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1.
Anticancer Res ; 41(9): 4619-4627, 2021 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-34475090

RESUMO

BACKGROUND: The real-world outcomes of patients with advanced invasive lobular carcinoma (ILC) of the breast are unclear because of its rarity. PATIENTS AND METHODS: We identified 435 patients with estrogen receptor-positive (ER+), HER2-negative (HER2-) advanced breast cancer treated at our Institute between 2002 and 2019, and analyzed their outcomes retrospectively. RESULTS: We identified 29 patients with advanced ILC. At presentation, they had a lower rate of lung metastasis (p=0.0053) but a higher rate of stomach metastasis (p=0.0379) compared with other patients with advanced breast cancer. Median overall survival did not differ; however, multivariate analyses showed that ILC histopathology was a risk factor for poorer overall survival (hazard ratio=3.43, p=0.0038) in patients with de novo stage IV ER+ HER2- breast cancer. Patients with ILC showed a markedly different patten of subsequent metastasis, such as less in the lung and more in the stomach, leptomeninges, and bone marrow. CONCLUSION: According to our retrospective study, in patients with de novo stage IV ER+ HER2- breast cancer, ILC histopathology was associated with increased risk of death.


Assuntos
Neoplasias da Mama/patologia , Carcinoma Ductal de Mama/patologia , Carcinoma Lobular/patologia , Receptor ErbB-2/metabolismo , Receptores de Estrogênio/metabolismo , Adulto , Idoso , Idoso de 80 Anos ou mais , Neoplasias da Mama/metabolismo , Neoplasias da Mama/mortalidade , Carcinoma Ductal de Mama/metabolismo , Carcinoma Ductal de Mama/mortalidade , Carcinoma Lobular/metabolismo , Carcinoma Lobular/mortalidade , Feminino , Humanos , Pessoa de Meia-Idade , Análise Multivariada , Metástase Neoplásica , Estadiamento de Neoplasias , Prognóstico , Estudos Retrospectivos , Análise de Sobrevida
2.
Medicine (Baltimore) ; 100(36): e27017, 2021 Sep 10.
Artigo em Inglês | MEDLINE | ID: mdl-34516491

RESUMO

RATIONALE: Metastatic gastric cancer patients with poor eastern cooperative oncology group performance status (PS) (≥3) were lack of effective anti-tumor strategies. They always lived with poor PS, severe and multiple symptoms, and usually resulted in extremely limited survival time. Herein, we reported a patient diagnosed with gastric cancer metastasized to multiple bones, along with lymphangitis carcinomatosa in lungs, harboring Her-2 and c-MET amplification with poor PS, positively responded to combinational therapy with trastuzumab and crizotinib. PATIENT CONCERNS: The patient complained of persistent cough and fatigue for 2 months, otherwise, she denied smoking, alcohol history, or any other medical or family history. DIAGNOSIS: With the biopsy results from gastroscopy, as well as computer tomography for chest and abdomen, the patient was diagnosed as gastric adenocarcinoma, with metastasis on lungs, left adrenal gland, retroperitoneal lymph nodes, and multiple bones. INTERVENTIONS: Because of the poor PS (PS = 3), as well as Her-2 and c-MET amplification, the patient received combination treatment with trastuzumab and crizotinib as salvage strategy. OUTCOMES: After 2 months' exposure of trastuzumab and crizotinib, symptoms including persistent cough, and chest distress were alleviated significantly. Simultaneously, chest computer tomography showed significant dissipation of lymphangitis carcinomatosa, as well as apparent reduction of pleural effusion. No adverse reactions including nausea, vomiting, diarrhea, or hypertension was observed during the following 2 months. LESSONS: The present case suggested that combinational therapy with trastuzumab and crizotinib might be effective in metastatic gastric cancer patients harboring Her-2 and c-MET amplification, even with a poor PS. It was also implied that gene sequencing might be valuable, especially in patients with limited treatment strategies.


Assuntos
Adenocarcinoma/tratamento farmacológico , Resistencia a Medicamentos Antineoplásicos/genética , Neoplasias Pulmonares/tratamento farmacológico , Neoplasias Gástricas/tratamento farmacológico , Adenocarcinoma/metabolismo , Adenocarcinoma/secundário , Protocolos de Quimioterapia Combinada Antineoplásica , Crizotinibe/administração & dosagem , Crizotinibe/uso terapêutico , Feminino , Humanos , Neoplasias Pulmonares/metabolismo , Neoplasias Pulmonares/secundário , Pessoa de Meia-Idade , Metástase Neoplásica , Proteínas Proto-Oncogênicas c-met/metabolismo , Receptor ErbB-2/metabolismo , Neoplasias Gástricas/metabolismo , Neoplasias Gástricas/patologia , Trastuzumab/administração & dosagem , Trastuzumab/uso terapêutico
3.
Int J Mol Sci ; 22(16)2021 Aug 19.
Artigo em Inglês | MEDLINE | ID: mdl-34445631

RESUMO

To better understand the etiology of inflammatory breast cancer (IBC) and identify potential therapies, we studied genomic alterations in IBC patients. Targeted, next-generation sequencing (NGS) was performed on cell-free DNA (cfDNA) (n = 33) and paired DNA from tumor tissues (n = 29) from 32 IBC patients. We confirmed complementarity between cfDNA and tumor tissue genetic profiles. We found a high incidence of germline variants in IBC patients that could be associated with an increased risk of developing the disease. Furthermore, 31% of IBC patients showed deficiencies in the homologous recombination repair (HRR) pathway (BRCA1, BRCA2, PALB2, RAD51C, ATM, BARD1) making them sensitive to poly (ADP-ribose) polymerase (PARP) inhibitors. We also characterized the tumor-infiltrating lymphocytes (TILs) in tumor tissue biopsies by studying several markers (CD4, CD8, FoxP3, CD20, PD-1, and PD-L1) through immunohistochemistry (IHC) staining. In 7 of 24 (29%) patients, tumor biopsies were positive for PD-L1 and PD-1 expression on TILs, making them sensitive to PD-1/PD-L1 blocking therapies. Our results provide a rationale for considering PARP inhibitors and PD-1/PDL1 blocking immunotherapy in qualifying IBC patients.


Assuntos
Biomarcadores Tumorais/genética , Ácidos Nucleicos Livres/genética , Neoplasias Inflamatórias Mamárias/patologia , Linfócitos do Interstício Tumoral/imunologia , Terapia de Alvo Molecular , Mutação , Microambiente Tumoral/imunologia , Adulto , Idoso , Antígeno B7-H1/genética , Antígeno B7-H1/metabolismo , Ácidos Nucleicos Livres/análise , Feminino , Seguimentos , Regulação Neoplásica da Expressão Gênica , Sequenciamento de Nucleotídeos em Larga Escala , Humanos , Neoplasias Inflamatórias Mamárias/genética , Neoplasias Inflamatórias Mamárias/imunologia , Pessoa de Meia-Idade , Prognóstico , Receptor ErbB-2/metabolismo , Receptores de Estrogênio/metabolismo , Receptores de Progesterona/metabolismo , Estudos Retrospectivos , Taxa de Sobrevida
4.
Lancet Oncol ; 22(9): 1290-1300, 2021 09.
Artigo em Inglês | MEDLINE | ID: mdl-34339623

RESUMO

BACKGROUND: Systemic therapies for metastatic biliary tract cancers are few, and patients have a median overall survival of less than 1 year. MyPathway evaluates the activity of US Food and Drug Administration-approved therapies in non-indicated tumours with potentially actionable molecular alterations. In this study, we present an analysis of patients with metastatic biliary tract cancers with HER2 amplification, overexpression, or both treated with a dual anti-HER2 regimen, pertuzumab plus trastuzumab, from MyPathway. METHODS: MyPathway is a non-randomised, multicentre, open-label, phase 2a, multiple basket study. Patients aged 18 years and older with previously treated metastatic biliary tract cancers with HER2 amplification, HER2 overexpression, or both and an Eastern Cooperative Oncology Group performance status of 0-2 were enrolled from 23 study sites in the USA and received intravenous pertuzumab (840 mg loading dose, then 420 mg every 3 weeks) plus trastuzumab (8 mg/kg loading dose, then 6 mg/kg every 3 weeks). The primary endpoint was investigator-assessed objective response rate according to Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1. The primary outcome and adverse events were analysed in all patients who received at least one dose of pertuzumab and trastuzumab. This trial is registered with ClinicalTrials.gov, NCT02091141, and is ongoing. FINDINGS: 39 patients enrolled in the MyPathway HER2 biliary tract cancer cohort between Oct 28, 2014, and May 29, 2019, were evaluable for anti-tumour activity by the March 10, 2020, data cutoff date. Median follow-up was 8·1 months (IQR 2·7-15·7). Nine of 39 patients achieved a partial response (objective response rate 23% [95% CI 11-39]). Grade 3-4 treatment-emergent adverse events were reported in 18 (46%) of 39 patients, most commonly increased alanine aminotransferase and increased aspartate aminotransferase (each five [13%] of 39). Treatment-related grade 3 adverse events were reported in three (8%) of 39 patients, including increased alanine aminotransferase, aspartate aminotransferase, blood alkaline phosphatase, and blood bilirubin. Serious treatment-emergent adverse events were observed in ten (26%) of 39 patients, of which only abdominal pain occurred in more than one patient (two [5%] of 39). There were no treatment-related serious adverse events, treatment-related grade 4 events, or deaths. INTERPRETATION: Treatment was well tolerated in patients with previously treated HER2-positive metastatic biliary tract cancer. The response rate is promising for the initiation of randomised, controlled trials of pertuzumab plus trastuzumab in this patient population. FUNDING: F Hoffmann-La Roche-Genentech.


Assuntos
Anticorpos Monoclonais Humanizados/uso terapêutico , Antineoplásicos Imunológicos/uso terapêutico , Neoplasias do Sistema Biliar/tratamento farmacológico , Receptor ErbB-2/metabolismo , Trastuzumab/uso terapêutico , Idoso , Neoplasias do Sistema Biliar/metabolismo , Neoplasias do Sistema Biliar/patologia , Efeitos Colaterais e Reações Adversas Relacionados a Medicamentos , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Metástase Neoplásica , Intervalo Livre de Progressão , Receptor ErbB-2/antagonistas & inibidores , Critérios de Avaliação de Resposta em Tumores Sólidos , Taxa de Sobrevida , Estados Unidos
5.
Gene ; 799: 145808, 2021 Oct 05.
Artigo em Inglês | MEDLINE | ID: mdl-34224831

RESUMO

We set out to uncover transcriptome and chromatin landscape changes that occur in HER2 + breast cancer (BC) cells upon acquiring resistance to trastuzumab. RNA-seq analysis was applied to two independently-derived BC cell lines with acquired resistance to trastuzumab (SKBr3.HerR and BT-474HerR) and their parental drug-sensitive cell lines (SKBr3 and BT-474). Chromatin landscape analysis indicated that the most significant increase in accessibility in resistant cells occurs in PPP1R1B within a segment spanning introns 1b through intron 3. Footprint analysis of this segment revealed that FoxJ3 (within intron 2) and Pou5A1/Sox2 (within inton 3) transcription factor motifs are protected in resistant cells. Overall, 344 shared genes were upregulated in both resistant cell lines relative to their parental counterparts and 453 shared genes were downregulated in both resistant cell lines relative to their parental counterparts. In resistant cells, genes associated with autophagy and mitochondria organization are upregulated and genes associated with ribosome assembly and cell cycle are downregulated relative to parental cells. The five top upregulated genes in drug-resistant breast cancer cells are APOD, AZGP1, ETV5, ALPP, and PPP1R1B. This is the first report of increased chromatin accessibility within PPP1R1B associated with its t-Darpp transcript increase, and points to a possible mechanism for its activation in trastuzumab-resistant cells.


Assuntos
Neoplasias da Mama/tratamento farmacológico , Neoplasias da Mama/genética , Cromatina/efeitos dos fármacos , Resistencia a Medicamentos Antineoplásicos/genética , Trastuzumab/farmacologia , Antineoplásicos Imunológicos/farmacologia , Autofagia/efeitos dos fármacos , Autofagia/genética , Neoplasias da Mama/patologia , Linhagem Celular Tumoral , Cromatina/genética , Fosfoproteína 32 Regulada por cAMP e Dopamina/genética , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Feminino , Fatores de Transcrição Forkhead/genética , Perfilação da Expressão Gênica , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Redes Reguladoras de Genes , Humanos , Receptor ErbB-2/metabolismo , Fatores de Transcrição SOXB1/genética
6.
Anticancer Res ; 41(8): 4143-4149, 2021 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-34281885

RESUMO

BACKGROUND/AIM: With advances in anti-HER2 treatment and improved prognoses of HER2-positive breast cancer, the American Society of Clinical Oncology and the American Society of Pathologists (ASCO/CAP) have revised the HER2 diagnostic guidelines several times. We examined how to respond clinically to the revisions of the interpretation of the immunohistochemistry (IHC) method. PATIENTS AND METHODS: We re-evaluated 254 patients diagnosed as HER2 IHC equivocal, who underwent fluorescence in situ hybridization (FISH) before and after the IHC diagnostic criteria update in 2013. RESULTS: Twenty of 131 (15.3%) IHC equivocal cases by the ASCO/CAP 2007 guideline were IHC score 3+ and one of 20 (0.76%) was negative for FISH. Five of 123 (4.1%) IHC equivocal cases by the ASCO/CAP 2013 guideline were negative for IHC as per the 2007 guideline and four were positive for FISH. CONCLUSION: After revision of the ASCO/CAP 2013 guideline, 3.3% of HER2-negative cases before the revision should have received anti-HER2 treatment.


Assuntos
Neoplasias da Mama/diagnóstico , Receptor ErbB-2/metabolismo , Antineoplásicos/uso terapêutico , Neoplasias da Mama/tratamento farmacológico , Neoplasias da Mama/metabolismo , Neoplasias da Mama/cirurgia , Feminino , Humanos , Imuno-Histoquímica , Hibridização in Situ Fluorescente , Guias de Prática Clínica como Assunto , Receptor ErbB-2/antagonistas & inibidores
7.
Cell Death Dis ; 12(7): 696, 2021 07 13.
Artigo em Inglês | MEDLINE | ID: mdl-34257270

RESUMO

Trastuzumab resistance negatively influences the clinical efficacy of the therapy for human epidermal growth factor receptor 2 (HER2) positive gastric cancer (GC), and the underlying mechanisms remain elusive. Exploring the mechanisms and finding effective approaches to address trastuzumab resistance are of great necessity. Here, we confirmed that endoplasmic reticulum (ER) stress-induced trastuzumab resistance by up-regulating miR-301a-3p in HER2-positive GC cells. Moreover, we elucidated that miR-301a-3p mediated trastuzumab resistance by down-regulating the expression of leucine-rich repeats and immunoglobulin-like domains containing protein 1 (LRIG1) and subsequently activating the expression of insulin-like growth factor 1 receptor (IGF-1R) and fibroblast growth factor receptor 1 (FGFR1) under ER stress. We also found that intercellular transfer of miR-301a-3p by exosomes disseminated trastuzumab resistance. The present study demonstrated that exosomal miR-301a-3p could serve as a non-invasive biomarker for trastuzumab resistance, which was maybe a novel potential therapeutic target to overcome trastuzumab resistance and improve the curative effect of trastuzumab in HER2-positive GC patients.


Assuntos
Antineoplásicos Imunológicos/farmacologia , Resistencia a Medicamentos Antineoplásicos , Estresse do Retículo Endoplasmático/efeitos dos fármacos , MicroRNAs/metabolismo , Receptor ErbB-2/antagonistas & inibidores , Neoplasias Gástricas/tratamento farmacológico , Trastuzumab/farmacologia , Animais , Apoptose/efeitos dos fármacos , Linhagem Celular Tumoral , Resistencia a Medicamentos Antineoplásicos/genética , Regulação Neoplásica da Expressão Gênica , Humanos , Masculino , Glicoproteínas de Membrana/genética , Glicoproteínas de Membrana/metabolismo , Camundongos Endogâmicos BALB C , Camundongos Nus , MicroRNAs/genética , Receptor ErbB-2/metabolismo , Receptor Tipo 1 de Fator de Crescimento de Fibroblastos/genética , Receptor Tipo 1 de Fator de Crescimento de Fibroblastos/metabolismo , Receptor IGF Tipo 1/genética , Receptor IGF Tipo 1/metabolismo , Transdução de Sinais , Neoplasias Gástricas/genética , Neoplasias Gástricas/metabolismo , Neoplasias Gástricas/patologia , Carga Tumoral/efeitos dos fármacos , Ensaios Antitumorais Modelo de Xenoenxerto
8.
J Enzyme Inhib Med Chem ; 36(1): 1553-1563, 2021 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-34251942

RESUMO

A series of 11 new substituted 1,5-dihydro-4,1-benzoxazepine derivatives was synthesised to study the influence of the methyl group in the 1-(benzenesulphonyl) moiety, the replacement of the purine by the benzotriazole bioisosteric analogue, and the introduction of a bulky substituent at position 6 of the purine, on the biological effects. Their inhibition against isolated HER2 was studied and the structure-activity relationships have been confirmed by molecular modelling studies. The most potent compound against isolated HER2 is 9a with an IC50 of 7.31 µM. We have investigated the effects of the target compounds on cell proliferation. The most active compound (7c) against all the tumour cell lines studied (IC50 0.42-0.86 µM) does not produce any modification in the expression of pro-caspase 3, but increases the caspase 1 expression, and promotes pyroptosis.


Assuntos
Antineoplásicos/farmacologia , Desenho de Fármacos , Inibidores de Proteínas Quinases/farmacologia , Receptor ErbB-2/antagonistas & inibidores , Antineoplásicos/síntese química , Antineoplásicos/química , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Relação Dose-Resposta a Droga , Ensaios de Seleção de Medicamentos Antitumorais , Humanos , Modelos Moleculares , Estrutura Molecular , Inibidores de Proteínas Quinases/síntese química , Inibidores de Proteínas Quinases/química , Receptor ErbB-2/metabolismo , Relação Estrutura-Atividade
9.
Int J Cancer ; 149(8): 1585-1592, 2021 10 15.
Artigo em Inglês | MEDLINE | ID: mdl-34213778

RESUMO

Incorporating dual human epidermal growth factor receptor 2 (HER2) blockade into neoadjuvant systemic therapy (NST) led to higher response in patients with HER2-positive breast cancer. However, axillary response to treatment regimens, including single or dual HER2 blockade, in patients with clinically node-positive breast cancer remains uncertain. Our study aimed to examine the pathologic axillary response according to the type of NST, that is, single or dual HER2 blockade. In our study, 546 patients with clinically node-positive, HER2-positive breast cancer who received NST followed by axillary surgery were retrospectively selected and divided into three groups: chemotherapy alone, chemotherapy + trastuzumab and chemotherapy + trastuzumab with pertuzumab. The primary outcome was the axillary pathologic complete response (pCR). Among 471 patients undergoing axillary lymph node dissection, the axillary pCR rates were 43.5%, 74.5% and 68.8% in patients who received chemotherapy alone, chemotherapy + trastuzumab and chemotherapy + trastuzumab with pertuzumab, respectively. There was no difference in axillary pCR rates between patients who received single or dual HER2 blockade (P = .379). Among patients receiving chemotherapy + trastuzumab, patients without breast pCR had the greatest risk for residual axillary metastases (relative risk, 9.8; 95% confidence interval, 3.2-14.9; P < .0001). In conclusion, adding trastuzumab to chemotherapy increased the axillary pCR rate in patients with clinically node-positive, HER2-positive breast cancer; furthermore, dual HER2-blockade with trastuzumab and pertuzumab did not elevate the axillary response compared with trastuzumab alone. Breast pCR could be a strong predictor for axillary pCR in clinically node-positive patients treated with HER2-targeting therapy.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Neoplasias da Mama/tratamento farmacológico , Linfonodos/patologia , Terapia Neoadjuvante/métodos , Receptor ErbB-2/antagonistas & inibidores , Receptor ErbB-2/metabolismo , Adulto , Idoso , Idoso de 80 Anos ou mais , Anticorpos Monoclonais Humanizados/administração & dosagem , Axila , Biomarcadores Tumorais , Neoplasias da Mama/metabolismo , Neoplasias da Mama/patologia , Feminino , Seguimentos , Regulação Neoplásica da Expressão Gênica , Humanos , Linfonodos/metabolismo , Metástase Linfática , Pessoa de Meia-Idade , Prognóstico , Estudos Retrospectivos , Taxa de Sobrevida , Trastuzumab/administração & dosagem
10.
Molecules ; 26(13)2021 Jun 28.
Artigo em Inglês | MEDLINE | ID: mdl-34203547

RESUMO

The effect of enhanced permeability and retention is often not sufficient for highly effective cancer therapy with nanoparticles, and the development of active targeted drug delivery systems based on nanoparticles is probably the main direction of modern cancer medicine. To meet the challenge, we developed polymer PLGA nanoparticles loaded with fluorescent photosensitive xanthene dye, Rose Bengal, and decorated with HER2-recognizing artificial scaffold protein, affibody ZHER2:342. The obtained 170 nm PLGA nanoparticles possess both fluorescent and photosensitive properties. Namely, under irradiation with the green light of 540 nm nanoparticles, they produced reactive oxygen species leading to cancer cell death. The chemical conjugation of PLGA with anti-HER2 affibody resulted in the selective binding of nanoparticles only to HER2-overexpressing cancer cells. HER2 is a receptor tyrosine kinase that belongs to the EGFR/ERbB family and is overexpressed in 30% of breast cancers, thus serving as a clinically relevant oncomarker. However, the standard targeting molecules such as full-size antibodies possess serious drawbacks, such as high immunogenicity and the need for mammalian cell production. We believe that the developed affibody-decorated targeted photosensitive PLGA nanoparticles will provide new solutions for ongoing problems in cancer diagnostics and treatment, as well in cancer theranostics.


Assuntos
Sistemas de Liberação de Medicamentos , Nanopartículas , Neoplasias/terapia , Copolímero de Ácido Poliláctico e Ácido Poliglicólico , Receptor ErbB-2/metabolismo , Proteínas Recombinantes de Fusão , Células A549 , Animais , Células CHO , Morte Celular/efeitos dos fármacos , Cricetulus , Humanos , Nanopartículas/química , Nanopartículas/uso terapêutico , Neoplasias/metabolismo , Neoplasias/patologia , Copolímero de Ácido Poliláctico e Ácido Poliglicólico/química , Copolímero de Ácido Poliláctico e Ácido Poliglicólico/farmacologia , Proteínas Recombinantes de Fusão/química , Proteínas Recombinantes de Fusão/farmacologia
11.
Int J Mol Sci ; 22(11)2021 Jun 07.
Artigo em Inglês | MEDLINE | ID: mdl-34200484

RESUMO

Breast cancer is one of the most commonly occurring cancers in women globally and is the primary cause of cancer mortality in females. BC is highly heterogeneous with various phenotypic expressions. The overexpression of HER2 is responsible for 15-30% of all invasive BC and is strongly associated with malignant behaviours, poor prognosis and decline in overall survival. Molecular imaging offers advantages over conventional imaging modalities, as it provides more sensitive and specific detection of tumours, as these techniques measure the biological and physiological processes at the cellular level to visualise the disease. Early detection and diagnosis of BC is crucial to improving clinical outcomes and prognosis. While HER2-specific antibodies and nanobodies may improve the sensitivity and specificity of molecular imaging, the radioisotope conjugation process may interfere with and may compromise their binding functionalities. Aptamers are single-stranded oligonucleotides capable of targeting biomarkers with remarkable binding specificity and affinity. Aptamers can be functionalised with radioisotopes without compromising target specificity. The attachment of different radioisotopes can determine the aptamer's functionality in the treatment of HER2(+) BC. Several HER2 aptamers and investigations of them have been described and evaluated in this paper. We also provide recommendations for future studies with HER2 aptamers to target HER2(+) BC.


Assuntos
Aptâmeros de Nucleotídeos/uso terapêutico , Biomarcadores Tumorais/metabolismo , Neoplasias da Mama/diagnóstico , Neoplasias da Mama/tratamento farmacológico , Receptor ErbB-2/antagonistas & inibidores , Receptor ErbB-2/metabolismo , Anticorpos de Domínio Único/uso terapêutico , Feminino , Humanos , Prognóstico
12.
Int J Mol Sci ; 22(13)2021 Jun 24.
Artigo em Inglês | MEDLINE | ID: mdl-34202896

RESUMO

The human epidermal growth factor receptor 2 (HER2) is a well-established oncogenic driver and a successful therapeutic target in several malignancies, such as breast and gastric cancers. HER2 alterations, including amplification and somatic mutations, have also been detected in a small but not negligible subset of patients affected by advanced colorectal cancer (aCRC). However, to date, there are no available oncotargets in this malignancy beyond RAS and BRAF that are available. Here we present an overview on the present predictive and prognostic role of HER2 expression in aCRC, as well as on its consequent potential therapeutic implications from preclinical investigations towards ongoing trials testing anti-HER2 agents in aCRC. While HER2's role as a molecular predictive biomarker for anti-EGFR therapies in CRC is recognized, HER2 prognostic value remains controversial. Moreover, thanks to the impressive and growing body of clinical evidence, HER2 is strongly emerging as a new potential actionable oncotarget in aCRC. In conclusion, in the foreseeable future, HER2-targeted therapeutic strategies may integrate the algorithm of aCRC treatment towards an increasingly tailored therapeutic approach to this disease.


Assuntos
Biomarcadores Tumorais , Neoplasias Colorretais/etiologia , Proteínas Proto-Oncogênicas B-raf/genética , Receptor ErbB-2/genética , Proteínas ras/genética , Animais , Neoplasias Colorretais/metabolismo , Neoplasias Colorretais/mortalidade , Neoplasias Colorretais/patologia , Gerenciamento Clínico , Suscetibilidade a Doenças , Receptores ErbB/antagonistas & inibidores , Receptores ErbB/genética , Receptores ErbB/metabolismo , Regulação Neoplásica da Expressão Gênica , Humanos , Terapia de Alvo Molecular , Prognóstico , Proteínas Proto-Oncogênicas B-raf/metabolismo , Receptor ErbB-2/metabolismo , Transdução de Sinais , Proteínas ras/metabolismo
13.
Molecules ; 26(10)2021 May 12.
Artigo em Inglês | MEDLINE | ID: mdl-34066245

RESUMO

Natural backbone-cyclized proteins have an increased thermostability and resistance towards proteases, characteristics that have sparked interest in head-to-tail cyclization as a method to stability-enhance proteins used in diagnostics and therapeutic applications, for example. In this proof-of principle study, we have produced and investigated a head-to-tail cyclized and HER2-specific ZHER2:342 Affibody dimer. The sortase A-mediated cyclization reaction is highly efficient (>95%) under optimized conditions, and renders a cyclic ZHER3:342-dimer with an apparent melting temperature, Tm, of 68 °C, which is 3 °C higher than that of its linear counterpart. Circular dichroism spectra of the linear and cyclic dimers looked very similar in the far-UV range, both before and after thermal unfolding to 90 °C, which suggests that cyclization does not negatively impact the helicity or folding of the cyclic protein. The cyclic dimer had an apparent sub-nanomolar affinity (Kd ~750 pM) to the HER2-receptor, which is a ~150-fold reduction in affinity relative to the linear dimer (Kd ~5 pM), but the anti-HER2 Affibody dimer remained a high-affinity binder even after cyclization. No apparent difference in proteolytic stability was detected in an endopeptidase degradation assay for the cyclic and linear dimers. In contrast, in an exopeptidase degradation assay, the linear dimer was shown to be completely degraded after 5 min, while the cyclic dimer showed no detectable degradation even after 60 min. We further demonstrate that a site-specifically DyLight 594-labeled cyclic dimer shows specific binding to HER2-overexpressing cells. Taken together, the results presented here demonstrate that head-to-tail cyclization can be an effective strategy to increase the stability of an Affibody dimer.


Assuntos
Aminoaciltransferases/metabolismo , Proteínas de Bactérias/metabolismo , Biocatálise , Neoplasias da Mama/metabolismo , Cisteína Endopeptidases/metabolismo , Multimerização Proteica , Receptor ErbB-2/metabolismo , Proteínas Recombinantes de Fusão/química , Proteínas Recombinantes de Fusão/metabolismo , Neoplasias da Mama/patologia , Dicroísmo Circular , Ciclização , Feminino , Humanos , Cinética , Células MCF-7 , Microscopia de Fluorescência , Peptídeo Hidrolases/metabolismo , Ligação Proteica , Estrutura Secundária de Proteína , Ressonância de Plasmônio de Superfície
14.
Cancer Treat Rev ; 99: 102229, 2021 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-34139476

RESUMO

Treatment of HER2-positive early breast cancer (EBC) continues to evolve with neoadjuvant (pre-operative) and adjuvant (post-operative) HER2-targeted therapies as standard of care. There are two important decision points. The first involves deciding between neoadjuvant therapy or proceeding directly to surgery. Neoadjuvant chemotherapy (NACT) plus pertuzumab-trastuzumab is appropriate for patients with high-risk HER2-positive EBC (tumour diameter ≥2 cm, and/or node-positive disease). Patients with node-negative disease and tumour diameter <2 cm are candidates for upfront surgery followed by paclitaxel for 12 weeks plus 18 cycles of trastuzumab, with the option to add pertuzumab (if pN+). The second decision point involves the pathohistological result at surgery after neoadjuvant therapy. Total pathological complete response (tpCR: ypT0/is, ypN0) is associated with improved survival endpoints. Patients with tumours ≥2 cm and/or node-positive disease at diagnosis who have a tpCR after dual blockade should continue pertuzumab-trastuzumab in the adjuvant setting to complete 1 year (18cycles) of treatment. For patients with invasive residual disease, 14cycles of post-neoadjuvant trastuzumab emtansine (T-DM1) therapy significantly increases invasive-DFS compared with trastuzumab. Extended adjuvant therapy with neratinib is an option in selected patients (HER2-positive and oestrogen receptor [ER]-positive) who have completed adjuvant trastuzumab-based therapy. Less aggressive chemotherapy regimens are recommended in populations with a lower risk of recurrence (patients with small tumours without axillary involvement; patients unlikely to tolerate anthracycline-taxane or taxane-carboplatin regimens). Ultimately, treatment recommendations should be consistent with local and international guidelines. Further studies will guide optimisation of treatment for patients with HER2-positive EBC according to the risk of disease recurrence.


Assuntos
Neoplasias da Mama/tratamento farmacológico , Neoplasias da Mama/cirurgia , Tomada de Decisões , Receptor ErbB-2/antagonistas & inibidores , Neoplasias da Mama/metabolismo , Neoplasias da Mama/patologia , Ensaios Clínicos Fase I como Assunto , Ensaios Clínicos Fase II como Assunto , Ensaios Clínicos Fase III como Assunto , Feminino , Humanos , Metástase Linfática , Oncologia/normas , Terapia Neoadjuvante , Inibidores de Proteínas Quinases/administração & dosagem , Ensaios Clínicos Controlados Aleatórios como Assunto , Receptor ErbB-2/metabolismo , Fatores de Risco
15.
Int J Cancer ; 149(8): 1593-1604, 2021 10 15.
Artigo em Inglês | MEDLINE | ID: mdl-34152598

RESUMO

Lung adenocarcinoma (LUAD) is the most common types among lung cancers generally arising from terminal airway and understanding of multistep carcinogenesis is crucial to develop novel therapeutic strategy for LUAD. Here we used human induced pluripotent stem cells (hiPSCs) to establish iHER2-hiPSCs in which doxycycline induced the expression of the oncoprotein human epidermal growth factor receptor 2 (HER2)/ERBB2. Lung progenitors that differentiated from iHER2-hiPSCs, which expressed NKX2-1/TTF-1 known as a lung lineage maker, were cocultured with human fetal fibroblast and formed human lung organoids (HLOs) comprising alveolar type 2-like cells. HLOs that overexpressed HER2 transformed to tumor-like structures similar to atypical adenomatous hyperplasia, which is known for lung precancerous lesion and upregulated the activities of oncogenic signaling cascades such as RAS/RAF/MAPK and PI3K/AKT/mTOR. The degree of morphological irregularity and proliferation capacity were significantly higher in HLOs from iHER2-hiPSCs. Moreover, the transcriptome profile of the HLOs shifted from a normal lung tissue-like state to one characteristic of clinical LUAD with HER2 amplification. Our results suggest that hiPSC-derived HLOs may serve as a model to recapitulate the early tumorigenesis of LUAD and would provide new insights into the molecular basis of tumor initiation and progression.


Assuntos
Adenocarcinoma de Pulmão/patologia , Carcinogênese , Regulação Neoplásica da Expressão Gênica , Células-Tronco Pluripotentes Induzidas/patologia , Neoplasias Pulmonares/patologia , Organoides/patologia , Receptor ErbB-2/metabolismo , Adenocarcinoma de Pulmão/genética , Adenocarcinoma de Pulmão/metabolismo , Biomarcadores Tumorais/genética , Biomarcadores Tumorais/metabolismo , Diferenciação Celular , Humanos , Células-Tronco Pluripotentes Induzidas/metabolismo , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/metabolismo , Organoides/metabolismo , Receptor ErbB-2/genética , Transcriptoma , Células Tumorais Cultivadas
16.
J Cancer Res Clin Oncol ; 147(10): 2955-2968, 2021 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-34156519

RESUMO

PURPOSE: Hepatocellular carcinoma (HCC), the most common manifestation of liver cancer, is one of the leading causes of cancer-related mortality worldwide with limited treatment options. Infigratinib, a pan-FGFR inhibitor, has shown a potent antitumour effect in HCC. However, drug resistance is often observed in long-term treatment. In this study, we examined the potential feedback mechanism(s) leading to infigratinib and explored a combination therapy to overcome resistance in HCC. METHODS: Patient-derived xenograft (PDX) tumours were subcutaneously implanted into SCID mice and were subsequently treated with infigratinib. Tumour growth was monitored over time, and tumour samples were subjected to immunohistochemistry and Western blotting. For drug combination studies, mice were treated with infigratinib and/or varlitinib. Gene overexpression and knockdown studies were conducted to investigate the relationship between EZH2 and ErbB activity in infigratinib resistance. RESULTS: Infigratinib-resistant tumours exhibited higher levels of p-ErbB2 and p-ErbB3, concomitant with an increase in EZH2 expression. Gene overexpression and knockdown studies revealed that EZH2 directly regulates the levels of p-ErbB2 and p-ErbB3 in acquired resistance to infigratinib. The addition of varlitinib effectively overcame infigratinib resistance and prolonged the antitumour response, with minimal toxicity. CONCLUSION: The upregulation of the ErbB family by EZH2 appears to contribute to infigratinib resistance. The combination of infigratinib and varlitinib showed a potent antitumour effect and did not result in additional toxicity, warranting further clinical investigation.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/farmacologia , Carcinoma Hepatocelular/tratamento farmacológico , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Proteína Potenciadora do Homólogo 2 de Zeste/metabolismo , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Receptor ErbB-2/metabolismo , Receptor Tipo 1 de Fator de Crescimento de Fibroblastos/antagonistas & inibidores , Animais , Anticorpos Monoclonais Humanizados/administração & dosagem , Apoptose , Biomarcadores Tumorais/genética , Biomarcadores Tumorais/metabolismo , Carcinoma Hepatocelular/metabolismo , Carcinoma Hepatocelular/patologia , Proliferação de Células , Proteína Potenciadora do Homólogo 2 de Zeste/genética , Humanos , Neoplasias Hepáticas/tratamento farmacológico , Neoplasias Hepáticas/metabolismo , Neoplasias Hepáticas/patologia , Masculino , Camundongos , Camundongos SCID , Compostos de Fenilureia/administração & dosagem , Inibidores de Proteínas Quinases/farmacologia , Pirimidinas/administração & dosagem , Receptor ErbB-2/genética , Células Tumorais Cultivadas , Ensaios Antitumorais Modelo de Xenoenxerto
17.
J Int Med Res ; 49(6): 300060521999552, 2021 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-34162268

RESUMO

OBJECTIVE: To investigate the clinical significance of cyclin-dependent kinase (CDK) 15 in breast cancer. METHODS: This prospective observational study enrolled 154 patients with breast cancer. Tumor tissues and paired paracancerous normal tissues were collected. Additionally, 85 samples of benign breast lesions were obtained from patients with mammary gland hyperplasia. Patient characteristics were recorded, and CDK15, human epidermal growth factor receptor (HER)2, estrogen receptor, progesterone receptor, and Ki67 immunohistochemical expression were determined. RESULTS: The rate of strong CDK15 expression was 63.6% (98/154) in breast cancer tissues, which was remarkably higher than that in benign breast lesions (34.1%, 29/85). Similarly, the ratio of strong CDK15 expression was markedly higher in tumor tissues (63.6%, 98/15) than in paracancerous normal tissues (27.3%, 42/154). Pearson's analysis showed that the CDK15 expression score was positively correlated with HER2 and Ki67. Patients with high CDK15 expression showed markedly higher ratios of TNM stage III to IV, lymph node metastasis, and increased tumor diameters but a significantly lower rate of ductal carcinoma in situ. The median survival time of these patients was significantly shorter. Kaplan-Meier curve analysis showed that low CDK15 expression predicted longer survival times. CONCLUSION: Upregulated CDK15 predicted poor clinical outcomes in breast cancer.


Assuntos
Neoplasias da Mama , Quinases Ciclina-Dependentes/genética , Biomarcadores Tumorais/genética , Neoplasias da Mama/diagnóstico , Neoplasias da Mama/genética , Neoplasias da Mama/patologia , Feminino , Humanos , Estadiamento de Neoplasias , Prognóstico , Receptor ErbB-2/genética , Receptor ErbB-2/metabolismo , Receptores de Estrogênio/metabolismo , Receptores de Progesterona/genética , Receptores de Progesterona/metabolismo , Regulação para Cima
18.
Life Sci ; 280: 119760, 2021 Sep 01.
Artigo em Inglês | MEDLINE | ID: mdl-34166713

RESUMO

Cardiotoxicity is a major side effect of the chemotherapeutic drug doxorubicin (Dox), which is further exacerbated when it is combined with trastuzumab, a standard care approach for Human Epidermal growth factor Receptor-type 2 (HER2) positive cancer patients. However, the molecular mechanisms of the underlying cardiotoxicity of this combination are still mostly elusive. Increased oxidative stress, impaired energetic substrate uses and topoisomerase IIB inhibition are among the biological processes proposed to explain Dox-induced cardiomyocyte dysfunction. Since cardiomyocytes express HER2, trastuzumab can also damage these cells by interfering with neuroregulin-1 signaling and mitogen-activated protein kinase (MAPK), phosphoinositide 3-kinase (PI3K)/Akt and focal adhesion kinase (FAK)-dependent pathways. Nevertheless, Dox and trastuzumab target other cardiac cell types, such as endothelial cells, fibroblasts, cardiac progenitor cells and leukocytes, which can contribute to the clinical cardiotoxicity observed. This review aims to summarize the current knowledge on the cardiac signaling pathways modulated by these two antineoplastic drugs highly used in the management of breast cancer, not only focusing on cardiomyocytes but also to broaden the knowledge of the potential impact on other cells found in the heart.


Assuntos
Antineoplásicos/efeitos adversos , Cardiotoxicidade/etiologia , Doxorrubicina/efeitos adversos , Trastuzumab/efeitos adversos , Animais , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Cardiotoxicidade/metabolismo , Cardiotoxicidade/patologia , Humanos , Miócitos Cardíacos/efeitos dos fármacos , Miócitos Cardíacos/metabolismo , Miócitos Cardíacos/patologia , Neoplasias/tratamento farmacológico , Neoplasias/metabolismo , Neoplasias/patologia , Neuregulina-1/metabolismo , Estresse Oxidativo/efeitos dos fármacos , Receptor ErbB-2/metabolismo , Transdução de Sinais/efeitos dos fármacos
19.
Nat Commun ; 12(1): 3528, 2021 06 10.
Artigo em Inglês | MEDLINE | ID: mdl-34112795

RESUMO

Breast tumors generally consist of a diverse population of cells with varying gene expression profiles. Breast tumor heterogeneity is a major factor contributing to drug resistance, recurrence, and metastasis after chemotherapy. Antibody-drug conjugates (ADCs) are emerging chemotherapeutic agents with striking clinical success, including T-DM1 for HER2-positive breast cancer. However, these ADCs often suffer from issues associated with intratumor heterogeneity. Here, we show that homogeneous ADCs containing two distinct payloads are a promising drug class for addressing this clinical challenge. Our conjugates show HER2-specific cell killing potency, desirable pharmacokinetic profiles, minimal inflammatory response, and marginal toxicity at therapeutic doses. Notably, a dual-drug ADC exerts greater treatment effect and survival benefit than does co-administration of two single-drug variants in xenograft mouse models representing intratumor HER2 heterogeneity and elevated drug resistance. Our findings highlight the therapeutic potential of the dual-drug ADC format for treating refractory breast cancer and perhaps other cancers.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/farmacologia , Neoplasias da Mama/tratamento farmacológico , Imunoconjugados/farmacologia , Receptor ErbB-2/imunologia , Animais , Antineoplásicos/farmacologia , Neoplasias da Mama/complicações , Linhagem Celular Tumoral , Feminino , Humanos , Imunoconjugados/farmacocinética , Imunoconjugados/uso terapêutico , Imunoconjugados/toxicidade , Imuno-Histoquímica , Inflamação/complicações , Camundongos , Oligopeptídeos/farmacologia , Oligopeptídeos/uso terapêutico , Receptor ErbB-2/metabolismo , Trastuzumab/farmacologia , Trastuzumab/uso terapêutico , Ensaios Antitumorais Modelo de Xenoenxerto
20.
Anticancer Res ; 41(6): 3099-3107, 2021 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-34083303

RESUMO

BACKGROUND/AIM: To determine the prognostic utility of trastuzumab-based chemotherapy based on human epidermal growth factor receptor 2 (HER2) expression in patients with para-aortic lymph node (PAN) metastasis from gastric cancer. PATIENTS AND METHODS: A total of 41 patients with clinical PAN metastasis from gastric cancer who underwent chemotherapy were retrospectively enrolled. RESULTS: Eighteen (43.9%) patients had HER2-positive tumors and consequently, received trastuzumab-based chemotherapy. A total of 11 patients underwent surgery. HER2 status was significantly correlated with the number of distant metastatic sites, the presence or absence of trastuzumab-based chemotherapy, and the presence or absence of gastrectomy. HER2-positive patients had significantly better prognosis than HER2-negative patients. Multivariate analysis identified age and trastuzumab-based chemotherapy based on HER2 status as an independent prognostic factor. CONCLUSION: Assessing HER2 expression and subsequent trastuzumab-based chemotherapy can be an effective method for determining the prognosis of patients with PAN metastasis from gastric cancer.


Assuntos
Aorta/patologia , Metástase Linfática , Receptor ErbB-2/metabolismo , Neoplasias Gástricas/patologia , Feminino , Humanos , Masculino , Prognóstico , Neoplasias Gástricas/metabolismo
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