targets are suitable for NIR-PIT. NIR-PIT has now been applied to many cancers expressing various cell-surface target proteins using monoclonal antibodies designed to bind to them. Moreover, NIR-PIT is not limited to tumor antigens but can also be used to kill specific host cells that create immune-permissive environments in which tumors grow. Moreover, multiple targets can be treated simultaneously with NIR-PIT using a cocktail of APCs. NIR-PIT can be used in combination with other therapies, such as immune checkpoint inhibitors, to enhance the therapeutic effect. Thus, NIR-PIT has great potential to treat a wide variety of cancers by targeting appropriate tumor cells, immune cells, or both, and can be augmented by other immunotherapies.
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Jalalvand M, Darbeheshti F, Rezaei N. Immune checkpoint inhibitors: review of the existing evidence and challenges in breast cancer. Immunotherapy 2021; 13:587-603. [PMID: 33775102 DOI: 10.2217/imt-2020-0283] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022] Open
Abstract
Cancer initiation and progression are associated with immune system responses. Tumor cells use various tricks to scape of immune system, such as activating immune checkpoint pathways that induce immunosuppressive functions. Among the different immune checkpoint receptors, CTLA-4 and PD-1/PD-L1 are prominent therapeutic targets in different cancers. Although the US FDA has approved some immune checkpoint inhibitors for several cancers, concerning breast cancer still different clinical trials are looking for optimizing efficacy and decreasing immune-related adverse events. This review will discuss the existing body of knowledge with regard to cross-talk between immune system and tumor cells and then explore immune checkpoint-related signaling pathways in the context of breast tumors. Finally, we highlight the application of different immune checkpoint blockers in breast cancer patients.
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Affiliation(s)
- Mobina Jalalvand
- Cancer Immunology Project (CIP), Universal Scientific Education & Research Network (USERN), Tehran, Iran.,School of medicine, Tehran University of Medical Sciences, Tehran, Iran
| | - Farzaneh Darbeheshti
- Department of Genetics, School of Medicine, Tehran University of Medical Sciences, Tehran, Iran.,Medical Genetics Network (MeGeNe), Universal Scientific Education & Research Network (USERN), Tehran, Iran
| | - Nima Rezaei
- Research Center for Immunodeficiencies, Children's Medical Center, Tehran University of Medical Sciences, Tehran 14194, Iran.,Department of Immunology, School of Medicine, Tehran University of Medical Sciences, Tehran 14194, Iran.,Network of Immunity in Infection, Malignancy & Autoimmunity (NIIMA), Universal Scientific Education & Research Network (USERN), Tehran 14194, Iran
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Singh S, Numan A, Maddiboyina B, Arora S, Riadi Y, Md S, Alhakamy NA, Kesharwani P. The emerging role of immune checkpoint inhibitors in the treatment of triple-negative breast cancer. Drug Discov Today 2021; 26:1721-1727. [PMID: 33745879 DOI: 10.1016/j.drudis.2021.03.011] [Citation(s) in RCA: 46] [Impact Index Per Article: 11.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/17/2020] [Revised: 01/16/2021] [Accepted: 03/14/2021] [Indexed: 12/13/2022]
Abstract
Triple-negative breast cancers (TNBCs) form a heterogeneous group of breast carcinomas that lack expression of estrogen receptor, progesterone receptor and epidermal growth factor receptor 2. In the past decade, immune checkpoint inhibitors (ICIs) have revolutionized the arena of cancer immunotherapy. Early results are now accumulating from trials involving the treatment of TNBCs with radical ICIs therapies, including combinational therapies that include ICI technologies. In this review, we provide a broad overview of the progress of immunotherapy-based treatments and discuss future opportunities for their use in TNBC.
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Affiliation(s)
- Sima Singh
- University Institute of Pharma Sciences, Chandigarh University, Gharuan, Mohali, Punjab 140413, India
| | - Arshid Numan
- State Key Laboratory of ASIC and System, SIST, Fudan University, 200433 Shanghai, China
| | - Balaji Maddiboyina
- Department of Pharmacy, NRK & KSR Gupta College of Pharmacy, Tenali, Guntur, 522202 AP, India
| | - Saahil Arora
- University Institute of Pharma Sciences, Chandigarh University, Gharuan, Mohali, Punjab 140413, India.
| | - Yassine Riadi
- Department of Pharmaceutical Chemistry, College of Pharmacy, Prince Sattam Bin Abdulaziz University, Al-Kharj 11942, Saudi Arabia
| | - Shadab Md
- Deptartment of Pharmaceutics, Faculty of Pharmacy, King Abdulaziz University, Jeddah 21589, Saudi Arabia; Center of Excellence for Drug Research & Pharmaceutical Industries, King Abdulaziz University, Jeddah 21589, Saudi Arabia
| | - Nabil A Alhakamy
- Deptartment of Pharmaceutics, Faculty of Pharmacy, King Abdulaziz University, Jeddah 21589, Saudi Arabia; Center of Excellence for Drug Research & Pharmaceutical Industries, King Abdulaziz University, Jeddah 21589, Saudi Arabia
| | - Prashant Kesharwani
- Department of Pharmaceutics, School of Pharmaceutical Education and Research, Jamia Hamdard, New Delhi 110062, India.
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Dass SA, Tan KL, Selva Rajan R, Mokhtar NF, Mohd Adzmi ER, Wan Abdul Rahman WF, Tengku Din TADAA, Balakrishnan V. Triple Negative Breast Cancer: A Review of Present and Future Diagnostic Modalities. MEDICINA (KAUNAS, LITHUANIA) 2021; 57:62. [PMID: 33445543 PMCID: PMC7826673 DOI: 10.3390/medicina57010062] [Citation(s) in RCA: 64] [Impact Index Per Article: 16.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 11/12/2020] [Revised: 12/15/2020] [Accepted: 12/15/2020] [Indexed: 12/12/2022]
Abstract
Triple-negative breast cancer (TNBC) is an aggressive breast type of cancer with no expression of estrogen receptor (ER), progesterone receptor (PR), and human epidermal growth factor receptor-2 (HER2). It is a highly metastasized, heterogeneous disease that accounts for 10-15% of total breast cancer cases with a poor prognosis and high relapse rate within five years after treatment compared to non-TNBC cases. The diagnostic and subtyping of TNBC tumors are essential to determine the treatment alternatives and establish personalized, targeted medications for every TNBC individual. Currently, TNBC is diagnosed via a two-step procedure of imaging and immunohistochemistry (IHC), which are operator-dependent and potentially time-consuming. Therefore, there is a crucial need for the development of rapid and advanced technologies to enhance the diagnostic efficiency of TNBC. This review discusses the overview of breast cancer with emphasis on TNBC subtypes and the current diagnostic approaches of TNBC along with its challenges. Most importantly, we have presented several promising strategies that can be utilized as future TNBC diagnostic modalities and simultaneously enhance the efficacy of TNBC diagnostic.
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Affiliation(s)
- Sylvia Annabel Dass
- Institute for Research in Molecular Medicine, Universiti Sains Malaysia, USM, Penang 11800, Malaysia; (S.A.D.); (K.L.T.); (R.S.R.)
| | - Kim Liu Tan
- Institute for Research in Molecular Medicine, Universiti Sains Malaysia, USM, Penang 11800, Malaysia; (S.A.D.); (K.L.T.); (R.S.R.)
| | - Rehasri Selva Rajan
- Institute for Research in Molecular Medicine, Universiti Sains Malaysia, USM, Penang 11800, Malaysia; (S.A.D.); (K.L.T.); (R.S.R.)
| | - Noor Fatmawati Mokhtar
- Institute for Research in Molecular Medicine, Universiti Sains Malaysia, Kubang Kerian, Kelantan 16150, Malaysia; (N.F.M.); (E.R.M.A.)
| | - Elis Rosliza Mohd Adzmi
- Institute for Research in Molecular Medicine, Universiti Sains Malaysia, Kubang Kerian, Kelantan 16150, Malaysia; (N.F.M.); (E.R.M.A.)
| | - Wan Faiziah Wan Abdul Rahman
- Department of Pathology, School of Medical Sciences, Health Campus, Kubang Kerian, Kelantan 16150, Malaysia;
- Breast Cancer Awareness & Research Unit, Hospital Universiti Sains Malaysia, Kubang Kerian, Kelantan 16150, Malaysia;
| | - Tengku Ahmad Damitri Al-Astani Tengku Din
- Breast Cancer Awareness & Research Unit, Hospital Universiti Sains Malaysia, Kubang Kerian, Kelantan 16150, Malaysia;
- Chemical Pathology Department, School of Medical Sciences, Health Campus, Kubang Kerian, Kelantan 16150, Malaysia
| | - Venugopal Balakrishnan
- Institute for Research in Molecular Medicine, Universiti Sains Malaysia, USM, Penang 11800, Malaysia; (S.A.D.); (K.L.T.); (R.S.R.)
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Purwanto I, Heriyanto DS, Widodo I, Hakimi M, Hardianti MS, Aryandono T, Haryana SM. MicroRNA-223 is Associated with Resistance Towards Platinum-based Chemotherapy and Worse Prognosis in Indonesian Triple-negative Breast Cancer Patients. BREAST CANCER-TARGETS AND THERAPY 2021; 13:1-7. [PMID: 33442288 PMCID: PMC7797287 DOI: 10.2147/bctt.s291014] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 11/12/2020] [Accepted: 12/05/2020] [Indexed: 12/15/2022]
Abstract
Purpose Determining the optimal strategy to implement systemic treatment modalities has been challenging in triple-negative breast cancer (TNBC). We aim to investigate the role of microRNA-223 (miR-223) as prognostic factor and predictor of response toward chemotherapy in TNBC. Patients and Methods We retrospectively analyzed the association of pretreatment miR-223 expression with clinicopathologic characteristics and 36-month overall survival (OS) of 53 all stages TNBC patients. Tumor level of miR-223 was measured using real-time quantitative polymerase chain reaction (expressed in fold change). Cutoff value for miR-223 was determined by using receiver operating curve (ROC). Kaplan-Meier curve was used to perform survival analysis. Results The optimum cutoff value for miR-223 was 23.435 (AUC: 0.706, 95%CI: 0.565-0.848; p:0.01; sensitivity: 78.6%; specificity: 56%) and was used to categorize mir-223 expression into over- and underexpressed group. Overexpression of miR-223 was associated with increased expression of EGFR (69.7% vs 35%, p: 0.022) and lower 36-month OS (33.3% vs 70%; median OS±SE (months): 25.66±1.58 vs 30.23±1.99; log rank p<0.05). Worse survival is observed in miR-223 overexpressed group receiving platinum-based chemotherapy compared to miR-223 underexpressed group (mean OS (95%CI) months: 24.7 (20.3-29.1) vs 34.3 (31.2-37.4); p<0.01), while no significant difference observed in non-platinum containing regimen. No significant association was observed between miR-223 expression with other clinicopathologic characteristics. Conclusion Overexpression of miR-223 is associated with increased expression of EGFR, worse prognosis, and resistance toward platinum-based chemotherapy in Indonesian TNBC patients.
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Affiliation(s)
- Ibnu Purwanto
- Division of Hematology and Medical Oncology, Department of Internal Medicine, Faculty of Medicine, Public Health, and Nursing, Gadjah Mada University/Dr Sardjito Hospital, Yogyakarta, Indonesia
| | - Didik Setyo Heriyanto
- Department of Anatomical Pathology, Faculty of Medicine, Public Health, and Nursing, Gadjah Mada University/Dr Sardjito Hospital, Yogyakarta, Indonesia
| | - Irianiwati Widodo
- Department of Anatomical Pathology, Faculty of Medicine, Public Health, and Nursing, Gadjah Mada University/Dr Sardjito Hospital, Yogyakarta, Indonesia
| | - Mohammad Hakimi
- Department of Clinical Epidemiology and Biostatistics Unit, Faculty of Medicine, Public Health, and Nursing, Gadjah Mada University/Dr Sardjito Hospital, Yogyakarta, Indonesia
| | - Mardiah Suci Hardianti
- Division of Hematology and Medical Oncology, Department of Internal Medicine, Faculty of Medicine, Public Health, and Nursing, Gadjah Mada University/Dr Sardjito Hospital, Yogyakarta, Indonesia
| | - Teguh Aryandono
- Department of Surgical Oncology, Faculty of Medicine, Public Health, and Nursing, Gadjah Mada University/Dr Sardjito Hospital, Yogyakarta, Indonesia
| | - Sofia Mubarika Haryana
- Department of Histology and Cell Biology, Faculty of Medicine, Public Health, and Nursing, Gadjah Mada University/Dr Sardjito Hospital, Yogyakarta, Indonesia
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Mamo M, Ye IC, DiGiacomo JW, Park JY, Downs B, Gilkes DM. Hypoxia Alters the Response to Anti-EGFR Therapy by Regulating EGFR Expression and Downstream Signaling in a DNA Methylation-Specific and HIF-Dependent Manner. Cancer Res 2020; 80:4998-5010. [PMID: 33023947 DOI: 10.1158/0008-5472.can-20-1232] [Citation(s) in RCA: 24] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/14/2020] [Revised: 08/05/2020] [Accepted: 10/01/2020] [Indexed: 01/09/2023]
Abstract
Intratumoral hypoxia occurs in 90% of solid tumors and is associated with a poor prognosis for patients. Cancer cells respond to hypoxic microenvironments by activating the transcription factors, hypoxia-inducible factor 1 (HIF1) and HIF2. Here, we studied the unique gene expression patterns of 31 different breast cancer cell lines exposed to hypoxic conditions. The EGFR, a member of the ErbB (avian erythroblastosis oncogene B) family of receptors that play a role in cell proliferation, invasion, metastasis, and apoptosis, was induced in seven of the 31 breast cancer cell lines by hypoxia. A functional hypoxia response element (HRE) was identified, which is activated upon HIF1 binding to intron 18 of the EGFR gene in cell lines in which EGFR was induced by hypoxia. CpG methylation of the EGFR HRE prevented induction under hypoxic conditions. The HRE of EGFR was methylated in normal breast tissue and some breast cancer cell lines, and could be reversed by treatment with DNA methyltransferase inhibitors. Induction of EGFR under hypoxia led to an increase in AKT, ERK, and Rb phosphorylation as well as increased levels of cyclin D1, A, B1, and E2F, and repression of p21 in an HIF1α-dependent manner, leading to cell proliferation and migration. Also, increased EGFR expression sensitized cells to EGFR inhibitors. Collectively, our data suggest that patients with hypoxic breast tumors and hypomethylated EGFR status may benefit from EGFR inhibitors currently used in the clinic. SIGNIFICANCE: Hypoxia sensitizes breast cancer cells to EGFR inhibitors in an HIF1α- and a methylation-specific manner, suggesting patients with hypoxic tumors may benefit from EGFR inhibitors already available in the clinic. GRAPHICAL ABSTRACT: http://cancerres.aacrjournals.org/content/canres/80/22/4998/F1.large.jpg.
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Affiliation(s)
- Mahelet Mamo
- Breast & Ovarian Cancer Program, Department of Oncology, The Johns Hopkins University School of Medicine, Baltimore, Maryland.,Doctoral Diversity Program, The Johns Hopkins University School of Medicine, Baltimore, Maryland
| | - I Chae Ye
- Breast & Ovarian Cancer Program, Department of Oncology, The Johns Hopkins University School of Medicine, Baltimore, Maryland.,Department of Chemical & Biomolecular Engineering and The Institute for NanoBioTechnology, The Johns Hopkins University, Baltimore, Maryland
| | - Josh W DiGiacomo
- Breast & Ovarian Cancer Program, Department of Oncology, The Johns Hopkins University School of Medicine, Baltimore, Maryland.,Department of Chemical & Biomolecular Engineering and The Institute for NanoBioTechnology, The Johns Hopkins University, Baltimore, Maryland
| | - Je Yeon Park
- Breast & Ovarian Cancer Program, Department of Oncology, The Johns Hopkins University School of Medicine, Baltimore, Maryland
| | - Bradley Downs
- Breast & Ovarian Cancer Program, Department of Oncology, The Johns Hopkins University School of Medicine, Baltimore, Maryland
| | - Daniele M Gilkes
- Breast & Ovarian Cancer Program, Department of Oncology, The Johns Hopkins University School of Medicine, Baltimore, Maryland. .,Doctoral Diversity Program, The Johns Hopkins University School of Medicine, Baltimore, Maryland.,Department of Chemical & Biomolecular Engineering and The Institute for NanoBioTechnology, The Johns Hopkins University, Baltimore, Maryland.,Cellular and Molecular Medicine Program, The Johns Hopkins University School of Medicine, Baltimore, Maryland
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Singh GK, Bajpai J, Joshi S, Prabhash K, Choughule A, Patil A, Gupta S, Badwe RA. Excellent response to erlotinib in breast carcinoma with rare EGFR mutation-a case report. Ecancermedicalscience 2020; 14:1092. [PMID: 33014134 PMCID: PMC7498275 DOI: 10.3332/ecancer.2020.1092] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/30/2020] [Indexed: 12/24/2022] Open
Abstract
Triple negative breast carcinoma is a problematic subtype with poor outcomes. Many clinical trials are underway to find possible target to increase treatment options. Epidermal growth factor receptor (EGFR) has emerged as one such molecule which is over expressed in some of these patients and can be targeted by tyrosine kinase inhibitors. We describe a diagnostically challenging case of metastatic breast carcinoma, with extensive lung disease and poor Eastern Cooperative Oncology Group (ECOG) performance status, which expressed an uncommon EGFR mutation (Exon 21L861Q) and which benefitted from erlotinib following failure of all primary treatment modalities. The case uncovers the presence of these unusual mutations in breast carcinoma and highlights the importance of performing molecular analysis and the appropriate targeted therapy. This approach can be an important problem-solving tool, especially in cases where the patient is not fit for the other standard treatment options.
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Affiliation(s)
- Gunjesh Kumar Singh
- Department of Medical Oncology, Tata Memorial Hospital, Mumbai 400012, India
| | - Jyoti Bajpai
- Department of Medical Oncology, Tata Memorial Hospital, Mumbai 400012, India
| | - Shalaka Joshi
- Department of Surgical Oncology, Tata Memorial Hospital, Mumbai 400012, India
| | - Kumar Prabhash
- Department of Medical Oncology, Tata Memorial Hospital, Mumbai 400012, India
| | - Anuradha Choughule
- Department of Molecular Biology, Tata Memorial Hospital, Mumbai 400012, India
| | - Asawari Patil
- Department of Pathology, Tata Memorial Hospital, Mumbai 400012, India
| | - Sudeep Gupta
- Department of Medical Oncology, Tata Memorial Hospital, Mumbai 400012, India
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Tafreshi NK, Morse DL, Lee MC. Narrowing the focus: Therapeutic cell surface targets for refractory triple-negative breast cancer. World J Clin Oncol 2020; 11:169-179. [PMID: 32355639 PMCID: PMC7186233 DOI: 10.5306/wjco.v11.i4.169] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/30/2019] [Revised: 03/25/2020] [Accepted: 03/30/2020] [Indexed: 02/06/2023] Open
Abstract
Triple-negative breast cancer (TNBC) is defined as a type of breast cancer with lack of expression of estrogen receptor, progesterone receptor and human epidermal growth factor 2 protein. In comparison to other types of breast cancer, TNBC characterizes for its aggressive behavior, more prone to early recurrence and a disease with poor response to molecular target therapy. Although TNBC is identified in only 25%-30% of American breast cancer cases annually, these tumors continue to be a therapeutic challenge for clinicians for several reasons: Tumor heterogeneity, limited and toxic systemic therapy options, and often resistance to current standard therapy, characterized by progressive disease on treatment, residual tumor after cytotoxic chemotherapy, and early recurrence after complete surgical excision. Cell-surface targeted therapies have been successful for breast cancer in general, however there are currently no approved cell-surface targeted therapies specifically indicated for TNBC. Recently, several cell-surface targets have been identified as candidates for treatment of TNBC and associated targeted therapies are in development. The purpose of this work is to review the current clinical challenges posed by TNBC, the therapeutic approaches currently in use, and provide an overview of developing cell surface targeting approaches to improve outcomes for treatment resistant TNBC.
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Affiliation(s)
- Narges K Tafreshi
- Department of Cancer Physiology, Moffitt Cancer Center, Tampa, FL 33612, United States
- Department of Physics, University of South Florida, Tampa, FL 33612, United States
- Division of Oncologic Sciences, University of South Florida, Tampa, FL 33612 FL, United States
| | - David L Morse
- Department of Cancer Physiology, Moffitt Cancer Center, Tampa, FL 33612, United States
- Department of Physics, University of South Florida, Tampa, FL 33612, United States
- Division of Oncologic Sciences, University of South Florida, Tampa, FL 33612 FL, United States
| | - Marie Catherine Lee
- Division of Oncologic Sciences, University of South Florida, Tampa, FL 33612 FL, United States
- Comprehensive Breast Program, Moffitt Cancer Center, Tampa, FL 33612, United States
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Diana A, Carlino F, Franzese E, Oikonomidou O, Criscitiello C, De Vita F, Ciardiello F, Orditura M. Early Triple Negative Breast Cancer: Conventional Treatment and Emerging Therapeutic Landscapes. Cancers (Basel) 2020; 12:E819. [PMID: 32235297 PMCID: PMC7225917 DOI: 10.3390/cancers12040819] [Citation(s) in RCA: 62] [Impact Index Per Article: 12.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/29/2020] [Revised: 03/19/2020] [Accepted: 03/27/2020] [Indexed: 12/13/2022] Open
Abstract
Triple negative breast cancers (TNBCs) are characterized by worse prognosis, higher propensity to earlier metastases, and shorter survival after recurrence compared with other breast cancer subtypes. Anthracycline- and taxane-based chemotherapy is still the mainstay of treatment in early stages, although several escalation approaches have been evaluated to improve survival outcomes. The addition of platinum salts to standard neoadjuvant chemotherapy (NACT) remains controversial due to the lack of clear survival advantage, and the use of adjuvant capecitabine represents a valid treatment option in TNBC patients with residual disease after NACT. Recently, several clinical trials showed promising results through the use of poly ADP-ribose polymerase (PARP) inhibitors and by incorporating immunotherapy with chemotherapy, enriching treatment options beyond conventional cytotoxic agents. In this review, we provided an overview on the current standard of care and a comprehensive update of the recent advances in the management of early stage TNBC and focused on the latest emerging biomarkers and their clinical application to select the best therapeutic strategy in this hard-to-treat population.
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Affiliation(s)
- Anna Diana
- Division of Medical Oncology, Department of Precision Medicine, School of Medicine, “Luigi Vanvitelli” University of Campania, 80131 Naples, Italy; (F.C.); (E.F.); (F.D.V.); (F.C.); (M.O.)
| | - Francesca Carlino
- Division of Medical Oncology, Department of Precision Medicine, School of Medicine, “Luigi Vanvitelli” University of Campania, 80131 Naples, Italy; (F.C.); (E.F.); (F.D.V.); (F.C.); (M.O.)
| | - Elisena Franzese
- Division of Medical Oncology, Department of Precision Medicine, School of Medicine, “Luigi Vanvitelli” University of Campania, 80131 Naples, Italy; (F.C.); (E.F.); (F.D.V.); (F.C.); (M.O.)
| | - Olga Oikonomidou
- Cancer Research UK, Edinburgh Centre, MRC Institute Genetics and Molecular Medicine, University of Edinburgh, Edinburgh EH4 2XR, UK;
| | | | - Ferdinando De Vita
- Division of Medical Oncology, Department of Precision Medicine, School of Medicine, “Luigi Vanvitelli” University of Campania, 80131 Naples, Italy; (F.C.); (E.F.); (F.D.V.); (F.C.); (M.O.)
| | - Fortunato Ciardiello
- Division of Medical Oncology, Department of Precision Medicine, School of Medicine, “Luigi Vanvitelli” University of Campania, 80131 Naples, Italy; (F.C.); (E.F.); (F.D.V.); (F.C.); (M.O.)
| | - Michele Orditura
- Division of Medical Oncology, Department of Precision Medicine, School of Medicine, “Luigi Vanvitelli” University of Campania, 80131 Naples, Italy; (F.C.); (E.F.); (F.D.V.); (F.C.); (M.O.)
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Yu K, Rohr J, Liu Y, Li M, Xu J, Wang K, Chai J, Zhao D, Liu Y, Ma J, Fan L, Wang Z, Guo S. Progress in triple negative breast carcinoma pathophysiology: Potential therapeutic targets. Pathol Res Pract 2020; 216:152874. [PMID: 32088086 DOI: 10.1016/j.prp.2020.152874] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/28/2019] [Revised: 01/17/2020] [Accepted: 02/11/2020] [Indexed: 12/17/2022]
Abstract
Triple-negative breast carcinoma (TNBC) is a subtype of breast carcinoma defined by negativity for estrogen receptor (ER) or progesterone receptor (PR) by immunohistochemical analysis and negativity for human epidermal growth factor receptor (Her2) by immunohistochemistry or in situ hybridization. TNBC is clinically marked by its high aggressiveness, particularly poor outcomes including a low survival rate, and the lack of specific and effective treatments. Therefore, new potential targets for the treatment of TNBC must be identified. This review summarizes recent evidence supporting novel targets and possible therapeutic regimens in the treatment of TNBC.
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Affiliation(s)
- Kangjie Yu
- State Key Laboratory of Tumor Biology, Department of Pathology, Xi Jing Hospital, the Fourth Military Medical University, Xi'an, Shaan Xi Province,710032, China
| | - Joseph Rohr
- Department of Pathology and Microbiology, University of Nebraska Medical Center, Omaha, NE, USA
| | - Yang Liu
- State Key Laboratory of Tumor Biology, Department of Pathology, Xi Jing Hospital, the Fourth Military Medical University, Xi'an, Shaan Xi Province,710032, China
| | - Mingyang Li
- State Key Laboratory of Tumor Biology, Department of Pathology, Xi Jing Hospital, the Fourth Military Medical University, Xi'an, Shaan Xi Province,710032, China
| | - Junpeng Xu
- State Key Laboratory of Tumor Biology, Department of Pathology, Xi Jing Hospital, the Fourth Military Medical University, Xi'an, Shaan Xi Province,710032, China
| | - Kaijing Wang
- State Key Laboratory of Tumor Biology, Department of Pathology, Xi Jing Hospital, the Fourth Military Medical University, Xi'an, Shaan Xi Province,710032, China
| | - Jia Chai
- State Key Laboratory of Tumor Biology, Department of Pathology, Xi Jing Hospital, the Fourth Military Medical University, Xi'an, Shaan Xi Province,710032, China
| | - Danhui Zhao
- State Key Laboratory of Tumor Biology, Department of Pathology, Xi Jing Hospital, the Fourth Military Medical University, Xi'an, Shaan Xi Province,710032, China
| | - Yixiong Liu
- State Key Laboratory of Tumor Biology, Department of Pathology, Xi Jing Hospital, the Fourth Military Medical University, Xi'an, Shaan Xi Province,710032, China
| | - Jing Ma
- State Key Laboratory of Tumor Biology, Department of Pathology, Xi Jing Hospital, the Fourth Military Medical University, Xi'an, Shaan Xi Province,710032, China
| | - Linni Fan
- State Key Laboratory of Tumor Biology, Department of Pathology, Xi Jing Hospital, the Fourth Military Medical University, Xi'an, Shaan Xi Province,710032, China
| | - Zhe Wang
- State Key Laboratory of Tumor Biology, Department of Pathology, Xi Jing Hospital, the Fourth Military Medical University, Xi'an, Shaan Xi Province,710032, China.
| | - Shuangping Guo
- State Key Laboratory of Tumor Biology, Department of Pathology, Xi Jing Hospital, the Fourth Military Medical University, Xi'an, Shaan Xi Province,710032, China.
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Huang M, Wu J, Ling R, Li N. Quadruple negative breast cancer. Breast Cancer 2020; 27:527-533. [PMID: 31939077 DOI: 10.1007/s12282-020-01047-6] [Citation(s) in RCA: 17] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/22/2019] [Accepted: 01/05/2020] [Indexed: 12/15/2022]
Abstract
Quadruple negative breast cancer (QNBC), lacking the expression of ER (estrogen receptor), PR (progesterone receptor), HER2 (human epidermal growth factor receptor-2) and AR (androgen receptor), was regarded as one breast cancer subtype with the worst prognosis. Recently, the molecular features of QNBC are not well understood. Different from AR-positive triple-negative breast cancer, QNBC is insensitive to conventional chemotherapeutic agents and has no efficient treatment targets. However, QNBC has been shown to express unique proteins that may be amenable to use in the development of targeted therapies. Here we reviewed the features of QNBC and proteins that may serve as effective targets for QNBC treatment, such as ACSL4, SKP2, immune checkpoint inhibitors, EGFR, MicroRNA signatures and Engrailed 1.
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Affiliation(s)
- Meiling Huang
- Department of Thyroid, Breast and Vascular Surgery, Xijing Hospital, The Fourth Military Medical University, Xi'an, 710032, China
| | - Jiang Wu
- Department of Thyroid, Breast and Vascular Surgery, Xijing Hospital, The Fourth Military Medical University, Xi'an, 710032, China
| | - Rui Ling
- Department of Thyroid, Breast and Vascular Surgery, Xijing Hospital, The Fourth Military Medical University, Xi'an, 710032, China.
| | - Nanlin Li
- Department of Thyroid, Breast and Vascular Surgery, Xijing Hospital, The Fourth Military Medical University, Xi'an, 710032, China.
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da Silva JL, Cardoso Nunes NC, Izetti P, de Mesquita GG, de Melo AC. Triple negative breast cancer: A thorough review of biomarkers. Crit Rev Oncol Hematol 2019; 145:102855. [PMID: 31927455 DOI: 10.1016/j.critrevonc.2019.102855] [Citation(s) in RCA: 142] [Impact Index Per Article: 23.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/14/2019] [Revised: 12/01/2019] [Accepted: 12/02/2019] [Indexed: 02/08/2023] Open
Abstract
Triple-negative breast cancer (TNBC) is defined as a type of breast cancer with lack of expression of estrogen receptor (ER), progesterone receptor (PR) and HER2 protein. The tumorigenesis is not likely to be driven by hormonal or HER2 pathway. In comparison to other types of breast cancer, TNBC stands out for its aggressive behavior, more prone to early recurrence. Historically, TNBC has been considered a disease with poor response to molecular target therapy, requiring better validation of biomarkers. Recent issues related to tumor heterogeneity have been widely discussed suggesting the subdivision of TNBC into different molecular subtypes. Through a complete research on the main published trials databases and platforms of ongoing clinical studies, the current manuscript was carried out in order to present a critical view of the role of immunohistochemical and molecular biomarkers for the prognosis and response prediction of TNBC to traditional therapy and new molecular target agents.
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Fenn K, Maurer M, Lee SM, Crew KD, Trivedi MS, Accordino MK, Hershman DL, Kalinsky K. Phase 1 Study of Erlotinib and Metformin in Metastatic Triple-Negative Breast Cancer. Clin Breast Cancer 2019; 20:80-86. [PMID: 31570268 DOI: 10.1016/j.clbc.2019.08.004] [Citation(s) in RCA: 16] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/11/2019] [Revised: 08/01/2019] [Accepted: 08/07/2019] [Indexed: 12/31/2022]
Abstract
BACKGROUND Epidermal growth factor receptor (EGFR) is frequently overexpressed in metastatic triple-negative breast cancer (mTNBC). One strategy for overcoming resistance to EGFR inhibition is concomitant inhibition of downstream signaling. The antidiabetic drug metformin inhibits both MAPK and PI3K/mTOR pathway signaling. We evaluated the combination of erlotinib and metformin in a phase 1 study of patients with mTNBC. PATIENTS AND METHODS Patients with mTNBC who had received at least one prior line of therapy for metastatic disease were eligible. Erlotinib dose was fixed at 150 mg daily. Metformin dose escalation was planned according to a 3 + 3 design. Dose-limiting toxicities (DLT) were assessed during the first 5 weeks of therapy. The primary objective was to determine the maximum tolerated dose of metformin with fixed-dose erlotinib. Secondary endpoints were response rate, stable disease rate, and progression-free survival. RESULTS Eight patients were enrolled. The median number of prior therapies for metastatic disease was 2.5 (range, 1-6). No DLT events were reported during the DLT assessment period. Most adverse events were grade 1/2. Grade 3 diarrhea despite maximum supportive care required dose reduction of metformin in one patient. Grade 3 rash led to study withdrawal in one patient. No grade 4 adverse events were reported. The best observed response was stable disease in 2 patients (25%). Median progression-free survival was 60 days (range, 36-61 days). CONCLUSION Erlotinib and metformin were well tolerated in a population of pretreated mTNBC patients but did not demonstrate efficacy in this population.
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Affiliation(s)
- Kathleen Fenn
- Department of Medicine, Columbia University Irving Medical Center, New York NY
| | | | - Shing M Lee
- Department of Biostatistics, Mailman School of Public Health, Columbia University, New York, NY
| | - Katherine D Crew
- Department of Medicine, Columbia University Irving Medical Center, New York NY
| | - Meghna S Trivedi
- Department of Medicine, Columbia University Irving Medical Center, New York NY
| | - Melissa K Accordino
- Department of Medicine, Columbia University Irving Medical Center, New York NY
| | - Dawn L Hershman
- Department of Medicine, Columbia University Irving Medical Center, New York NY
| | - Kevin Kalinsky
- Department of Medicine, Columbia University Irving Medical Center, New York NY.
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Ku A, Chan C, Aghevlian S, Cai Z, Cescon D, Bratman SV, Ailles L, Hedley DW, Reilly RM. MicroSPECT/CT Imaging of Cell-Line and Patient-Derived EGFR-Positive Tumor Xenografts in Mice with Panitumumab Fab Modified with Hexahistidine Peptides To Enable Labeling with 99mTc(I) Tricarbonyl Complex. Mol Pharm 2019; 16:3559-3568. [PMID: 31242384 DOI: 10.1021/acs.molpharmaceut.9b00422] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/29/2022]
Abstract
We aimed to investigate the feasibility of conjugating synthetic hexahistidine peptides (His6) peptides to panitumumab Fab (PmFab) to enable labeling with [99mTc(H2O)3(CO)3]+ complex and study these radioimmunoconjugates for imaging EGFR-overexpressing tumor xenografts in mice by microSPECT/CT. Fab were reacted with a 10-fold excess of sulfo-SMCC to introduce maleimide functional groups for reaction with the terminal thiol on peptides [CGYGGHHHHHH] that harbored the His6 motif. Modification of Fab with His6 peptides was assessed by SDS-PAGE/Western blot, and the number of His6 peptides introduced was quantified by a radiometric assay incorporating 123I-labeled peptides into the conjugation reaction. Radiolabeling was achieved by incubation of PmFab-His6 in PBS, pH 7.0, with [99mTc(H2O)3(CO)3]+ in a 1.4 MBq/μg ratio. The complex was prepared by adding [99mTcO4]- to an Isolink kit (Paul Scherrer Institute). Immunoreactivity was assessed in a direct (saturation) binding assay using MDA-MB-468 human triple-negative breast cancer (TNBC) cells. Tumor and normal tissue uptake and imaging properties of 99mTc-PmFab-His6 (70 μg; 35-40 MBq) injected i.v. (tail vein) were compared to irrelevant 99mTc-Fab 3913 in NOD/SCID mice engrafted subcutaneously (s.c.) with EGFR-overexpressing MDA-MB-468 or PANC-1 human pancreatic ductal carcinoma (PDCa) cell-line derived xenografts (CLX) at 4 and 24 h post injection (p.i.). In addition, tumor imaging studies were performed with 99mTc-PmFab-His6 in mice with patient-derived tumor xenografts (PDX) of TNBC, PDCa, and head and neck squamous cell carcinoma (HNSCC). Biodistribution studies in nontumor bearing Balb/c mice were performed to project the radiation absorbed doses for imaging studies in humans with 99mTc-PmFab-His6. PmFab was derivatized with 0.80 ± 0.03 His6 peptides. Western blot and SDS-PAGE confirmed the presence of His6 peptides. 99mTc-PmFab-His6 was labeled to high radiochemical purity (≥95%), and the Kd for binding to EGFR on MDA-MB-468 cells was 5.5 ± 0.4 × 10-8 mol/L. Tumor uptake of 99mTc-PmFab-His6 at 24 h p.i. was significantly (P < 0.05) higher than irrelevant 99mTc-Fab 3913 in mice with MDA-MB-468 tumors (14.9 ± 3.1%ID/g vs 3.0 ± 0.9%ID/g) and in mice with PANC-1 tumors (5.6 ± 0.6 vs 0.5 ± 0.1%ID/g). In mice implanted orthotopically in the pancreas with the same PDCa PDX, tumor uptake at 24 h p.i. was 4.2 ± 0.2%ID/g. Locoregional metastases of these PDCa tumors in the peritoneum exhibited slightly and significantly lower uptake than the primary tumors (3.1 ± 0.3 vs 4.2 ± 0.3%ID/g; P = 0.02). In mice implanted with different TNBC or HNSCC PDX, tumor uptake at 24 h p.i. was variable and ranged from 3.7 to 11.4%ID/g and 3.8-14.5%ID/g, respectively. MicroSPECT/CT visualized all CLX and PDX tumor xenografts at 4 and 24 h p.i. Dosimetry estimates revealed that in humans, the whole body dose from administration of 740-1110 MBq of 99mTc-PmFab-His6 would be 2-3 mSv, which is less than for a 99mTc-medronate bone scan (4 mSv).
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Affiliation(s)
- Anthony Ku
- Department of Pharmaceutical Sciences , University of Toronto , 144 College Street , Toronto , ON M5S 3M2 , Canada
| | - Conrad Chan
- Department of Pharmaceutical Sciences , University of Toronto , 144 College Street , Toronto , ON M5S 3M2 , Canada
| | - Sadaf Aghevlian
- Department of Pharmaceutical Sciences , University of Toronto , 144 College Street , Toronto , ON M5S 3M2 , Canada
| | - Zhongli Cai
- Department of Pharmaceutical Sciences , University of Toronto , 144 College Street , Toronto , ON M5S 3M2 , Canada
| | | | | | | | | | - Raymond M Reilly
- Department of Pharmaceutical Sciences , University of Toronto , 144 College Street , Toronto , ON M5S 3M2 , Canada.,Department of Medical Imaging , University of Toronto , 263 McCaul Street , Toronto , ON M5T 1W7 , Canada.,Toronto General Research Institute and Joint Department of Medical Imaging , University Health Network , 200 Elizabeth Street , Toronto , ON M5G 2C4 , Canada
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Hwang SY, Park S, Kwon Y. Recent therapeutic trends and promising targets in triple negative breast cancer. Pharmacol Ther 2019; 199:30-57. [PMID: 30825473 DOI: 10.1016/j.pharmthera.2019.02.006] [Citation(s) in RCA: 151] [Impact Index Per Article: 25.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/13/2018] [Accepted: 02/04/2019] [Indexed: 12/14/2022]
Abstract
Breast cancer accounts for 25% of all types of cancer in women, and triple negative breast cancer (TNBC) comprises around 15~20% of breast cancers. Conventional chemotherapy and radiation are the primary systemic therapeutic strategies; no other FDA-approved targeted therapies are yet available as for TNBC. TNBC is generally characterized by a poor prognosis and high rates of proliferation and metastases. Due to these aggressive features and lack of targeted therapies, numerous attempts have been made to discover viable molecular targets for TNBC. Massive cohort studies, clinical trials, and in-depth analyses have revealed diverse molecular alterations in TNBC; however, controversy exists as to whether many of these changes are beneficial or detrimental in caner progression. Here we review the complicated tumorigenic processes and discuss critical findings and therapeutic trends in TNBC with a focus on promising therapeutic approaches, the clinical trials currently underway, and potent experimental compounds under preclinical and evaluation.
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Affiliation(s)
- Soo-Yeon Hwang
- College of Pharmacy, Graduate School of Pharmaceutical Sciences, Ewha Womans University, Seoul 03760, Republic of Korea
| | - Seojeong Park
- College of Pharmacy, Graduate School of Pharmaceutical Sciences, Ewha Womans University, Seoul 03760, Republic of Korea
| | - Youngjoo Kwon
- College of Pharmacy, Graduate School of Pharmaceutical Sciences, Ewha Womans University, Seoul 03760, Republic of Korea.
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Hossein-Nejad-Ariani H, Althagafi E, Kaur K. Small Peptide Ligands for Targeting EGFR in Triple Negative Breast Cancer Cells. Sci Rep 2019; 9:2723. [PMID: 30804365 PMCID: PMC6389950 DOI: 10.1038/s41598-019-38574-y] [Citation(s) in RCA: 59] [Impact Index Per Article: 9.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/10/2018] [Accepted: 12/28/2018] [Indexed: 11/09/2022] Open
Abstract
The efficacy of chemotherapy for cancer treatment can be increased by targeted drug delivery to the cancer cells. This is particularly important for triple negative breast cancer (TNBC) for which chemotherapy is a major form of treatment. Here we designed and screened a library of 30 peptides starting with a previously reported epidermal growth factor receptor (EGFR) targeting peptide GE11 (YHWYGYTPQNVI). A direct peptide array-whole cell binding assay, where the peptides are conjugated to a cellulose membrane, was used to identify four peptides with enhanced binding to TNBC cells. Next, the four peptides were synthesized as FITC-labelled soluble peptides to study their direct uptake by TNBC cells using flow cytometry. The results showed that peptide analogue 22 had several fold higher uptake by the TNBC cells compared to the lead peptide GE11. The specific uptake of the peptide analogue 22 was confirmed by competition experiment using pure EGF protein. Further, peptide 22 showed dose dependent uptake by the TNBC MDA-MB-231 cells (105) with uptake saturating at around 2 μM peptide concentration. Thus, peptide 22 is a promising EGFR specific TNBC cell binding peptide that can be conjugated directly to a chemotherapeutic drug or to nanoparticles for targeted drug delivery to enhance the efficacy of chemotherapy for TNBC treatment.
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Affiliation(s)
- Hanieh Hossein-Nejad-Ariani
- Chapman University School of Pharmacy (CUSP), Harry and Diane Rinker Health Science Campus, Chapman University, Irvine, California, 92618-1908, USA
| | - Emad Althagafi
- Chapman University School of Pharmacy (CUSP), Harry and Diane Rinker Health Science Campus, Chapman University, Irvine, California, 92618-1908, USA
| | - Kamaljit Kaur
- Chapman University School of Pharmacy (CUSP), Harry and Diane Rinker Health Science Campus, Chapman University, Irvine, California, 92618-1908, USA.
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Epidermal growth factor receptor (EGFR) overexpression in triple-negative breast cancer: association with clinicopathologic features and prognostic parameters. SURGICAL AND EXPERIMENTAL PATHOLOGY 2019. [DOI: 10.1186/s42047-018-0029-0] [Citation(s) in RCA: 13] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/06/2023] Open
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