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1.
Expert Opin Ther Targets ; : 1-10, 2022 Jun 02.
Artigo em Inglês | MEDLINE | ID: mdl-35634856

RESUMO

INTRODUCTION: Despite advances in the treatment of acute myeloid leukemia (AML), long-term survival remains low. In 1994, it was proposed that leukemic stem cells (LSCs) played a key role in relapsed and refractory disease. LSCs are capable of self-renewal, proliferation, differentiation, immune evasion, and drug resistance through several unique mechanisms. More recent leukemia drug development initiatives have included efforts to target LSCs. With LSCs, the challenge with such drug design is finding a way to selectively target LSCs while sparing normal hematopoietic stem cells (HSCs). AREAS COVERED: In this review, we explore the evolving knowledge of the unique LSC biology and physiology in the scientific literature, while noting the several agents that have been designed throughout the years to target this subgroup of leukemic cells. Our review includes discussion on chimeric antigen receptor T cells, monoclonal antibodies, antibody-drug conjugates against cell surface markers, signaling pathway targets, pro-apoptotic agents, epigenetic regulators, and more. EXPERT OPINION: As our understanding of the intricate pathophysiology of LSCs continues to grow, it is clear that targeting such heterogenous cells successfully will require a thoughtful and multi-modal approach.

2.
Nat Med ; 28(6): 1212-1223, 2022 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-35618837

RESUMO

The treatment landscape of acute myeloid leukemia (AML) is evolving, with promising therapies entering clinical translation, yet patient responses remain heterogeneous, and biomarkers for tailoring treatment are lacking. To understand how disease heterogeneity links with therapy response, we determined the leukemia cell hierarchy makeup from bulk transcriptomes of more than 1,000 patients through deconvolution using single-cell reference profiles of leukemia stem, progenitor and mature cell types. Leukemia hierarchy composition was associated with functional, genomic and clinical properties and converged into four overall classes, spanning Primitive, Mature, GMP and Intermediate. Critically, variation in hierarchy composition along the Primitive versus GMP or Primitive versus Mature axes were associated with response to chemotherapy or drug sensitivity profiles of targeted therapies, respectively. A seven-gene biomarker derived from the Primitive versus Mature axis was associated with response to 105 investigational drugs. Cellular hierarchy composition constitutes a novel framework for understanding disease biology and advancing precision medicine in AML.


Assuntos
Leucemia Mieloide Aguda , Biomarcadores , Humanos , Leucemia Mieloide Aguda/tratamento farmacológico , Leucemia Mieloide Aguda/genética , Leucemia Mieloide Aguda/metabolismo
7.
Nat Commun ; 13(1): 614, 2022 02 01.
Artigo em Inglês | MEDLINE | ID: mdl-35105868

RESUMO

Distinct lung stem cells give rise to lung adenocarcinoma (LUAD) and squamous cell carcinoma (LUSC). ΔNp63, the p53 family member and p63 isoform, guides the maturation of these stem cells through the regulation of their self-renewal and terminal differentiation; however, the underlying mechanistic role regulated by ∆Np63 in lung cancer development has remained elusive. By utilizing a ΔNp63-specific conditional knockout mouse model and xenograft models of LUAD and LUSC, we found that ∆Np63 promotes non-small cell lung cancer by maintaining the lung stem cells necessary for lung cancer cell initiation and progression in quiescence. ChIP-seq analysis of lung basal cells, alveolar type 2 (AT2) cells, and LUAD reveals robust ∆Np63 regulation of a common landscape of enhancers of cell identity genes. Importantly, one of these genes, BCL9L, is among the enhancer associated genes regulated by ∆Np63 in Kras-driven LUAD and mediates the oncogenic effects of ∆Np63 in both LUAD and LUSC. Accordingly, high BCL9L levels correlate with poor prognosis in LUAD patients. Taken together, our findings provide a unifying oncogenic role for ∆Np63 in both LUAD and LUSC through the regulation of a common landscape of enhancer associated genes.


Assuntos
Carcinoma Pulmonar de Células não Pequenas/genética , Regulação Neoplásica da Expressão Gênica , Neoplasias Pulmonares/genética , Adenocarcinoma de Pulmão/genética , Adenocarcinoma de Pulmão/patologia , Animais , Carcinoma de Células Escamosas/genética , Carcinoma de Células Escamosas/patologia , Linhagem Celular Tumoral , Proliferação de Células , Epitélio , Feminino , Humanos , Pulmão/patologia , Neoplasias Pulmonares/patologia , Masculino , Camundongos , Camundongos Knockout
8.
Nat Commun ; 12(1): 7081, 2021 12 06.
Artigo em Inglês | MEDLINE | ID: mdl-34873156

RESUMO

Histology plays an essential role in therapeutic decision-making for lung cancer patients. However, the molecular determinants of lung cancer histology are largely unknown. We conduct whole-exome sequencing and microarray profiling on 19 micro-dissected tumor regions of different histologic subtypes from 9 patients with lung cancers of mixed histology. A median of 68.9% of point mutations and 83% of copy number aberrations are shared between different histologic components within the same tumors. Furthermore, different histologic components within the tumors demonstrate similar subclonal architecture. On the other hand, transcriptomic profiling reveals shared pathways between the same histologic subtypes from different patients, which is supported by the analyses of the transcriptomic data from 141 cell lines and 343 lung cancers of different histologic subtypes. These data derived from mixed histologic subtypes in the setting of identical genetic background and exposure history support that the histologic fate of lung cancer cells is associated with transcriptomic features rather than the genomic profiles in most tumors.


Assuntos
Perfilação da Expressão Gênica/métodos , Regulação Neoplásica da Expressão Gênica , Genômica/métodos , Neoplasias Pulmonares/genética , Transcriptoma/genética , Adenocarcinoma/genética , Idoso , Carcinoma de Células Grandes/genética , Carcinoma Neuroendócrino/genética , Carcinoma Pulmonar de Células não Pequenas/genética , Carcinoma de Células Escamosas/genética , Linhagem Celular Tumoral , Humanos , Neoplasias Pulmonares/classificação , Pessoa de Meia-Idade , Fenótipo , Carcinoma de Pequenas Células do Pulmão/genética , Sequenciamento Completo do Exoma/métodos
9.
Nat Commun ; 12(1): 6071, 2021 10 18.
Artigo em Inglês | MEDLINE | ID: mdl-34663807

RESUMO

In contrast to the curative effect of allogenic stem cell transplantation in acute myeloid leukemia via T cell activity, only modest responses are achieved with checkpoint-blockade therapy, which might be explained by T cell phenotypes and T cell receptor (TCR) repertoires. Here, we show by paired single-cell RNA analysis and TCR repertoire profiling of bone marrow cells in relapsed/refractory acute myeloid leukemia patients pre/post azacytidine+nivolumab treatment that the disease-related T cell subsets are highly heterogeneous, and their abundance changes following PD-1 blockade-based treatment. TCR repertoires expand and primarily emerge from CD8+ cells in patients responding to treatment or having a stable disease, while TCR repertoires contract in therapy-resistant patients. Trajectory analysis reveals a continuum of CD8+ T cell phenotypes, characterized by differential expression of granzyme B and a bone marrow-residing memory CD8+ T cell subset, in which a population with stem-like properties expressing granzyme K is enriched in responders. Chromosome 7/7q loss, on the other hand, is a cancer-intrinsic genomic marker of PD-1 blockade resistance in AML. In summary, our study reveals that adaptive T cell plasticity and genomic alterations determine responses to PD-1 blockade in acute myeloid leukemia.


Assuntos
Inibidores de Checkpoint Imunológico/uso terapêutico , Leucemia Mieloide Aguda/tratamento farmacológico , Receptor de Morte Celular Programada 1/antagonistas & inibidores , Receptores de Antígenos de Linfócitos T/metabolismo , Linfócitos T/efeitos dos fármacos , Idoso , Idoso de 80 Anos ou mais , Azacitidina/uso terapêutico , Medula Óssea/efeitos dos fármacos , Medula Óssea/imunologia , Linfócitos T CD8-Positivos/efeitos dos fármacos , Linfócitos T CD8-Positivos/imunologia , Linfócitos T CD8-Positivos/metabolismo , Deleção Cromossômica , Cromossomos Humanos Par 7/genética , Resistencia a Medicamentos Antineoplásicos/genética , Granzimas/metabolismo , Humanos , Leucemia Mieloide Aguda/genética , Leucemia Mieloide Aguda/imunologia , Pessoa de Meia-Idade , Nivolumabe/uso terapêutico , Receptores de Antígenos de Linfócitos T/genética , Análise de Célula Única , Subpopulações de Linfócitos T/efeitos dos fármacos , Subpopulações de Linfócitos T/imunologia , Subpopulações de Linfócitos T/metabolismo , Linfócitos T/imunologia , Linfócitos T/metabolismo , Transcriptoma/efeitos dos fármacos
10.
Blood Adv ; 5(22): 4569-4574, 2021 11 23.
Artigo em Inglês | MEDLINE | ID: mdl-34555853

RESUMO

Acute myeloid leukemia (AML) remains a difficult disease to treat disease. In a phase 2 clinical trial in patients with relapsed/refractory AML, combining the hypomethylating agent, azacitidine, with the PD-1 checkpoint inhibitor, nivolumab, demonstrated encouraging response rates (33%), median event-free, and overall survival, compared with a historical cohort of contemporary patients treated with azacitidine-based therapies, with an acceptable safety profile. Biomarkers of response are yet to be determined. In this study, we leveraged a multiplexed immune assay to assess the functional states of CD4+ and CD8+ cells at a single-cell level in pretherapy bone marrows in 16 patients with relapsed/refractory AML treated with azacitidine/nivolumab. Effector CD4+ but not CD8+ cells had distinct polyfunctional groups and were associated with responses and better outcomes. Further evaluation of the polyfunctional strength index composition across cell types revealed that interferon-gamma (IFN-γ) and tumor necrosis factor-alpha (TNF-α) were the major drivers of enhanced polyfunctionality index of pretherapy CD4+ subset, whereas Granzyme B, IFN-γ, MIP-1b, and TNF-α drove the nonsignificantly enhanced pretreatment Polyfunctional Strength Index of CD8+ subset in the responders. Single-cell polyfunctional assays were predictive of response in AML and may have a potential role as a biomarker in the wider sphere of immunotherapy.


Assuntos
Leucemia Mieloide Aguda , Proteômica , Azacitidina/uso terapêutico , Linfócitos T CD4-Positivos , Linfócitos T CD8-Positivos , Humanos , Leucemia Mieloide Aguda/tratamento farmacológico
11.
Leuk Lymphoma ; 62(14): 3402-3410, 2021 12.
Artigo em Inglês | MEDLINE | ID: mdl-34380367

RESUMO

Myeloid sarcoma (MS) in the setting of concomitant medullary AML is relatively well described, while much less is known about patients presenting with MS with <20% bone marrow blasts. We conducted a retrospective analysis of 56 patients with MS with <20% marrow blasts seen at MD Anderson between 2005 and 2020. The prevalence of MS without medullary AML was 1.4% among all newly diagnosed AML patients. The majority (75%) of patients had a single known anatomic site involved, with the skin (34%) being the most frequent. The most common histologic subtype was monocytic, and 11% of patients had a known history of an antecedent hematologic disorder. The majority of patients (70%) received frontline intensive chemotherapy induction, with 75% of those evaluable attaining complete or partial responses. The median overall survival (OS) and event-free survival (EFS) were 3.41 and 3.07 years, respectively. Patients with bone marrow blasts of ≥5% or medullary relapse had inferior outcomes, while age (>60 years) was not associated with outcomes. There was a suggestion that patients with isolated leukemia cutis may have had better outcomes compared to patients with other organ involvement, but this did not reach statistical significance. Most patients who had cytogenetic analysis had a diploid karyotype within their MS and bone marrow. RAS pathway mutations were enriched in MS at diagnosis, and at time of medullary relapse. Our study provides a large dataset summarizing the clinical and molecular analysis of patients with MS with <20% BM blasts and suggests that monitoring for medullary leukemia is important for early detection of relapse.


Assuntos
Leucemia Mieloide Aguda , Sarcoma Mieloide , Medula Óssea/patologia , Humanos , Leucemia Mieloide Aguda/genética , Pessoa de Meia-Idade , Prognóstico , Recidiva , Estudos Retrospectivos , Sarcoma Mieloide/diagnóstico , Sarcoma Mieloide/genética
12.
Front Oncol ; 11: 668162, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34055635

RESUMO

Bruton tyrosine kinase (BTK) is a validated target for treatment of B-cell malignancies, and oral inhibitors of BTK have emerged as a standard of care for these diseases. Acalabrutinib is a second generation, highly selective, potent, covalent BTK inhibitor that exhibits minimal off-target activity in in vitro assays, providing the potential to improve tolerability over the first-in-class BTK inhibitor, ibrutinib. Acalabrutinib was approved for the treatment of relapsed/refractory mantle cell lymphoma (MCL) and chronic lymphocytic leukemia (CLL) in the US in 2017 and 2019, respectively. Acalabrutinib is also undergoing trials for other B-cell malignancies, both as monotherapy and in combinations. In this review, we discuss results from clinical trials evaluating the efficacy and safety of acalabrutinib in patients with CLL, MCL, and Waldenstrom's macroglobulinemia. Recent phase 3 data showed that acalabrutinib improved progression-free survival (PFS) compared with rituximab plus idelalisib or rituximab plus bendamustine in patients with relapsed/refractory CLL, and acalabrutinib with or without obinutuzumab improved PFS compared with chlorambucil plus obinutuzumab in patients with treatment-naïve CLL. Overall, acalabrutinib had a tolerable safety profile, with most adverse events being grade 1/2 severity (most commonly headache and diarrhea) and a low rate of discontinuation due to adverse events.

13.
Front Immunol ; 12: 659625, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33912187

RESUMO

Aberrant T-cell function is implicated in the pathogenesis of myelodysplastic syndrome (MDS). Monitoring the T-cell receptor (TCR) repertoire can provide insights into T-cell adaptive immunity. Previous studies found skewed TCR repertoires in MDS compared to healthy patients; however these studies that leverage mRNA-based spectratyping have limitations. Furthermore, evaluating the TCR repertoire in context of hypomethylating agents (HMAs) treatment can provide insights into the dynamics of T-cell mediated responses in MDS. We conducted immunosequencing of the CDR3 regions of TCRß chains in bone marrows of 11 MDS patients prior to treatment (n=11 bone marrows prior to treatment), and in at least 2 timepoints for each patient following treatment (n=26 bone marrow aspirates post-treatment) with (HMA), alongside analyzing bone marrows from 4 healthy donors as controls. TCR repertoires in MDS patients were more clonal and less diverse than healthy donors. However, unlike previous reports, we did not observe significant skewness in CDR3 length or spectratyping. The global metrics of TCR profiling including richness, clonality, overlaps were not significantly changed in responders or non-responders following treatment with HMAs. However, we found an emergence of novel clonotypes in MDS patients who responded to treatment, while non-responders had a higher frequency of contracted clonotypes following treatment. By applying GLIPH2 for antigen prediction, we found rare TCR specificity clusters shared by TCR clonotypes from different patients at pre- or following treatment. Our data show clear differences in TCR repertoires of MDS compared with healthy patients and that novel TCR clonotype emergence in response to HMA therapy was correlated with response. This suggests that response to HMA therapy may be partially driven by T-cell mediated immunity and that the immune-based therapies, which target the adaptive immune system, may play a significant role in select patients with MDS.


Assuntos
Azacitidina/uso terapêutico , Metilação de DNA/efeitos dos fármacos , Decitabina/uso terapêutico , Síndromes Mielodisplásicas/genética , Receptores de Antígenos de Linfócitos T alfa-beta/genética , Idoso , Idoso de 80 Anos ou mais , Células Clonais/efeitos dos fármacos , Células Clonais/imunologia , Células Clonais/metabolismo , Estudos de Coortes , Regiões Determinantes de Complementaridade/genética , Regiões Determinantes de Complementaridade/imunologia , Inibidores Enzimáticos/uso terapêutico , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Síndromes Mielodisplásicas/tratamento farmacológico , Síndromes Mielodisplásicas/imunologia , Reação em Cadeia da Polimerase/métodos , Receptores de Antígenos de Linfócitos T alfa-beta/imunologia , Análise de Sequência de DNA/métodos , Linfócitos T/efeitos dos fármacos , Linfócitos T/imunologia , Linfócitos T/metabolismo , Resultado do Tratamento
15.
Front Oncol ; 11: 705627, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34422660

RESUMO

Acute myeloid leukemia (AML) is a heterogeneous disease with variable responses to therapy. Cytogenetic and genomic features are used to classify AML patients into prognostic and treatment groups. However, these molecular characteristics harbor significant patient-to-patient variability and do not fully account for AML heterogeneity. RNA-based classifications have also been applied in AML as an alternative approach, but transcriptomic grouping is strongly associated with AML morphologic lineages. We used a training cohort of newly diagnosed AML patients and conducted unsupervised RNA-based classification after excluding lineage-associated genes. We identified three AML patient groups that have distinct biological pathways associated with outcomes. Enrichment of inflammatory pathways and downregulation of HOX pathways were associated with improved outcomes, and this was validated in 2 independent cohorts. We also identified a group of AML patients who harbored high metabolic and mTOR pathway activity, and this was associated with worse clinical outcomes. Using a comprehensive reverse phase protein array, we identified higher mTOR protein expression in the highly metabolic group. We also identified a positive correlation between degree of resistance to venetoclax and mTOR activation in myeloid and lymphoid cell lines. Our approach of integrating RNA, protein, and genomic data uncovered lineage-independent AML patient groups that share biologic mechanisms and can inform outcomes independent of commonly used clinical and demographic variables; these groups could be used to guide therapeutic strategies.

16.
Cancer Res ; 80(13): 2833-2847, 2020 07 01.
Artigo em Inglês | MEDLINE | ID: mdl-32312834

RESUMO

ΔNp63 is a transcription factor of the p53 family and has crucial functions in normal development and disease. The expression pattern of ΔNp63 in human cancer suggests dynamic regulation of this isoform during cancer progression and metastasis. Many primary and metastatic tumors express high levels of ΔNp63, while ΔNp63 loss is crucial for tumor dissemination, indicating an oscillatory expression of ΔNp63 during cancer progression. Here, we use genetically engineered orthotopic mouse models of breast cancer to show that while depletion of ΔNp63 inhibits primary mammary adenocarcinoma development, oscillatory expression of ΔNp63 in established tumors is crucial for metastatic dissemination in breast cancer. A TGFß-regulated miRNA network acted as upstream regulators of this oscillatory expression of ΔNp63 during cancer progression. This work sheds light on the pleiotropic roles of ΔNp63 in cancer and unveils critical functions of TGFß in the metastatic process. SIGNIFICANCE: This study unveils TGFß signaling and a network of four miRNAs as upstream regulators of ΔNp63, providing key information for the development of therapeutic strategies to treat cancers that commonly overexpress ΔNp63.


Assuntos
Biomarcadores Tumorais/genética , Neoplasias da Mama/patologia , Regulação Neoplásica da Expressão Gênica , Neoplasias Pulmonares/secundário , MicroRNAs/genética , Fatores de Transcrição/metabolismo , Fator de Crescimento Transformador beta/metabolismo , Proteínas Supressoras de Tumor/metabolismo , Adenocarcinoma/genética , Adenocarcinoma/metabolismo , Adenocarcinoma/patologia , Animais , Apoptose , Neoplasias da Mama/genética , Neoplasias da Mama/metabolismo , Carcinoma de Células Escamosas/genética , Carcinoma de Células Escamosas/metabolismo , Carcinoma de Células Escamosas/patologia , Proliferação de Células , Feminino , Humanos , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/metabolismo , Camundongos , Camundongos Nus , Mutação , Prognóstico , Análise Espaço-Temporal , Fatores de Transcrição/genética , Fator de Crescimento Transformador beta/genética , Células Tumorais Cultivadas , Proteínas Supressoras de Tumor/genética , Neoplasias da Bexiga Urinária/genética , Neoplasias da Bexiga Urinária/metabolismo , Neoplasias da Bexiga Urinária/patologia , Ensaios Antitumorais Modelo de Xenoenxerto
17.
Am J Case Rep ; 21: e918878, 2020 Mar 21.
Artigo em Inglês | MEDLINE | ID: mdl-32198341

RESUMO

BACKGROUND Primary cardiac tumors are rare and mostly benign. Cardiac sarcomas are the most common malignant neoplasms of the heart and harbor a dismal prognosis of 6 to 12 months. The diagnosis of cardiac sarcomas may be challenging. Treatment entails surgical resection despite the high rate of recurrence, as well as adjuvant chemotherapy. CASE REPORT In this report, we discuss a case of a 58-year-old male with undifferentiated pleomorphic primary cardiac sarcomas who received multiple lines of treatment that included surgery, chemotherapy, and targeted therapy and was alive more than 4 years after his diagnosis. Herein, we discuss the different treatment regimens utilized and we present detailed imaging of his case findings at different treatment stages. CONCLUSIONS Treatment of undifferentiated pleomorphic cardiac sarcoma requires a multidisciplinary approach. Surgery and adjuvant treatment are commonly utilized, while neoadjuvant treatment is under investigation.


Assuntos
Neoplasias Cardíacas/diagnóstico por imagem , Neoplasias Cardíacas/terapia , Histiocitoma Fibroso Maligno/diagnóstico por imagem , Histiocitoma Fibroso Maligno/terapia , Procedimentos Cirúrgicos Cardíacos , Quimiorradioterapia Adjuvante , Quimioterapia Adjuvante , Neoplasias Cardíacas/diagnóstico , Histiocitoma Fibroso Maligno/diagnóstico , Humanos , Masculino , Pessoa de Meia-Idade , Terapia Neoadjuvante , Prognóstico , Fatores de Tempo
18.
Cancer Res ; 80(12): 2484-2497, 2020 06 15.
Artigo em Inglês | MEDLINE | ID: mdl-32156775

RESUMO

TAp63 is a p53 family member and potent tumor and metastasis suppressor. Here, we show that TAp63-/- mice exhibit an increased susceptibility to ultraviolet radiation-induced cutaneous squamous cell carcinoma (cuSCC). A human-to-mouse comparison of cuSCC tumors identified miR-30c-2* and miR-497 as underexpressed in TAp63-deficient cuSCC. Reintroduction of these miRNAs significantly inhibited the growth of cuSCC cell lines and tumors. Proteomic profiling of cells expressing either miRNA showed downregulation of cell-cycle progression and mitosis-associated proteins. A mouse to human and cross-platform comparison of RNA-sequencing and proteomics data identified a 7-gene signature, including AURKA, KIF18B, PKMYT1, and ORC1, which were overexpressed in cuSCC. Knockdown of these factors in cuSCC cell lines suppressed tumor cell proliferation and induced apoptosis. In addition, selective inhibition of AURKA suppressed cuSCC cell proliferation, induced apoptosis, and showed antitumor effects in vivo. Finally, treatment with miR-30c-2* or miR-497 miRNA mimics was highly effective in suppressing cuSCC growth in vivo. Our data establish TAp63 as an essential regulator of novel miRNAs that can be therapeutically targeted for potent suppression of cuSCC. SIGNIFICANCE: This study provides preclinical evidence for the use of miR-30c-2*/miR-497 delivery and AURKA inhibition in the treatment of cuSCC, which currently has no FDA-approved targeted therapies.See related commentary by Parrales and Iwakuma, p. 2439.


Assuntos
Carcinoma de Células Escamosas , MicroRNAs , Neoplasias Cutâneas , Animais , Aurora Quinase A/genética , Carcinoma de Células Escamosas/genética , Proliferação de Células/genética , Humanos , Proteínas de Membrana , Camundongos , MicroRNAs/genética , Proteínas Tirosina Quinases , Proteômica , Neoplasias Cutâneas/genética , Raios Ultravioleta
19.
Clin Cancer Res ; 26(4): 892-901, 2020 02 15.
Artigo em Inglês | MEDLINE | ID: mdl-31694833

RESUMO

PURPOSE: The optimal systemic treatment for pulmonary large-cell neuroendocrine carcinoma (LCNEC) is still under debate. Previous studies showed that LCNEC with different genomic characteristics might respond differently to different chemotherapy regimens. In this study, we sought to investigate genomic subtyping using cell-free DNA (cfDNA) analysis in advanced LCNEC and assess its potential prognostic and predictive value. EXPERIMENTAL DESIGN: Tumor DNA and cfDNA from 63 patients with LCNEC were analyzed by target-captured sequencing. Survival and response analyses were applied to 54 patients with advanced stage incurable disease who received first-line chemotherapy. RESULTS: The mutation landscape of frequently mutated cancer genes in LCNEC from cfDNA closely resembled that from tumor DNA, which led to a 90% concordance in genomic subtyping. The 63 patients with LCNEC were classified into small-cell lung cancer (SCLC)-like and non-small cell lung cancer (NSCLC)-like LCNEC based on corresponding genomic features derived from tumor DNA and/or cfDNA. Overall, patients with SCLC-like LCNEC had a shorter overall survival than those with NSCLC-like LCNEC despite higher response rate (RR) to chemotherapy. Furthermore, treatment with etoposide-platinum was associated with superior response and survival in SCLC-like LCNEC compared with pemetrexed-platinum and gemcitabine/taxane-platinum doublets, while treatment with gemcitabine/taxane-platinum led to a shorter survival compared with etoposide-platinum or pemetrexed-platinum in patients with NSCLC-like LCNEC. CONCLUSIONS: Genomic subtyping has potential in prognostication and therapeutic decision-making for patients with LCNEC and cfDNA analysis may be a reliable alternative for genomic profiling of LCNEC.


Assuntos
Carcinoma de Células Grandes/genética , Carcinoma Neuroendócrino/genética , Ácidos Nucleicos Livres/genética , Neoplasias Pulmonares/genética , Adulto , Idoso , Idoso de 80 Anos ou mais , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Hidrocarbonetos Aromáticos com Pontes/administração & dosagem , Carcinoma de Células Grandes/sangue , Carcinoma de Células Grandes/tratamento farmacológico , Carcinoma de Células Grandes/patologia , Carcinoma Neuroendócrino/sangue , Carcinoma Neuroendócrino/tratamento farmacológico , Carcinoma Neuroendócrino/patologia , Ácidos Nucleicos Livres/sangue , Desoxicitidina/administração & dosagem , Desoxicitidina/análogos & derivados , Etoposídeo/administração & dosagem , Feminino , Genômica , Sequenciamento de Nucleotídeos em Larga Escala/métodos , Humanos , Neoplasias Pulmonares/sangue , Neoplasias Pulmonares/tratamento farmacológico , Neoplasias Pulmonares/patologia , Masculino , Pessoa de Meia-Idade , Mutação , Compostos Organoplatínicos/administração & dosagem , Pemetrexede/administração & dosagem , Prognóstico , Taxa de Sobrevida , Taxoides/administração & dosagem
20.
Cancer Manag Res ; 11: 8817-8828, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31632141

RESUMO

Fms-related-tyrosine kinase 3 (FLT3) mutations occur in approximately a third of acute myeloid leukemia (AML) patients and confer an adverse prognosis. Numerous studies have evaluated FLT3 targeting as single agent and in combination approaches in frontline and relapsed AML. At this time, midostaurin, a multikinase inhibitor, is the only FLT3-inhibitor that is US FDA approved to be used in combination with induction therapy in the frontline FLT3-mutated AML setting based on improved overall survival noted in the RATIFY Phase III trial. The utility of midostaurin in maintenance post stem cell transplantation has shown promising results and further studies are still ongoing. In this review, we discuss the studies that led to the inception of midostaurin as a targeted kinase inhibitor, its evaluation in AML, the early clinical trials and the large Phase III clinical trial that led to its eventual US FDA-approval in FLT3-mutated AML. Our review also discusses data on midostaurin adverse effects, mechanisms of resistance and limitations of its utility. We further discuss emerging second-generation FLT3 inhibitors, with a focus on quizartinib and gilteritinib and future directions to enhance FLT3-inhibitor efficacy and overcome mechanisms of resistance.

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