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1.
Anticancer Res ; 40(4): 1943-1951, 2020 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-32234883

RESUMO

BACKGROUND/AIM: Targeted receptor tyrosine kinase inhibitor (TKI) is a standard treatment in advanced renal cell carcinoma (RCC). However, the role of PTEN in TKI resistance remains poorly understood. We aimed to determine the functional role of PTEN knockout and analyse the predictive significance of PTEN expression for TKI treatment in RCC. MATERIALS AND METHODS: We developed PTEN knockout cells in RCC cell lines using the CRISPR-Cas9 system and analysed the effect of PTEN knockout on spheroid formation and resistance to sunitinib and sorafenib. RESULTS: PTEN knockout promoted spheroid formation and decreased sunitinib/sorafenib sensitivity in RCC cell lines. PTEN immunohistochemistry in 74 metastatic RCCs treated with sunitinib and sorafenib revealed negative PTEN expression in 23% of samples. Kaplan-Meier analysis showed a significant association of negative PTEN expression with poor progression-free survival in metastatic RCC treated with sunitinib and sorafenib (p=0.024) or sunitinib alone (p=0.009). CONCLUSION: PTEN may be a biomarker and therapeutic target in patients with metastatic RCC.


Assuntos
Carcinoma de Células Renais/tratamento farmacológico , PTEN Fosfo-Hidrolase/genética , Sorafenibe/farmacologia , Sunitinibe/farmacologia , Biomarcadores Tumorais/genética , Sistemas CRISPR-Cas , Carcinoma de Células Renais/genética , Carcinoma de Células Renais/patologia , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Feminino , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Técnicas de Inativação de Genes , Humanos , Estimativa de Kaplan-Meier , Masculino , Intervalo Livre de Progressão , Inibidores de Proteínas Quinases/farmacologia , Esferoides Celulares/efeitos dos fármacos
2.
Crit Rev Oncol Hematol ; 149: 102921, 2020 May.
Artigo em Inglês | MEDLINE | ID: mdl-32172222

RESUMO

Patients diagnosed with non-clear renal cell carcinoma have often been excluded from clinical trials due to the shortage of treatments available, the low incidence of tumours with non-clear histology, and the corresponding diversity of intrinsic molecular features. This approach led to a knowledge gap in finding the optimal treatment for patients diagnosed with non-clear cell renal carcinoma. Cabozantinib, a potent multiple tyrosine kinase receptor inhibitor, has been recently investigated in patients with non-clear cell histologies of renal cell cancer. In this review, we have summarized available data on the use of cabozantinib in non-clear renal cell carcinoma.


Assuntos
Anilidas/uso terapêutico , Anticorpos Monoclonais/uso terapêutico , Antineoplásicos/uso terapêutico , Carcinoma de Células Renais/tratamento farmacológico , Neoplasias Renais/tratamento farmacológico , Piridinas/uso terapêutico , Intervalo Livre de Doença , Humanos , Inibidores de Proteínas Quinases
3.
Anticancer Res ; 40(3): 1527-1534, 2020 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-32132053

RESUMO

We report a case of rapid evolution of polycystic liver disease in a 76-year-old patient with metastatic renal cell carcinoma who underwent treatment with numerous antineoplastic agents. The aim was to identify a causative etiology for these hepatic cysts of unclear origin. The cystic lesions of the patient were ultimately innumerable and developed rapidly, more than tripling the total liver volume from complete absence over the course of 24 months. The hepatic lesions continued to grow despite an otherwise moderate tumor response. Prior to patient death, the patient remained relatively asymptomatic from the cyst burden and was without signs of grossly metastatic disease. This rapid development of polycystic liver disease most likely represents a previously unseen medication side-effect of cabozantinib or pazopanib. It is important to identify adverse effects of novel antineoplastic agents in this time of oncological medical discovery.


Assuntos
Carcinoma de Células Renais/complicações , Cistos/complicações , Neoplasias Renais/complicações , Hepatopatias/complicações , Idoso , Anilidas/administração & dosagem , Anilidas/efeitos adversos , Carcinoma de Células Renais/tratamento farmacológico , Carcinoma de Células Renais/patologia , Cistos/induzido quimicamente , Cistos/etiologia , Cistos/patologia , Humanos , Neoplasias Renais/tratamento farmacológico , Neoplasias Renais/patologia , Hepatopatias/etiologia , Hepatopatias/patologia , Masculino , Metástase Neoplásica , Piridinas/administração & dosagem , Piridinas/efeitos adversos , Pirimidinas/administração & dosagem , Pirimidinas/efeitos adversos , Sulfonamidas/administração & dosagem , Sulfonamidas/efeitos adversos
4.
Medicine (Baltimore) ; 99(13): e19570, 2020 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-32221075

RESUMO

To evaluate the safety and efficiency of sunitinib and sorafenib in the treatment of renal cell carcinoma (RCC).Databases were searched up till February 28, 2018. Two reviewers independently assessed trials for eligibility, quality, and extracted relevant data. Results are expressed as risk ratio (RR) or hazard ratio (HR) with 95% confidence intervals (CI). Six studies including 3112 patients were accessed. Sorafenib group exhibited higher median progression-free survival (mPFS) compared to sunitinib group (MD, -1.30; 95% CI, -2.56 to -0.03), especially in the first-line treatment (MD, -1.33; 95% CI, -2.61 to -0.04). However, sunitinib significantly reduced the risk of progression-free survival (PFS) compared to sorafenib (HR, 0.71; 95% CI, 0.6-0.82). Sunitinib also significantly reduced risk of overall survival (OS) compared to sorafenib (HR, 0.79; 95% CI, 0.65-0.92), while median OS was similar in both groups (MD, -0.48; 95% CI, -3.40-2.43). With regards to safety, the risk of rash (RR, 0.31, 95% CI, 0.12-0.79) was greater in sunitinib than sorafenib group, while the risk of decreased appetite (RR 2.10, 95% CI: 1.33-3.30) and dehydration (RR 2.73, 95% CI: 1.14-6.56) was smaller in contrast.Based on risk of PFS and OS, sunitinib was a better treatment option for RCC treatment while patients faced with severe skin reaction. And for those Asian patients classified under MSKCC moderate risk, whether in first or second-line treatment, had difficulty in feeding, sorafenib is a better choice for prolong mPFS.


Assuntos
Antineoplásicos/uso terapêutico , Carcinoma de Células Renais/tratamento farmacológico , Neoplasias Renais/tratamento farmacológico , Sorafenibe/uso terapêutico , Sunitinibe/uso terapêutico , Antineoplásicos/administração & dosagem , Antineoplásicos/efeitos adversos , Carcinoma de Células Renais/mortalidade , Carcinoma de Células Renais/patologia , Intervalo Livre de Doença , Humanos , Neoplasias Renais/mortalidade , Neoplasias Renais/patologia , Modelos de Riscos Proporcionais , Sorafenibe/administração & dosagem , Sorafenibe/efeitos adversos , Sunitinibe/administração & dosagem , Sunitinibe/efeitos adversos
5.
Urologe A ; 59(2): 155-161, 2020 Feb.
Artigo em Alemão | MEDLINE | ID: mdl-32006060

RESUMO

Current pivotal phase 3 studies have permanently changed the first-line treatment landscape in metastatic renal cell carcinoma. These studies showed that immune checkpoint combinations were more efficacious than sunitinib, a previous standard of care. Nivolumab plus ipilimumab is characterized by a survival advantage, a high rate of complete response and durable remission in patients with intermediate and unfavorable prognosis. Despite frequent immune-mediated side effects, fewer symptoms and a better quality of life were observed compared to sunitinib. Pembrolizumab or avelumab plus axitinib were characterized by an improved PFS and a high response rate with a low rate of intrinsic resistance. In addition, a significant survival benefit was achieved with pembrolizumab plus axitinib. The side effect profile is driven by the "chronic" toxicity of axitinib, but there is additional risk of immune-mediated side effects of the PD-1/PD-L1 immune checkpoint inhibitors. The quality-of-life data published so far do not suggest any improvement compared to the previous standard sunitinib. The PD-1/PD-L1 immune-check-point inhibitors thus form the "backbone" of the first-line therapy of metastatic renal cell carcinoma. Monotherapy with VEGFR-TKI remains an option in cases with contraindications and possibly for subgroups with favorable prognosis.


Assuntos
Antineoplásicos Imunológicos/farmacologia , Protocolos de Quimioterapia Combinada Antineoplásica/administração & dosagem , Carcinoma de Células Renais/tratamento farmacológico , Imunomodulação/efeitos dos fármacos , Neoplasias Renais/tratamento farmacológico , Metástase Neoplásica/tratamento farmacológico , Anticorpos Monoclonais/administração & dosagem , Antineoplásicos Imunológicos/uso terapêutico , Axitinibe/administração & dosagem , Carcinoma de Células Renais/imunologia , Carcinoma de Células Renais/patologia , Humanos , Ipilimumab/administração & dosagem , Neoplasias Renais/imunologia , Neoplasias Renais/patologia , Metástase Neoplásica/patologia , Nivolumabe/administração & dosagem , Qualidade de Vida , Sunitinibe/administração & dosagem , Resultado do Tratamento
6.
Cancer Treat Rev ; 84: 101966, 2020 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-32044644

RESUMO

Anti-angiogenic treatment is an important option that has changed the therapeutic landscape in various tumors, particularly in patients affected by renal cell carcinoma (RCC). Agents that block signaling pathways governing tumor angiogenesis have raised high expectations among clinicians. Vascular endothelial growth factor receptor-tyrosine kinase inhibitors (VEGFR-TKIs) comprise a heterogeneous class of drugs with distinct pharmacological profiles, including potency, selectivity, pharmacokinetics and drug-drug interactions. Among them, tivozanib is one of the last TKIs introduced in the clinical practice; this drug selectively targets VEGFRs, it is characterized by a favorable pharmacokinetics and safety profile and has been approved as first-line treatment for patients with metastatic RCC (mRCC). In this article, we describe the clinical pharmacology of selected VEGFR-TKIs used for the treatment of mRCC, highlighting the relevant differences; moreover we aim to define the main pharmacologic characteristics of these drug.


Assuntos
Inibidores da Angiogênese/farmacologia , Carcinoma de Células Renais/tratamento farmacológico , Neoplasias Renais/tratamento farmacológico , Inibidores de Proteínas Quinases/farmacologia , Receptores de Fatores de Crescimento do Endotélio Vascular/antagonistas & inibidores , Inibidores da Angiogênese/efeitos adversos , Inibidores da Angiogênese/uso terapêutico , Anilidas/efeitos adversos , Anilidas/farmacologia , Anilidas/uso terapêutico , Axitinibe/efeitos adversos , Axitinibe/farmacologia , Axitinibe/uso terapêutico , Interações Medicamentosas , Humanos , Compostos de Fenilureia/efeitos adversos , Compostos de Fenilureia/farmacologia , Compostos de Fenilureia/uso terapêutico , Inibidores de Proteínas Quinases/efeitos adversos , Inibidores de Proteínas Quinases/uso terapêutico , Piridinas/efeitos adversos , Piridinas/farmacologia , Piridinas/uso terapêutico , Pirimidinas/efeitos adversos , Pirimidinas/farmacologia , Pirimidinas/uso terapêutico , Quinolinas/efeitos adversos , Quinolinas/farmacologia , Quinolinas/uso terapêutico , Sorafenibe/efeitos adversos , Sorafenibe/farmacologia , Sorafenibe/uso terapêutico , Sulfonamidas/efeitos adversos , Sulfonamidas/farmacologia , Sulfonamidas/uso terapêutico , Sunitinibe/efeitos adversos , Sunitinibe/farmacologia , Sunitinibe/uso terapêutico
7.
Nat Rev Urol ; 17(3): 137-150, 2020 03.
Artigo em Inglês | MEDLINE | ID: mdl-32020040

RESUMO

Kidney cancer has unique features that make this malignancy attractive for therapeutic approaches that target components of the immune system. Immune checkpoint inhibition is a well-established part of kidney cancer treatment, and rapid advances continue to be made in this field. Initial preclinical studies that elucidated the biology of the programmed cell death 1 (PD-1), programmed cell death 1 ligand 1 (PD-L1) and cytotoxic T lymphocyte antigen 4 (CTLA-4) immune checkpoints led to a series of clinical trials that resulted in regulatory approval of nivolumab and the combination of ipilimumab plus nivolumab for the treatment of advanced renal cell carcinoma. Subsequent data led to approvals of combination strategies of immune checkpoint inhibition plus agents that target the vascular endothelial growth factor receptor and a shift in the current standard of renal cell carcinoma care. However, controversies remain regarding the optimal therapy selection and treatment strategy for individual patients, which might be eventually overcome by current intensive efforts in biomarker research. That work includes evaluation of tumour cell PD-L1 expression, gene expression signatures, CD8+ T cell density and others. In the future, further advances in the understanding of immune checkpoint biology might reveal new therapeutic targets beyond PD-1, PD-L1 and CTLA-4, as well as new combination approaches.


Assuntos
Antineoplásicos Imunológicos/uso terapêutico , Antígeno B7-H1/antagonistas & inibidores , Antígeno CTLA-4/antagonistas & inibidores , Carcinoma de Células Renais/tratamento farmacológico , Neoplasias Renais/tratamento farmacológico , Receptor de Morte Celular Programada 1/antagonistas & inibidores , Antineoplásicos Imunológicos/imunologia , Antineoplásicos Imunológicos/farmacologia , Antígeno B7-H1/imunologia , Antígeno B7-H1/farmacologia , Antígeno CTLA-4/imunologia , Carcinoma de Células Renais/imunologia , Pontos de Checagem do Ciclo Celular/efeitos dos fármacos , Pontos de Checagem do Ciclo Celular/imunologia , Quimioterapia Combinada , Humanos , Imunoterapia/métodos , Neoplasias Renais/imunologia , Receptor de Morte Celular Programada 1/imunologia
8.
Int J Nanomedicine ; 15: 81-95, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32021166

RESUMO

Purpose: We intended to design G250 antigen-targeting temsirolimus-loaded nanobubbles (G250-TNBs) based on the targeted drug delivery system and to combine G250-TNBs with ultrasound targeted nanobubble destruction (UTND) to achieve a synergistic treatment for renal cell carcinoma (RCC). Methods: The filming-rehydration method was combined with mechanical shock and electrostatic interactions to prepare temsirolimus-loaded nanobubbles (TNBs). G250-TNBs were prepared by attaching anti-G250 nanobodies to the surface of TNBs using the biotin-streptavidin-bridge method. The ability of G250-TNBs to target the G250 antigen of RCC cells and the synergistic efficacy of G250-TNBs and UTND in the treatment of RCC were assessed. Results: The average diameter of the prepared G250-TNBs was 368.7 ± 43.4 nm, the encapsulation efficiency was 68.59% ± 5.43%, and the loading efficiency was 5.23% ± 0.91%. In vitro experiments showed that the affinity of G250-TNBs to the human RCC 786-O cells was significantly higher than that of TNBs (P <0.05), and the inhibitory effect on 786-O cell proliferation and the induction of 786-O cell apoptosis was significantly enhanced in the group treated with G250-TNBs and UTND (G250-TNBs+ UTND group) compared with the other groups (P <0.05). In a nude mouse xenograft model, compared with TNBs, G250-TNBs could target the transplanted tumors and thus significantly enhance the ultrasound imaging of the tumors. Compared with all other groups, the G250-TNBs+UTND group exhibited a significantly lower tumor volume, a higher tumor growth inhibition rate, and a higher apoptosis index (P <0.05). Conclusion: The combined G250-TNBs and UTND treatment can deliver anti-tumor drugs to local areas of RCC, increase the local effective drug concentration, and enhance anti-tumor efficacy, thus providing a potential novel method for targeted therapy of RCC.


Assuntos
Antígenos de Neoplasias , Carcinoma de Células Renais/tratamento farmacológico , Sistemas de Liberação de Medicamentos/métodos , Neoplasias Renais/tratamento farmacológico , Nanoestruturas/química , Sirolimo/análogos & derivados , Animais , Antineoplásicos/administração & dosagem , Antineoplásicos/farmacologia , Apoptose/efeitos dos fármacos , Carcinoma de Células Renais/diagnóstico por imagem , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Humanos , Neoplasias Renais/diagnóstico por imagem , Camundongos Nus , Nanoestruturas/administração & dosagem , Sirolimo/administração & dosagem , Sirolimo/farmacologia , Ultrassonografia de Intervenção , Ensaios Antitumorais Modelo de Xenoenxerto
9.
Hinyokika Kiyo ; 66(1): 13-17, 2020 Jan.
Artigo em Japonês | MEDLINE | ID: mdl-32028750

RESUMO

Antibodies that inhibit the function of PD-1, PD-L1, and CTLA4 increase the tumor immune response and suppress tumor growth. These immune checkpoint inhibitors have also been introduced into the treatment of metastatic renal cancer. We report combination therapywith nivolumab and ipilimumab in a case of renal cancer with bone metastasis and subsequent removal of the primarytumor. The patient was a 67-year-old male. Computed tomography (CT) revealed a 6.5×5.6 cm renal tumor in the left kidney, with osteolytic metastasis to the left 11th rib and thoracic spine. Irradiation of 30 Gy was performed for the thoracic spine tumors. Then, nivolumab+ipilimumab combination therapywas continued for a total of 4 courses. In addition, 4 courses of nivolumab monotherapywere added. CT after therapyrevealed a 15. 4% decrease in the length-wise diameter and increase in internal necrosis in the left kidneytumor, as well as shrinkage, absorption reduction, and appearance of a hardened border in the bone metastasis. Therefore, transabdominal left nephrectomywas performed. The histopathological diagnosis was clear cell carcinoma pT1bN0, grade 2. The renal cancer tissue was mostlyinternal necrosis, and the viable tumor comprised approximately10%. Marked infiltration of predominantlyCD8-positive lymphocytes to the primarytumor site was observed. Postoperatively, nivolumab was discontinued and the patient is under observation. In the specimens from 2 patients treated using pazopanib, a tyrosine kinase inhibitor, prior to renal cell cancer removal, there were fewer CD8- and CD4-positive cells infiltrating the renal cancer than after the combination therapy.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Carcinoma de Células Renais , Neoplasias Renais , Idoso , Carcinoma de Células Renais/tratamento farmacológico , Humanos , Ipilimumab , Neoplasias Renais/tratamento farmacológico , Masculino , Nivolumabe , Inibidores de Proteínas Quinases
10.
Nat Commun ; 11(1): 661, 2020 01 31.
Artigo em Inglês | MEDLINE | ID: mdl-32005826

RESUMO

High dose interleukin-2 (IL-2) is active against metastatic melanoma and renal cell carcinoma, but treatment-associated toxicity and expansion of suppressive regulatory T cells (Tregs) limit its use in patients with cancer. Bempegaldesleukin (NKTR-214) is an engineered IL-2 cytokine prodrug that provides sustained activation of the IL-2 pathway with a bias to the IL-2 receptor CD122 (IL-2Rß). Here we assess the therapeutic impact and mechanism of action of NKTR-214 in combination with anti-PD-1 and anti-CTLA-4 checkpoint blockade therapy or peptide-based vaccination in mice. NKTR-214 shows superior anti-tumor activity over native IL-2 and systemically expands anti-tumor CD8+ T cells while inducing Treg depletion in tumor tissue but not in the periphery. Similar trends of intratumoral Treg dynamics are observed in a small cohort of patients treated with NKTR-214. Mechanistically, intratumoral Treg depletion is mediated by CD8+ Teff-associated cytokines IFN-γ and TNF-α. These findings demonstrate that NKTR-214 synergizes with T cell-mediated anti-cancer therapies.


Assuntos
Carcinoma de Células Renais/tratamento farmacológico , Interleucina-2/análogos & derivados , Melanoma/tratamento farmacológico , Polietilenoglicóis/administração & dosagem , Pró-Fármacos/administração & dosagem , Linfócitos T Reguladores/imunologia , Animais , Anticorpos Monoclonais Humanizados/administração & dosagem , Linfócitos T CD8-Positivos/imunologia , Carcinoma de Células Renais/genética , Carcinoma de Células Renais/imunologia , Estudos de Coortes , Quimioterapia Combinada , Feminino , Humanos , Interferon gama/genética , Interferon gama/imunologia , Interleucina-2/administração & dosagem , Interleucina-2/agonistas , Interleucina-2/imunologia , Ipilimumab/administração & dosagem , Ativação Linfocitária/efeitos dos fármacos , Melanoma/genética , Melanoma/imunologia , Camundongos , Camundongos Endogâmicos C57BL , Receptores de Interleucina-2/genética , Receptores de Interleucina-2/imunologia , Fator de Necrose Tumoral alfa/genética , Fator de Necrose Tumoral alfa/imunologia
11.
Nat Commun ; 11(1): 929, 2020 02 17.
Artigo em Inglês | MEDLINE | ID: mdl-32066735

RESUMO

Current treatments for clear cell renal cell cancer (ccRCC) are insufficient because two-thirds of patients with metastases progress within two years. Here we report the identification and characterization of a cancer stem cell (CSC) population in ccRCC. CSCs are quantitatively correlated with tumor aggressiveness and metastasis. Transcriptional profiling and single cell sequencing reveal that these CSCs exhibit an activation of WNT and NOTCH signaling. A significant obstacle to the development of rational treatments has been the discrepancy between model systems and the in vivo situation of patients. To address this, we use CSCs to establish non-adherent sphere cultures, 3D tumor organoids, and xenografts. Treatment with WNT and NOTCH inhibitors blocks the proliferation and self-renewal of CSCs in sphere cultures and organoids, and impairs tumor growth in patient-derived xenografts in mice. These findings suggest that our approach is a promising route towards the development of personalized treatments for individual patients.


Assuntos
Antineoplásicos/farmacologia , Carcinoma de Células Renais/tratamento farmacológico , Neoplasias Renais/tratamento farmacológico , Células-Tronco Neoplásicas/efeitos dos fármacos , Receptores Notch/antagonistas & inibidores , Proteínas Wnt/antagonistas & inibidores , Adulto , Idoso , Idoso de 80 Anos ou mais , Animais , Antineoplásicos/uso terapêutico , Compostos Bicíclicos Heterocíclicos com Pontes/farmacologia , Carcinoma de Células Renais/patologia , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Feminino , Compostos Heterocíclicos com 3 Anéis/farmacologia , Humanos , Rim/patologia , Neoplasias Renais/patologia , Masculino , Camundongos , Pessoa de Meia-Idade , Células-Tronco Neoplásicas/patologia , Cultura Primária de Células , Pirimidinonas/farmacologia , RNA Interferente Pequeno/metabolismo , Receptores Notch/metabolismo , Transdução de Sinais/efeitos dos fármacos , Análise de Célula Única , Esferoides Celulares , Proteínas Wnt/metabolismo , Ensaios Antitumorais Modelo de Xenoenxerto
12.
Urologe A ; 59(2): 149-154, 2020 Feb.
Artigo em Alemão | MEDLINE | ID: mdl-32076796

RESUMO

In view of a considerable risk of recurrence especially in patients with a high-risk profile after organ-sparing surgery or nephrectomy, adjuvant treatment seems to make sense in renal cell carcinoma. After the failed attempts using older immunotherapeutics or vaccination therapies, new hope was put in the panel of targeted VEGF/R inhibitors. But the results from these studies published so far are also disappointing. In this context the instruments for selecting the best suitable patients for adjuvant trials have to be discussed. It remains to be seen whether using the same selection criteria as in ongoing trials with checkpoint inhibitors will show better results.


Assuntos
Carcinoma de Células Renais/terapia , Quimioterapia Adjuvante/métodos , Neoplasias Renais/terapia , Inibidores de Proteínas Quinases/uso terapêutico , Receptores de Fatores de Crescimento do Endotélio Vascular/uso terapêutico , Antineoplásicos Imunológicos/uso terapêutico , Carcinoma de Células Renais/tratamento farmacológico , Humanos , Neoplasias Renais/tratamento farmacológico , Terapia de Alvo Molecular/métodos , Recidiva Local de Neoplasia , Nefrectomia , Receptores de Fatores de Crescimento do Endotélio Vascular/antagonistas & inibidores
14.
Nature ; 577(7791): 549-555, 2020 01.
Artigo em Inglês | MEDLINE | ID: mdl-31942075

RESUMO

Treatment with immune checkpoint blockade (ICB) has revolutionized cancer therapy. Until now, predictive biomarkers1-10 and strategies to augment clinical response have largely focused on the T cell compartment. However, other immune subsets may also contribute to anti-tumour immunity11-15, although these have been less well-studied in ICB treatment16. A previously conducted neoadjuvant ICB trial in patients with melanoma showed via targeted expression profiling17 that B cell signatures were enriched in the tumours of patients who respond to treatment versus non-responding patients. To build on this, here we performed bulk RNA sequencing and found that B cell markers were the most differentially expressed genes in the tumours of responders versus non-responders. Our findings were corroborated using a computational method (MCP-counter18) to estimate the immune and stromal composition in this and two other ICB-treated cohorts (patients with melanoma and renal cell carcinoma). Histological evaluation highlighted the localization of B cells within tertiary lymphoid structures. We assessed the potential functional contributions of B cells via bulk and single-cell RNA sequencing, which demonstrate clonal expansion and unique functional states of B cells in responders. Mass cytometry showed that switched memory B cells were enriched in the tumours of responders. Together, these data provide insights into the potential role of B cells and tertiary lymphoid structures in the response to ICB treatment, with implications for the development of biomarkers and therapeutic targets.


Assuntos
Linfócitos B/imunologia , Carcinoma de Células Renais/tratamento farmacológico , Carcinoma de Células Renais/imunologia , Imunoterapia , Melanoma/tratamento farmacológico , Melanoma/imunologia , Estruturas Linfoides Terciárias/imunologia , Linfócitos B/citologia , Linfócitos B/metabolismo , Biomarcadores Tumorais/análise , Carcinoma de Células Renais/patologia , Carcinoma de Células Renais/cirurgia , Pontos de Checagem do Ciclo Celular/efeitos dos fármacos , Pontos de Checagem do Ciclo Celular/imunologia , Células Clonais/citologia , Células Clonais/imunologia , Células Clonais/metabolismo , Células Dendríticas Foliculares/citologia , Células Dendríticas Foliculares/imunologia , Regulação Neoplásica da Expressão Gênica , Humanos , Memória Imunológica/imunologia , Espectrometria de Massas , Melanoma/patologia , Melanoma/cirurgia , Metástase Neoplásica/genética , Fenótipo , Prognóstico , RNA-Seq , Receptores Imunológicos/imunologia , Análise de Célula Única , Linfócitos T/citologia , Linfócitos T/imunologia , Transcriptoma
15.
Adv Exp Med Biol ; 1217: 173-186, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-31898228

RESUMO

Posttranslational protein modifications play an important role in regulating protein stability and cellular function. There are at least eight Cullin family members. Among them, Cullin-2 forms a functional E3 ligase complex with elongin B, elongin C, RING-box protein 1 (RBX1, also called ROC1), as well as the substrate recognition subunit (SRS) to promote the substrate ubiquitination and degradation. In this book chapter, we will review Cullin-2 E3 ligase complexes that include various SRS proteins, including von Hippel Lindau (pVHL), leucine-rich repeat protein-1 (LRR-1), preferentially expressed antigen of melanoma (PRAME), sex-determining protein FEM-1 and early embryogenesis protein ZYG-11. We will focus on the VHL signaling pathway in clear cell renal cell carcinoma (ccRCC), which may reveal various therapeutic avenues in treating this lethal cancer.


Assuntos
Carcinoma de Células Renais/enzimologia , Proteínas Culina/metabolismo , Neoplasias Renais/enzimologia , Animais , Carcinoma de Células Renais/tratamento farmacológico , Humanos , Neoplasias Renais/tratamento farmacológico , Ligação Proteica , Fatores de Transcrição/metabolismo , Proteína Supressora de Tumor Von Hippel-Lindau/metabolismo
16.
Artigo em Inglês | MEDLINE | ID: mdl-31931326

RESUMO

Cabozantinib is a novel multi-target tyrosine kinase inhibitor recently approved in metastatic renal cell carcinoma (mRCC) leading to frequent severe toxicities requiring empirical dose reduction. Therapeutic drug monitoring (TDM) could help to predict the risk for severe toxicities by quickly detecting overexposed patients followed by prospective adaptive dosing strategy. To achieve this goal, a simple and rapid assay to monitor cabozantinib plasma concentration was developed and validated. After a single precipitation step with 87% recovery, cabozantinib was assayed by liquid chromatography tandem mass spectrometry (electrospray ionization interface) over a 25-5000 ng/ml range covering usual plasma levels in clinical setting. For cabozantinib and cabozantinib 2H4 used as internal standard, quantification was performed using the m/z 502 â†’ m/z 323 and m/z 506 â†’ m/z 323 transitions, respectively. Analytical runtime was 5 min. Both inter-days and intra-day accuracy and precision were <15%. When tested in routine clinical practice in a subset of mRCC patients treated with standard 60 mg quaque die (QD) dosing, the method proved to be fully adapted and neither analytical interferences nor matrix effect was observed. Results showed that cabozantinib trough levels were highly variable among patients (i.e., 973 ± 501 ng/ml, CV = 52%), calling for implementing TDM in patients with mRCC to monitor exposure levels and evaluate concentration-response relationship.


Assuntos
Anilidas/sangue , Antineoplásicos/sangue , Cromatografia Líquida/métodos , Monitoramento de Medicamentos/métodos , Espectrometria de Massas/métodos , Piridinas/sangue , Anilidas/uso terapêutico , Antineoplásicos/uso terapêutico , Carcinoma de Células Renais/tratamento farmacológico , Humanos , Neoplasias Renais/tratamento farmacológico , Modelos Lineares , Piridinas/uso terapêutico , Reprodutibilidade dos Testes , Sensibilidade e Especificidade
17.
Int J Cancer ; 146(5): 1435-1444, 2020 03 01.
Artigo em Inglês | MEDLINE | ID: mdl-31335987

RESUMO

The mammalian target of rapamycin (mTOR) pathway inhibitors are key drugs for the treatment of many tumor types, however, there are no predictive biomarkers in clinical use. Here, we performed a molecular and immunohistochemical characterization of key mTOR pathway components in a series of 105 renal cell carcinoma patients treated with rapalogs, aimed at identifying markers of treatment response. Mutational analysis in MTOR, TSC1 and TSC2 was performed through targeted next-generation sequencing (NGS), and immunohistochemistry (IHC) was performed for PTEN, pAKT, pS6K1, pS6 and p21. Among patients with NGS data, 11 of 87 (13%) had mTOR pathway mutations (8 in MTOR, 1 in TSC1 and 2 in TSC2). When comparing the molecular data to the response of the patients, we found that partial response was more frequent in cases with mTOR pathway mutations than in those without mutations (odds ratio [OR] = 0.08, 95% confidence interval [CI] = 0.008-0.79, p = 0.030 univariate; p = 0.038 multivariable). Regarding IHC, negative PTEN staining was detected in 58% of the tumors, and it was more frequent in rapalog responder patients (OR = 0.24, 95% CI = 0.065-0.86, p = 0.029 univariate; p = 0.029 multivariable). Mutations and PTEN IHC were not mutually exclusive events and its combination improved response prediction (OR = 0.16, 95% CI = 0.04-0.62, p = 0.008 univariate; p = 0.013 multivariable). The staining of other proteins did not show and association with response and no association with PFS was observed in unselected patients. In conclusion, our findings suggest that mTOR pathway mutations, negative PTEN IHC and their combination are potential markers of rapalog response.


Assuntos
Antineoplásicos/farmacologia , Biomarcadores Tumorais/genética , Carcinoma de Células Renais/tratamento farmacológico , Resistencia a Medicamentos Antineoplásicos/genética , Neoplasias Renais/tratamento farmacológico , Adulto , Idoso , Idoso de 80 Anos ou mais , Antineoplásicos/uso terapêutico , Biomarcadores Tumorais/antagonistas & inibidores , Biomarcadores Tumorais/metabolismo , Carcinoma de Células Renais/genética , Carcinoma de Células Renais/mortalidade , Análise Mutacional de DNA , Everolimo/farmacologia , Everolimo/uso terapêutico , Feminino , Seguimentos , Humanos , Rim/patologia , Neoplasias Renais/genética , Neoplasias Renais/mortalidade , Masculino , Pessoa de Meia-Idade , Mutação , PTEN Fosfo-Hidrolase/metabolismo , Prognóstico , Intervalo Livre de Progressão , Estudos Prospectivos , Transdução de Sinais/efeitos dos fármacos , Transdução de Sinais/genética , Sirolimo/análogos & derivados , Sirolimo/farmacologia , Sirolimo/uso terapêutico , Serina-Treonina Quinases TOR/antagonistas & inibidores , Serina-Treonina Quinases TOR/genética , Serina-Treonina Quinases TOR/metabolismo , Proteína 1 do Complexo Esclerose Tuberosa/genética , Proteína 2 do Complexo Esclerose Tuberosa/genética
18.
Int J Cancer ; 146(4): 1052-1063, 2020 02 15.
Artigo em Inglês | MEDLINE | ID: mdl-31259424

RESUMO

Sorafenib provides survival benefits in patients with advanced renal cell carcinoma (RCC), but its use is hampered by acquired drug resistance. It is important to fully clarify the molecular mechanisms of sorafenib resistance, which can help to avoid, delay or reverse drug resistance. Extracellular vesicles (EVs) can mediate intercellular communication by delivering effector molecules between cells. Here, we studied whether EVs are involved in sorafenib resistance of RCC and its possible molecular mechanisms. Using differential centrifugation, EVs were isolated from established sorafenib-resistant RCC cells (786-0 and ACHN), and EVs derived from sorafenib-resistant cells were uptaken by sensitive parental RCC cells and thus promoted drug resistance. Elevated exogenous miR-31-5p within EVs effectively downregulated MutL homolog 1 (MLH1) expression and thus promoted sorafenib resistance in vitro. Mice experiments also confirmed that miR-31-5p could mediate drug sensitivity in vivo. In addition, low expression of MLH1 was observed in sorafenib-resistant RCC cells and upregulation of MLH1 expression restored the sensitivity of resistant cell lines to sorafenib. Finally, miR-31-5p level in circulating EVs of RCC patients with progressive disease (PD) during sorafenib therapy was higher when compared to that in the pretherapy status. In conclusion, EVs shuttled miR-31-5p can transfer resistance information from sorafenib-resistant cells to sensitive cells by directly targeting MLH1, and thus magnify the drug resistance information to the whole tumor. Furthermore, miR-31-5p and MLH1 could be promising predictive biomarkers and therapeutic targets to prevent sorafenib resistance.


Assuntos
Carcinoma de Células Renais/tratamento farmacológico , Vesículas Extracelulares/metabolismo , MicroRNAs/metabolismo , Proteína 1 Homóloga a MutL/metabolismo , Sorafenibe/farmacologia , Animais , Antineoplásicos/farmacologia , Carcinoma de Células Renais/genética , Carcinoma de Células Renais/metabolismo , Vesículas Extracelulares/genética , Humanos , Neoplasias Renais/tratamento farmacológico , Neoplasias Renais/genética , Neoplasias Renais/metabolismo , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Nus , Proteína 1 Homóloga a MutL/biossíntese , Proteína 1 Homóloga a MutL/genética , Ensaios Antitumorais Modelo de Xenoenxerto
19.
Int J Cancer ; 146(6): 1643-1651, 2020 03 15.
Artigo em Inglês | MEDLINE | ID: mdl-31318983

RESUMO

The treatment landscape in metastatic renal cell carcinoma has changed fundamentally over the last decade by the development of antiangiogenic agents, mammalian target of rapamycin inhibitors and immunotherapy. Outside of the context of a clinical trial, the treatments are used sequentially. We describe results under real-life conditions of a sequential treatment strategy, before the era of immunotherapy. All patients were treated according to their prognostic score (either Memorial Sloan Kettering Cancer Center or International Metastatic Renal Cell Carcinoma Database Consortium) for advanced renal cell carcinoma. A treatment strategy involving 1 to 4 lines was determined including a rechallenge criterion for the repeat use of a treatment class. Three hundred forty-four patients were included over 3 years. Overall survival was 57 months in patients with good or intermediate prognosis and 19 months in patients with poor prognosis. In the former group, the proportions of patients treated with 2 to 4 treatment lines were 70%, 38% and 16%, respectively. The best objective response rates for lines 1 to 4 were 46%, 36%, 16% and 17%, respectively. Grade III/IV toxicity did not appear to be cumulative. The recommended strategy was followed in 68% of patients. A large proportion of patients with good or intermediate prognosis who progress after two lines of treatment still have a performance status good enough to receive a systemic treatment, which justifies such a strategy. Overall survival of patients with good and intermediate prognosis was long, suggesting a benefit from the applied approach. These results might be used as selection criterion for the treatment of patients in the era of immune checkpoint inhibitors.


Assuntos
Inibidores da Angiogênese/uso terapêutico , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Carcinoma de Células Renais/tratamento farmacológico , Neoplasias Renais/tratamento farmacológico , Inibidores de Proteínas Quinases/uso terapêutico , Adulto , Idoso , Idoso de 80 Anos ou mais , Bevacizumab/uso terapêutico , Carcinoma de Células Renais/mortalidade , Everolimo/uso terapêutico , Feminino , França/epidemiologia , Humanos , Neoplasias Renais/mortalidade , Masculino , Pessoa de Meia-Idade , Terapia de Alvo Molecular/efeitos adversos , Terapia de Alvo Molecular/métodos , Seleção de Pacientes , Prognóstico , Estudos Prospectivos , Fatores de Risco , Análise de Sobrevida , Fatores de Tempo
20.
Cancer Sci ; 111(1): 112-126, 2020 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-31675763

RESUMO

Drug repositioning is an emerging approach to developing novel cancer treatments. Vorinostat is a histone deacetylase inhibitor approved for cancer treatment, but it could attenuate its anticancer activity by activating the mTOR pathway. The HMG-CoA reductase inhibitor fluvastatin reportedly activates the mTOR inhibitor AMP-activated protein kinase (AMPK), and we thought that it would potentiate vorinostat's anticancer activity in renal cancer cells. The combination of vorinostat and fluvastatin induced robust apoptosis and inhibited renal cancer growth effectively both in vitro and in vivo. Vorinostat activated the mTOR pathway, as evidenced by the phosphorylation of ribosomal protein S6, and fluvastatin inhibited this phosphorylation by activating AMPK. Fluvastatin also enhanced vorinostat-induced histone acetylation. Furthermore, the combination induced endoplasmic reticulum (ER) stress that was accompanied by aggresome formation. We also found that there was a positive feedback cycle among AMPK activation, histone acetylation, and ER stress induction. This is the first study to report the beneficial combined effect of vorinostat and fluvastatin in cancer cells.


Assuntos
Antineoplásicos/farmacologia , Carcinoma de Células Renais/tratamento farmacológico , Fluvastatina/farmacologia , Neoplasias Renais/tratamento farmacológico , Vorinostat/farmacologia , Acetilação/efeitos dos fármacos , Apoptose/efeitos dos fármacos , Carcinoma de Células Renais/metabolismo , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Sinergismo Farmacológico , Estresse do Retículo Endoplasmático/efeitos dos fármacos , Inibidores de Histona Desacetilases/farmacologia , Humanos , Ácidos Hidroxâmicos/farmacologia , Inibidores de Hidroximetilglutaril-CoA Redutases/farmacologia , Neoplasias Renais/metabolismo , Fosforilação/efeitos dos fármacos , Serina-Treonina Quinases TOR/metabolismo
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