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1.
Aging (Albany NY) ; 11(9): 2874-2888, 2019 May 09.
Artigo em Inglês | MEDLINE | ID: mdl-31076561

RESUMO

Certain dietary interventions might improve the therapeutic index of cancer treatments. An alternative to the "drug plus diet" approach is the pharmacological reproduction of the metabolic traits of such diets. Here we explored the impact of adding metformin to an established therapeutic regimen on the systemic host metabolism of cancer patients. A panel of 11 serum metabolites including markers of mitochondrial function and intermediates/products of folate-dependent one-carbon metabolism were measured in paired baseline and post-treatment sera obtained from HER2-positive breast cancer patients randomized to receive either metformin combined with neoadjuvant chemotherapy and trastuzumab or an equivalent regimen without metformin. Metabolite profiles revealed a significant increase of the ketone body ß-hydroxybutyrate and of the TCA intermediate α-ketoglutarate in the metformin-containing arm. A significant relationship was found between the follow-up levels of homocysteine and the ability of treatment arms to achieve a pathological complete response (pCR). In the metformin-containing arm, patients with significant elevations of homocysteine tended to have a higher probability of pCR. The addition of metformin to an established anti-cancer therapeutic regimen causes a fasting-mimicking modification of systemic host metabolism. Circulating homocysteine could be explored as a clinical pharmacodynamic biomarker linking the antifolate-like activity of metformin and biological tumor response.

2.
Oncotarget ; 9(86): 35687-35704, 2018 Nov 02.
Artigo em Inglês | MEDLINE | ID: mdl-30479698

RESUMO

The METTEN study assessed the efficacy, tolerability, and safety of adding metformin to neoadjuvant chemotherapy plus trastuzumab in early HER2-positive breast cancer (BC). Women with primary, non-metastatic HER2-positive BC were randomized (1:1) to receive metformin (850 mg twice-daily) for 24 weeks concurrently with 12 cycles of weekly paclitaxel plus trastuzumab, followed by four cycles of 3-weekly FE75C plus trastuzumab (arm A), or equivalent regimen without metformin (arm B), followed by surgery. Primary endpoint was the rate of pathological complete response (pCR) in the per-protocol efficacy population. pCR rate was numerically higher in the metformin-containing arm A (19 of 29 patients [65.5%, 95% CI: 47.3-80.1]) than in arm B (17 of 29 patients [58.6%, 95% CI: 40.7-74.5]; OR 1.34 [95% CI: 0.46-3.89], P = 0.589). The rate of breast-conserving surgery was 79.3% and 58.6% in arm A and B (P = 0.089), respectively. Blood metformin concentrations (6.2 µmol/L, 95% CI: 3.6-8.8) were within the therapeutic range. Seventy-six percent of patients completed the metformin-containing regimen; 13% of patients in arm A dropped out because of metformin-related gastrointestinal symptoms. The most common adverse events (AEs) of grade ≥3 were neutropenia in both arms and diarrhea in arm A. None of the serious AEs was deemed to be metformin-related. Addition of anti-diabetic doses of metformin to a complex neoadjuvant regimen was well tolerated and safe. Because the study was underpowered relative to its primary endpoint, the efficacy data should be interpreted with caution.

3.
Oncotarget ; 6(32): 32317-38, 2015 Oct 20.
Artigo em Inglês | MEDLINE | ID: mdl-26474458

RESUMO

Clinically HER2+ (cHER2+) breast cancer (BC) can no longer be considered a single BC disease entity in terms of trastuzumab responsiveness. Here we propose a framework for predicting the response of cHER2+ to trastuzumab that integrates the molecular distinctions of intrinsic BC subtypes with recent knowledge on cancer stem cell (CSC) biology. First, we consider that two interchangeable populations of epithelial-like, aldehyde dehydrogenase (ALDH)-expressing and mesenchymal-like, CD44+CD24-/low CSCs can be found in significantly different proportions across all intrinsic BC subtypes. Second, we overlap all the intrinsic subtypes across cHER2+ BC to obtain a continuum of mixed phenotypes in which one extreme exhibits a high identity with ALDH+ CSCs and the other extreme exhibits a high preponderance of CD44+CD24-/low CSCs. The differential enrichment of trastuzumab-responsive ALDH+ CSCs versus trastuzumab-refractory CD44+CD24-/low CSCs can explain both the clinical behavior and the primary efficacy of trastuzumab in each molecular subtype of cHER2+ (i.e., HER2-enriched/cHER2+, luminal A/cHER2+, luminal B/cHER2+, basal/cHER2+, and claudin-low/cHER2+). The intrinsic plasticity determining the epigenetic ability of cHER2+ tumors to switch between epithelial and mesenchymal CSC states will vary across the continuum of mixed phenotypes, thus dictating their intratumoral heterogeneity and, hence, their evolutionary response to trastuzumab. Because CD44+CD24-/low mesenchymal-like CSCs distinctively possess a highly endocytic activity, the otherwise irrelevant HER2 can open the door to a type of "Trojan horse" approach by employing antibody-drug conjugates such as T-DM1, which will allow a rapid and CSC-targeted delivery of cytotoxic drugs to therapeutically manage trastuzumab-unresponsive basal/cHER2+ BC. Contrary to the current dichotomous model used clinically, our model proposes that a reclassification of cHER2+ tumors based on the spectrum of molecular BC subtypes might inform on their CSC-determined sensitivity to trastuzumab, thus providing a better delineation of the predictive value of cHER2+ in BC by incorporating CSCs-driven intra-tumor heterogeneity into clinical decisions.


Assuntos
Neoplasias da Mama/tratamento farmacológico , Células-Tronco Neoplásicas/efeitos dos fármacos , Receptor ErbB-2/antagonistas & inibidores , Trastuzumab/uso terapêutico , Aldeído Desidrogenase/metabolismo , Antineoplásicos/imunologia , Antineoplásicos/uso terapêutico , Neoplasias da Mama/classificação , Neoplasias da Mama/metabolismo , Epigênese Genética , Transição Epitelial-Mesenquimal/efeitos dos fármacos , Transição Epitelial-Mesenquimal/genética , Feminino , Humanos , Receptores de Hialuronatos/metabolismo , Modelos Biológicos , Células-Tronco Neoplásicas/metabolismo , Fenótipo , Receptor ErbB-2/imunologia , Receptor ErbB-2/metabolismo , Trastuzumab/imunologia , Resultado do Tratamento
4.
Oncotarget ; 6(9): 7104-22, 2015 Mar 30.
Artigo em Inglês | MEDLINE | ID: mdl-25742793

RESUMO

There is an urgent need to refine the prognostic taxonomy of HER2+ breast carcinomas and develop easy-to-use, clinic-based prediction algorithms to distinguish between good- and poor- responders to trastuzumab-based therapy. Building on earlier studies suggesting that HER2+ tumors enriched with molecular and morpho-immunohistochemical features classically ascribed to basal-like tumors are highly aggressive and refractory to trastuzumab, we investigated the prognostic and predictive value of the basal-HER2+ phenotype in HER2-overexpressing tumors. Our retrospective cohort study of a consecutive series of 152 HER2+ primary invasive ductal breast carcinomas first confirmed the existence of a distinct subgroup co-expressing HER2 protein and basal cytokeratin markers CK5/6, the so-called basal-HER2+ phenotype. Basal-HER2+ phenotype (≥10% of cells showing positive CK5/6 staining), but not estrogen receptor status, was significantly associated with inferior overall survival by univariate analysis and predicted worsened disease free survival after accounting for strong prognostic variables such as tumor size at diagnosis in stepwise multivariate analysis. In the sub-cohort of HER2+ patients treated with trastuzumab-based adjuvant/neoadjuvant therapy, basal-HER2+ phenotype was found to be the sole independent prognostic marker for a significantly inferior time to treatment failure in multivariate analysis. A CK5/6-based immunohistochemical fingerprint may provide a simple, rapid, and accurate method for re-classifying women diagnosed with HER2+ breast cancer in a manner that can improve prognosis and therapeutic planning in patients with clinically aggressive basal-HER2+ tumors who are not likely to benefit from trastuzumab-based therapy.


Assuntos
Neoplasias da Mama/metabolismo , Carcinoma Ductal de Mama/metabolismo , Resistencia a Medicamentos Antineoplásicos , Queratina-5/metabolismo , Queratina-6/metabolismo , Receptor ErbB-2/metabolismo , Trastuzumab/química , Adulto , Idoso , Algoritmos , Neoplasias da Mama/tratamento farmacológico , Carcinoma Ductal de Mama/tratamento farmacológico , Intervalo Livre de Doença , Feminino , Humanos , Imunofenotipagem , Estimativa de Kaplan-Meier , Pessoa de Meia-Idade , Fenótipo , Valor Preditivo dos Testes , Prognóstico , Estudos Prospectivos , Estudos Retrospectivos , Resultado do Tratamento
5.
Menopause ; 21(2): 188-91, 2014 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-23982110

RESUMO

OBJECTIVE: Overexpression of fatty acid synthase (FASN), the enzyme involved in the de novo synthesis of fatty acids, has been reported in several human carcinomas, including breast cancer, and has been related to poor prognosis. Our aim was to analyze the association of FASN tumor tissue expression with clinicopathological and anthropometrical features in early-stage breast cancer patients. METHODS: We prospectively studied 53 women with early-stage breast cancer who were treated with surgical operation and postoperative chemotherapy. RESULTS: Menopause status and age were strongly associated with higher levels of FASN tumor expression (P < 0.005 and P = 0.038, respectively). Body mass index and pathological stage were also related to FASN tumor expression. CONCLUSIONS: Our findings suggest that FASN could be a potential therapeutic target in postmenopausal breast cancer patients. However, further studies are needed.


Assuntos
Neoplasias da Mama/enzimologia , Ácido Graxo Sintase Tipo I/genética , Menopausa/genética , Adulto , Idoso , Distribuição da Gordura Corporal , Índice de Massa Corporal , Neoplasias da Mama/patologia , Neoplasias da Mama/cirurgia , Quimioterapia Adjuvante , Estudos Transversais , Feminino , Expressão Gênica , Humanos , Pessoa de Meia-Idade , Obesidade/enzimologia , Prognóstico , Estudos Prospectivos , Espanha
6.
Oncotarget ; 4(9): 1484-95, 2013 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-23986086

RESUMO

Cancer cells expressing constitutively active phosphatidylinositol-3 kinase (PI3K) are proliferative regardless of the absence of insulin, and they form dietary restriction (DR)-resistant tumors in vivo. Because the binding of insulin to its receptors activates the PI3K/AKT/mammalian target of rapamycin (mTOR) signaling cascade, activating mutations in the PIK3CA oncogene may determine tumor response to DR-like pharmacological strategies targeting the insulin and mTOR pathways. The anti-diabetic drug metformin is a stereotypical DR mimetic that exerts its anti-cancer activity through a dual mechanism involving insulin-related (systemic) and mTOR-related (cell-autonomous) effects. However, it remains unclear whether PIK3CA-activating mutations might preclude the anti-cancer activity of metformin in vivo. To model the oncogenic PIK3CA-driven early stages of cancer, we used the clonal breast cancer cell line MCF10DCIS.com, which harbors the gain-of-function H1047R hot-spot mutation in the catalytic domain of the PI3KCA gene and has been shown to form DR-refractory xenotumors. To model PIK3CA-activating mutations in late stages of cancer, we took advantage of the isogenic conversion of a PIK3CA-wild-type tumor into a PIK3CA H1047R-mutated tumor using the highly metastatic colorectal cancer cell line SW48. MCF10DCIS.com xenotumors, although only modestly affected by treatment with oral metformin (approximately 40% tumor growth inhibition), were highly sensitive to the intraperitoneal (i.p.) administration of metformin, the anti-cancer activity of which increased in a time-dependent manner and reached >80% tumor growth inhibition by the end of the treatment. Metformin treatment via the i.p. route significantly reduced the proliferation factor mitotic activity index (MAI) and decreased tumor cellularity in MCF10DCIS.com cancer tissues. Whereas SW48-wild-type (PIK3CA+/+) cells rapidly formed metformin-refractory xenotumors in mice, ad libitum access to water containing metformin significantly reduced the growth of SW48-mutated (PIK3CAH1047R/+) xenotumors by approximately 50%. Thus, metformin can no longer be considered as a bona fide DR mimetic, at least in terms of anti-cancer activity, because tumors harboring the insulin-unresponsive, DR-resistant, PIK3CA-activating mutation H1047R remain sensitive to the anti-tumoral effects of the drug. Given the high prevalence of PIK3CA mutations in human carcinomas and the emerging role of PIK3CA mutation status in the treatment selection process, these findings might have a significant impact on the design of future trials evaluating the potential of combining metformin with targeted therapy.


Assuntos
Neoplasias da Mama/tratamento farmacológico , Neoplasias da Mama/genética , Metformina/farmacologia , Fosfatidilinositol 3-Quinases/genética , Animais , Neoplasias da Mama/enzimologia , Neoplasias da Mama/patologia , Processos de Crescimento Celular/efeitos dos fármacos , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , Classe I de Fosfatidilinositol 3-Quinases , Dieta , Feminino , Humanos , Camundongos , Camundongos Nus , Fosfatidilinositol 3-Quinases/metabolismo , Distribuição Aleatória , Transdução de Sinais , Serina-Treonina Quinases TOR/metabolismo , Ensaios Antitumorais Modelo de Xenoenxerto
7.
Oncotarget ; 3(4): 395-8, 2012 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-22565037

RESUMO

Trastuzumab-refractory breast cancer stem cells (CSCs) could also explain the high rate of primary resistance to single-agent trastuzumab in HER2 gene-amplified breast cancer patients. The identification of agents with strong selective toxicity for trastuzumab-resistant breast CSCs may have tremendous relevance for how HER2+ breast cancer patients should be treated. Using the human breast cancer cell line JIMT-1, which was established from the pleural metastasis of a patient who was clinically resistant to trastuzumab ab initio, we examined whether preferential killing of the putative CD44+CD24-/low breast CSC population might be sufficient to overcome primary resistance to trastuzumab in vivo. Because recent studies have shown that the anti-diabetic biguanide metformin can exert antitumor effects by targeted killing of CSC-like cells, we explored whether metformin's ability to preferentially kill breast cancer initiating CD44+CD24-/low cells may have the potential to sensitize JIMT-1 xenograft mouse models to trastuzumab. Upon isolation for breast cancer initiating CD44+CD24-/low cells by employing magnetic activated cell sorting, we observed the kinetics of metformin-induced killing drastically varied among CSC and non-CSC subpopulations. Metformin's cell killing effect increased dramatically by more than 10-fold in CD44+CD24-/low breast CSC cells compared to non-CD44+CD24-/low immunophenotypes. While seven-weeks treatment length with trastuzumab likewise failed to reduce tumor growth of JIMT-1 xenografts, systemic treatment with metformin as single agent resulted in a significant two-fold reduction in tumor volume. When trastuzumab was combined with concurrent metformin, tumor volume decreased sharply by more than four-fold. Given that metformin-induced preferential killing of breast cancer initiating CD44+CD24-/low subpopulations is sufficient to overcome in vivo primary resistance to trastuzumab, the incorporation of metformin into trastuzumab-based regimens may provide a valuable strategy for treatment of HER2+ breast cancer patients.


Assuntos
Anticorpos Monoclonais Humanizados/uso terapêutico , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Neoplasias da Mama/tratamento farmacológico , Metformina/uso terapêutico , Células-Tronco Neoplásicas/metabolismo , Animais , Anticorpos Monoclonais Humanizados/administração & dosagem , Anticorpos Monoclonais Humanizados/efeitos adversos , Neoplasias da Mama/metabolismo , Neoplasias da Mama/patologia , Antígeno CD24/metabolismo , Linhagem Celular Tumoral , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Feminino , Humanos , Receptores de Hialuronatos/metabolismo , Metformina/administração & dosagem , Metformina/efeitos adversos , Camundongos , Camundongos Nus , Células-Tronco Neoplásicas/efeitos dos fármacos , Células-Tronco Neoplásicas/patologia , Receptor ErbB-2/metabolismo , Trastuzumab , Carga Tumoral/efeitos dos fármacos , Ensaios Antitumorais Modelo de Xenoenxerto
8.
J Clin Oncol ; 23(34): 8717-23, 2005 Dec 01.
Artigo em Inglês | MEDLINE | ID: mdl-16260698

RESUMO

PURPOSE: To assess the efficacy of a risk-adapted treatment policy for patients with stage I seminoma by using universally accepted risk criteria. PATIENTS AND METHODS: Between 1999 and 2003, 314 patients with clinical stage I seminoma after orchiectomy were prospectively included. One hundred patients (31.8%) presented no risk factors and were managed with surveillance. In contrast, 131 patients (41.7%) had tumors larger than 4 cm, 33 patients (10.5%) had rete testis involvement, and 50 patients (15.9%) had both risk factors. All the latter received two courses of adjuvant carboplatin. RESULTS: Chemotherapy was well tolerated, as only 17 patients (7.9%) presented grade 3 to 4 toxicity. Relapses were observed in six patients (6.0%) on surveillance and in seven patients (3.3%) treated with carboplatin (0.8% of tumors larger than 4 cm, 9.1% of those involving the rete testis, and 6.0% of patients with both risk criteria). All were located at the retroperitoneum, except for one at the spermatic cord. Median tumor size was 25 mm (range, 11 to 70 mm), and median time to relapse was 9 months (range, 4 to 28 months). All patients were rendered disease-free with chemotherapy (etoposide plus cisplatin). Median follow-up was 34 months (range, 12 to 72 months). The actuarial 5-year disease-free survival rate was 93.4% for patients on surveillance and 96.2% for patients treated with adjuvant chemotherapy. Overall 5-year survival was 100%. CONCLUSION: Adjuvant carboplatin is effective in reducing the relapse rate in patients with stage I seminoma and risk factors. A risk-adapted strategy is safe and feasible and should be considered an alternative to systematic approaches, such as irradiation, chemotherapy, or surveillance.


Assuntos
Antineoplásicos/uso terapêutico , Carboplatina/uso terapêutico , Seminoma/tratamento farmacológico , Neoplasias Testiculares/tratamento farmacológico , Adolescente , Adulto , Fatores Etários , Idoso , Antineoplásicos/efeitos adversos , Carboplatina/efeitos adversos , Quimioterapia Adjuvante , Gonadotropina Coriônica Humana Subunidade beta/sangue , Intervalo Livre de Doença , Seguimentos , Humanos , Masculino , Pessoa de Meia-Idade , Análise Multivariada , Recidiva Local de Neoplasia/prevenção & controle , Estadiamento de Neoplasias , Neutropenia/induzido quimicamente , Orquiectomia , Estudos Prospectivos , Fatores de Risco , Seminoma/patologia , Seminoma/cirurgia , Neoplasias Testiculares/patologia , Neoplasias Testiculares/cirurgia , Resultado do Tratamento , Vômito/induzido quimicamente
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