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1.
Mol Cancer ; 23(1): 93, 2024 May 08.
Artigo em Inglês | MEDLINE | ID: mdl-38720314

RESUMO

BACKGROUND: Circulating tumor cells (CTCs) hold immense promise for unraveling tumor heterogeneity and understanding treatment resistance. However, conventional methods, especially in cancers like non-small cell lung cancer (NSCLC), often yield low CTC numbers, hindering comprehensive analyses. This study addresses this limitation by employing diagnostic leukapheresis (DLA) to cancer patients, enabling the screening of larger blood volumes. To leverage DLA's full potential, this study introduces a novel approach for CTC enrichment from DLAs. METHODS: DLA was applied to six advanced stage NSCLC patients. For an unbiased CTC enrichment, a two-step approach based on negative depletion of hematopoietic cells was used. Single-cell (sc) whole-transcriptome sequencing was performed, and CTCs were identified based on gene signatures and inferred copy number variations. RESULTS: Remarkably, this innovative approach led to the identification of unprecedented 3,363 CTC transcriptomes. The extensive heterogeneity among CTCs was unveiled, highlighting distinct phenotypes related to the epithelial-mesenchymal transition (EMT) axis, stemness, immune responsiveness, and metabolism. Comparison with sc transcriptomes from primary NSCLC cells revealed that CTCs encapsulate the heterogeneity of their primary counterparts while maintaining unique CTC-specific phenotypes. CONCLUSIONS: In conclusion, this study pioneers a transformative method for enriching CTCs from DLA, resulting in a substantial increase in CTC numbers. This allowed the creation of the first-ever single-cell whole transcriptome in-depth characterization of the heterogeneity of over 3,300 NSCLC-CTCs. The findings not only confirm the diagnostic value of CTCs in monitoring tumor heterogeneity but also propose a CTC-specific signature that can be exploited for targeted CTC-directed therapies in the future. This comprehensive approach signifies a major leap forward, positioning CTCs as a key player in advancing our understanding of cancer dynamics and paving the way for tailored therapeutic interventions.


Assuntos
Biomarcadores Tumorais , Carcinoma Pulmonar de Células não Pequenas , Leucaférese , Neoplasias Pulmonares , Células Neoplásicas Circulantes , Fenótipo , Células Neoplásicas Circulantes/patologia , Células Neoplásicas Circulantes/metabolismo , Humanos , Carcinoma Pulmonar de Células não Pequenas/genética , Carcinoma Pulmonar de Células não Pequenas/diagnóstico , Carcinoma Pulmonar de Células não Pequenas/patologia , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/patologia , Neoplasias Pulmonares/diagnóstico , Análise de Célula Única/métodos , Transcriptoma , Transição Epitelial-Mesenquimal/genética , Perfilação da Expressão Gênica , Linhagem Celular Tumoral
2.
Int J Mol Sci ; 25(7)2024 Apr 03.
Artigo em Inglês | MEDLINE | ID: mdl-38612799

RESUMO

EGFR exon 20 (EGFR Ex20) insertion mutations in non-small cell lung cancer (NSCLC) are insensitive to traditional EGFR tyrosine kinase inhibitors (TKIs). Mobocertinib is the only approved TKI specifically designed to target EGFR Ex20. We performed an international, real-world safety and efficacy analysis on patients with EGFR Ex20-positive NSCLC enrolled in a mobocertinib early access program. We explored the mechanisms of resistance by analyzing postprogression biopsies, as well as cross-resistance to amivantamab. Data from 86 patients with a median age of 67 years and a median of two prior lines of treatment were analyzed. Treatment-related adverse events (TRAEs) occurred in 95% of patients. Grade ≥3 TRAEs were reported in 38% of patients and included diarrhea (22%) and rash (8%). In 17% of patients, therapy was permanently discontinued, and two patients died due to TRAEs. Women were seven times more likely to discontinue treatment than men. In the overall cohort, the objective response rate to mobocertinib was 34% (95% CI, 24-45). The response rate in treatment-naïve patients was 27% (95% CI, 8-58). The median progression-free and overall survival was 5 months (95% CI, 3.5-6.5) and 12 months (95% CI, 6.8-17.2), respectively. The intracranial response rate was limited (13%), and one-third of disease progression cases involved the brain. Mobocertinib also showed antitumor activity following EGFR Ex20-specific therapy and vice versa. Potential mechanisms of resistance to mobocertinib included amplifications in MET, PIK3CA, and NRAS. Mobocertinib demonstrated meaningful efficacy in a real-world setting but was associated with considerable gastrointestinal and cutaneous toxicity.


Assuntos
Compostos de Anilina , Carcinoma Pulmonar de Células não Pequenas , Indóis , Neoplasias Pulmonares , Pirimidinas , Masculino , Humanos , Feminino , Idoso , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Carcinoma Pulmonar de Células não Pequenas/genética , Neoplasias Pulmonares/tratamento farmacológico , Neoplasias Pulmonares/genética , Receptores ErbB/genética , Éxons
3.
Ann Hematol ; 102(2): 323-328, 2023 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-36576532

RESUMO

Relapse in patients with acute myeloid leukemia (AML) is common and is associated with a dismal prognosis. Treatment options are limited and the understanding of molecular response patterns is still challenging. We analyzed the clonal response patterns of 15 patients with relapsed/refractory AML treated with selinexor in a phase II trial (SAIL). DNA was analyzed at three time points and showed a decline of mutated alleles in FLT3, SF3B1, and TP53 under SAIL treatment. Overall survival (OS) was similar between patients with declining versus persisting clones. We show an interesting long-term course of a patient who relapsed after allogeneic stem cell transplantation (alloHCT) with SF3B1- and SRSF2-mutated AML and received selinexor as maintenance treatment for 4 years. Measurable residual disease (MRD) remained detectable for 2 weeks after donor lymphocyte infusion (DLI) in this patient and then remained negative under selinexor maintenance treatment. Selinexor was tolerated well and was stopped after 4 years of SAIL treatment. We present an exploratory study and identify subclonal patterns of patients treated with selinexor.


Assuntos
Transplante de Células-Tronco Hematopoéticas , Leucemia Mieloide Aguda , Humanos , Leucemia Mieloide Aguda/tratamento farmacológico , Leucemia Mieloide Aguda/genética , Prognóstico , Recidiva
4.
Int J Mol Sci ; 24(17)2023 Aug 29.
Artigo em Inglês | MEDLINE | ID: mdl-37686200

RESUMO

Analysis of circulating tumor DNA (ctDNA) is a potential minimally invasive molecular tool to guide treatment decision-making and disease monitoring. A suitable diagnostic-grade platform is required for the detection of tumor-specific mutations with high sensitivity in the circulating cell-free DNA (ccfDNA) of cancer patients. In this multicenter study, the ccfDNA of 72 patients treated for advanced-stage non-small cell lung cancer (NSCLC) was evaluated using the UltraSEEK® Lung Panel on the MassARRAY® System, covering 73 hotspot mutations in EGFR, KRAS, BRAF, ERBB2, and PIK3CA against mutation-specific droplet digital PCR (ddPCR) and routine tumor tissue NGS. Variant detection accuracy at primary diagnosis and during disease progression, and ctDNA dynamics as a marker of treatment efficacy, were analyzed. A multicenter evaluation using reference material demonstrated an overall detection rate of over 90% for variant allele frequencies (VAFs) > 0.5%, irrespective of ccfDNA input. A comparison of UltraSEEK® and ddPCR analyses revealed a 90% concordance. An 80% concordance between therapeutically targetable mutations detected in tumor tissue NGS and ccfDNA UltraSEEK® analysis at baseline was observed. Nine of 84 (11%) tumor tissue mutations were not covered by UltraSEEK®. A decrease in ctDNA levels at 4-6 weeks after treatment initiation detected with UltraSEEK® correlated with prolonged median PFS (46 vs. 6 weeks; p < 0.05) and OS (145 vs. 30 weeks; p < 0.01). Using plasma-derived ccfDNA, the UltraSEEK® Lung Panel with a mid-density set of the most common predictive markers for NSCLC is an alternative tool to detect mutations both at diagnosis and during disease progression and to monitor treatment response.


Assuntos
Carcinoma Pulmonar de Células não Pequenas , Ácidos Nucleicos Livres , DNA Tumoral Circulante , Neoplasias Pulmonares , Humanos , DNA Tumoral Circulante/genética , Carcinoma Pulmonar de Células não Pequenas/diagnóstico , Carcinoma Pulmonar de Células não Pequenas/genética , Neoplasias Pulmonares/diagnóstico , Neoplasias Pulmonares/genética , Mutação , Progressão da Doença , Pulmão
5.
Int J Mol Sci ; 22(13)2021 Jun 29.
Artigo em Inglês | MEDLINE | ID: mdl-34209696

RESUMO

Up to 40% of advance lung, melanoma and breast cancer patients suffer from brain metastases (BM) with increasing incidence. Here, we assessed whether circulating tumor cells (CTCs) in peripheral blood can serve as a disease surrogate, focusing on CD44 and CD74 expression as prognostic markers for BM. We show that a size-based microfluidic approach in combination with a semi-automated cell recognition system are well suited for CTC detection in BM patients and allow further characterization of tumor cells potentially derived from BM. CTCs were found in 50% (7/14) of breast cancer, 50% (9/18) of non-small cell lung cancer (NSCLC) and 36% (4/11) of melanoma patients. The next-generation sequencing (NGS) analysis of nine single CTCs from one breast cancer patient revealed three different CNV profile groups as well as a resistance causing ERS1 mutation. CD44 and CD74 were expressed on most CTCs and their expression was strongly correlated, whereas matched breast cancer BM tissues were much less frequently expressing CD44 and CD74 (negative in 46% and 54%, respectively). Thus, plasticity of CD44 and CD74 expression during trafficking of CTCs in the circulation might be the result of adaptation strategies.


Assuntos
Antígenos de Diferenciação de Linfócitos B/genética , Neoplasias Encefálicas/genética , Neoplasias Encefálicas/secundário , Antígenos de Histocompatibilidade Classe II/genética , Receptores de Hialuronatos/genética , Células Neoplásicas Circulantes/metabolismo , Antígenos de Diferenciação de Linfócitos B/metabolismo , Biomarcadores Tumorais , Neoplasias Encefálicas/diagnóstico , Neoplasias da Mama/patologia , Carcinoma Pulmonar de Células não Pequenas/patologia , Linhagem Celular Tumoral , Feminino , Antígenos de Histocompatibilidade Classe II/metabolismo , Humanos , Receptores de Hialuronatos/metabolismo , Imuno-Histoquímica , Masculino , Mutação , Sequenciamento Completo do Genoma
6.
Int J Cancer ; 145(3): 857-868, 2019 08 01.
Artigo em Inglês | MEDLINE | ID: mdl-30694523

RESUMO

We analyzed the predictive potential of pretreatment soluble carbonic anhydrase IX levels (sCAIX) for the efficacy of bevacizumab in the phase III neoadjuvant GeparQuinto trial. sCAIX was determined by enzyme-linked immunosorbent assay (ELISA). Correlations between sCAIX and pathological complete response (pCR), disease-free and overall survival (DFS, OS) were assessed with logistic and Cox proportional hazard regression models using bootstrapping for robust estimates and internal validation. 1,160 HER2-negative patient sera were analyzed, of whom 577 received bevacizumab. Patients with low pretreatment sCAIX had decreased pCR rates (12.1 vs. 20.1%, p = 0.012) and poorer DFS (adjusted 5-year DFS 71.4 vs. 80.5 months, p = 0.010) compared to patients with high sCAIX when treated with neoadjuvant chemotherapy (NCT). For patients with low sCAIX, pCR rates significantly improved upon addition of bevacizumab to NCT (12.1 vs. 20.4%; p = 0.017), which was not the case in patients with high sCAIX (20.1% for NCT vs. 17.0% for NCT-B, p = 0.913). When analyzing DFS we found that bevacizumab improved 5-year DFS for patients with low sCAIX numerically but not significantly (71.4 vs. 78.5 months; log rank 0.234). In contrast, addition of bevacizumab worsened 5-year DFS for patients with high sCAIX (81 vs. 73.6 months, log-rank 0.025). By assessing sCAIX levels we identified a patient cohort in breast cancer that is potentially undertreated with NCT alone. Bevacizumab improved pCR rates in this group, suggesting sCAIX is a predictive biomarker for bevacizumab with regards to treatment response. Our data also show that bevacizumab is not beneficial in patients with high sCAIX.


Assuntos
Antígenos de Neoplasias/sangue , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Neoplasias da Mama/tratamento farmacológico , Neoplasias da Mama/enzimologia , Anidrase Carbônica IX/sangue , Adulto , Idoso , Bevacizumab/administração & dosagem , Biomarcadores Tumorais/sangue , Quimioterapia Adjuvante , Ciclofosfamida/administração & dosagem , Intervalo Livre de Doença , Docetaxel/administração & dosagem , Epirubicina/administração & dosagem , Feminino , Humanos , Pessoa de Meia-Idade , Terapia Neoadjuvante , Adulto Jovem
7.
Br J Haematol ; 183(2): 235-241, 2018 10.
Artigo em Inglês | MEDLINE | ID: mdl-30378121

RESUMO

This open-label, multicentre phase I/II study determined the maximum tolerated dose (MTD), safety and efficacy of clofarabine administered with cytarabine and idarubicin in newly diagnosed acute myeloid leukaemia (AML) patients lacking favourable genetic aberrations. The MTD was 30 mg/m2 clofarabine for patients below and above 60 years. The most frequently reported grade 3-4 non-haematological adverse events were infectious and gastrointestinal toxicities. Complete remission (CR)/CR with incomplete recovery rate was 67%. Allogeneic haematopoietic cell transplantation in first remission was feasible in a high proportion of younger AML patients and probably contributed to the favourable outcome compared to historical controls.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Leucemia Mieloide Aguda/tratamento farmacológico , Adulto , Idoso , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Clofarabina/administração & dosagem , Clofarabina/efeitos adversos , Citarabina/administração & dosagem , Citarabina/efeitos adversos , Relação Dose-Resposta a Droga , Feminino , Transplante de Células-Tronco Hematopoéticas , Humanos , Idarubicina/administração & dosagem , Idarubicina/efeitos adversos , Quimioterapia de Indução/métodos , Masculino , Dose Máxima Tolerável , Pessoa de Meia-Idade , Indução de Remissão
8.
J Biol Chem ; 290(42): 25275-92, 2015 Oct 16.
Artigo em Inglês | MEDLINE | ID: mdl-26296892

RESUMO

CD2AP is an adaptor protein involved in membrane trafficking, with essential roles in maintaining podocyte function within the kidney glomerulus. CD2AP contains three Src homology 3 (SH3) domains that mediate multiple protein-protein interactions. However, a detailed comparison of the molecular binding preferences of each SH3 remained unexplored, as well as the discovery of novel interactors. Thus, we studied the binding properties of each SH3 domain to the known interactor Casitas B-lineage lymphoma protein (c-CBL), conducted a peptide array screen based on the recognition motif PxPxPR and identified 40 known or novel candidate binding proteins, such as RIN3, a RAB5-activating guanine nucleotide exchange factor. CD2AP SH3 domains 1 and 2 generally bound with similar characteristics and specificities, whereas the SH3-3 domain bound more weakly to most peptide ligands tested yet recognized an unusually extended sequence in ALG-2-interacting protein X (ALIX). RIN3 peptide scanning arrays revealed two CD2AP binding sites, recognized by all three SH3 domains, but SH3-3 appeared non-functional in precipitation experiments. RIN3 recruited CD2AP to RAB5a-positive early endosomes via these interaction sites. Permutation arrays and isothermal titration calorimetry data showed that the preferred binding motif is Px(P/A)xPR. Two high-resolution crystal structures (1.65 and 1.11 Å) of CD2AP SH3-1 and SH3-2 solved in complex with RIN3 epitopes 1 and 2, respectively, indicated that another extended motif is relevant in epitope 2. In conclusion, we have discovered novel interaction candidates for CD2AP and characterized subtle yet significant differences in the recognition preferences of its three SH3 domains for c-CBL, ALIX, and RIN3.


Assuntos
Proteínas Adaptadoras de Transdução de Sinal/metabolismo , Proteínas de Transporte/metabolismo , Proteínas do Citoesqueleto/metabolismo , Fatores de Troca do Nucleotídeo Guanina/metabolismo , Proteínas ras/metabolismo , Domínios de Homologia de src , Proteínas Adaptadoras de Transdução de Sinal/química , Sequência de Aminoácidos , Sítios de Ligação , Biologia Computacional , Cristalografia por Raios X , Proteínas do Citoesqueleto/química , Células HEK293 , Humanos , Dados de Sequência Molecular , Homologia de Sequência de Aminoácidos
9.
Br J Haematol ; 169(5): 694-700, 2015 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-25818407

RESUMO

Acute myeloid leukaemia (AML) with FLT3 mutation has a dismal prognosis in elderly patients. Treatment with a combination of FLT3 inhibitors and standard chemotherapy has not been extensively studied. Therefore, we instigated a phase I/II clinical trial of chemotherapy with cytosine arabinoside (Ara-C)/daunorubicin induction (7+3) followed by three cycles of intermediate-dose Ara-C consolidation in 22 AML patients with activating FLT3 mutations. Sunitinib was added at predefined dose levels and as maintenance therapy for 2 years. At dose level 1, sunitinib 25 mg daily continuously from day 1 onwards resulted in two cases with dose-limiting toxicity (DLT), prolonged haemotoxicity and hand-foot syndrome. At dose level -1, sunitinib 25 mg was restricted to days 1-7 of each chemotherapy cycle. One DLT was observed in six evaluable patients. Six additional patients were treated in an extension phase. Thirteen of 22 patients (59%; 8/14 with FLT3-internal tandem duplication and 5/8 with FLT3-tyrosine kinase domain) achieved a complete remission/complete remission with incomplete blood count recovery. For the 17 patients included at the lower dose level, median overall, relapse-free and event-free survival were 1·6, 1·0 and 0·4 years, respectively. Four out of five analysed patients with relapse during maintenance therapy lost their initial FLT3 mutation, suggesting outgrowth of FLT3 wild-type subclones.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Leucemia Mieloide Aguda/tratamento farmacológico , Leucemia Mieloide Aguda/genética , Mutação , Tirosina Quinase 3 Semelhante a fms/genética , Fatores Etários , Idoso , Antineoplásicos/administração & dosagem , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Feminino , Humanos , Indóis/administração & dosagem , Leucemia Mieloide Aguda/diagnóstico , Leucemia Mieloide Aguda/mortalidade , Masculino , Pessoa de Meia-Idade , Pirróis/administração & dosagem , Indução de Remissão , Sunitinibe , Resultado do Tratamento
11.
Blood ; 122(14): 2443-52, 2013 Oct 03.
Artigo em Inglês | MEDLINE | ID: mdl-23982172

RESUMO

Acute myeloid leukemia (AML) represents a clonal disease of hematopoietic progenitors characterized by acquired heterogenous genetic changes that alter normal mechanisms of proliferation, self-renewal, and differentiation.(1) Although 40% to 45% of patients younger than 65 years of age can be cured with current therapies, only 10% of older patients reach long-term survival.(1) Because only very few novel AML drugs were approved in the past 2 decades, there is an urgent need to identify novel targets and therapeutic strategies to treat underserved AML patients. We report here that Axl, a member of the Tyro3, Axl, Mer receptor tyrosine kinase family,(2-4) represents an independent prognostic marker and therapeutic target in AML. AML cells induce expression and secretion of the Axl ligand growth arrest-specific gene 6 (Gas6) by bone marrow-derived stromal cells (BMDSCs). Gas6 in turn mediates proliferation, survival, and chemoresistance of Axl-expressing AML cells. This Gas6-Axl paracrine axis between AML cells and BMDSCs establishes a chemoprotective tumor cell niche that can be abrogated by Axl-targeting approaches. Axl inhibition is active in FLT3-mutated and FLT3 wild-type AML, improves clinically relevant end points, and its efficacy depends on presence of Gas6 and Axl. Axl inhibition alone or in combination with chemotherapy might represent a novel therapeutic avenue for AML.


Assuntos
Células da Medula Óssea/metabolismo , Leucemia Mieloide Aguda/metabolismo , Comunicação Parácrina/fisiologia , Proteínas Proto-Oncogênicas/metabolismo , Receptor Cross-Talk/fisiologia , Receptores Proteína Tirosina Quinases/metabolismo , Animais , Antineoplásicos/farmacocinética , Western Blotting , Ensaios Clínicos como Assunto , Modelos Animais de Doenças , Ensaio de Imunoadsorção Enzimática , Feminino , Humanos , Peptídeos e Proteínas de Sinalização Intercelular/metabolismo , Estimativa de Kaplan-Meier , Leucemia Mieloide Aguda/tratamento farmacológico , Leucemia Mieloide Aguda/genética , Masculino , Camundongos , Prognóstico , Reação em Cadeia da Polimerase em Tempo Real , Células Estromais/metabolismo , Ensaios Antitumorais Modelo de Xenoenxerto , Receptor Tirosina Quinase Axl
12.
Future Oncol ; 10(7): 1157-65, 2014 May.
Artigo em Inglês | MEDLINE | ID: mdl-24947257

RESUMO

Volasertib is a potent inhibitor of Polo-like kinase (PLK) 1 and to lesser extent also PLK2 and PLK3. PLKs are key regulators of the cell cycle and volasertib blocks cells in G2-M phase of the cell cycle. The compound has been evaluated in Phase I and II studies in acute myeloid leukemia and solid tumors. Side effects are mainly hematological. In acute myeloid leukemia (AML), a randomized Phase II study has been conducted in elderly patients unfit for intensive chemotherapy. Patients have been randomized to a combination of volarsetib and low-dose cytarabine versus low-dose cytarabine alone. Preliminary results show significantly higher rates of complete remission and of complete remission with incomplete hematological recovery in the combination versus the monotherapy arm, with 31% and 13%, respectively. Longer event-free survival was observed with the combination with 5.6 versus 2.3 months, respectively (p = 0.0237). These encouraging data supported the initiation of an international Phase III trial, which currently underway, to confirm these results. Volasertib has not yet been approved for regular clinical use.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/farmacologia , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Leucemia Mieloide Aguda/tratamento farmacológico , Animais , Citarabina/administração & dosagem , Doenças Desmielinizantes , Intervalo Livre de Doença , Avaliação Pré-Clínica de Medicamentos , Humanos , Inibidores de Proteínas Quinases/administração & dosagem , Pteridinas/administração & dosagem , Ensaios Clínicos Controlados Aleatórios como Assunto
13.
J Thorac Oncol ; 19(5): 803-817, 2024 May.
Artigo em Inglês | MEDLINE | ID: mdl-38096950

RESUMO

INTRODUCTION: Programmed death-ligand 1 expression currently represents the only validated predictive biomarker for immune checkpoint inhibition in metastatic NSCLC in the clinical routine, but it has limited value in distinguishing responses. Assessment of KRAS and TP53 mutations (mut) as surrogate for an immunosupportive tumor microenvironment (TME) might help to close this gap. METHODS: A total of 696 consecutive patients with programmed death-ligand 1-high (≥50%), nonsquamous NSCLC, having received molecular testing within the German National Network Genomic Medicine Lung Cancer between 2017 and 2020, with Eastern Cooperative Oncology Group performance status less than or equal to 1 and pembrolizumab as first-line palliative treatment, were included into this retrospective cohort analysis. Treatment efficacy and outcome according to KRAS/TP53 status were correlated with TME composition and gene expression analysis of The Cancer Genome Atlas lung adenocarcinoma cohort. RESULTS: Proportion of KRASmut and TP53mut was 53% (G12C 25%, non-G12C 28%) and 51%, respectively. In KRASmut patients, TP53 comutations increased response rates (G12C: 69.7% versus 46.5% [TP53mut versus wild-type (wt)], p = 0.004; non-G12C: 55.4% versus 39.5%, p = 0.03), progression-free survival (G12C: hazard ratio [HR] = 0.59, p = 0.009, non-G12C: HR = 0.7, p = 0.047), and overall survival (G12C: HR = 0.72, p = 0.16, non-G12C: HR = 0.56, p = 0.002), whereas no differences were observed in KRASwt patients. After a median follow-up of 41 months, G12C/TP53mut patients experienced the longest progression-free survival and overall survival (33.7 and 65.3 mo), which correlated with high tumor-infiltrating lymphocyte densities in the TME and up-regulation of interferon gamma target genes. Proinflammatory pathways according to TP53 status (mut versus wt) were less enhanced and not different in non-G12C and KRASwt, respectively. CONCLUSIONS: G12C/TP53 comutations identify a subset of patients with a very favorable long-term survival with immune checkpoint inhibitor monotherapy, mediated by highly active interferon gamma signaling in a proinflammatory TME.


Assuntos
Anticorpos Monoclonais Humanizados , Carcinoma Pulmonar de Células não Pequenas , Neoplasias Pulmonares , Mutação , Proteínas Proto-Oncogênicas p21(ras) , Proteína Supressora de Tumor p53 , Humanos , Neoplasias Pulmonares/tratamento farmacológico , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/patologia , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Carcinoma Pulmonar de Células não Pequenas/genética , Carcinoma Pulmonar de Células não Pequenas/patologia , Proteínas Proto-Oncogênicas p21(ras)/genética , Masculino , Feminino , Anticorpos Monoclonais Humanizados/uso terapêutico , Proteína Supressora de Tumor p53/genética , Idoso , Estudos Retrospectivos , Pessoa de Meia-Idade , Alemanha , Antineoplásicos Imunológicos/uso terapêutico , Idoso de 80 Anos ou mais , Antígeno B7-H1/metabolismo , Antígeno B7-H1/genética , Adulto , Resultado do Tratamento
14.
Acta Haematol ; 129(2): 121-5, 2013.
Artigo em Inglês | MEDLINE | ID: mdl-23207728

RESUMO

BACKGROUND: Xeroderma pigmentosum (XP) is an autosomal recessive inherited disease characterized by extreme sensitivity to sunlight. Normal individuals harboring XPD polymorphisms are at increased risk for developing acute lymphoblastic leukemia and acute myeloid leukemia (AML). CASE REPORT: A 33-year-old male XP patient was diagnosed with acute megakaryoblastic leukemia with a complex karyotype. He received standard induction chemotherapy with cytarabine and daunorubicin. After the first cycle of chemotherapy, persistence of blasts was seen and a re-induction cycle with cytarabine, fludarabine, and idarubicin was administered resulting in complete remission. Due to the high-risk profile of his AML, allogeneic stem cell transplantation (SCT) was performed. Following a conditioning regimen with busulfan and cyclophosphamide, the patient received a matched related SCT from his HLA-identical sister. Despite the existence of his DNA repair gene mutation, chemotherapy was normally tolerated by the patient. Unfortunately, he died due to severe sepsis and relapse of AML 45 days after SCT. CONCLUSION: The XPD mutation in our patient may have contributed to the emergence of his high-risk AML. Despite the existence of a DNA repair gene mutation, our XP patient could be treated with full doses of AML-type chemotherapy including allogeneic SCT without encountering unusual toxicity.


Assuntos
Leucemia Megacarioblástica Aguda/etiologia , Leucemia Mieloide Aguda/etiologia , Xeroderma Pigmentoso/complicações , Adulto , Aneuploidia , Citarabina/administração & dosagem , Reparo do DNA/genética , Daunorrubicina/administração & dosagem , Evolução Fatal , Transplante de Células-Tronco Hematopoéticas , Humanos , Idarubicina/administração & dosagem , Leucemia Megacarioblástica Aguda/genética , Leucemia Megacarioblástica Aguda/terapia , Leucemia Mieloide Aguda/genética , Leucemia Mieloide Aguda/terapia , Masculino , Terapia Neoadjuvante , Recidiva , Indução de Remissão , Transplante Homólogo , Vidarabina/administração & dosagem , Vidarabina/análogos & derivados , Xeroderma Pigmentoso/genética
15.
Mol Cell Proteomics ; 10(12): M111.011635, 2011 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-21955398

RESUMO

Tumors of the head and neck represent a molecularly diverse set of human cancers, but relatively few proteins have actually been shown to drive the disease at the molecular level. To identify new targets for individualized diagnosis or therapeutic intervention, we performed a kinase centric chemical proteomics screen and quantified 146 kinases across 34 head and neck squamous cell carcinoma (HNSCC) cell lines using intensity-based label-free mass spectrometry. Statistical analysis of the profiles revealed significant intercell line differences for 42 kinases (p < 0.05), and loss of function experiments using siRNA in high and low expressing cell lines identified kinases including EGFR, NEK9, LYN, JAK1, WEE1, and EPHA2 involved in cell survival and proliferation. EGFR inhibition by the small molecule inhibitors lapatinib, gefitinib, and erlotinib as well as siRNA led to strong reduction of viability in high but not low expressing lines, confirming EGFR as a drug target in 10-20% of HNSCC cell lines. Similarly, high, but not low EPHA2-expressing cells showed strongly reduced viability concomitant with down-regulation of AKT and ERK signaling following EPHA2 siRNA treatment or EPHA1-Fc ligand exposure, suggesting that EPHA2 is a novel drug target in HNSCC. This notion is underscored by immunohistochemical analyses showing that high EPHA2 expression is detected in a subset of HNSCC tissues and is associated with poor prognosis. Given that the approved pan-SRC family kinase inhibitor dasatinib is also a very potent inhibitor of EPHA2, our findings may lead to new therapeutic options for HNSCC patients. Importantly, the strategy employed in this study is generic and therefore also of more general utility for the identification of novel drug targets and molecular pathway markers in tumors. This may ultimately lead to a more rational approach to individualized cancer diagnosis and therapy.


Assuntos
Carcinoma/enzimologia , Receptor EphA2/metabolismo , Neoplasias da Língua/enzimologia , Carcinoma/tratamento farmacológico , Proteínas de Ciclo Celular/metabolismo , Linhagem Celular Tumoral , Sobrevivência Celular , Receptores ErbB/metabolismo , Técnicas de Silenciamento de Genes , Humanos , Janus Quinase 1/metabolismo , Terapia de Alvo Molecular , Quinases Relacionadas a NIMA , Proteínas Nucleares/metabolismo , Inibidores de Proteínas Quinases/farmacologia , Proteínas Quinases/metabolismo , Proteínas Serina-Treonina Quinases/metabolismo , Proteínas Tirosina Quinases/metabolismo , Proteômica , Proteínas Proto-Oncogênicas c-met/metabolismo , Interferência de RNA , Receptor EphA2/genética , Proteína Serina-Treonina Quinase 2 de Interação com Receptor/metabolismo , Análise Serial de Tecidos , Neoplasias da Língua/tratamento farmacológico , Quinases da Família src/genética , Quinases da Família src/metabolismo
16.
Clin Lung Cancer ; 24(6): 568-572, 2023 09.
Artigo em Inglês | MEDLINE | ID: mdl-37169628

RESUMO

INTRODUCTION: Pemetrexed-based immunochemotherapy represents an established standard of care as first line treatment for non-oncogenic driven metastatic non-small cell lung adenocarcinoma (NSCLC/ADC). However, retrospective analyses revealed better outcomes for pemetrexed-free regimens compared to pemetrexed-containing regimens in patients with thyroid transcription factor 1 (TTF-1) negative NSCLC/ADC. The multicenter, phase II, randomized, open-label ANTELOPE trial evaluates whether atezolizumab, carboplatin and nab-paclitaxel is superior to pembrolizumab, cis-/carboplatin and pemetrexed in TTF-1 negative NSCLC/ADC. METHODS: Eligible participants are ≥18 years of age, with histologically or cytologically confirmed, treatment-naïve stage IV TTF-1 negative NSCLC/ADC without actionable genomic alterations or PD-L1-overexpression (TPS ≥50%) and will be randomized in a 1:1 fashion to pemetrexed-free (group A) vs. pemetrexed-based (group B) immunochemotherapy. The primary endpoint of this trial is overall survival (OS). RESULTS: Enrollment will start in Q2 2023 at 30 sites in Germany with a planned inclusion of 136 participants. CONCLUSION: ANTELOPE will provide efficacy outcomes of the current standard-of-care for the specific subset of TTF-1 negative NSCLC/ADC in a head-to-head comparison of approved immunochemotherapy regimens.


Assuntos
Adenocarcinoma de Pulmão , Adenocarcinoma , Carcinoma Pulmonar de Células não Pequenas , Neoplasias Pulmonares , Humanos , Adenocarcinoma/tratamento farmacológico , Adenocarcinoma de Pulmão/tratamento farmacológico , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Carboplatina , Carcinoma Pulmonar de Células não Pequenas/patologia , Neoplasias Pulmonares/patologia , Pemetrexede/uso terapêutico , Platina/uso terapêutico , Estudos Retrospectivos , Fator Nuclear 1 de Tireoide
17.
Cancer Biol Med ; 19(11)2022 12 05.
Artigo em Inglês | MEDLINE | ID: mdl-36476337

RESUMO

Lung cancer remains the leading cause of cancer-associated mortality worldwide, but with the emergence of oncogene targeted therapies, treatment options have tremendously improved. Owing to their biological relevance, members of the ERBB receptor family, including the EGF receptor (EGFR), HER2, HER3 and HER4, are among the best studied oncogenic drivers. Activating EGFR mutations are frequently observed in non-small cell lung cancer (NSCLC), and small molecule tyrosine kinase inhibitors (TKIs) are the established first line treatment option for patients whose tumors bear "typical/classical" EGFR mutations (exon 19 deletions, L858R point mutations). Additionally, new TKIs are rapidly evolving with better efficacy to overcome primary and secondary treatment resistance (e.g., that due to T790M or C797S resistance mutations). Some atypical EGFR mutations, such as the most frequent exon 20 insertions, exhibit relative resistance to earlier generation TKIs through steric hindrance. In this subgroup, newer TKIs, such as mobocertinib and the bi-specific antibody amivantamab have recently been approved, whereas less frequent atypical EGFR mutations remain understudied. In contrast to EGFR, HER2 has long remained a challenging target, but better structural understanding has led to the development of newer generations of TKIs. The recent FDA approval of the antibody-drug conjugate trastuzumab-deruxtecan for pretreated patients with HER2 mutant NSCLC has been an important therapeutic breakthrough. HER3 and HER4 also exert oncogenic potential, and targeted treatment approaches are being developed, particularly for HER3. Overall, strategies to inhibit the oncogenic function of ERBB receptors in NSCLC are currently evolving at an unprecedented pace; therefore, this review summarizes current treatment standards and discusses the outlook for future developments.


Assuntos
Carcinoma Pulmonar de Células não Pequenas , Neoplasias Pulmonares , Humanos , Receptores ErbB/genética , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Carcinoma Pulmonar de Células não Pequenas/genética , Neoplasias Pulmonares/tratamento farmacológico , Neoplasias Pulmonares/genética , Mutação , Inibidores de Proteínas Quinases/farmacologia , Inibidores de Proteínas Quinases/uso terapêutico
18.
Lung Cancer ; 164: 46-51, 2022 02.
Artigo em Inglês | MEDLINE | ID: mdl-34998106

RESUMO

OBJECTIVES: Immune checkpoint inhibitors (ICI) have significantly improved outcome of patients with advanced NSCLC and recently also showed benefit in early-stage disease. Patients with oligometastatic disease (OMD) harbor limited metastases, resectable primary tumors and derive benefit from treatment with multimodal locally ablative and systemic therapy approaches. Nothing is known about feasibility and efficacy of neoadjuvant ICI in this setting. MATERIAL AND METHODS: We here provide data from a multicenter retrospective study comprising 13 patients with NSCLC and OMD (≤3 distant metastases) from 5 university medical centers in Germany who have been treated with neoadjuvant ICI alone (n = 4) or in combination with chemotherapy (CT) (n = 9) prior to resection of the primary tumor. We analyzed complete (pCR) and major pathological remission (MPR) rates. RESULTS: These data show that neoadjuvant immunotherapy applied mostly in combination with CT results in high rates of pCR and MPR (54 and 69%, respectively). Up to now, 85% of patients are free of progression with a median follow-up of 9 months (3-28 months). Single cell RNASeq analysis of tumor tissue from one patient treated with CT-ICI indicates a strong predominance of adaptive immune cell populations over a small minority of epithelial (tumor) cells. CONCLUSION: Neoadjuvant ICI with or without CT is a promising therapeutic concept in patients with OMD.


Assuntos
Carcinoma Pulmonar de Células não Pequenas , Neoplasias Pulmonares , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Humanos , Inibidores de Checkpoint Imunológico , Neoplasias Pulmonares/tratamento farmacológico , Terapia Neoadjuvante , Estudos Retrospectivos
19.
Eur J Cancer ; 170: 106-118, 2022 07.
Artigo em Inglês | MEDLINE | ID: mdl-35598358

RESUMO

BACKGROUND: EGFR exon20 insertions (ex20ins) are targeted by novel compounds in non-small-cell lung cancer (NSCLC). However, data about outcome under conventional therapies and the influence of molecular features are scarce. PATIENTS AND METHODS: We retrospectively analysed 118 patients with evaluation of radiologic response based on RECIST v1.1. TP53 status was available for 88 cases. RESULTS: Platinum doublets and chemoimmunotherapy showed similar response rates (20-25%), disease control rates (80%) and median progression-free survival (mPFS, ≈7 months), which were longer compared to monochemotherapy (9%, 59%, 4.1 months), EGFR inhibitors (0%, 46%, 3.0) and PD-(L)1 inhibitors (0%, 30%, 2.1; p < 0.05). Overall survival (OS) was not dependent on the choice of first-line treatment, but related to more lines of systemic therapy (p < 0.05). TP53 mutations and brain metastases were associated with shorter PFS under platinum doublets and EGFR inhibitors (HR 3.3-6.1, p < 0.01), and shorter OS for patients receiving both treatments (p < 0.05). More tumour CD8+ and less Th1 cells were associated with longer OS independent of brain and TP53 status (p < 0.01). No difference in outcome was noted according to the ex20ins site and use of pemetrexed (vs. other cytotoxics) or bevacizumab. Long-lasting responses (>1 year) occasionally occurred under EGFR inhibitors for both 'near-' and 'far-loop' variants. CONCLUSIONS: Platinum doublets and chemoimmunotherapy have the highest activity with ORR of 20-25% and mPFS of approximately 7 months, regardless of the cytotoxic partner, while PD-(L)1 inhibitors show limited efficacy. TP53 mutations, brain metastases and a lower tumour CD8/Th1-cell ratio are independently associated with shorter survival.


Assuntos
Antineoplásicos , Carcinoma Pulmonar de Células não Pequenas , Receptores ErbB , Neoplasias Pulmonares , Proteína Supressora de Tumor p53 , Antineoplásicos/uso terapêutico , Neoplasias Encefálicas/genética , Neoplasias Encefálicas/secundário , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Carcinoma Pulmonar de Células não Pequenas/genética , Carcinoma Pulmonar de Células não Pequenas/patologia , Receptores ErbB/genética , Éxons , Humanos , Neoplasias Pulmonares/tratamento farmacológico , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/patologia , Mutação , Platina/uso terapêutico , Inibidores de Proteínas Quinases/uso terapêutico , Estudos Retrospectivos , Microambiente Tumoral/genética , Proteína Supressora de Tumor p53/genética
20.
Sci Adv ; 7(33)2021 08.
Artigo em Inglês | MEDLINE | ID: mdl-34389533

RESUMO

Malignant pleural effusion (MPE) results from the capacity of several human cancers to metastasize to the pleural cavity. No effective treatments are currently available, reflecting our insufficient understanding of the basic mechanisms leading to MPE progression. Here, we found that efferocytosis through the receptor tyrosine kinases AXL and MERTK led to the production of interleukin-10 (IL-10) by four distinct pleural cavity macrophage (Mφ) subpopulations characterized by different metabolic states and cell chemotaxis properties. In turn, IL-10 acts on dendritic cells (DCs) inducing the production of tissue inhibitor of metalloproteinases 1 (TIMP1). Genetic ablation of Axl and Mertk in Mφs or IL-10 receptor in DCs or Timp1 substantially reduced MPE progression. Our results delineate an inflammatory cascade-from the clearance of apoptotic cells by Mφs, to production of IL-10, to induction of TIMP1 in DCs-that facilitates MPE progression. This inflammatory cascade offers a series of therapeutic targets for MPE.

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