RESUMO
AMG 256 is a bi-specific, heteroimmunoglobulin molecule with an anti-PD-1 antibody domain and a single IL-21 mutein domain on the C-terminus. Nonclinical studies in cynomolgus monkeys revealed that AMG 256 administration led to the development of immunogenicity-mediated responses and indicated that the IL-21 mutein domain of AMG 256 could enhance the anti-drug antibody response directed toward the monoclonal antibody domain. Anti-AMG 256 IgE were also observed in cynomolgus monkeys. A first-in-human (FIH) study in patients with advanced solid tumors was designed with these risks in mind. AMG 256 elicited ADA in 28 of 33 subjects (84.8%). However, ADA responses were only robust and exposure-impacting at the 2 lowest doses. At mid to high doses, ADA responses remained low magnitude and all subjects maintained exposure, despite most subjects developing ADA. Limited drug-specific IgE were also observed during the FIH study. ADA responses were not associated with any type of adverse event. The AMG 256 program represents a unique case where nonclinical studies informed on the risk of immunogenicity in humans, due to the IL-21-driven nature of the response.
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Anticorpos Monoclonais , Interleucinas , Receptor de Morte Celular Programada 1 , Animais , Humanos , Macaca fascicularis , Imunoglobulina ERESUMO
INTRODUCTION: The coronavirus disease 2019 (COVID-19) pandemic has resulted in a widespread adoption of telehealth (phone and video consultations) in cancer care worldwide. The aim of this study was to determine patient satisfaction with telehealth consultations with their medical oncologist at a tertiary cancer centre in Sydney, Australia. METHODS: Patients who attended a routine telehealth appointment at the medical oncology outpatient clinic were recruited to complete a questionnaire containing 16 items, each on a 5-point Likert scale regarding satisfaction levels in various aspects of telehealth and their willingness to continue telehealth after the pandemic. Patients were also invited to provide suggestions for improvement. RESULTS: In total, 150 patients were invited to participate, and 103 valid questionnaires were returned. Median age was 63 years (range: 25-90), 49% of patients were male, 63% of patients had advanced cancer and 81% were on active treatment. In total, 95% of participants indicated that they were satisfied (score ≥4) with telehealth. 82% of participants preferred to continue telehealth consultations after the coronavirus disease 2019 pandemic, but ideally with a mix of telehealth and in-person consultations. Phone appointments (vs. video, p < 0.002), patients with advanced cancer (vs. early, p < 0.036) and pre-chemotherapy/immunotherapy/targeted therapy treatment reviews (vs. follow-up appointments, p < 0.001) were significantly associated with a willingness to continue telehealth. DISCUSSION: Patients were overwhelmingly satisfied with telehealth during the study period and were willing to continue telehealth for some appointments beyond the coronavirus disease 2019 pandemic. More research into the effectiveness, safety and implementation of telehealth to compliment traditional face-to-face services for patient-centred cancer care is required.
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Breast cancers are complex cellular ecosystems where heterotypic interactions play central roles in disease progression and response to therapy. However, our knowledge of their cellular composition and organization is limited. Here we present a single-cell and spatially resolved transcriptomics analysis of human breast cancers. We developed a single-cell method of intrinsic subtype classification (SCSubtype) to reveal recurrent neoplastic cell heterogeneity. Immunophenotyping using cellular indexing of transcriptomes and epitopes by sequencing (CITE-seq) provides high-resolution immune profiles, including new PD-L1/PD-L2+ macrophage populations associated with clinical outcome. Mesenchymal cells displayed diverse functions and cell-surface protein expression through differentiation within three major lineages. Stromal-immune niches were spatially organized in tumors, offering insights into antitumor immune regulation. Using single-cell signatures, we deconvoluted large breast cancer cohorts to stratify them into nine clusters, termed 'ecotypes', with unique cellular compositions and clinical outcomes. This study provides a comprehensive transcriptional atlas of the cellular architecture of breast cancer.
Assuntos
Neoplasias da Mama/genética , Neoplasias da Mama/patologia , Análise de Célula Única , Transcriptoma/genética , Linfócitos B/imunologia , Antígeno B7-H1/genética , Biomarcadores Tumorais/genética , Neoplasias da Mama/imunologia , Linfócitos T CD8-Positivos/imunologia , Células Endoteliais/metabolismo , Feminino , Regulação Neoplásica da Expressão Gênica/genética , Humanos , Macrófagos/citologia , Macrófagos/imunologia , Proteínas de Membrana/genética , Células Mieloides/imunologia , Células Mieloides/metabolismo , Análise de Sequência de RNA , Microambiente Tumoral , Proteínas Supressoras de Tumor/genéticaRESUMO
BACKGROUND: Particular breast cancer subtypes pose a clinical challenge due to limited targeted therapeutic options and/or poor responses to the existing targeted therapies. While cell lines provide useful pre-clinical models, patient-derived xenografts (PDX) and organoids (PDO) provide significant advantages, including maintenance of genetic and phenotypic heterogeneity, 3D architecture and for PDX, tumor-stroma interactions. In this study, we applied an integrated multi-omic approach across panels of breast cancer PDXs and PDOs in order to identify candidate therapeutic targets, with a major focus on specific FGFRs. METHODS: MS-based phosphoproteomics, RNAseq, WES and Western blotting were used to characterize aberrantly activated protein kinases and effects of specific FGFR inhibitors. PDX and PDO were treated with the selective tyrosine kinase inhibitors AZD4547 (FGFR1-3) and BLU9931 (FGFR4). FGFR4 expression in cancer tissue samples and PDOs was assessed by immunohistochemistry. METABRIC and TCGA datasets were interrogated to identify specific FGFR alterations and their association with breast cancer subtype and patient survival. RESULTS: Phosphoproteomic profiling across 18 triple-negative breast cancers (TNBC) and 1 luminal B PDX revealed considerable heterogeneity in kinase activation, but 1/3 of PDX exhibited enhanced phosphorylation of FGFR1, FGFR2 or FGFR4. One TNBC PDX with high FGFR2 activation was exquisitely sensitive to AZD4547. Integrated 'omic analysis revealed a novel FGFR2-SKI fusion that comprised the majority of FGFR2 joined to the C-terminal region of SKI containing the coiled-coil domains. High FGFR4 phosphorylation characterized a luminal B PDX model and treatment with BLU9931 significantly decreased tumor growth. Phosphoproteomic and transcriptomic analyses confirmed on-target action of the two anti-FGFR drugs and also revealed novel effects on the spliceosome, metabolism and extracellular matrix (AZD4547) and RIG-I-like and NOD-like receptor signaling (BLU9931). Interrogation of public datasets revealed FGFR2 amplification, fusion or mutation in TNBC and other breast cancer subtypes, while FGFR4 overexpression and amplification occurred in all breast cancer subtypes and were associated with poor prognosis. Characterization of a PDO panel identified a luminal A PDO with high FGFR4 expression that was sensitive to BLU9931 treatment, further highlighting FGFR4 as a potential therapeutic target. CONCLUSIONS: This work highlights how patient-derived models of human breast cancer provide powerful platforms for therapeutic target identification and analysis of drug action, and also the potential of specific FGFRs, including FGFR4, as targets for precision treatment.
Assuntos
Neoplasias da Mama/tratamento farmacológico , Modelos Biológicos , Inibidores de Proteínas Quinases/uso terapêutico , Receptores de Fatores de Crescimento de Fibroblastos/antagonistas & inibidores , Animais , Neoplasias da Mama/genética , Neoplasias da Mama/metabolismo , Neoplasias da Mama/patologia , Proteínas de Ligação a DNA/genética , Humanos , Camundongos , Terapia de Alvo Molecular , Mutação , Organoides/efeitos dos fármacos , Organoides/metabolismo , Fosforilação , Medicina de Precisão , Inibidores de Proteínas Quinases/farmacologia , Proteínas Proto-Oncogênicas/genética , Receptores de Fatores de Crescimento de Fibroblastos/genética , Receptores de Fatores de Crescimento de Fibroblastos/metabolismo , Neoplasias de Mama Triplo Negativas/tratamento farmacológico , Neoplasias de Mama Triplo Negativas/genética , Neoplasias de Mama Triplo Negativas/metabolismo , Neoplasias de Mama Triplo Negativas/patologia , Ensaios Antitumorais Modelo de XenoenxertoRESUMO
BACKGROUND: High throughput single-cell RNA sequencing (scRNA-Seq) has emerged as a powerful tool for exploring cellular heterogeneity among complex human cancers. scRNA-Seq studies using fresh human surgical tissue are logistically difficult, preclude histopathological triage of samples, and limit the ability to perform batch processing. This hindrance can often introduce technical biases when integrating patient datasets and increase experimental costs. Although tissue preservation methods have been previously explored to address such issues, it is yet to be examined on complex human tissues, such as solid cancers and on high throughput scRNA-Seq platforms. METHODS: Using the Chromium 10X platform, we sequenced a total of ~ 120,000 cells from fresh and cryopreserved replicates across three primary breast cancers, two primary prostate cancers and a cutaneous melanoma. We performed detailed analyses between cells from each condition to assess the effects of cryopreservation on cellular heterogeneity, cell quality, clustering and the identification of gene ontologies. In addition, we performed single-cell immunophenotyping using CITE-Seq on a single breast cancer sample cryopreserved as solid tissue fragments. RESULTS: Tumour heterogeneity identified from fresh tissues was largely conserved in cryopreserved replicates. We show that sequencing of single cells prepared from cryopreserved tissue fragments or from cryopreserved cell suspensions is comparable to sequenced cells prepared from fresh tissue, with cryopreserved cell suspensions displaying higher correlations with fresh tissue in gene expression. We showed that cryopreservation had minimal impacts on the results of downstream analyses such as biological pathway enrichment. For some tumours, cryopreservation modestly increased cell stress signatures compared to freshly analysed tissue. Further, we demonstrate the advantage of cryopreserving whole-cells for detecting cell-surface proteins using CITE-Seq, which is impossible using other preservation methods such as single nuclei-sequencing. CONCLUSIONS: We show that the viable cryopreservation of human cancers provides high-quality single-cells for multi-omics analysis. Our study guides new experimental designs for tissue biobanking for future clinical single-cell RNA sequencing studies.
Assuntos
Bancos de Espécimes Biológicos , Criopreservação , Genômica , Neoplasias/diagnóstico , Análise de Célula Única , Biomarcadores Tumorais , Criopreservação/métodos , Criopreservação/normas , Perfilação da Expressão Gênica/métodos , Regulação da Expressão Gênica , Genômica/métodos , Sequenciamento de Nucleotídeos em Larga Escala , Humanos , Imunofenotipagem , Neoplasias/etiologia , Especificidade de Órgãos/genética , Análise de Sequência de RNA/métodos , Transdução de Sinais , Análise de Célula Única/métodosRESUMO
PURPOSE: Fear of cancer recurrence (FCR) affects 50%-70% of cancer survivors. This multicenter, single-arm study sought to determine the participant-rated usefulness of an oncologist-delivered FCR intervention. METHODS: Women who completed treatment for early breast cancer (could be receiving endocrine therapy) with baseline FCR > 0 were invited to participate. FCR was measured using a validated 42-item FCR Inventory. The brief oncologist-delivered intervention entailed (1) FCR normalization; (2) provision of personalized prognostic information; (3) recurrence symptoms education, (4) advice on managing worry, and (5) referral to psycho-oncologist if FCR was high. FCR, depression, and anxiety were assessed preintervention (T0), at 1 week (T1), and 3 months (T2) postintervention. The primary outcome was participant-rated usefulness. Secondary outcomes included feasibility and efficacy. RESULTS: Five oncologists delivered the intervention to 61/255 women invited. Mean age was 58 ± 12 years. Mean time since breast cancer diagnosis was 2.5 ± 1.3 years. Forty-three women (71%) were on adjuvant endocrine therapy. Of 58 women who completed T1 assessment, 56 (97%) found the intervention to be useful. FCR severity decreased significantly at T1 (F = 18.5, effect size = 0.39, P < .0001) and T2 (F = 24, effect size = 0.68, P < .0001) compared with baseline. There were no changes in unmet need or depression or anxiety. Mean consultation length was 22 minutes (range, 7-47 minutes), and mean intervention length was 8 minutes (range, 2-20 minutes). The intervention was perceived as useful and feasible by oncologists. CONCLUSION: A brief oncologist-delivered intervention to address FCR is useful and feasible, and has preliminary efficacy in reducing FCR. Plans for a cluster randomized trial are underway.
Assuntos
Neoplasias da Mama , Sobreviventes de Câncer , Transtornos Fóbicos , Idoso , Neoplasias da Mama/terapia , Medo , Feminino , Humanos , Pessoa de Meia-Idade , Recidiva Local de NeoplasiaRESUMO
The role of the androgen receptor (AR) in estrogen receptor (ER)-α-positive breast cancer is controversial, constraining implementation of AR-directed therapies. Using a diverse, clinically relevant panel of cell-line and patient-derived models, we demonstrate that AR activation, not suppression, exerts potent antitumor activity in multiple disease contexts, including resistance to standard-of-care ER and CDK4/6 inhibitors. Notably, AR agonists combined with standard-of-care agents enhanced therapeutic responses. Mechanistically, agonist activation of AR altered the genomic distribution of ER and essential co-activators (p300, SRC-3), resulting in repression of ER-regulated cell cycle genes and upregulation of AR target genes, including known tumor suppressors. A gene signature of AR activity positively predicted disease survival in multiple clinical ER-positive breast cancer cohorts. These findings provide unambiguous evidence that AR has a tumor suppressor role in ER-positive breast cancer and support AR agonism as the optimal AR-directed treatment strategy, revealing a rational therapeutic opportunity.
Assuntos
Androgênios/farmacologia , Neoplasias da Mama/genética , Receptor alfa de Estrogênio/genética , Receptores Androgênicos/genética , Neoplasias da Mama/tratamento farmacológico , Neoplasias da Mama/patologia , Linhagem Celular Tumoral , Proliferação de Células/genética , Quinase 4 Dependente de Ciclina/antagonistas & inibidores , Quinase 4 Dependente de Ciclina/genética , Quinase 6 Dependente de Ciclina/antagonistas & inibidores , Quinase 6 Dependente de Ciclina/genética , Feminino , Humanos , Células MCF-7 , Coativador 3 de Receptor Nuclear/genética , Receptores Androgênicos/efeitos dos fármacos , Transdução de Sinais/efeitos dos fármacosRESUMO
BACKGROUND: Nivolumab has been associated with immune-related adverse events, including nephritis, with acute interstitial nephritis being the most commonly reported renal manifestation. CASE: We describe the first case to our knowledge of minimal change disease with nephrotic syndrome associated with the PD-1 checkpoint inhibitor, Nivolumab. Minimal change disease has been reported with other immune checkpoint inhibitors; however, this is the first reported case with Nivolumab. We report development of nephrotic syndrome with acute kidney injury in a 57-year-old man, 1 month after commencement of Nivolumab for metastatic squamous cell carcinoma of the tongue. Minimal change disease was confirmed by renal biopsy. Management with corticosteroids and cessation of Nivolumab failed to improve kidney function or nephrosis. CONCLUSION: This case adds to current literature identifying minimal change as an additional complication of immune checkpoint inhibitor-associated acute kidney injury. Given the increasing use of immune checkpoint inhibitors for a range of malignancies, nephrologists, oncologist and generalists should be aware of the spectrum of kidney pathologies associated with their use.
Assuntos
Autoimunidade/efeitos dos fármacos , Nefrose Lipoide/diagnóstico , Nivolumabe/efeitos adversos , Carcinoma de Células Escamosas de Cabeça e Pescoço/terapia , Neoplasias da Língua/terapia , Quimioterapia Adjuvante/efeitos adversos , Quimioterapia Adjuvante/métodos , Evolução Fatal , Humanos , Masculino , Pessoa de Meia-Idade , Nefrose Lipoide/induzido quimicamente , Nefrose Lipoide/imunologia , Cuidados Paliativos/métodos , Carcinoma de Células Escamosas de Cabeça e Pescoço/imunologia , Carcinoma de Células Escamosas de Cabeça e Pescoço/secundário , Neoplasias da Língua/imunologia , Neoplasias da Língua/patologiaRESUMO
The tumour stroma regulates nearly all stages of carcinogenesis. Stromal heterogeneity in human triple-negative breast cancers (TNBCs) remains poorly understood, limiting the development of stromal-targeted therapies. Single-cell RNA sequencing of five TNBCs revealed two cancer-associated fibroblast (CAF) and two perivascular-like (PVL) subpopulations. CAFs clustered into two states: the first with features of myofibroblasts and the second characterised by high expression of growth factors and immunomodulatory molecules. PVL cells clustered into two states consistent with a differentiated and immature phenotype. We showed that these stromal states have distinct morphologies, spatial relationships and functional properties in regulating the extracellular matrix. Using cell signalling predictions, we provide evidence that stromal-immune crosstalk acts via a diverse array of immunoregulatory molecules. Importantly, the investigation of gene signatures from inflammatory-CAFs and differentiated-PVL cells in independent TNBC patient cohorts revealed strong associations with cytotoxic T-cell dysfunction and exclusion, respectively. Such insights present promising candidates to further investigate for new therapeutic strategies in the treatment of TNBCs.
Assuntos
Neoplasias de Mama Triplo Negativas/imunologia , Evasão Tumoral , Matriz Extracelular/imunologia , Matriz Extracelular/patologia , Feminino , Humanos , RNA-Seq , Células Estromais/imunologia , Células Estromais/patologia , Linfócitos T Citotóxicos/imunologia , Linfócitos T Citotóxicos/patologia , Neoplasias de Mama Triplo Negativas/patologiaRESUMO
Formulated forms of cancer therapeutics enhance the efficacy of treatment by more precise targeting, increased bioavailability of drugs, and an aptitude of some delivery systems to overcome multiple drug resistance of tumors. Drug carriers acquire importance for anti-cancer interventions via targeting tumor-associated macrophages with active molecules capable to either eliminate them or change their polarity. Although several packaged drug forms have reached the market, there is still a high demand for novel carrier systems to hurdle limitations of existing drugs on active molecules, toxicity, bioeffect, and stability. Here, we report a facile assembly and delivery methodology for biodegradable polymeric multilayer capsules (PMC) with the purpose of further use in injectable drug formulations for lung cancer therapy via direct erosion of tumors and suppression of the tumor-promoting function of macrophages in the tumor microenvironment. We demonstrate delivery of low-molecular-weight drug molecules to lung cancer cells and macrophages and provide details on in vivo distribution, cellular uptake, and disintegration of the developed PMC. Poly-l-arginine and dextran sulfate alternately adsorb on a â¼500 nm CaCO3 sacrificial template followed by removal of the inorganic core to obtain hollow capsules for consequent loading with drug molecules, gemcitabine or clodronate. The capsules further compacted upon loading down to â¼250 nm in diameter via heat treatment. A comparative study of the capsule internalization rate in vitro and in vivo reveals the benefits of a diminished carrier size. We show that macrophages and epithelial cells of the lungs and liver internalize capsules with efficacy higher than 75%. Using an in vivo mouse model of lung cancer, we also confirm that tumor lungs better retain smaller capsules than the healthy lung tissue. The pronounced cytotoxic effect of the encapsulated gemcitabine on lung cancer cells and the ability of the encapsulated clodronate to block the tumor-promoting function of macrophages prove the efficacy of the developed capsule loading method in vitro. Our study taken as a whole demonstrates the great potential of the developed PMC for in vivo treatment of cancer via transporting active molecules, including those that are water-soluble with low molecular weight, to both cancer cells and macrophages through the bloodstream.
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Antineoplásicos , Composição de Medicamentos/métodos , Sistemas de Liberação de Medicamentos/métodos , Neoplasias Pulmonares/metabolismo , Animais , Antineoplásicos/química , Antineoplásicos/farmacocinética , Antineoplásicos/farmacologia , Cápsulas , Desoxicitidina/análogos & derivados , Desoxicitidina/química , Desoxicitidina/farmacocinética , Desoxicitidina/farmacologia , Macrófagos/metabolismo , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Polímeros/química , Polímeros/metabolismo , Distribuição Tecidual , GencitabinaRESUMO
Monitoring the condition of transformer oil is considered to be one of the preventive maintenance measures and it is very critical in ensuring the safety as well as optimal performance of the equipment. Various oil properties and contents in oil can be monitored such as acidity, furanic compounds and color. The current method is used to determine the color index (CI) of transformer oil produces an error of 0.5 in measurement, has high risk of human handling error, additional expense such as sampling and transportations, and limited samples can be measured per day due to safety and health reasons. Therefore, this work proposes the determination of CI of transformer oil using ultraviolet-to-visible (UV-Vis) spectroscopy. Results show a good correlation between the CI of transformer oil and the absorbance spectral responses of oils from 300 nm to 700 nm. Modeled equations were developed to relate the CI of the oil with the cutoff wavelength and absorbance, and with the area under the curve from 360 nm to 600 nm. These equations were verified with another set of oil samples. The equation that describes the relationship between cutoff wavelength, absorbance and CI of the oil shows higher accuracy with root mean square error (RMSE) of 0.1961.
RESUMO
The cellular and molecular basis of stromal cell recruitment, activation and crosstalk in carcinomas is poorly understood, limiting the development of targeted anti-stromal therapies. In mouse models of triple negative breast cancer (TNBC), Hedgehog ligand produced by neoplastic cells reprograms cancer-associated fibroblasts (CAFs) to provide a supportive niche for the acquisition of a chemo-resistant, cancer stem cell (CSC) phenotype via FGF5 expression and production of fibrillar collagen. Stromal treatment of patient-derived xenografts with smoothened inhibitors (SMOi) downregulates CSC markers expression and sensitizes tumors to docetaxel, leading to markedly improved survival and reduced metastatic burden. In the phase I clinical trial EDALINE, 3 of 12 patients with metastatic TNBC derived clinical benefit from combination therapy with the SMOi Sonidegib and docetaxel chemotherapy, with one patient experiencing a complete response. These studies identify Hedgehog signaling to CAFs as a novel mediator of CSC plasticity and an exciting new therapeutic target in TNBC.
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Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Células-Tronco Neoplásicas/efeitos dos fármacos , Neoplasias de Mama Triplo Negativas/tratamento farmacológico , Adulto , Idoso , Anilidas/administração & dosagem , Animais , Compostos de Bifenilo/administração & dosagem , Linhagem Celular Tumoral , Docetaxel/administração & dosagem , Feminino , Humanos , Camundongos Endogâmicos NOD , Camundongos Knockout , Camundongos SCID , Pessoa de Meia-Idade , Células-Tronco Neoplásicas/metabolismo , Piridinas/administração & dosagem , Resultado do Tratamento , Neoplasias de Mama Triplo Negativas/genética , Neoplasias de Mama Triplo Negativas/metabolismo , Ensaios Antitumorais Modelo de XenoenxertoRESUMO
Expansion of neoplastic lesions generates the initial signal that instigates the creation of a tumor niche. Nontransformed cell types within the microenvironment continuously coevolve with tumor cells to promote tumorigenesis. Here, we identify p38MAPK as a key component of human lung cancer, and specifically stromal interactomes, which provides an early, protumorigenic signal in the tissue microenvironment. We found that lung cancer growth depends on short-distance cues produced by the cancer niche in a p38-dependent manner. We identified fibroblast-specific hyaluronan synthesis at the center of p38-driven tumorigenesis, which regulates early stromal fibroblast activation, the conversion to carcinoma-associated fibroblasts (CAFs), and cancer cell proliferation. Systemic down-regulation of p38MAPK signaling in a knock-in model with substitution of activating Tyr182 to phenylalanine or conditional ablation of p38 in fibroblasts has a significant tumor-suppressive effect on K-ras lung tumorigenesis. Furthermore, both Kras-driven mouse lung tumors and orthotopically grown primary human lung cancers show a significant sensitivity to both a chemical p38 inhibitor and an over-the-counter inhibitor of hyaluronan synthesis. We propose that p38MAPK-hyaluronan-dependent reprogramming of the tumor microenvironment plays a critical role in driving lung tumorigenesis, while blocking this process could have far-reaching therapeutic implications.
Assuntos
Carcinogênese/genética , Carcinogênese/patologia , Ácido Hialurônico/metabolismo , Neoplasias Pulmonares/fisiopatologia , Microambiente Tumoral/genética , Proteínas Quinases p38 Ativadas por Mitógeno/genética , Proteínas Quinases p38 Ativadas por Mitógeno/metabolismo , Animais , Antineoplásicos/farmacologia , Proliferação de Células , Transformação Celular Neoplásica/efeitos dos fármacos , Transformação Celular Neoplásica/genética , Reprogramação Celular/genética , Modelos Animais de Doenças , Ativação Enzimática/efeitos dos fármacos , Fibroblastos , Regulação Neoplásica da Expressão Gênica , Técnicas de Introdução de Genes , Humanos , Camundongos , Inibidores de Proteínas Quinases/farmacologia , Transdução de Sinais/efeitos dos fármacos , Células Tumorais Cultivadas , Proteínas Quinases p38 Ativadas por Mitógeno/antagonistas & inibidoresRESUMO
Despite the progress achieved in breast cancer screening and therapeutic innovations, the basal-like subtype of breast cancer (BLBC) still represents a particular clinical challenge. In order to make an impact on survival in this type of aggressive breast cancer, new targeted therapeutic agents are urgently needed. Aberrant activation of the Hedgehog (Hh) signalling pathway has been unambiguously tied to cancer development and progression in a variety of solid malignancies, and the recent approval of vismodegib, an orally bioavailable small-molecule inhibitor of Smoothened, validates Hh signalling as a valuable therapeutic target. A number of recent publications have highlighted a role for Hh signalling in breast cancer models and clinical specimens. Interestingly, Hh ligand overexpression is associated with the BLBC phenotype and a poor outcome in terms of metastasis and breast cancer-related death. In this review, we provide a comprehensive overview of the canonical Hh signalling pathway in mammals, highlight its roles in mammary gland development and breast carcinogenesis and discuss its potential therapeutic value in BLBC.