RESUMO
Acute myeloid leukemia (AML) is a heterogeneous disease and the most common form of acute leukemia with a poor prognosis. Due to its complexity, the disease requires the identification of biomarkers for reliable prognosis. To identify potential disease genes that regulate patient prognosis, we used differential co-expression network analysis and transcriptomics data from relapsed, refractory, and previously untreated AML patients based on their response to treatment in the present study. In addition, we combined functional genomics and transcriptomics data to identify novel and therapeutically potential systems biomarkers for patients who do or do not respond to treatment. As a result, we constructed co-expression networks for response and non-response cases and identified a highly interconnected group of genes consisting of SECISBP2L, MAN1A2, PRPF31, VASP, and SNAPC1 in the response network and a group consisting of PHTF2, SLC11A2, PDLIM5, OTUB1, and KLRD1 in the non-response network, both of which showed high prognostic performance with hazard ratios of 4.12 and 3.66, respectively. Remarkably, ETS1, GATA2, AR, YBX1, and FOXP3 were found to be important transcription factors in both networks. The prognostic indicators reported here could be considered as a resource for identifying tumorigenesis and chemoresistance to farnesyltransferase inhibitor. They could help identify important research directions for the development of new prognostic and therapeutic techniques for AML.
Assuntos
Leucemia Mieloide Aguda , Humanos , Farnesiltranstransferase/genética , Farnesiltranstransferase/uso terapêutico , Leucemia Mieloide Aguda/tratamento farmacológico , Leucemia Mieloide Aguda/genética , Prognóstico , Perfilação da Expressão Gênica/métodos , Inibidores Enzimáticos/uso terapêutico , Fatores de Transcrição/genética , Biomarcadores Tumorais/genéticaRESUMO
BACKGROUND: Ulcerative colitis (UC) is the most prevalent chronic inflammatory immune bowel disease. The modernization of lifestyle accompanied by the stress to cope with the competition has resulted in a new range of complications where stress became a critical contributing factor for many diseases, including UC. Hence there is an urgent need to develop a dual role in curtailing both systemic and neuroinflammation. Perillyl alcohol (POH) is a natural essential oil found in lavender, peppermint, cherries etc and has been widely studied for its strong anti-inflammatory, antioxidant and anti-stress properties. HYPOTHESIS/PURPOSE: POH regulates the various inflammatory signaling cascades involved in chronic inflammation by inhibiting farnesyltransferase enzyme. Several studies reported that POH could inhibit the phosphorylation of NF-κB, STAT3 and promote the endogenous antioxidant enzymes like Nrf2 via farnesyltransferase enzyme inhibition. Also, the effects of POH against UC is not known yet. Thus, this study aims to explore the anti-ulcerative properties of POH on stress aggravated ulcerative colitis in C57BL/6 mice. METHODS: Ulcerative colitis was induced by duel exposure of chronic restraint stress (day 1 to day 28) and 2.5% dextran sulphate sodium (day8 to day14) in mice. POH treatment 100 and 200 mg/kg was administred from day14 ti day28 following oral route of administration. Disease activity index, colonoscopy, western blot analysis and histological analysis, neurotransmitter analysis and Gene expression studies were perofomerd to asses the anti-colitis effects of POH. RESULTS: The treatment reversed the oxidative stress and inflammatory response by inhibiting TLR4/NF-kB pathway, and IL-6/JAK2/STAT3 pathway in both isolated mice colons and brains. The inhibition of these pathways resulted in a decrease in pro-inflammatory cytokines like IL-6, IL-1ß and TNF-α. The treatment improved the physiological and histological changes with decreased ulcerations as examined by colonic endoscopy and Haematoxylin and Eosin staining. The treatment also improved the behavior response as it increased mobility time which was reduced by chronic restrained stress. This was due to increased satiety neurotransmitters like dopamine and serotonin and decreased cortisol in mice brains. CONCLUSION: These results infer that POH has significant anti-colitis activity on chronic restraint stress aggravated DSS-induced UC in mice.
Assuntos
Colite Ulcerativa , Óleos Voláteis , Animais , Anti-Inflamatórios/farmacologia , Anti-Inflamatórios/uso terapêutico , Antioxidantes/farmacologia , Antioxidantes/uso terapêutico , Colite Ulcerativa/induzido quimicamente , Colite Ulcerativa/tratamento farmacológico , Citocinas , Sulfato de Dextrana/efeitos adversos , Dopamina , Amarelo de Eosina-(YS)/efeitos adversos , Farnesiltranstransferase/metabolismo , Farnesiltranstransferase/farmacologia , Farnesiltranstransferase/uso terapêutico , Hidrocortisona/farmacologia , Interleucina-6/farmacologia , Camundongos , Camundongos Endogâmicos C57BL , Monoterpenos , Fator 2 Relacionado a NF-E2/metabolismo , NF-kappa B/metabolismo , Óleos Voláteis/farmacologia , Serotonina/farmacologia , Transdução de Sinais , Receptor 4 Toll-Like/metabolismo , Fator de Necrose Tumoral alfa/metabolismoRESUMO
Hutchinson-Gilford progeria syndrome (HGPS) is a rare genetic disorder characterized by premature ageing and early death at a mean age of 14.7 years. At the molecular level, HGPS is caused by a de novo heterozygous mutation in LMNA, the gene encoding A-type lamins (mainly lamin A and C) and nuclear proteins, which have important cellular functions related to structure of the nuclear envelope. The LMNA mutation leads to the synthesis of a truncated prelamin A protein (called progerin), which cannot undergo normal processing to mature lamin A. In normal cells, prelamin A processing involves four posttranslational processing steps catalysed by four different enzymes. In HGPS cells, progerin accumulates as a farnesylated and methylated intermediate in the nuclear envelope where it is toxic and causes nuclear shape abnormalities and senescence. Numerous efforts have been made to target and reduce the toxicity of progerin, eliminate its synthesis and enhance its degradation, but as of today, only the use of farnesyltransferase inhibitors is approved for clinical use in HGPS patients. Here, we review the main current strategies that are being evaluated for treating HGPS, and we focus on efforts to target the posttranslational processing of progerin.
Assuntos
Progéria , Adolescente , Farnesiltranstransferase/genética , Farnesiltranstransferase/metabolismo , Farnesiltranstransferase/uso terapêutico , Humanos , Lamina Tipo A/genética , Lamina Tipo A/metabolismo , Proteínas Nucleares/genética , Progéria/tratamento farmacológico , Progéria/genética , Progéria/metabolismo , Processamento de Proteína Pós-TraducionalRESUMO
Small cell lung cancer (SCLC) lacks effective treatments to overcome chemoresistance. Here we established multiple human chemoresistant xenograft models through long-term intermittent chemotherapy, mimicking clinically relevant therapeutic settings. We show that chemoresistant SCLC undergoes metabolic reprogramming relying on the mevalonate (MVA)-geranylgeranyl diphosphate (GGPP) pathway, which can be targeted using clinically approved statins. Mechanistically, statins induce oxidative stress accumulation and apoptosis through the GGPP synthase 1 (GGPS1)-RAB7A-autophagy axis. Statin treatment overcomes both intrinsic and acquired SCLC chemoresistance in vivo across different SCLC PDX models bearing high GGPS1 levels. Moreover, we show that GGPS1 expression is negatively associated with survival in patients with SCLC. Finally, we demonstrate that combined statin and chemotherapy treatment resulted in durable responses in three patients with SCLC who relapsed from first-line chemotherapy. Collectively, these data uncover the MVA-GGPP pathway as a metabolic vulnerability in SCLC and identify statins as a potentially effective treatment to overcome chemoresistance.
Assuntos
Inibidores de Hidroximetilglutaril-CoA Redutases , Neoplasias Pulmonares , Carcinoma de Pequenas Células do Pulmão , Linhagem Celular Tumoral , Farnesiltranstransferase/uso terapêutico , Humanos , Inibidores de Hidroximetilglutaril-CoA Redutases/farmacologia , Neoplasias Pulmonares/tratamento farmacológico , Ácido Mevalônico/farmacologia , Fosfatos de Poli-Isoprenil , Carcinoma de Pequenas Células do Pulmão/tratamento farmacológicoRESUMO
Human papilloma virus (HPV)-negative head and neck squamous cell carcinoma (HNSCC) is a common cancer worldwide with an unmet need for more effective, less toxic treatments. Currently, both the disease and the treatment of HNSCC cause significant mortality and morbidity. Targeted therapies hold new promise for patients with HPV-negative status whose tumors harbor oncogenic HRAS mutations. Recent promising clinical results have renewed interest in the development of farnesyltransferase inhibitors (FTIs) as a therapeutic strategy for HRAS-mutant cancers. With the advent of clinical evaluation of the FTI tipifarnib for the treatment of HRAS-mutant HNSCC, we investigated the activity of tipifarnib and inhibitors of HRAS effector signaling in HRAS-mutant HNSCC cell lines. First, we validated that HRAS is a cancer driver in HRAS-mutant HNSCC lines. Second, we showed that treatment with the FTI tipifarnib largely phenocopied HRAS silencing, supporting HRAS as a key target of FTI antitumor activity. Third, we performed reverse-phase protein array analyses to profile FTI treatment-induced changes in global signaling, and conducted CRISPR/Cas9 genetic loss-of-function screens to identify previously unreported genes and pathways that modulate sensitivity to tipifarnib. Fourth, we determined that concurrent inhibition of HRAS effector signaling (ERK, PI3K, mTORC1) increased sensitivity to tipifarnib treatment, in part by overcoming tipifarnib-induced compensatory signaling. We also determined that ERK inhibition could block tipifarnib-induced epithelial-to-mesenchymal transition, providing a potential basis for the effectiveness of this combination. Our results support future investigations of these and other combination treatments for HRAS mutant HNSCC.
Assuntos
Carcinoma de Células Escamosas , Neoplasias de Cabeça e Pescoço , Infecções por Papillomavirus , Carcinoma de Células Escamosas/genética , Linhagem Celular Tumoral , Farnesiltranstransferase/metabolismo , Farnesiltranstransferase/uso terapêutico , Neoplasias de Cabeça e Pescoço/tratamento farmacológico , Neoplasias de Cabeça e Pescoço/genética , Humanos , Proteínas Proto-Oncogênicas p21(ras)/genética , Proteínas Proto-Oncogênicas p21(ras)/metabolismo , Carcinoma de Células Escamosas de Cabeça e Pescoço/tratamento farmacológico , Carcinoma de Células Escamosas de Cabeça e Pescoço/genéticaRESUMO
The management of the myelodysplastic syndromes (MDS) requires insight into the complex biology of the disease. Despite this challenge, two recent developments have contributed significantly to advancements in the treatment of MDS: (i) improvements in classification systems and prognostic models; and (ii) the emergence of US FDA-approved agents such as lenalidomide, azacitidine and decitabine. Prior to these developments, supportive care measures consisting of blood and platelet transfusions, haematopoietic growth factors and antimicrobials remained standard of care for the treatment of MDS. As a result of these developments, clinicians are able to provide patient-tailored therapy for specific MDS subgroups. Clinical trials addressing combination therapies with multiple investigational agents as well as novel combination regimens are ongoing. This review focuses on supportive care modalities, the approved agents indicated for the treatment of MDS and future directions for the treatment of MDS, including agents under clinical investigation.
Assuntos
Síndromes Mielodisplásicas/tratamento farmacológico , Nucleotídeos de Adenina/farmacologia , Nucleotídeos de Adenina/uso terapêutico , Anemia/tratamento farmacológico , Arabinonucleosídeos/farmacologia , Arabinonucleosídeos/uso terapêutico , Benzamidas , Medula Óssea/fisiopatologia , Clofarabina , Metilação de DNA/efeitos dos fármacos , Drogas em Investigação/farmacologia , Drogas em Investigação/uso terapêutico , Farnesiltranstransferase/antagonistas & inibidores , Farnesiltranstransferase/farmacologia , Farnesiltranstransferase/uso terapêutico , Inibidores de Histona Desacetilases/farmacologia , Inibidores de Histona Desacetilases/uso terapêutico , Humanos , Mesilato de Imatinib , Imunossupressores/farmacologia , Imunossupressores/uso terapêutico , Quelantes de Ferro/farmacologia , Quelantes de Ferro/uso terapêutico , Lenalidomida , Piperazinas/farmacologia , Piperazinas/uso terapêutico , Pirimidinas/farmacologia , Pirimidinas/uso terapêutico , Receptores Fc/uso terapêutico , Proteínas Recombinantes de Fusão/farmacologia , Proteínas Recombinantes de Fusão/uso terapêutico , Fatores de Risco , Talidomida/análogos & derivados , Talidomida/farmacologia , Talidomida/uso terapêutico , Trombopoetina/farmacologia , Trombopoetina/uso terapêuticoRESUMO
Recently, new targets have been identified in head and neck squamous cell carcinomas (HNSCC) as playing key roles in tumour proliferation and metastases. The first target that has led to the approval of a molecularly based therapy in HNSCC has been the epidermal growth factor receptor (EGFR). Indeed, cetuximab, a monoclonal antibody directed against EGFR, has recently been approved in combination with radiation therapy in patients with locally advanced HNSCC, and in patients with platinum-refractory recurrent or metastatic (R/M) HNSCC. This review discusses novel targeted anticancer agents that do not exclusively target EGFR. The initial assessments of novel agents have typically been in patients with heavily pre-treated R/M HNSCC, with response rates and times to progression that are often disappointing. Evaluation of novel agents in the pre-operative 'window' setting, or as first-line therapy for R/M disease, may offer a more optimal understanding of their molecular and clinical effects.
Assuntos
Carcinoma de Células Escamosas/tratamento farmacológico , Neoplasias de Cabeça e Pescoço/tratamento farmacológico , Inibidores da Angiogênese/uso terapêutico , Anticorpos Monoclonais/uso terapêutico , Receptores ErbB/uso terapêutico , Farnesiltranstransferase/uso terapêutico , Humanos , Proteínas Nucleares/antagonistas & inibidores , Proteína Quinase C/antagonistas & inibidores , Inibidores de Proteínas Quinases/uso terapêutico , Receptores Proteína Tirosina Quinases/antagonistas & inibidores , Sirolimo/antagonistas & inibidoresRESUMO
Farnesyl transferase inhibitors (FTIs), a novel class of anticancer agents that competitively inhibit farnesyl protein transferase, are currently being developed and tested across a wide range of human cancers. Myeloid malignancies are reasonable disease targets in that they likely overexpress relevant biologic targets, such as Ras, mitogen-activated protein kinase (MAPK), or AKT. Several phase I clinical trials using FTIs in myeloid malignancies have been performed, demonstrating enzyme target inhibition, low toxicity, and anticancer activity. Many phase II trials are now under way, aiming to assess the response rate and to identify the actual downstream signal transduction targets that may be modified by these agents. It is expected that results from these trials will optimize the role of FTIs in patients with myeloid disorders by identifying patient and disease characteristics that will predict for response, facilitating their incorporation into current therapeutic strategies and providing insight into effective methods of combining FTIs with other antineoplastics.
Assuntos
Ensaios Clínicos Fase II como Assunto , Farnesiltranstransferase/antagonistas & inibidores , Síndromes Mielodisplásicas/diagnóstico , Síndromes Mielodisplásicas/tratamento farmacológico , Transtornos Mieloproliferativos/diagnóstico , Transtornos Mieloproliferativos/tratamento farmacológico , Relação Dose-Resposta a Droga , Esquema de Medicação , Farnesiltranstransferase/uso terapêutico , Feminino , Humanos , Masculino , Dose Máxima Tolerável , Síndromes Mielodisplásicas/mortalidade , Transtornos Mieloproliferativos/mortalidade , Prognóstico , Medição de Risco , Índice de Gravidade de Doença , Análise de Sobrevida , Resultado do TratamentoRESUMO
BACKGROUND: Multiple myeloma (MM) is an incurable malignancy. Recent insights into its biology has allowed the use of novel therapies targeting not only the deregulated intracellular signaling in MM cells but also its interaction with the bone marrow microenvironment that confers drug resistance, growth, and survival advantage to the malignant cells. METHODS: We review and summarize the recent advances in our knowledge of myeloma biology as well as the mechanism of action and clinical efficacy for novel therapeutic agents in clinical trials. RESULTS: Several novel therapeutic agents are currently in clinical trials. Thalidomide is already established for both initial and salvage treatment. Bortezomib is being tested alone and in combination with conventional chemotherapy in various settings. Other agents are less effective in producing response but have been able to stabilize disease in patients with relapsed and/or refractory disease, such as arsenic trioxide, farnesyltransferase inhibitors, 2-methoxyestradiol, and vascular endothelial growth factor receptor inhibitors. Insights into drug resistance mechanism have also led to the development of novel agents that sensitize myeloma cells to chemotherapy (Bcl-2 antisense). Gene expression studies have in many instances identified pathways other than the intended target of the drug and have provided insights into the therapeutic mechanisms. CONCLUSIONS: In the future, patients with MM will have more therapeutic options available than ever before. The challenge will be to identify patient subgroups that will benefit most from the different therapies and then determine how these biologically based therapies could be combined and incorporated into the overall management of patients.