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1.
Lung Cancer ; 133: 117-122, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-31200817

RESUMO

INTRODUCTION: Despite all treatment advances, lung cancer is still the main cause of death worldwide. Treatment for resectable stage IIIA remains controversial including definitive chemoradiotherapy and induction treatment followed by surgery. After definitive chemoradiation up to 35% of patients will relapse locally. Experience with salvage resection after definitive chemoradiotherapy in lung cancer is limited. We present our experience in 27 patients who underwent surgical resection after definitive treatment. PATIENTS AND METHODS: Between January 2007 and December 2016, 27 patients were evaluated in our department for surgical resection after receiving definitive chemoradiation treatment in different institutions. We conducted a retrospective study gathering the following data: age, gender, clinical and pathologic stage, histology, chemotherapy treatment regimen, radiotherapy dosage, surgical procedure and complications. Time between surgical resection and last follow-up was used to calculate Overall Survival (OS). Disease-Free Survival (DFS) was calculated from surgical resection to diagnosis of relapse. RESULTS: Most of the patients were men with a median age of 56.09 years. Median follow-up time was 46.94 months. All patients received platinum-based chemotherapy regimen and high-dose radiotherapy, except for one patient who received 45 Gy. Lobectomy and bilobectomy was performed in 7 patients each, and pneumonectomy in 13. Complications appeared in 5 patients. Bronchopleural fistula appeared in two patients, and only one death in the early postoperative period. The analysis showed an OS of 75.56 months, with 1-year, 3-year and 5-year survival of 74.1%, 57.8% and 53.3% respectively. CONCLUSION: Salvage surgery in selected patients is technically feasible, with low morbidity and mortality rates and good long-term outcomes.

2.
Invest New Drugs ; 2019 May 07.
Artigo em Inglês | MEDLINE | ID: mdl-31065954

RESUMO

Background Fibroblast growth factors (FGFs) have a fundamental role in cancer. Sequestering FGFs with GSK3052230 (FP-1039) blocks their ability to activate FGFRs while avoiding toxicities associated with small molecule inhibitors of FGFR, including hyperphosphatemia and retinal, nail, and skin toxicities. Methods A multicenter, open-label, phase Ib study evaluated weekly GSK3052230 added to pemetrexed/cisplatin in patients with treatment-naive, unresectable malignant pleural mesothelioma. Doses were escalated according to a 3 + 3 design, followed by cohort expansion at the maximum tolerated dose (MTD). Endpoints included safety, overall response rate, progression-free survival, and pharmacokinetics. Results 36 patients were dosed at 10, 15, and 20 mg/kg doses of GSK3052230. Three dose-limiting toxicities were observed at 20 mg/kg and one at 15 mg/kg. The MTD was defined as 15 mg/kg and used for cohort expansion. The most common treatment-related adverse events (AEs) were nausea (56%), decreased appetite (36%), infusion reactions (36%), decreased neutrophil counts (36%), and fatigue (33%). The confirmed ORR was 39% (95% CI: 23.1-56.5) (14/36 PRs) and 47% had stable disease (17/36), giving a disease control rate of 86%. At 15 mg/kg GSK3052230 (n = 25), the ORR was 44% (95% CI: 24.4-65.1), and the median PFS was 7.4 months (95% CI: 6.7-13.4). Four patients had disease control for over 1 year, and three were still ongoing. Conclusion At 15 mg/kg weekly, GSK3052230 was well tolerated in combination with pemetrexed/cisplatin and durable responses were observed. Importantly, AEs associated with small molecule inhibitors of FGFR were not observed, as predicted by the unique mechanism of action of this drug.

3.
Nat Commun ; 10(1): 1812, 2019 04 18.
Artigo em Inglês | MEDLINE | ID: mdl-31000705

RESUMO

Non-small cell lung cancer (NSCLC) tumors harboring mutations in EGFR ultimately relapse to therapy with EGFR tyrosine kinase inhibitors (EGFR TKIs). Here, we show that resistant cells without the p.T790M or other acquired mutations are sensitive to the Aurora B (AURKB) inhibitors barasertib and S49076. Phospho-histone H3 (pH3), a major product of AURKB, is increased in most resistant cells and treatment with AURKB inhibitors reduces the levels of pH3, triggering G1/S arrest and polyploidy. Senescence is subsequently induced in cells with acquired mutations while, in their absence, polyploidy is followed by cell death. Finally, in NSCLC patients, pH3 levels are increased after progression on EGFR TKIs and high pH3 baseline correlates with shorter survival. Our results reveal that AURKB activation is associated with acquired resistance to EGFR TKIs, and that AURKB constitutes a potential target in NSCLC progressing to anti-EGFR therapy and not carrying resistance mutations.


Assuntos
Antineoplásicos/farmacologia , Aurora Quinase B/metabolismo , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Neoplasias Pulmonares/tratamento farmacológico , Inibidores de Proteínas Quinases/farmacologia , Adulto , Idoso , Idoso de 80 Anos ou mais , Animais , Antineoplásicos/uso terapêutico , Aurora Quinase B/antagonistas & inibidores , Aurora Quinase B/genética , Carcinoma Pulmonar de Células não Pequenas/genética , Carcinoma Pulmonar de Células não Pequenas/mortalidade , Carcinoma Pulmonar de Células não Pequenas/patologia , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Progressão da Doença , Resistencia a Medicamentos Antineoplásicos/genética , Receptores ErbB/antagonistas & inibidores , Receptores ErbB/genética , Feminino , Pontos de Checagem da Fase G1 do Ciclo Celular/efeitos dos fármacos , Histonas/metabolismo , Humanos , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/mortalidade , Neoplasias Pulmonares/patologia , Masculino , Camundongos , Pessoa de Meia-Idade , Organofosfatos/farmacologia , Organofosfatos/uso terapêutico , Fosforilação/efeitos dos fármacos , Poliploidia , Inibidores de Proteínas Quinases/uso terapêutico , Quinazolinas/farmacologia , Quinazolinas/uso terapêutico , RNA Interferente Pequeno/metabolismo , Análise de Sobrevida , Resultado do Tratamento , Ensaios Antitumorais Modelo de Xenoenxerto
4.
Clin Cancer Res ; 2018 Oct 16.
Artigo em Inglês | MEDLINE | ID: mdl-30327308

RESUMO

Purpose: This study examined safety, pharmacokinetics, and efficacy of veliparib, a PARP inhibitor, combined with carboplatin and etoposide in patients with extensive-stage (ED) small cell lung cancer (SCLC) and other solid tumors.Experimental Design: The 3 + 3 design was used for dose escalation of oral veliparib in combination with carboplatin (AUC 5 on day 1) and etoposide (100 mg/m2 on days 1-3) in 21-day cycles. Veliparib dose was explored from 80 to 240 mg b.i.d. on 7-day, 14-day, or continuous schedules. Patients without disease progression continued on maintenance monotherapy (veliparib 400 mg b.i.d.) until disease progression or unacceptable toxicity.Results: Thirty-nine patients were enrolled to determine the recommended phase II dose of 240 mg veliparib for 14 days combined with carboplatin and etoposide based on long-term tolerability. Dose-limiting toxicity occurred in 1 patient (grade 2 toxic motor polyneuropathy) at veliparib 240 mg b.i.d. for 7 days. Most common adverse events related to veliparib were nausea (39%), fatigue (39%), and hematologic toxicities. Continuous dosing of veliparib 240 mg b.i.d. with carboplatin and etoposide resulted in excessive chemotherapy dose delays due to hematologic toxicity (grade 3/4 neutropenia/thrombocytopenia). Etoposide pharmacokinetics was not affected by veliparib. Confirmed responses occurred in 17 of 39 (44%) and 16 of 25 (64%) of all enrolled and ED SCLC patients, respectively. At the RP2D, confirmed responses occurred in 6 of 13 (46%) and 5 of 6 (83%) of all enrolled and ED SCLC patients, respectively.Conclusions: Veliparib (240 mg b.i.d. 14 days) plus carboplatin/etoposide can be safely combined. Phase II of this study is ongoing in first-line patients with ED SCLC. Clin Cancer Res; 1-10. ©2018 AACR.

5.
Ther Adv Med Oncol ; 10: 1758835918793105, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-30181782

RESUMO

A coordinated action of innate and adaptive immune responses is required to efficiently combat a microbial infection. It has now become clear that cancer therapies also largely benefit when both arms of the immune response are engaged. In this review, we will briefly describe the current knowledge of innate immunity and how this can be utilized to prime tumors for a better response to immune checkpoint inhibitors. Comments on compounds in development and ongoing clinical trials will be provided.

6.
Oncotarget ; 9(29): 20617-20630, 2018 Apr 17.
Artigo em Inglês | MEDLINE | ID: mdl-29755676

RESUMO

Brain metastases constitute a challenge in the management of patients with HER2-positive breast cancer treated with anti-HER2 systemic therapies. Here we sought to define the repertoire of mutations private to or enriched for in HER2-positive brain metastases. Massively parallel sequencing targeting all exons of 254 genes frequently mutated in breast cancers and/or related to DNA repair was used to characterize the spatial and temporal heterogeneity of HER2-positive breast cancers and their brain metastases in six patients. Data were analyzed with state-of-the-art bioinformatics algorithms and selected mutations were validated with orthogonal methods. Spatial and temporal inter-lesion genetic heterogeneity was observed in the HER2-positive brain metastases from an index patient subjected to a rapid autopsy. Genetic alterations restricted to the brain metastases included mutations in cancer genes FGFR2, PIK3CA and ATR, homozygous deletion in CDKN2A and amplification in KRAS. Shifts in clonal composition and the acquisition of additional mutations in the progression from primary HER2-positive breast cancer to brain metastases following anti-HER2 therapy were investigated in additional five patients. Likely pathogenic mutations private to or enriched in the brain lesions affected cancer and clinically actionable genes, including ATR, BRAF, FGFR2, MAP2K4, PIK3CA, RAF1 and TP53. Changes in clonal composition and the acquisition of additional mutations in brain metastases may affect potentially actionable genes in HER2-positive breast cancers. Our observations have potential clinical implications, given that treatment decisions for patients with brain metastatic disease are still mainly based on biomarkers assessed in the primary tumor.

7.
J Thorac Oncol ; 13(9): 1324-1337, 2018 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-29751136

RESUMO

INTRODUCTION: Mutations in EGFR correlate with impaired response to immune checkpoint inhibitors and the development of novel immunotherapeutic approaches for EGFR mutant NSCLC is of particular interest. Immunization against epidermal growth factor (EGF) has shown efficacy in a phase III trial including unselected NSCLC patients, but little was known about the mechanisms involved in the effects of the anti-EGF antibodies generated by vaccination (anti-EGF VacAbs) or their activity in tumor cells with EGFR mutations. METHODS: The EGFR-mutant, NSCLC cell lines H1975, and PC9, together with several gefitinib and osimertinib-resistant cells derived from PC9, were treated with anti-EGF VacAbs and/or EGFR tyrosine kinase inhibitors (TKIs). Cell viability was analyzed by proliferation assays, cell cycle by fluorescence-activated cell sorting analysis, and levels of RNA and proteins by quantitative retro-transcription polymerase chain reaction and Western blotting. RESULTS: Anti-EGF VacAbs generated in rabbits suppressed EGF-induced cell proliferation and cycle progression and inhibited downstream EGFR signaling in EGFR-mutant cells. Sera from patients immunized with an EGF vaccine were also able to block activation of EGFR effectors. In combination, the anti-EGF VacAbs significantly enhanced the antitumor activity of all TKIs tested, suppressed Erk1/2 phosphorylation, blocked the activation of signal transducer and activator of transcription 3 (STAT3) and downregulated the expression of AXL receptor tyrosine kinase (AXL). Finally, anti-EGF VacAbs significantly delayed the emergence in vitro of EGFR TKI resistant clones. CONCLUSIONS: EGFR-mutant patients can derive benefit from immunization against EGF, particularly if combined with EGFR TKIs. A phase I trial of an EGF vaccine in combination with afatinib has been initiated.

8.
Onco Targets Ther ; 11: 1117-1120, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-29535536

RESUMO

Fusion of the anaplastic lymphoma receptor tyrosine kinase gene (ALK) with the echinoderm microtubule-associated protein 4 gene (EML4) is the second most common actionable alteration in non-small-cell lung cancer, with a frequency of 5%. Here, we present a case of an EML4-ALK-positive patient with an atypical in-frame insertion from the LTBP1 gene in the canonical junction of variant 1. The patient was a 39-year-old never-smoker female diagnosed with Stage IV lung adenocarcinoma. A core biopsy was negative for EGFR and KRAS mutations but positive for ALK immunohistochemistry and fluorescence in situ hybridization. When submitted to nCounter, the sample showed a 3'/5' imbalance indicative of an ALK rearrangement, but failed to give a positive signal for any of the variants tested. Finally, a band with a molecular weight higher than expected appeared after reverse transcriptase-polymerase chain reaction analysis. When Sanger sequencing was performed, the band revealed an atypical EML4-ALK fusion gene with an in-frame 129 bp insertion. A 115 bp segment of the insertion corresponded to an intronic region of LTBP1, a gene located in the short arm of chromosome 2, between ALK and EML4. The patient received crizotinib and showed a good therapeutic response that is still ongoing after 12 months. Our result suggests that short in-frame insertions of other genes in the EML4-ALK junction do not affect the sensitivity of the EML4-ALK fusion protein to crizotinib.

10.
EBioMedicine ; 29: 112-127, 2018 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-29433983

RESUMO

Epidermal growth factor receptor (EGFR)-mutation-positive non-smallcell lung cancer (NSCLC) is incurable, despite high rates of response to EGFR tyrosine kinase inhibitors (TKIs). We investigated receptor tyrosine kinases (RTKs), Src family kinases and focal adhesion kinase (FAK) as genetic modifiers of innate resistance in EGFR-mutation-positive NSCLC. We performed gene expression analysis in two cohorts (Cohort 1 and Cohort 2) of EGFR-mutation-positive NSCLC patients treated with EGFR TKI. We evaluated the efficacy of gefitinib or osimertinib with the Src/FAK/Janus kinase 2 (JAK2) inhibitor, TPX0005 in vitro and in vivo. In Cohort 1, CUB domain-containing protein-1 (CDCP1) was an independent negative prognostic factor for progression-free survival (hazard ratio of 1.79, p=0.0407) and overall survival (hazard ratio of 2.23, p=0.0192). A two-gene model based on AXL and CDCP1 expression was strongly associated with the clinical outcome to EGFR TKIs, in both cohorts of patients. Our preclinical experiments revealed that several RTKs and non-RTKs, were up-regulated at baseline or after treatment with gefitinib or osimertinib. TPX-0005 plus EGFR TKI suppressed expression and activation of RTKs and downstream signaling intermediates. Co-expression of CDCP1 and AXL is often observed in EGFR-mutation-positive tumors, limiting the efficacy of EGFR TKIs. Co-treatment with EGFR TKI and TPX-0005 warrants testing.


Assuntos
Antígenos CD/genética , Carcinoma Pulmonar de Células não Pequenas/genética , Carcinoma Pulmonar de Células não Pequenas/mortalidade , Moléculas de Adesão Celular/genética , Receptores ErbB/genética , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/mortalidade , Mutação , Proteínas de Neoplasias/genética , Proteínas Proto-Oncogênicas/genética , Receptores Proteína Tirosina Quinases/genética , Adulto , Idoso , Idoso de 80 Anos ou mais , Animais , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Carcinoma Pulmonar de Células não Pequenas/patologia , Moléculas de Adesão Celular/agonistas , Sobrevivência Celular , Modelos Animais de Doenças , Resistencia a Medicamentos Antineoplásicos , Ativação Enzimática , Receptores ErbB/antagonistas & inibidores , Feminino , Perfilação da Expressão Gênica , Regulação Neoplásica da Expressão Gênica , Humanos , Neoplasias Pulmonares/patologia , Masculino , Camundongos , Pessoa de Meia-Idade , Modelos Biológicos , Proteínas de Neoplasias/agonistas , Proteômica/métodos , Proteínas Proto-Oncogênicas/agonistas , RNA Interferente Pequeno/genética , RNA Interferente Pequeno/metabolismo , Receptores Proteína Tirosina Quinases/agonistas , Análise de Sobrevida , Ensaios Antitumorais Modelo de Xenoenxerto
11.
Ther Adv Med Oncol ; 10: 1758834017745012, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-29383034

RESUMO

Treatment for advanced non-small cell lung cancer (NSCLC) has been significantly improved in recent years with the incorporation of drugs targeting antiangiogenesis and more specifically genomic alterations such as the EGFR mutations and ALK translocations. However, most patients invariably progress and die. The emergence of immune checkpoint inhibitors targeting the pathways involved in tumor-induced immunosuppression have redefined the management of the disease, achieving significant long-lasting responses with manageable safety profiles, regardless of histology. Still, response rates with immunotherapy are deemed suboptimal. Current efforts are focusing on new potential combination strategies with synergistic antitumor activity, using immune checkpoint blockade as a partner for targeted agents. Herein we discuss the available data on the combined use of immunotherapy, including PD-1/PD-L1 and CTLA-4 inhibitors, with EGFR and ALK inhibitors and comment on the current status of immunotherapy plus antiangiogenic drugs for molecularly unselected advanced NSCLC.

12.
Ther Adv Med Oncol ; 10: 1758834017749748, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-29383037

RESUMO

Background: Programmed death-ligand 1 (PD-L1) may be induced by oncogenic signals or can be upregulated via interferon gamma (IFN-γ). We have explored whether the expression of IFNG, the gene encoding IFN-γ, is associated with clinical response to the immune checkpoint blockade in non-small cell lung cancer (NSCLC) and melanoma patients. The role of inflammation-associated transcription factors STAT3, IKBKE, STAT1 and other associated genes has also been examined. Methods: Total RNA from 17 NSCLC and 21 melanoma patients was analyzed by quantitative reverse transcription PCR. STAT3 and Rantes, YAP1 and CXCL5, DNMT1, RIG1 and TET1, EOMES, IFNG, PD-L1 and CTLA4, IKBKE and NFATC1 mRNA were examined. PD-L1 protein expression in tumor and immune cells and stromal infiltration of CD8+ T-cells were also evaluated. Progression-free survival and overall survival were estimated. Results: A total of 17 NSCLC patients received nivolumab and 21 melanoma patients received pembrolizumab. Progression-free survival with nivolumab was significantly longer in NSCLC patients with high versus low IFNG expression (5.1 months versus 2 months, p = 0.0124). Progression-free survival with pembrolizumab was significantly longer in melanoma patients with high versus low IFNG expression (5.0 months versus 1.9 months, p = 0.0099). Significantly longer overall survival was observed for melanoma patients with high versus low IFNG expression (not reached versus 10.2 months p = 0.0183). There was a trend for longer overall survival for NSCLC patients with high versus low IFNG expression. Conclusions: IFN-γ is an important marker for prediction of response to immune checkpoint blockade. Further research is warranted in order to validate whether IFNG is more accurate than PD-L1.

13.
Nat Commun ; 8(1): 410, 2017 09 04.
Artigo em Inglês | MEDLINE | ID: mdl-28871105

RESUMO

Non-small-cell lung cancer patients with activating epidermal growth factor receptor (EGFR) mutations typically benefit from EGFR tyrosine kinase inhibitor treatment. However, virtually all patients succumb to acquired EGFR tyrosine kinase inhibitor resistance that occurs via diverse mechanisms. The diversity and unpredictability of EGFR tyrosine kinase inhibitor resistance mechanisms presents a challenge for developing new treatments to overcome EGFR tyrosine kinase inhibitor resistance. Here, we show that Akt activation is a convergent feature of acquired EGFR tyrosine kinase inhibitor resistance, across a spectrum of diverse, established upstream resistance mechanisms. Combined treatment with an EGFR tyrosine kinase inhibitor and Akt inhibitor causes apoptosis and synergistic growth inhibition in multiple EGFR tyrosine kinase inhibitor-resistant non-small-cell lung cancer models. Moreover, phospho-Akt levels are increased in most clinical specimens obtained from EGFR-mutant non-small-cell lung cancer patients with acquired EGFR tyrosine kinase inhibitor resistance. Our findings provide a rationale for clinical trials testing Akt and EGFR inhibitor co-treatment in patients with elevated phospho-Akt levels to therapeutically combat the heterogeneity of EGFR tyrosine kinase inhibitor resistance mechanisms.EGFR-mutant non-small cell lung cancer are often resistant to EGFR tyrosine kinase inhibitor treatment. In this study, the authors show that resistant tumors display high Akt activation and that a combined treatment with AKT inhibitors causes synergistic tumour growth inhibition in vitro and in vivo.


Assuntos
Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Receptores ErbB/antagonistas & inibidores , Receptores ErbB/metabolismo , Neoplasias Pulmonares/metabolismo , Proteínas Proto-Oncogênicas c-akt/metabolismo , Animais , Apoptose , Carcinoma Pulmonar de Células não Pequenas/genética , Linhagem Celular Tumoral , Análise Mutacional de DNA , Resistencia a Medicamentos Antineoplásicos , Ativação Enzimática , Feminino , Humanos , Neoplasias Pulmonares/tratamento farmacológico , Neoplasias Pulmonares/genética , Camundongos , Camundongos SCID , Mutação , Transplante de Neoplasias , Proteômica , Transdução de Sinais
14.
J Natl Cancer Inst ; 109(9)2017 09 01.
Artigo em Inglês | MEDLINE | ID: mdl-28376152

RESUMO

Background: The efficacy of epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) in EGFR-mutant non-small cell lung cancer (NSCLC) is limited by adaptive activation of cell survival signals. We hypothesized that both signal transducer and activator of transcription 3 (STAT3) and Src-YES-associated protein 1 (YAP1) signaling are dually activated during EGFR TKI treatment to limit therapeutic response. Methods: We used MTT and clonogenic assays, immunoblotting, and quantitative polymerase chain reaction to evaluate the efficacy of EGFR TKI alone and in combination with STAT3 and Src inhibition in three EGFR-mutant NSCLC cell lines. The Chou-Talalay method was used for the quantitative determination of drug interaction. We examined tumor growth inhibition in one EGFR-mutant NSCLC xenograft model (n = 4 mice per group). STAT3 and YAP1 expression was evaluated in tumors from 119 EGFR-mutant NSCLC patients (64 in an initial cohort and 55 in a validation cohort) by quantitative polymerase chain reaction. Kaplan-Meier and Cox regression analyses were used to assess the correlation between survival and gene expression. All statistical tests were two-sided. Results: We discovered that lung cancer cells survive initial EGFR inhibitor treatment through activation of not only STAT3 but also Src-YAP1 signaling. Cotargeting EGFR, STAT3, and Src was synergistic in two EGFR-mutant NSCLC cell lines with a combination index of 0.59 (95% confidence interval [CI] = 0.54 to 0.63) for the PC-9 and 0.59 (95% CI = 0.54 to 0.63) for the H1975 cell line. High expression of STAT3 or YAP1 predicted worse progression-free survival (hazard ratio [HR] = 3.02, 95% CI = 1.54 to 5.93, P = .001, and HR = 2.57, 95% CI = 1.30 to 5.09, P = .007, respectively) in an initial cohort of 64 EGFR-mutant NSCLC patients treated with firstline EGFR TKIs. Similar results were observed in a validation cohort. Conclusions: Our study uncovers a coordinated signaling network centered on both STAT3 and Src-YAP signaling that limits targeted therapy response in lung cancer and identifies an unforeseen rational upfront polytherapy strategy to minimize residual disease and enhance clinical outcomes.


Assuntos
Proteínas Adaptadoras de Transdução de Sinal/metabolismo , Adenocarcinoma/tratamento farmacológico , Adenocarcinoma/metabolismo , Receptores ErbB/metabolismo , Neoplasias Pulmonares/tratamento farmacológico , Neoplasias Pulmonares/metabolismo , Fosfoproteínas/metabolismo , Fator de Transcrição STAT3/metabolismo , Proteínas Adaptadoras de Transdução de Sinal/antagonistas & inibidores , Proteínas Adaptadoras de Transdução de Sinal/biossíntese , Proteínas Adaptadoras de Transdução de Sinal/genética , Adenocarcinoma/genética , Adenocarcinoma de Pulmão , Adulto , Idoso , Idoso de 80 Anos ou mais , Animais , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Linhagem Celular Tumoral , Receptores ErbB/antagonistas & inibidores , Receptores ErbB/genética , Feminino , Humanos , Neoplasias Pulmonares/genética , Masculino , Camundongos , Camundongos Nus , Pessoa de Meia-Idade , Fosfoproteínas/antagonistas & inibidores , Fosfoproteínas/biossíntese , Fosfoproteínas/genética , Inibidores de Proteínas Quinases/administração & dosagem , RNA Mensageiro/biossíntese , RNA Mensageiro/genética , Estudos Retrospectivos , Fator de Transcrição STAT3/antagonistas & inibidores , Fator de Transcrição STAT3/biossíntese , Fator de Transcrição STAT3/genética , Transdução de Sinais
15.
Clin Chem ; 63(3): 751-760, 2017 03.
Artigo em Inglês | MEDLINE | ID: mdl-28073897

RESUMO

BACKGROUND: Anaplastic lymphoma receptor tyrosine kinase (ALK), ROS proto-oncogene 1, receptor tyrosine kinase (ROS1), and ret proto-oncogene (RET) fusions are present in 5%-7% of patients with advanced non-small-cell lung cancer (NSCLC); their accurate identification is critical to guide targeted therapies. FISH and immunohistochemistry (IHC) are considered the gold standards to determine gene fusions, but they have limitations. The nCounter platform is a potentially useful genomic tool for multiplexed detection of gene fusions, but has not been validated in the clinical setting. METHODS: Formalin-fixed, paraffin embedded (FFPE) samples from 108 patients with advanced NSCLC were analyzed with an nCounter-based assay and the results compared with FISH, IHC, and reverse transcription PCR (RT-PCR). Data on response to fusion kinase inhibitors was retrospectively collected in a subset of 29 patients. RESULTS: Of 108 FFPE samples, 98 were successfully analyzed by nCounter (91%), which identified 55 fusion-positive cases (32 ALK, 21 ROS1, and 2 RET). nCounter results were highly concordant with IHC for ALK (98.5%, CI = 91.8-99.7), while 11 discrepancies were found compared with FISH (87.5% concordance, CI = 79.0-92.9). For ROS1, nCounter showed similar agreement with IHC and FISH (87.2% and 85.9%), but a substantial number of samples were positive only by 1 or 2 techniques. Of the 25 patients deriving clinical benefit from fusion kinase inhibitors, 24 were positive by nCounter and 22 by FISH. CONCLUSIONS: nCounter compares favorably with IHC and FISH and can be used for identifying patients with advanced NSCLC positive for ALK/ROS1/RET fusion genes.


Assuntos
Carcinoma Pulmonar de Células não Pequenas/genética , Proteínas de Fusão Oncogênica/genética , Inclusão em Parafina , Proteínas Tirosina Quinases/genética , Proteínas Proto-Oncogênicas c-ret/genética , Proteínas Proto-Oncogênicas/genética , RNA Mensageiro/análise , Receptores Proteína Tirosina Quinases/genética , Fixação de Tecidos , Quinase do Linfoma Anaplásico , Linhagem Celular Tumoral , Formaldeído , Humanos , Imuno-Histoquímica , Hibridização in Situ Fluorescente , Neoplasias Pulmonares/genética , Proteínas Tirosina Quinases/metabolismo , Proteínas Proto-Oncogênicas/metabolismo , Proteínas Proto-Oncogênicas c-ret/metabolismo , RNA Mensageiro/genética , Receptores Proteína Tirosina Quinases/metabolismo , Reação em Cadeia da Polimerase Via Transcriptase Reversa
16.
Clin Pharmacol Drug Dev ; 6(3): 280-291, 2017 May.
Artigo em Inglês | MEDLINE | ID: mdl-27545757

RESUMO

The efficacy and safety of alectinib, a central nervous system-active and selective anaplastic lymphoma kinase (ALK) inhibitor, has been demonstrated in patients with ALK-positive (ALK+) non-small cell lung cancer (NSCLC) progressing on crizotinib. Alectinib is mainly metabolized by cytochrome P450 3A (CYP3A) to a major similarly active metabolite, M4. Alectinib and M4 show evidence of weak time-dependent inhibition and small induction of CYP3A in vitro. We present results from 3 fixed-sequence studies evaluating drug-drug interactions for alectinib through CYP3A. Studies NP28990 and NP29042 enrolled 17 and 24 healthy subjects, respectively, and investigated potent CYP3A inhibition with posaconazole and potent CYP3A induction through rifampin, respectively, on the single oral dose pharmacokinetics (PK) of alectinib. A substudy of the global phase 2 NP28673 study enrolled 15 patients with ALK+ NSCLC to determine the effect of multiple doses of alectinib on the single oral dose PK of midazolam, a sensitive substrate of CYP3A. Potent CYP3A inhibition or induction resulted in only minor effects on the combined exposure of alectinib and M4. Multiple doses of alectinib did not influence midazolam exposure. These results suggest that dose adjustments may not be needed when alectinib is coadministered with CYP3A inhibitors or inducers or for coadministered CYP3A substrates.


Assuntos
Carbazóis/farmacocinética , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Neoplasias Pulmonares/tratamento farmacológico , Midazolam/administração & dosagem , Piperidinas/farmacocinética , Rifampina/administração & dosagem , Triazóis/administração & dosagem , Adulto , Quinase do Linfoma Anaplásico , Carbazóis/administração & dosagem , Carcinoma Pulmonar de Células não Pequenas/genética , Citocromo P-450 CYP3A/metabolismo , Relação Dose-Resposta a Droga , Feminino , Humanos , Neoplasias Pulmonares/genética , Masculino , Midazolam/farmacologia , Pessoa de Meia-Idade , Piperidinas/administração & dosagem , Receptores Proteína Tirosina Quinases/antagonistas & inibidores , Receptores Proteína Tirosina Quinases/genética , Rifampina/farmacologia , Resultado do Tratamento , Triazóis/farmacologia , Adulto Jovem
17.
Transl Lung Cancer Res ; 5(5): 511-516, 2016 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-27826532

RESUMO

Circulating free DNA (cfDNA) is obtained from serum or plasma by non-invasive methods such as a simple blood draw, a technique known as "liquid biopsy". Genetic analyses of driver alterations in cfDNA have proved very effective to predict survival and treatment response of cancer patients according to tumoral cfDNA burden in blood. Non-small cell lung cancer (NSCLC) patients with higher concentration of tumoral cfDNA in blood have, on average, shorter progression-free survival (PFS) and overall survival (OS). Regarding specific genetic alterations, KRAS proto-oncogene, GTPase (KRAS) is one of the main genes involved in NSCLC and several studies have been performed to determine its value as a predictive and prognostic biomarker in liquid biopsy. Unfortunately, to date no strong conclusions can be drawn since they have yielded contradictory results. Therefore, further investigations are necessary to establish the value of KRAS testing in liquid biopsy as prognostic or predictive factor in NSCLC. Herein, we review the current knowledge on the importance of KRAS as prognostic and predictive biomarker using non-invasive approaches and the scientific data available regarding its application in clinical practice for treatment of NSCLC.

18.
Transl Lung Cancer Res ; 5(5): 525-531, 2016 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-27826534

RESUMO

Obtaining a biopsy of solid tumors requires invasive procedures that strongly limit patient compliance. In contrast, a blood extraction is safe, can be performed at many time points during the course disease and encourages appropriate therapy modifications, potentially improving the patient's clinical outcome and quality of life. Fusion of the tyrosine kinase genes anaplastic lymphoma kinase (ALK), C-ROS oncogen 1 (ROS 1), rearranged during transfection (RET) and neurotrophic tyrosine kinase 1 (NTRK1) occur in 1-5% of lung adenocarcinomas and constitute therapeutic targets for tyrosine kinase inhibitors. In addition, a MET splicing variant of exon 14, has been reported in 2-4% of lung adenocarcinoma and recent studies suggests that targeted therapies inhibiting MET signaling would be beneficial for patients with this alteration. In this review, we will summarize the new techniques recently developed to detect ALK, RET, ROS and NTRK1 fusions and MET exon 14 splicing variant in liquid biopsy using plasma, serum, circulating tumor cells (CTCs), platelets and exosomes as starting material.

19.
Oncotarget ; 7(35): 56619-56627, 2016 Aug 30.
Artigo em Inglês | MEDLINE | ID: mdl-27447748

RESUMO

Approximately 50% of metastatic melanoma patients harbor BRAF mutations. Several treatment options including the combination of BRAF and MEK inhibitors (BRAF/MEKi) and immunotherapy (mainly anti CTLA-4 and anti PD-1 antibodies), have been shown to improve survival in these patients. Although preclinical data support the synergistic effect of both modalities in combination, data confirming the activity and tolerability of these combinations are not yet available in the clinical setting. Herein, we report the case of a melanoma patient treated with sequential BRAF/MEKi (dabrafenib plus trametinib) followed by the anti CTLA-4 antibody ipilimumab who achieved a pathological complete response. Unfortunately, the patient died due to fatal gastrointestinal (GI) toxicity. Analysis of the BRAFV600E mutation in circulating tumoral DNA (ctDNA) from peripheral blood samples and serial tumor tissue biopsies throughout treatment demonstrated a good correlation with clinical evolution.


Assuntos
Trato Gastrointestinal/efeitos dos fármacos , Imidazóis/efeitos adversos , Ipilimumab/efeitos adversos , Melanoma/tratamento farmacológico , Oximas/efeitos adversos , Piridonas/efeitos adversos , Pirimidinonas/efeitos adversos , Neoplasias Cutâneas/tratamento farmacológico , Antineoplásicos Imunológicos/administração & dosagem , Antineoplásicos Imunológicos/efeitos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Biópsia , Neoplasias Ósseas/tratamento farmacológico , Neoplasias Ósseas/secundário , DNA de Neoplasias/sangue , Evolução Fatal , Humanos , Imidazóis/administração & dosagem , MAP Quinase Quinase Quinases/antagonistas & inibidores , Masculino , Melanoma/metabolismo , Pessoa de Meia-Idade , Mutação , Células Neoplásicas Circulantes/metabolismo , Oximas/administração & dosagem , Proteínas Proto-Oncogênicas B-raf/antagonistas & inibidores , Piridonas/administração & dosagem , Pirimidinonas/administração & dosagem , Neoplasias Cutâneas/metabolismo , Resultado do Tratamento
20.
Front Med (Lausanne) ; 3: 69, 2016.
Artigo em Inglês | MEDLINE | ID: mdl-28066769

RESUMO

Liquid biopsy analyses are already incorporated in the routine clinical practice in many hospitals and oncology departments worldwide, improving the selection of treatments and monitoring of lung cancer patients. Although they have not yet reached its full potential, liquid biopsy-based tests will soon be as widespread as "standard" biopsies and imaging techniques, offering invaluable diagnostic, prognostic, and predictive information. This review summarizes the techniques available for the isolation and analysis of circulating free DNA and RNA, exosomes, tumor-educated platelets, and circulating tumor cells from the blood of cancer patients, presents the methodological challenges associated with each of these materials, and discusses the clinical applications of liquid biopsy testing in lung cancer.

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