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Nat Commun ; 12(1): 5006, 2021 08 18.
Artigo em Inglês | MEDLINE | ID: mdl-34408135


Obesity is a strong risk factor for cancer progression, posing obesity-related cancer as one of the leading causes of death. Nevertheless, the molecular mechanisms that endow cancer cells with metastatic properties in patients affected by obesity remain unexplored.Here, we show that IL-6 and HGF, secreted by tumor neighboring visceral adipose stromal cells (V-ASCs), expand the metastatic colorectal (CR) cancer cell compartment (CD44v6 + ), which in turn secretes neurotrophins such as NGF and NT-3, and recruits adipose stem cells within tumor mass. Visceral adipose-derived factors promote vasculogenesis and the onset of metastatic dissemination by activation of STAT3, which inhibits miR-200a and enhances ZEB2 expression, effectively reprogramming CRC cells into a highly metastatic phenotype. Notably, obesity-associated tumor microenvironment provokes a transition in the transcriptomic expression profile of cells derived from the epithelial consensus molecular subtype (CMS2) CRC patients towards a mesenchymal subtype (CMS4). STAT3 pathway inhibition reduces ZEB2 expression and abrogates the metastatic growth sustained by adipose-released proteins. Together, our data suggest that targeting adipose factors in colorectal cancer patients with obesity may represent a therapeutic strategy for preventing metastatic disease.

Tecido Adiposo/citologia , Reprogramação Celular , Neoplasias do Colo/fisiopatologia , Células-Tronco Neoplásicas/citologia , Nicho de Células-Tronco , Tecido Adiposo/metabolismo , Animais , Neoplasias do Colo/genética , Neoplasias do Colo/metabolismo , Neoplasias do Colo/patologia , Fator de Crescimento de Hepatócito/genética , Fator de Crescimento de Hepatócito/metabolismo , Humanos , Interleucina-6/genética , Interleucina-6/metabolismo , Masculino , Camundongos , Camundongos SCID , MicroRNAs/genética , MicroRNAs/metabolismo , Metástase Neoplásica , Células-Tronco/citologia , Células-Tronco/metabolismo , Homeobox 2 de Ligação a E-box com Dedos de Zinco/genética , Homeobox 2 de Ligação a E-box com Dedos de Zinco/metabolismo
Crit Rev Oncol Hematol ; 162: 103334, 2021 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-33865994


The phosphatidylinositol 3-kinase (PI3K)/protein kinase B (AKT)/mammalian target of rapamycin (mTOR) signaling pathway is commonly deregulated in many human tumors, including breast cancer. Somatic mutations of the PI3K alpha catalytic subunit (PIK3CA) are the most common cause of pathway hyperactivation. Hence, several PI3K inhibitors have been investigated with one of them, alpelisib, recently approved for the treatment of endocrine sensitive, PIK3CA mutated, metastatic breast cancer. Unfortunately, all patients receiving a PI3K inhibitor eventually develop resistance to these compounds. Mechanisms of resistance include oncogenic PI3K alterations, pathway reactivation through upstream or downstream effectors and enhancement of parallel pro-survival pathways. We review the prognostic and predictive role of PI3K alterations in breast cancer, focusing on resistance to PI3K inhibitors and on biomarkers with potential clinical relevance. We also discuss combination strategies that may overcome resistance to PI3K inhibitors, thus increasing the efficacy of these drugs in breast cancer.

Neoplasias da Mama , Fosfatidilinositol 3-Quinase , Neoplasias da Mama/tratamento farmacológico , Neoplasias da Mama/genética , Feminino , Humanos , Mutação , Fosfatidilinositol 3-Quinases/genética , Inibidores de Proteínas Quinases/farmacologia , Inibidores de Proteínas Quinases/uso terapêutico , Serina-Treonina Quinases TOR
Clin Lung Cancer ; 22(4): e637-e641, 2021 07.
Artigo em Inglês | MEDLINE | ID: mdl-33642178


BACKGROUND: The deeper knowledge of non-small-cell lung cancer (NSCLC) biology and the discovery of driver molecular alterations have opened the era of precision medicine in lung oncology, thus significantly revolutionizing the diagnostic and therapeutic approach to NSCLC. In Italy, however, molecular assessment remains heterogeneous across the country, and numbers of patients accessing personalized treatments remain relatively low. Nationwide programs have demonstrated that the creation of consortia represent a successful strategy to increase the number of patients with a molecular classification. PATIENTS AND METHODS: The Alliance Against Cancer (ACC), a network of 25 Italian Research Institutes, has developed a targeted sequencing panel for the detection of genomic alterations in 182 genes in patients with a diagnosis of NSCLC (ACC lung panel). One thousand metastatic NSCLC patients will be enrolled onto a prospective trial designed to measure the sensitivity and specificity of the ACC lung panel as a tool for molecular screening compared to standard methods. RESULTS AND CONCLUSION: The ongoing trial is part of a nationwide strategy of ACC to develop infrastructures and improve competences to make the Italian research institutes independent for genomic profiling of cancer patients.

Am J Clin Oncol ; 44(3): 105-108, 2021 03 01.
Artigo em Inglês | MEDLINE | ID: mdl-33481372


OBJECTIVE: Eribulin mesylate (EM) is a fully synthetic macrocyclic ketone analogue of the marine natural product halichondrin. EM has been reported to be active in metastatic breast cancer. In this paper, we report efficacy and safety of data of EM in a retrospective, real-world series of patients with poor prognosis, hormone-refractory, or triple-negative metastatic breast cancer. MATERIALS AND METHODS: The analysis was carried out at 4 interrelated oncology centers. EM was delivered at the dose of 1.4 mg/m2 in 100 mL of normal saline over 2 to 5 minutes on days 1 and 8 every 21 days. EM was continued until disease progression or unacceptable toxicity. Side effects were reported every cycle as per standard clinical practice and graded according to NCI-CTCAE, version 4.0. Time-to-progression and overall survival were reported. RESULTS: In this series of 90 patients the overall response rate was 22%, and 21% and 23% in the hormonal-resistant group and the triple-negative one, respectively. Stable disease was recorded in 24%, 21%, and 27%, respectively, in the whole series, the hormonal-resistant group, and the triple-negative one, respectively. Time-to-progression was 3.5 months (range, 1 to 22 mo) in the whole series and 3.0 months (range, 1 to 14.7 mo) and 3.4 months (range, 2.2 to 16.2 mo) in the hormonal-resistant group and the triple-negative one, respectively. Overall survival reached a median of 11.4 months. CONCLUSIONS: This multicenter study, albeit retrospective, demonstrates the activity of this combination as third-line chemotherapy option in a challenging clinical setting such as triple-negative or hormone-resistant patients with breast cancer progressing after several lines of hormonal manipulations.

Antineoplásicos/uso terapêutico , Furanos/uso terapêutico , Cetonas/uso terapêutico , Neoplasias de Mama Triplo Negativas/tratamento farmacológico , Adulto , Idoso , Antineoplásicos/efeitos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Feminino , Furanos/administração & dosagem , Furanos/efeitos adversos , Humanos , Cetonas/administração & dosagem , Cetonas/efeitos adversos , Pessoa de Meia-Idade , Neoplasias Hormônio-Dependentes/tratamento farmacológico , Neoplasias Hormônio-Dependentes/mortalidade , Neoplasias Hormônio-Dependentes/patologia , Estudos Retrospectivos , Resultado do Tratamento , Neoplasias de Mama Triplo Negativas/mortalidade , Neoplasias de Mama Triplo Negativas/patologia
Genes (Basel) ; 10(9)2019 09 13.
Artigo em Inglês | MEDLINE | ID: mdl-31540307


Thyroid cancer comprises different clinical and histological entities. Whereas differentiated (DTCs) malignancies are sensitive to radioiodine therapy, anaplastic (ATCs) and medullary (MTCs) tumors do not uptake radioactive iodine and display aggressive features associated with a poor prognosis. Moreover, in a majority of DTCs, disease evolution leads to the progressive loss of iodine sensitivity. Hence, iodine-refractory DTCs, along with ATCs and MTCs, require alternative treatments reflective of their different tumor biology. In the last decade, the molecular mechanisms promoting thyroid cancer development and progression have been extensively studied. This has led to a better understanding of the genomic landscape, displayed by thyroid malignancies, and to the identification of novel therapeutic targets. Indeed, several pharmacological compounds have been developed for iodine-refractory tumors, with four multi-target tyrosine kinase inhibitors already available for DTCs (sorafenib and lenvatinib) and MTCs (cabozantib and vandetanib), and a plethora of drugs currently being evaluated in clinical trials. In this review, we will describe the genomic alterations and biological processes intertwined with thyroid cancer development, also providing a thorough overview of targeted drugs already tested or under investigation for these tumors. Furthermore, given the existing preclinical evidence, we will briefly discuss the potential role of immunotherapy as an additional therapeutic strategy for the treatment of thyroid cancer.

Neoplasias da Glândula Tireoide/metabolismo , Antineoplásicos/uso terapêutico , Humanos , Sistema de Sinalização das MAP Quinases , Inibidores de Proteínas Quinases/uso terapêutico , Receptores Proteína Tirosina Quinases/antagonistas & inibidores , Receptores Proteína Tirosina Quinases/genética , Receptores Proteína Tirosina Quinases/metabolismo , Neoplasias da Glândula Tireoide/tratamento farmacológico , Neoplasias da Glândula Tireoide/genética
Int J Mol Sci ; 20(13)2019 Jul 02.
Artigo em Inglês | MEDLINE | ID: mdl-31269742


The Insulin-like growth factor (IGF) axis is one of the best-established drivers of thyroid transformation, as thyroid cancer cells overexpress both IGF ligands and their receptors. Thyroid neoplasms encompass distinct clinical and biological entities as differentiated thyroid carcinomas (DTC)-comprising papillary (PTC) and follicular (FTC) tumors-respond to radioiodine therapy, while undifferentiated tumors-including poorly-differentiated (PDTC) or anaplastic thyroid carcinomas (ATCs)-are refractory to radioactive iodine and exhibit limited responses to chemotherapy. Thus, safe and effective treatments for the latter aggressive thyroid tumors are urgently needed. Despite a strong preclinical rationale for targeting the IGF axis in thyroid cancer, the results of the available clinical studies have been disappointing, possibly because of the crosstalk between IGF signaling and other pathways that may result in resistance to targeted agents aimed against individual components of these complex signaling networks. Based on these observations, the combinations between IGF-signaling inhibitors and other anti-tumor drugs, such as DNA damaging agents or kinase inhibitors, may represent a promising therapeutic strategy for undifferentiated thyroid carcinomas. In this review, we discuss the role of the IGF axis in thyroid tumorigenesis and also provide an update on the current knowledge of IGF-targeted combination therapies for thyroid cancer.

Carcinogênese/metabolismo , Transdução de Sinais , Somatomedinas/metabolismo , Neoplasias da Glândula Tireoide/metabolismo , Animais , Antineoplásicos/farmacologia , Antineoplásicos/uso terapêutico , Carcinogênese/efeitos dos fármacos , Carcinogênese/patologia , Humanos , Terapia de Alvo Molecular , Transdução de Sinais/efeitos dos fármacos , Neoplasias da Glândula Tireoide/tratamento farmacológico , Neoplasias da Glândula Tireoide/patologia