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1.
Br J Cancer ; 128(12): 2227-2235, 2023 06.
Artigo em Inglês | MEDLINE | ID: mdl-37087488

RESUMO

BACKGROUND: Indoleamine 2,3-dioxygenase 1 (IDO1), an interferon-inducible enzyme, contributes to tumor immune intolerance. Immune checkpoint inhibition may increase interferon levels; combining IDO1 inhibition with immune checkpoint blockade represents an attractive strategy. Epigenetic agents trigger interferon responses and may serve as an immunotherapy priming method. We evaluated whether epigenetic therapy plus IDO1 inhibition and immune checkpoint blockade confers clinical benefit to patients with advanced solid tumors. METHODS: ECHO-206 was a Phase I/II study where treatment-experienced patients with advanced solid tumors (N = 70) received azacitidine plus an immunotherapy doublet (epacadostat [IDO1 inhibitor] and pembrolizumab). Sequencing of treatment was also assessed. Primary endpoints were safety/tolerability (Phase I), maximum tolerated dose (MTD) or pharmacologically active dose (PAD; Phase I), and investigator-assessed objective response rate (ORR; Phase II). RESULTS: In Phase I, no dose-limiting toxicities were reported, the MTD was not reached; a PAD was not determined. ORR was 5.7%, with four partial responses. The most common treatment-related adverse events (AEs) were fatigue (42.9%) and nausea (42.9%). Twelve (17.1%) patients experienced ≥1 fatal AE, one of which (asthenia) was treatment-related. CONCLUSIONS: Although the azacitidine-epacadostat-pembrolizumab regimen was well tolerated, it was not associated with substantial clinical response in patients with advanced solid tumors previously exposed to immunotherapy.


Assuntos
Azacitidina , Neoplasias , Humanos , Azacitidina/efeitos adversos , Inibidores de Checkpoint Imunológico/uso terapêutico , Neoplasias/tratamento farmacológico , Neoplasias/genética , Neoplasias/patologia , Interferons/uso terapêutico
2.
Crit Care Med ; 50(12): 1701-1713, 2022 12 01.
Artigo em Inglês | MEDLINE | ID: mdl-36226977

RESUMO

OBJECTIVES: Evaluate the safety and efficacy of the Janus kinase (JAK)1/JAK2 inhibitor ruxolitinib in COVID-19-associated acute respiratory distress syndrome requiring mechanical ventilation. DESIGN: Phase 3 randomized, double-blind, placebo-controlled trial Ruxolitinib in Participants With COVID-19-Associated Acute Respiratory Distress Syndrome Who Require Mechanical Ventilation (RUXCOVID-DEVENT; NCT04377620). SETTING: Hospitals and community-based private or group practices in the United States (29 sites) and Russia (4 sites). PATIENTS: Eligible patients were greater than or equal to 12 years old, hospitalized with severe acute respiratory syndrome coronavirus 2 infection, and mechanically ventilated with a Pa o2 /F io2 of less than or equal to 300 mm Hg within 6 hours of randomization. INTERVENTIONS: Patients were randomized 2:2:1 to receive twice-daily ruxolitinib 15 mg, ruxolitinib 5 mg, or placebo, each plus standard therapy. MEASUREMENTS AND MAIN RESULTS: The primary endpoint, 28-day mortality, was tested for each ruxolitinib group versus placebo using a mixed-effects logistic regression model and one-tailed significance test (significance threshold: p < 0.025); no type 1 error was allocated to secondary endpoints. Between May 24, 2020 and December 15, 2020, 211 patients (age range, 24-87 yr) were randomized (ruxolitinib 15/5 mg, n = 77/87; placebo, n = 47). Acute respiratory distress syndrome was categorized as severe in 27% of patients (58/211) at randomization; 90% (190/211) received concomitant steroids. Day-28 mortality was 51% (39/77; 95% CI, 39-62%) for ruxolitinib 15 mg, 53% (45/85; 95% CI, 42-64%) for ruxolitinib 5 mg, and 70% (33/47; 95% CI, 55-83%) for placebo. Neither ruxolitinib 15 mg (odds ratio, 0.46 [95% CI, 0.201-1.028]; one-sided p = 0.029) nor 5 mg (odds ratio, 0.42 [95% CI, 0.171-1.023]; one-sided p = 0.028) significantly reduced 28-day mortality versus placebo. Numerical improvements with ruxolitinib 15 mg versus placebo were observed in secondary outcomes including ventilator-, ICU-, and vasopressor-free days. Rates of overall and serious treatment-emergent adverse events were similar across treatments. CONCLUSIONS: The observed reduction in 28-day mortality rate between ruxolitinib and placebo in mechanically ventilated patients with COVID-19-associated acute respiratory distress syndrome was not statistically significant; however, the trial was underpowered owing to early termination.


Assuntos
Tratamento Farmacológico da COVID-19 , COVID-19 , Síndrome do Desconforto Respiratório , Humanos , Adulto Jovem , Adulto , Pessoa de Meia-Idade , Idoso , Idoso de 80 Anos ou mais , COVID-19/complicações , SARS-CoV-2 , Síndrome do Desconforto Respiratório/tratamento farmacológico , Respiração Artificial , Resultado do Tratamento
3.
Cancer Discov ; 12(6): 1482-1499, 2022 06 02.
Artigo em Inglês | MEDLINE | ID: mdl-35254416

RESUMO

Blocking the activity of the programmed cell death protein 1 (PD-1) inhibitory receptor with therapeutic antibodies against either the ligand (PD-L1) or PD-1 itself has proven to be an effective treatment modality for multiple cancers. Contrasting with antibodies, small molecules could demonstrate increased tissue penetration, distinct pharmacology, and potentially enhanced antitumor activity. Here, we describe the identification and characterization of INCB086550, a novel, oral, small-molecule PD-L1 inhibitor. In vitro, INCB086550 selectively and potently blocked the PD-L1/PD-1 interaction, induced PD-L1 dimerization and internalization, and induced stimulation-dependent cytokine production in primary human immune cells. In vivo, INCB086550 reduced tumor growth in CD34+ humanized mice and induced T-cell activation gene signatures, consistent with PD-L1/PD-1 pathway blockade. Preliminary data from an ongoing phase I study confirmed PD-L1/PD-1 blockade in peripheral blood cells, with increased immune activation and tumor growth control. These data support continued clinical evaluation of INCB086550 as an alternative to antibody-based therapies. SIGNIFICANCE: We have identified a potent small-molecule inhibitor of PD-L1, INCB086550, which has biological properties similar to PD-L1/PD-1 monoclonal antibodies and may represent an alternative to antibody therapy. Preliminary clinical data in patients demonstrated increased immune activation and tumor growth control, which support continued clinical evaluation of this approach. See related commentary by Capparelli and Aplin, p. 1413. This article is highlighted in the In This Issue feature, p. 1397.


Assuntos
Antígeno B7-H1 , Neoplasias , Animais , Humanos , Inibidores de Checkpoint Imunológico , Ativação Linfocitária , Camundongos , Neoplasias/tratamento farmacológico , Receptor de Morte Celular Programada 1
4.
Carcinogenesis ; 30(11): 1841-7, 2009 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-19805574

RESUMO

The small GTPase Ras is mutated to remain in the active oncogenic state in one-third of human cancers, thereby promoting tumorigenesis. It has recently come to light that one consequence of oncogenic Ras signaling is secretion of cytokines vascular endothelial growth factor (VEGF), interleukin 6 (IL6), hCXCL1 (Gro-alpha) and hCXCL8 (IL8). As the latter two belong to the ELR+ Cys-X-Cys (CXC) chemokine family, we investigated whether the entire family of ELR+ CXC chemokines plays a role in oncogenic Ras-mediated tumorigenesis. We now demonstrate that oncogenic Ras induced the expression and secretion of the ELR+ CXC chemokine family in different tumorigenic human cells and that these chemokines are elevated in tumor specimens. Moreover, genetic ablation of the common receptor for these chemokines, mCXCR2, reduced oncogenic Ras-driven tumorigenesis in mice. Taken together, we suggest that oncogenic Ras induces the secretion of the ELR+ CXC chemokine family to promote tumorigenesis. This chemokine signature may identify the presence of Ras activation in cancer and perhaps even serve as targets for oncogenic Ras-driven tumor cells.


Assuntos
Quimiocinas CXC/biossíntese , Regulação Neoplásica da Expressão Gênica , Genes ras , Neoplasias/genética , Animais , Linhagem Celular Tumoral , Transformação Celular Neoplásica/genética , Quimiocinas CXC/genética , Quimiocinas CXC/metabolismo , Humanos , Camundongos , Camundongos Endogâmicos BALB C , Camundongos SCID , Transplante de Neoplasias , Neoplasias/metabolismo , Receptores de Interleucina-8B/antagonistas & inibidores , Receptores de Interleucina-8B/genética , Receptores de Interleucina-8B/metabolismo , Neoplasias Cutâneas/genética , Neoplasias Cutâneas/metabolismo , Neoplasias Cutâneas/patologia
5.
Curr Biol ; 16(24): 2385-94, 2006 Dec 19.
Artigo em Inglês | MEDLINE | ID: mdl-17174914

RESUMO

BACKGROUND: The Ral guanine nucleotide-exchange factors (RalGEFs) serve as key effectors for Ras oncogene transformation of immortalized human cells. RalGEFs are activators of the highly related RalA and RalB small GTPases, although only the former has been found to promote Ras-mediated growth transformation of human cells. In the present study, we determined whether RalA and RalB also had divergent roles in promoting the aberrant growth of pancreatic cancers, which are characterized by the highest occurrence of Ras mutations. RESULTS: We now show that inhibition of RalA but not RalB expression universally reduced the transformed and tumorigenic growth in a panel of ten genetically diverse human pancreatic cancer cell lines. Despite the apparent unimportant role of RalB in tumorigenic growth, it was nevertheless critical for invasion in seven of nine pancreatic cancer cell lines and for metastasis as assessed by tail-vein injection of three different tumorigenic cell lines tested. Moreover, both RalA and RalB were more commonly activated in pancreatic tumor tissue than other Ras effector pathways. CONCLUSIONS: RalA function is critical to tumor initiation, whereas RalB function is more important for tumor metastasis in the tested cell lines and thus argues for critical, but distinct, roles of Ral proteins during the dynamic progression of Ras-driven pancreatic cancers.


Assuntos
Adenocarcinoma/patologia , Metástase Neoplásica , Neoplasias Pancreáticas/patologia , Proteínas ral de Ligação ao GTP/fisiologia , Adenocarcinoma/fisiopatologia , Animais , Linhagem Celular Tumoral , Transformação Celular Neoplásica , Humanos , Camundongos , Invasividade Neoplásica , Transplante de Neoplasias , Neoplasias Pancreáticas/fisiopatologia , Transplante Heterólogo
6.
Mol Cancer Res ; 17(2): 508-520, 2019 02.
Artigo em Inglês | MEDLINE | ID: mdl-30266754

RESUMO

Isocitrate dehydrogenase 1 (IDH1) is the most commonly mutated metabolic enzyme in human malignancy. A heterozygous genetic alteration, arginine 132, promotes the conversion of α-ketoglutarate to D-2-hydroxyglutarate (2-HG). Although pharmacologic inhibitors of mutant IDH1 are promising, resistance mechanisms to targeted therapy are not understood. Additionally, the role of wild-type IDH1 (WT.IDH1) in cancer requires further study. Recently, it was observed that the regulatory RNA-binding protein, HuR (ELAVL1), protects nutrient-deprived cancer cells without IDH1 mutations, by stabilizing WT.IDH1 transcripts. In the present study, a similar regulatory effect on both mutant (Mut.IDH1) and WT.IDH1 transcripts in heterozygous IDH1-mutant tumors is observed. In ribonucleoprotein immunoprecipitation assays of IDH1-mutant cell lines, wild-type and mutant IDH1 mRNAs each bound to HuR. Both isoforms were profoundly downregulated at the mRNA and protein levels after genetic suppression of HuR (siRNAs or CRISPR deletion) in HT1080 (R132C IDH1 mutation) and BT054 cells (R132H). Proliferation and invasion were adversely affected after HuR suppression and metabolomic studies revealed a reduction in Pentose Phosphate Pathway metabolites, nucleotide precursors, and 2-HG levels. HuR-deficient cells were especially sensitive to stress, including low glucose conditions or a mutant IDH1 inhibitor (AGI-5198). IDH1-mutant cancer cells were rescued by WT.IDH1 overexpression to a greater extent than Mut.IDH1 overexpression under these conditions. This study reveals the importance of HuR's regulation of both mutant and wild-type IDH1 in tumors harboring a heterozygous IDH1 mutation with implications for therapy. IMPLICATIONS: This study highlights the HuR-IDH1 (mutant and wild-type IDH1) regulatory axis as a critical, actionable therapeutic target in IDH1-mutated cancer, and incomplete blockade of the entire HuR-IDH1 survival axis would likely diminish the efficacy of drugs that selectively target only the mutant isoenzyme.


Assuntos
Proteína Semelhante a ELAV 1/metabolismo , Isocitrato Desidrogenase/metabolismo , Animais , Linhagem Celular Tumoral , Regulação para Baixo , Proteína Semelhante a ELAV 1/antagonistas & inibidores , Proteína Semelhante a ELAV 1/genética , Fibrossarcoma/genética , Fibrossarcoma/metabolismo , Fibrossarcoma/patologia , Xenoenxertos , Humanos , Isocitrato Desidrogenase/genética , Isoenzimas/genética , Isoenzimas/metabolismo , Masculino , Camundongos , Camundongos Nus , Mutação
7.
Clin Cancer Res ; 25(2): 724-734, 2019 01 15.
Artigo em Inglês | MEDLINE | ID: mdl-30266763

RESUMO

PURPOSE: Heritable genetic variations can affect the inflammatory tumor microenvironment, which can ultimately affect cancer susceptibility and clinical outcomes. Recent evidence indicates that IDO2, a positive modifier in inflammatory disease models, is frequently upregulated in pancreatic ductal adenocarcinoma (PDAC). A unique feature of IDO2 in humans is the high prevalence of two inactivating single-nucleotide polymorphisms (SNP), which affords the opportunity to carry out loss-of-function studies directly in humans. In this study, we sought to address whether genetic loss of IDO2 may influence PDAC development and responsiveness to treatment.Experimental Design: Transgenic Ido2 +/+ and Ido2 -/- mice in which oncogenic KRAS is activated in pancreatic epithelial cells were evaluated for PDAC. Two patient data sets (N = 200) were evaluated for the two IDO2-inactivating SNPs together with histologic, RNA expression, and clinical survival data. RESULTS: PDAC development was notably decreased in the Ido2 -/- mice (30% vs. 10%, P < 0.05), with a female predominance similar to the association observed for one of the human SNPs. In patients, the biallelic occurrence of either of the two IDO2-inactivating SNPs was significantly associated with markedly improved disease-free survival in response to adjuvant radiotherapy (P < 0.01), a treatment modality that has been highly debated due to its variable efficacy. CONCLUSIONS: The results of this study provide genetic support for IDO2 as a contributing factor in PDAC development and argue that IDO2 genotype analysis has the immediate potential to influence the PDAC care decision-making process through stratification of those patients who stand to benefit from adjuvant radiotherapy.


Assuntos
Biomarcadores Tumorais , Indolamina-Pirrol 2,3,-Dioxigenase/genética , Neoplasias Pancreáticas/genética , Neoplasias Pancreáticas/patologia , Proteínas Proto-Oncogênicas p21(ras)/genética , Alelos , Animais , Linhagem Celular Tumoral , Transformação Celular Neoplásica/genética , Transformação Celular Neoplásica/metabolismo , Modelos Animais de Doenças , Progressão da Doença , Feminino , Genótipo , Humanos , Masculino , Camundongos , Camundongos Transgênicos , Mutação , Neoplasias Pancreáticas/radioterapia , Polimorfismo de Nucleotídeo Único , Resultado do Tratamento , Ensaios Antitumorais Modelo de Xenoenxerto
8.
J Pancreat Cancer ; 4(1): 1-3, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-30631849

RESUMO

Background: This case study examines the feasibility of application of an acceptance-based behavioral therapy, acceptance and commitment therapy (ACT), to a patient with end-stage metastatic pancreatic cancer, depression, and anxiety, as a form of integrative palliative care. Case Presentation: ACT allowed the patient to identify her values of resuming her religious connection, improving relationships with family members and trusted friends, and organizing her affairs before death. As a result, the patient was able to remain engaged in cancer treatments despite side effects that she had previously deemed intolerable. She was able to move toward her values despite health-related and depression-related obstacles. Furthermore, she successfully reconnected with her religious faith, and with her parents, spent time with her family, and deepened relationships with close friends before her death. Her quality of life was much improved by a combination of ACT and cancer treatments, suggesting that ACT may be a feasible mental health adjunct for palliative care in end-stage pancreatic cancer. Conclusion: ACT was well received by this patient with metastatic pancreatic cancer, improving ability to cope with anxiety, depression, and treatment side effects, thereby accepting and managing her cancer more effectively.

9.
Methods Enzymol ; 407: 637-47, 2006.
Artigo em Inglês | MEDLINE | ID: mdl-16757358

RESUMO

Transgenic mice, cultured murine cells, and human cancer cell lines have widely been used to study Ras oncogenesis. Although extremely valuable systems, they could not be used to study Ras function in genetically defined human cells. In this regard, Ras is required for tumor formation in normal human somatic cells expressing SV-40 T/t antigens, which inactivate the tumor suppressors p53 and Rb and activate the oncogene c-Myc, and hTERT, the catalytic subunit of telomerase. Such a system allows not only the general requirements of Ras to be dissected in matched cells from different organisms or tissues but also the individual pathways required for tumor growth to be defined in human cells. This review will detail the methods of creating stable T/t Ag, TERT, Ras-expressing cell lines, as well as commonly used techniques of soft agar and xenograft tumor formation.


Assuntos
Transformação Celular Neoplásica , Proteínas ras/fisiologia , Animais , Antígenos Virais de Tumores/biossíntese , Técnicas de Cultura de Células/métodos , Humanos , Camundongos , Subunidades Proteicas/biossíntese , Vírus 40 dos Símios/imunologia , Telomerase/biossíntese , Transfecção
10.
Discov Med ; 21(114): 117-23, 2016 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-27011047

RESUMO

Pancreatic cancer is predicted by the Pancreatic Cancer Action Network to soon become the 2nd leading cause of cancer related deaths in this country. This cannot be attributed to a lack of resources focused on interrogating the genomic landscape of pancreatic cancer genomes. Additionally, a large number of researchers and federal dollars have been directed towards inhibiting the most frequent genetic lesion in pancreatic cancer, Kras. Even with these advances, cytotoxic chemotherapy is currently the best option for patients with metastatic disease. Besides developing better early detection strategies, translating our knowledge of the molecular aspects of pancreatic cancer to the clinic via a targeted, personalized medicine approach may be the best way to dramatically improve patient outcomes. Herein, we briefly describe the scope of the problem in targeting pancreatic cancer on both the cellular and molecular levels. We also outline some promising, ongoing efforts to develop better therapeutic interventions for this deadly disease. For instance, we discuss novel strategies to target molecules and pathways that go beyond targeting genetic mutations and the level of transcriptional gene regulation. Finally, we summarize a clinical trial that is designed to answer the question whether with the available arsenal of drugs and molecular targets, can we now "personalize" therapy for pancreatic cancer patients?


Assuntos
Neoplasias Pancreáticas/terapia , Medicina de Precisão , Adenocarcinoma/genética , Adenocarcinoma/terapia , Ensaios Clínicos como Assunto , Genômica , Humanos , Neoplasias Pancreáticas/genética , Microambiente Tumoral
11.
Int J Biol Sci ; 12(3): 273-82, 2016.
Artigo em Inglês | MEDLINE | ID: mdl-26929734

RESUMO

Pancreatic cancer (pancreatic ductal adenocarcinoma, PDA) is infamously moving to the top of the list as one of the most lethal cancers with an overall 5 year survival rate of 7%. Multiple genomic-based and molecular characterization studies of PDA specimens and established animal models have provided the field with multiple targets and a progression model of this disease. Still, to date, the best therapeutic options are surgery and combination cytotoxic therapies. In general, even in the best case scenario (i.e., an early stage diagnosis and a response to a specific therapy), most of these fortunate patients' PDA cells acquire or exert resistance mechanisms and eventually kill the patient. Herein, we touch on a growing field of investigation that focuses on PDA cell therapeutic resistance mechanisms. We examine extrinsic elements (i.e., the tumor microenvironment, hypoxia) to the intrinsic processes within the cell (i.e., post-transcriptional gene regulation and somatic mutations) that are important for therapeutic efficacy and resistance. Even as better targeted and personalized approaches move through the clinical trial pipeline the discussed resistance mechanisms will most likely play a role in the management of this deadly disease.


Assuntos
Neoplasias Pancreáticas/patologia , Animais , Carcinoma Ductal Pancreático/metabolismo , Carcinoma Ductal Pancreático/patologia , Humanos , Neoplasias Pancreáticas/metabolismo , Microambiente Tumoral/fisiologia
12.
Case Rep Pancreat Cancer ; 1(1): 7-10, 2015.
Artigo em Inglês | MEDLINE | ID: mdl-30631802

RESUMO

Background: Ampullary adenocarcinomas are a rare subset of periampullary tumors with an overall poor prognosis. Treatment decisions are generally extrapolated from pancreatic chemotherapy protocols and consist mainly of traditional chemotherapy drugs. There are no known targets for therapeutic intervention in ampullary adenocarcinoma at this time. Next generation sequencing and other novel molecular profiling of tumors, including circulating tumor DNA (ctDNA), have recently made it possible to better understand tumor biology and elucidate driver mutations which are amenable to targeted therapy. This case describes the use of novel DNA sequencing technology to provide a targeted treatment option, HER-2 inhibition, in a patient with HER-2 overexpressing ampullary adenocarcinoma. This is the first time this has been described in the literature. Case presentation: The patient is a 63-year-old Caucasian man who initially presented with symptoms of obstructive jaundice and was found to have a periampullary tumor. He underwent resection of his tumor and pathology confirmed a stage IIB ampullary adenocarcinoma. He unfortunately developed a recurrence in the liver and lung two years later. Next generation sequencing of his tumor at the time of resection as well as ctDNA analysis demonstrated a HER-2 overexpressing tumor. Following first line therapy with FOLFOX he had progression and was treated with trastuzumab and pertuzumab with stabilization of his disease prior to his ultimate demise from multifocal pneumonia. Conclusion: The use of next generation sequencing as well as ctDNA technology generated a novel therapeutic intervention in our patient. As these techniques become more widespread, it is likely more targeted therapies will be used in these difficult to treat diseases.

13.
Mol Interv ; 8(1): 22-7, 2008 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-18332481

RESUMO

The Ras family of small guanosine triphosphatases normally transmit signals from cell surface receptors to the interior of the cell. Stimulation of cell surface receptors leads to the activation of guanine exchange factors, which, in turn, convert Ras from an inactive GDP-bound state to an active GTP-bound state. However, in one third of human cancers, RAS is mutated and remains in the constitutively active GTP-bound state. In this oncogenic state, RAS activates a constellation of signaling that is known to promote tumorigenesis. One consequence of this oncogenic RAS signal in cancer cells is the upregulation of the cytokines interleukin (IL)-6, IL-8, and chemokine growth-regulated oncogene 1 (GRO-1). We review the evidence supporting a role for these cytokines in oncogenic RAS-driven solid tumors.


Assuntos
Citocinas/metabolismo , Neoplasias/tratamento farmacológico , Proteína Oncogênica p21(ras)/metabolismo , Transdução de Sinais , Animais , Quimiocina CXCL1/metabolismo , Citocinas/genética , Regulação Neoplásica da Expressão Gênica , Humanos , Interleucina-6/metabolismo , Interleucina-8/metabolismo , Neoplasias/fisiopatologia , Proteína Oncogênica p21(ras)/genética
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