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1.
Int J Cancer ; 147(2): 413-422, 2020 07 15.
Artigo em Inglês | MEDLINE | ID: mdl-31714586

RESUMO

Endometrial cancers have high rates of phosphoinositide 3-kinase (PI3K) pathway alterations. MK-2206 is an allosteric inhibitor of AKT, an effector kinase of PI3K signals. We hypothesized patients with tumors harboring PIK3CA mutations would be more likely to benefit from MK-2206 than those without PIK3CA mutation. A Phase II study was performed in patients with recurrent endometrial cancer; all histologies except carcinosarcoma were eligible. Up to two prior chemotherapy lines were permitted, excluding prior treatment with PI3K pathway inhibitors. The first 18 patients were treated with MK-2206 200 mg weekly. Due to unacceptable toxicity, dose was reduced to 135 mg. Co-primary endpoints were objective response rate (ORR) and progression-free survival at 6 months (6moPFS). Thirty-seven patients were enrolled (one ineligible). By somatic PIK3CA mutation analysis, nine patients were mutant (MT) [one with partial response (PR)/6moPFS, two with 6moPFS]. Twenty-seven patients were wild-type (WT) (one PR and four 6moPFS). Most common toxicities were rash (44%), fatigue (41%), nausea (42%) and hyperglycemia (31%). Grade 3 and 4 toxicities occurred in 25 and 17% of patients, respectively. Exploratory analysis found serous histology had greater 6moPFS as compared to all other histologies (5/8 vs. 2/28, p = 0.003). PTEN expression was associated with median time to progression (p = 0.04). No other significant associations with PI3K pathway alterations were identified. There is limited single agent activity of MK-2206 in PIK3CA MT and PIK3CA WT endometrial cancer populations. Activity was detected in patients with serous histology and due to their poor outcomes warrants further study (NCT01307631).


Assuntos
Classe I de Fosfatidilinositol 3-Quinases/genética , Neoplasias do Endométrio/tratamento farmacológico , Compostos Heterocíclicos com 3 Anéis/administração & dosagem , Mutação , Recidiva Local de Neoplasia/tratamento farmacológico , Adulto , Idoso , Esquema de Medicação , Neoplasias do Endométrio/genética , Feminino , Compostos Heterocíclicos com 3 Anéis/efeitos adversos , Humanos , Pessoa de Meia-Idade , Recidiva Local de Neoplasia/genética , Medicina de Precisão , Resultado do Tratamento
2.
Invest New Drugs ; 38(6): 1774-1783, 2020 12.
Artigo em Inglês | MEDLINE | ID: mdl-32410080

RESUMO

Background Overcoming resistance to anti-epidermal growth factor receptor (EGFR) monoclonal antibodies (mAbs) in patients with KRAS wildtype (WT) metastatic colorectal cancer (mCRC) could help meet the needs of patients with limited treatment options. Methods In this phase 1b study, patients with N/KRAS WT, MET-positive mCRC who had progressed following anti-EGFR mAb treatment received escalating oral doses of capmatinib (150, 300, and 400 mg) twice daily plus weekly intravenous cetuximab (at the approved dose). The primary objective was to establish a recommended dose for expansion (RDE) of capmatinib in combination with cetuximab. Safety, preliminary activity, pharmacokinetics, and pharmacodynamics were also explored. Results Thirteen patients were enrolled. No patients experienced a dose-limiting toxicity at investigated doses; the RDE was established as capmatinib 400 mg twice daily plus cetuximab. All patients experienced adverse events (AEs) suspected to be related to the study treatment. Five patients (38.5%) reported study-drug-related AEs of grade 3/4 in severity. No patients achieved a complete or partial response according to RECIST v1.1; however, tumor shrinkage of 29-44% was observed in 4 patients. Conclusions Capmatinib plus cetuximab was well tolerated. Preliminary signs of activity were observed. Further investigation is warranted to obtain efficacy data and refine predictive biomarkers of response. Clinical trial registration NCT02205398.


Assuntos
Antineoplásicos/administração & dosagem , Protocolos de Quimioterapia Combinada Antineoplásica/administração & dosagem , Benzamidas/administração & dosagem , Cetuximab/administração & dosagem , Neoplasias Colorretais/tratamento farmacológico , Imidazóis/administração & dosagem , Inibidores de Proteínas Quinases/administração & dosagem , Proteínas Proto-Oncogênicas c-met/antagonistas & inibidores , Triazinas/administração & dosagem , Adulto , Idoso , Antineoplásicos/efeitos adversos , Antineoplásicos/farmacocinética , Protocolos de Quimioterapia Combinada Antineoplásica/farmacocinética , Benzamidas/efeitos adversos , Benzamidas/farmacocinética , Linhagem Celular Tumoral , Cetuximab/efeitos adversos , Cetuximab/farmacocinética , Neoplasias Colorretais/genética , Neoplasias Colorretais/metabolismo , Neoplasias Colorretais/patologia , Progressão da Doença , Resistencia a Medicamentos Antineoplásicos , Receptores ErbB/antagonistas & inibidores , Feminino , Neoplasias de Cabeça e Pescoço/tratamento farmacológico , Humanos , Imidazóis/efeitos adversos , Imidazóis/farmacocinética , Masculino , Dose Máxima Tolerável , Pessoa de Meia-Idade , Inibidores de Proteínas Quinases/efeitos adversos , Inibidores de Proteínas Quinases/farmacocinética , Proteínas Proto-Oncogênicas c-met/metabolismo , Critérios de Avaliação de Resposta em Tumores Sólidos , Carcinoma de Células Escamosas de Cabeça e Pescoço/tratamento farmacológico , Triazinas/efeitos adversos , Triazinas/farmacocinética , Proteínas ras/genética
3.
Cancer Sci ; 110(4): 1340-1351, 2019 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-30724423

RESUMO

Capmatinib is a highly specific, potent and selective MET inhibitor. This was an open-label, multicenter, dose-escalation, phase I study conducted in Japanese patients with advanced solid tumors (not selected based on their MET status). The primary objective was to determine the maximum tolerated dose (MTD) and/or highest studied dose being safe. Secondary objectives included safety, pharmacokinetics and preliminary antitumor activity. Dose escalation was guided by a Bayesian Logistic Regression Model dependent on dose-limiting toxicities (DLT) in cycle 1. Of 44 adult Japanese patients with confirmed advanced solid tumors enrolled, 29 received capmatinib capsules (doses ranging from 100 mg once daily [q.d.] to 600 mg twice daily [b.i.d.]) and 15 received tablets (200 mg b.i.d. and 400 mg b.i.d.). DLT occurred in two patients: grade 2 suicidal ideation (600 mg b.i.d. capsule) and grade 3 depression (400 mg b.i.d. tablet). MTD was not reached. The highest studied dose determined to be safe as tablet was 400 mg b.i.d., whereas it is not yet determined for capsules. Most common adverse events suspected to be drug-related were increased blood creatinine, nausea, decreased appetite, vomiting and diarrhea. Following repeated daily dosing up to day 15 by q.d. or b.i.d. regimen using capsules, median time to reach maximum plasma drug concentration (Tmax ) was 1.0-4.0 hours; absorption was more rapid after dosing using tablets, with median Tmax of 1.0 hour on both days 1 and 15. Eight patients had a best overall response of stable disease. These data support further clinical development of capmatinib.


Assuntos
Antineoplásicos/administração & dosagem , Imidazóis/administração & dosagem , Neoplasias/tratamento farmacológico , Neoplasias/patologia , Inibidores de Proteínas Quinases/administração & dosagem , Triazinas/administração & dosagem , Idoso , Idoso de 80 Anos ou mais , Antineoplásicos/efeitos adversos , Antineoplásicos/farmacocinética , Benzamidas , Biomarcadores , Feminino , Humanos , Imidazóis/efeitos adversos , Imidazóis/farmacocinética , Masculino , Pessoa de Meia-Idade , Metástase Neoplásica , Estadiamento de Neoplasias , Neoplasias/metabolismo , Neoplasias/mortalidade , Inibidores de Proteínas Quinases/efeitos adversos , Inibidores de Proteínas Quinases/farmacocinética , Análise de Sobrevida , Resultado do Tratamento , Triazinas/efeitos adversos , Triazinas/farmacocinética
4.
Immunity ; 29(1): 79-89, 2008 Jul 18.
Artigo em Inglês | MEDLINE | ID: mdl-18571443

RESUMO

DR3 (TRAMP, LARD, WSL-1, TNFRSF25) is a death-domain-containing tumor necrosis factor (TNF)-family receptor primarily expressed on T cells. TL1A, the TNF-family ligand for DR3, can costimulate T cells, but the physiological function of TL1A-DR3 interactions in immune responses is not known. Using DR3-deficient mice, we identified DR3 as the receptor responsible for TL1A-induced T cell costimulation and dendritic cells as the likely source for TL1A during T cell activation. Despite its role in costimulation, DR3 was not required for in vivo T cell priming, for polarization into T helper 1 (Th1), Th2, or Th17 effector cell subtypes, or for effective control of infection with Toxoplasma gondii. Instead, DR3 expression was required on T cells for immunopathology, local T cell accumulation, and cytokine production in Experimental Autoimmune Encephalomyelitis (EAE) and allergic lung inflammation, disease models that depend on distinct effector T cell subsets. DR3 could be an attractive therapeutic target for T cell-mediated autoimmune and allergic diseases.


Assuntos
Linfócitos T CD4-Positivos/imunologia , Diferenciação Celular/imunologia , Inflamação/imunologia , Ativação Linfocitária/imunologia , Membro 25 de Receptores de Fatores de Necrose Tumoral/imunologia , Subpopulações de Linfócitos T/imunologia , Animais , Linfócitos T CD4-Positivos/citologia , Linfócitos T CD4-Positivos/metabolismo , Proliferação de Células , Encefalomielite Autoimune Experimental/imunologia , Inflamação/metabolismo , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Membro 25 de Receptores de Fatores de Necrose Tumoral/metabolismo , Hipersensibilidade Respiratória/imunologia , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Subpopulações de Linfócitos T/citologia , Subpopulações de Linfócitos T/metabolismo , Toxoplasmose/imunologia , Membro 15 da Superfamília de Ligantes de Fatores de Necrose Tumoral/imunologia , Membro 15 da Superfamília de Ligantes de Fatores de Necrose Tumoral/metabolismo
5.
J Immunol ; 194(8): 3567-82, 2015 Apr 15.
Artigo em Inglês | MEDLINE | ID: mdl-25786692

RESUMO

The TNF family cytokine TL1A (Tnfsf15) costimulates T cells and type 2 innate lymphocytes (ILC2) through its receptor DR3 (Tnfrsf25). DR3-deficient mice have reduced T cell accumulation at the site of inflammation and reduced ILC2-dependent immune responses in a number of models of autoimmune and allergic diseases. In allergic lung disease models, immunopathology and local Th2 and ILC2 accumulation is reduced in DR3-deficient mice despite normal systemic priming of Th2 responses and generation of T cells secreting IL-13 and IL-4, prompting the question of whether TL1A promotes the development of other T cell subsets that secrete cytokines to drive allergic disease. In this study, we find that TL1A potently promotes generation of murine T cells producing IL-9 (Th9) by signaling through DR3 in a cell-intrinsic manner. TL1A enhances Th9 differentiation through an IL-2 and STAT5-dependent mechanism, unlike the TNF-family member OX40, which promotes Th9 through IL-4 and STAT6. Th9 differentiated in the presence of TL1A are more pathogenic, and endogenous TL1A signaling through DR3 on T cells is required for maximal pathology and IL-9 production in allergic lung inflammation. Taken together, these data identify TL1A-DR3 interactions as a novel pathway that promotes Th9 differentiation and pathogenicity. TL1A may be a potential therapeutic target in diseases dependent on IL-9.


Assuntos
Asma/imunologia , Diferenciação Celular/imunologia , Interleucina-9/imunologia , Membro 25 de Receptores de Fatores de Necrose Tumoral/imunologia , Linfócitos T Auxiliares-Indutores/imunologia , Membro 15 da Superfamília de Ligantes de Fatores de Necrose Tumoral/imunologia , Animais , Asma/genética , Asma/patologia , Diferenciação Celular/genética , Inflamação/genética , Inflamação/imunologia , Inflamação/patologia , Interleucina-13/genética , Interleucina-13/imunologia , Interleucina-4/genética , Interleucina-4/imunologia , Interleucina-9/genética , Camundongos , Camundongos Knockout , Membro 25 de Receptores de Fatores de Necrose Tumoral/genética , Transdução de Sinais/genética , Transdução de Sinais/imunologia , Linfócitos T Auxiliares-Indutores/patologia , Membro 15 da Superfamília de Ligantes de Fatores de Necrose Tumoral/genética
6.
Gynecol Oncol ; 141(1): 43-8, 2016 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-27016228

RESUMO

OBJECTIVE: Rapamycin analogs have reproducible but modest efficacy in endometrial cancer (EC). Identification of molecular biomarkers that predict benefit could guide clinical development. METHODS: Fixed primary tissue and whole blood were collected prospectively from patients enrolled on GOG 248. DNA was isolated from macro-dissected tumors and blood; next-generation sequence analysis was performed on a panel of cancer related genes. Associations between clinical outcomes [response rate (RR) 20%; progression-free survival (PFS) median 4.9months] and mutations (PTEN, PIK3CA, PIK3R1, KRAS, CTNNB1, AKT1, TSC1, TSC2, NF1, FBXW7) were explored. RESULTS: Sequencing data was obtained from tumors of 55 of the 73 enrolled pts. Mutation rates were consistent with published reports: mutations in PTEN (45%), PIK3CA (29%), PIK3R1 (24%), K-RAS (16%), CTNNB1 (18%) were common and mutations in AKT1 (4%), TSC1 (2%), TSC2 (2%), NF1 (9%) and FBXW7 (4%) were less common. Increased PFS (HR 0.16; 95% CI 0.01-0.78) and RR (response difference 0.83; 95% CI 0.03-0.99) were noted for AKT1 mutation. An increase in PFS (HR 0.46; 95% CI 0.20-0.97) but not RR (response difference 0.00, 95% CI -0.34-0.34) was identified for CTNNB1 mutation. Both patients with TSC mutations had an objective response. There were no statistically significant associations between mutations in PIK3CA, PTEN, PIK3R1, or KRAS and PFS or RR. CONCLUSIONS: Mutations in AKT1, TSC1 and TSC2 are rare, but may predict clinical benefit from temsirolimus. CTNNB1 mutations were associated with longer PFS on temsirolimus.


Assuntos
Neoplasias do Endométrio/genética , Acetato de Megestrol/administração & dosagem , Mutação , Sirolimo/análogos & derivados , Tamoxifeno/administração & dosagem , Classe I de Fosfatidilinositol 3-Quinases , Neoplasias do Endométrio/tratamento farmacológico , Neoplasias do Endométrio/mortalidade , Feminino , Humanos , PTEN Fosfo-Hidrolase/genética , Fosfatidilinositol 3-Quinases/genética , Estudos Prospectivos , Proteínas Proto-Oncogênicas c-akt/genética , Sirolimo/administração & dosagem , Sirolimo/uso terapêutico , Proteína 1 do Complexo Esclerose Tuberosa , Proteínas Supressoras de Tumor/genética
7.
Rheumatology (Oxford) ; 54(7): 1294-301, 2015 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-25661469

RESUMO

OBJECTIVES: Young people with inflammatory arthritis can have severe disease warranting biologic therapy. They face complex treatment decisions, with profound consequences. This study aimed to explore the influence of individuals outside the care team (trusted others) on the treatment decisions made by young people, in particular their decisions about biologic therapies. METHODS: Young people (16-25 years of age) with inflammatory arthritis and experience of treatment decision making were recruited from three NHS Hospital Trusts. Twenty-five were interviewed, plus 11 trusted others identified by young people as being involved in their decision making, as well as 6 health professionals. The data were analysed using coding, memoing and mapping techniques and the findings were tested through a series of focus groups. RESULTS: Young people initially emphasized their decisional autonomy, typically describing people other than health professionals as limited in influence. However, discussions revealed the involvement--in deliberation and enactment--of a range of other people. This cast of trusted others was small and largely consistent; mothers played a particularly prominent role, providing cognitive, practical and emotional support. Members of the wider cast of trusted others were involved in more limited but still significant ways. CONCLUSION: Young people claim autonomy but other people enable this. The network of relationships in which they are embedded is distinctive and evolving. Mothers play a supporting role well into early adulthood; in contrast, partners are involved in far more limited ways. As such, the applicability of adult models of decision making is unclear. This must be taken into account if the support provided by professionals is to be optimally tailored to young people's needs.


Assuntos
Artrite Juvenil/tratamento farmacológico , Produtos Biológicos/uso terapêutico , Tomada de Decisões , Pessoal de Saúde/psicologia , Pais/psicologia , Espondilite Anquilosante/tratamento farmacológico , Confiança/psicologia , Adolescente , Adulto , Artrite Juvenil/psicologia , Artrite Psoriásica/tratamento farmacológico , Artrite Psoriásica/psicologia , Artrite Reumatoide/tratamento farmacológico , Artrite Reumatoide/psicologia , Feminino , Grupos Focais , Humanos , Entrevistas como Assunto , Masculino , Aceitação pelo Paciente de Cuidados de Saúde/psicologia , Espondilite Anquilosante/psicologia , Medicina Estatal , Reino Unido , Adulto Jovem
8.
Saudi Pharm J ; 22(4): 338-42, 2014 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-25161378

RESUMO

The availability of suppositories in Hungary, especially in clinical pharmacy practice, is usually provided by extemporaneous preparations. Due to the known advantages of rectal drug administration, its benefits are frequently utilized in pediatrics. However, errors during the extemporaneous manufacturing process can lead to non-homogenous drug distribution within the dosage units. To determine the root cause of these errors and provide corrective actions, we studied suppository samples prepared with exactly known errors using both cerimetric titration and HPLC technique. Our results show that the most frequent technological error occurs when the pharmacist fails to use the correct displacement factor in the calculations which could lead to a 4.6% increase/decrease in the assay in individual dosage units. The second most important source of error can occur when the molding excess is calculated solely for the suppository base. This can further dilute the final suppository drug concentration causing the assay to be as low as 80%. As a conclusion we emphasize that the application of predetermined displacement factors in calculations for the formulation of suppositories is highly important, which enables the pharmacist to produce a final product containing exactly the determined dose of an active substance despite the different densities of the components.

9.
J Clin Oncol ; 42(2): 180-191, 2024 Jan 10.
Artigo em Inglês | MEDLINE | ID: mdl-37788412

RESUMO

PURPOSE: Effective treatments for resectable non-small-cell lung cancer (NSCLC) are limited and relapse rates are high. The interleukin (IL)-1ß pathway has been linked with tumor development and progression, including in the Canakinumab Anti-Inflammatory Thrombosis Outcomes cardiovascular study in which IL-1ß pathway inhibition with canakinumab reduced lung cancer incidence and mortality in an exploratory analysis. METHODS: CANOPY-A (ClinicalTrials.gov identifier: NCT03447769) is a phase III, randomized, double-blind, multicenter study of canakinumab versus placebo for adult patients with stage II-IIIA or IIIB (T >5 cm, N2-positives II-IIIB; American Joint Committee on Cancer/Union for International Cancer Control version 8), completely resected NSCLC who had received adjuvant cisplatin-based chemotherapy. The primary end point was disease-free survival (DFS) and the key secondary end point was overall survival (OS). RESULTS: In total, 1,382 patients were randomized to 200 mg canakinumab (n = 693) or placebo (n = 689) once every 3 weeks for 18 cycles. Grade ≥3 adverse events (AEs) were reported in 20.8% and 19.6% of patients receiving canakinumab and placebo, respectively; AEs led to discontinuation in 4.3% and 4.1% of patients in these groups, respectively. This study did not meet its primary end point. Median DFS was 35.0 months (canakinumab arm) and 29.7 months (placebo arm; hazard ratio, 0.94; 95% CI, 0.78 to 1.14; one-sided P = .258). DFS subgroup analyses did not show any meaningful differences between arms. As expected, because of canakinumab-driven IL-1ß pathway inhibition, C-reactive protein and IL-6 levels decreased in the canakinumab arm versus placebo arm, but had no correlation with differential clinical outcomes. OS was not formally tested as DFS was not statistically significant. CONCLUSION: CANOPY-A did not show a DFS benefit of adding canakinumab after surgery and adjuvant cisplatin-based chemotherapy in patients with resected, stage II-III NSCLC. No new safety signals were identified with canakinumab.


Assuntos
Carcinoma Pulmonar de Células não Pequenas , Neoplasias Pulmonares , Adulto , Humanos , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Carcinoma Pulmonar de Células não Pequenas/cirurgia , Neoplasias Pulmonares/tratamento farmacológico , Neoplasias Pulmonares/cirurgia , Cisplatino , Recidiva Local de Neoplasia/tratamento farmacológico , Quimioterapia Adjuvante , Método Duplo-Cego
10.
Cancer ; 119(21): 3776-83, 2013 Nov 01.
Artigo em Inglês | MEDLINE | ID: mdl-24037752

RESUMO

BACKGROUND: Cervical cancer is the second leading cause of cancer deaths among women worldwide. The objective of this study was to describe the most common oncogenic mutations in cervical cancers and to explore genomic differences between the 2 most common histologic subtypes: adenocarcinoma and squamous cell carcinoma. METHODS: A high-throughput genotyping platform, termed Oncomap, was used to interrogate 80 cervical tumors for 1250 known mutations in 139 cancer genes. Samples were analyzed using a mass spectrometry-based genotyping platform and were validated using orthogonal chemistry. Epidermal growth factor receptor (EGFR) mutations were further validated by massive parallel sequencing. Human papilloma virus (HPV) genotyping also was performed. RESULTS: Validated mutations were detected in 48 of 80 tumors (60%) examined. The highest mutation rates were in the genes phosphatidylinositol 3-kinase, catalytic subunit α (PIK3CA) (31.3%); Kirsten rat sarcoma viral oncogene homolog (KRAS) (8.8%); and EGFR (3.8%). PIK3CA mutation rates did not differ significantly between adenocarcinomas and squamous cell carcinomas (25% vs 37.5%, respectively; P = .33). In contrast, KRAS mutations were identified only in adenocarcinomas (17.5% vs 0%; P = .01), and a novel EGFR mutation was detected only in squamous cell carcinomas (0% vs 7.5%; P = .24). There were no associations between HPV-16 or HPV-18 and somatic mutations or overall survival. In adjusted analyses, PIK3CA mutations were associated with shorter survival (67.1 months vs 90.3 months; hazard ratio, 9.1; 95% confidence interval, 2.8-29.5 months; P < .001). CONCLUSIONS: Cervical cancers harbor high rates of potentially targetable oncogenic mutations. In addition, cervical squamous cell carcinoma and adenocarcinoma have distinct molecular profiles, suggesting that clinical outcomes may be improved with the use of more tailored treatment strategies, including PI3K and MEK inhibitors.


Assuntos
Adenocarcinoma/genética , Carcinoma de Células Escamosas/genética , Mutação , Oncogenes/genética , Neoplasias do Colo do Útero/genética , Adenocarcinoma/epidemiologia , Adenocarcinoma/mortalidade , Adenocarcinoma/virologia , Adulto , Carcinoma de Células Escamosas/epidemiologia , Carcinoma de Células Escamosas/mortalidade , Carcinoma de Células Escamosas/virologia , Classe I de Fosfatidilinositol 3-Quinases , Estudos de Coortes , Análise Mutacional de DNA/estatística & dados numéricos , Feminino , Frequência do Gene , Genes erbB-1/genética , Genótipo , Humanos , Pessoa de Meia-Idade , Fosfatidilinositol 3-Quinases/genética , Programa de SEER/estatística & dados numéricos , Neoplasias do Colo do Útero/epidemiologia , Neoplasias do Colo do Útero/mortalidade , Neoplasias do Colo do Útero/virologia
11.
Mol Pharm ; 10(8): 2849-57, 2013 Aug 05.
Artigo em Inglês | MEDLINE | ID: mdl-23768126

RESUMO

To enhance the immune activity of vaccine adjuvants polyinosinic:polycytidylic acid (poly I:C) and CpG acetalated dextran (Ac-DEX) microparticles can be used. Ac-DEX is a biodegradable and water-insoluble polymer that degrades significantly faster at pH 5.0 (phagosomal pH) than at pH 7.4 and has tunable degradation rates that can range from hours to months. This is an ideal characteristic for delivery of an antigen and adjuvant within the lysosomal compartment of a phagocytic cell. We evaluated poly I:C and CpG encapsulated in Ac-DEX microparticles using RAW macrophages as a model antigen-presenting cell. These cells were cultured with poly I:C or CpG in their free form, encapsulated in a fast degrading Ac-DEX, in slow degrading Ac-DEX, or in the Food and Drug Administration-approved polymer poly(lactic-co-glycolic acid) (PLGA). Ac-DEX had higher encapsulation efficiencies for both poly I:C and CpG than PLGA. Furthermore, poly I:C or CpG encapsulated in Ac-DEX also showed, in general, a significantly stronger immunostimulatory response than PLGA and unencapsulated CpG or poly I:C, which was indicated by a higher rate of nitric oxide release and increased levels of cytokines such as TNF-α, IL-6, IL-10, and IFN-γ. Overall, we have illustrated a method for enhancing the delivery of these vaccine adjuvants to further enhance the development of Ac-DEX vaccine formulations.


Assuntos
Fosfatos de Dinucleosídeos/metabolismo , Poli I-C/metabolismo , Receptores Toll-Like/agonistas , Animais , Linhagem Celular , Dextranos/química , Macrófagos/efeitos dos fármacos , Macrófagos/metabolismo , Camundongos , Microscopia de Força Atômica
12.
Pharm Res ; 30(5): 1349-61, 2013 May.
Artigo em Inglês | MEDLINE | ID: mdl-23354770

RESUMO

PURPOSE: A rapid immune response is required to prevent death from Anthrax, caused by Bacillus anthracis. METHOD: We formulated a vaccine carrier comprised of acetalated dextran microparticles encapsulating recombinant protective antigen (rPA) and resiquimod (a toll-like receptor 7/8 agonist). RESULTS: We were able to protect against triplicate lethal challenge by vaccinating twice (Days 0, 7) and then aggressively challenging on Days 14, 21, 28. A significantly higher level of antibodies was generated by day 14 with the encapsulated group compared to the conventional rPA and alum group. Antibodies produced by the co-encapsulated group were only weakly-neutralizing in toxin neutralization; however, survival was not dependent on toxin neutralization, as all vaccine formulations survived all challenges except control groups. Post-mortem culture swabs taken from the hearts of vaccinated groups that did not produce significant neutralizing titers failed to grow B. anthracis. CONCLUSIONS: Results indicate that protective antibodies are not required for rapid protection; indeed, cytokine results indicate that T cell protection may play a role in protection from anthrax. We report the first instance of use of a particulate carrier to generate a rapid protective immunity against anthrax.


Assuntos
Vacinas contra Antraz/uso terapêutico , Antraz/prevenção & controle , Bacillus anthracis/imunologia , Dextranos/química , Portadores de Fármacos/química , Acetilação , Animais , Antraz/imunologia , Antraz/microbiologia , Vacinas contra Antraz/administração & dosagem , Vacinas contra Antraz/imunologia , Formação de Anticorpos , Antígenos de Bactérias/administração & dosagem , Antígenos de Bactérias/imunologia , Antígenos de Bactérias/uso terapêutico , Toxinas Bacterianas/administração & dosagem , Toxinas Bacterianas/imunologia , Toxinas Bacterianas/uso terapêutico , Imidazóis/administração & dosagem , Imidazóis/uso terapêutico , Camundongos , Receptores Toll-Like/agonistas , Vacinação , Vacinas de Subunidades Antigênicas/administração & dosagem , Vacinas de Subunidades Antigênicas/imunologia , Vacinas de Subunidades Antigênicas/uso terapêutico
13.
Proc Natl Acad Sci U S A ; 107(12): 5652-7, 2010 Mar 23.
Artigo em Inglês | MEDLINE | ID: mdl-20231466

RESUMO

Bone marrow stromal cells [BMSCs; also known as mesenchymal stem cells (MSCs)] effectively suppress inflammatory responses in acute graft-versus-host disease in humans and in a number of disease models in mice. Many of the studies concluded that BMSC-driven immunomodulation is mediated by the suppression of proinflammatory Th1 responses while rebalancing the Th1/Th2 ratio toward Th2. In this study, using a ragweed induced mouse asthma model, we studied if BMSCs could be beneficial in an allergic, Th2-dominant environment. When BMSCs were injected i.v. at the time of the antigen challenge, they protected the animals from the majority of asthma-specific pathological changes, including inhibition of eosinophil infiltration and excess mucus production in the lung, decreased levels of Th2 cytokines (IL-4, IL-5, and IL-13) in bronchial lavage, and lowered serum levels of Th2 immunoglobulins (IgG1 and IgE). To explore the mechanism of the effect we used BMSCs isolated from a variety of knockout mice, performed in vivo blocking of cytokines and studied the effect of asthmatic serum and bronchoalveolar lavage from ragweed challenged animals on the BMSCs in vitro. Our results suggest that IL-4 and/or IL-13 activate the STAT6 pathway in the BMSCs resulting in an increase of their TGF-beta production, which seems to mediate the beneficial effect, either alone, or together with regulatory T cells, some of which might be recruited by the BMSCs. These data suggest that, in addition to focusing on graft-versus-host disease and autoimmune diseases, allergic conditions--specifically therapy resistant asthma--might also be a likely target of the recently discovered cellular therapy approach using BMSCs.


Assuntos
Asma/imunologia , Células-Tronco Mesenquimais/imunologia , Fator de Crescimento Transformador beta/imunologia , Ambrosia/efeitos adversos , Ambrosia/imunologia , Animais , Asma/etiologia , Asma/patologia , Asma/terapia , Líquido da Lavagem Broncoalveolar/citologia , Líquido da Lavagem Broncoalveolar/imunologia , Citocinas/deficiência , Citocinas/genética , Citocinas/metabolismo , Modelos Animais de Doenças , Humanos , Terapia de Imunossupressão , Técnicas In Vitro , Pulmão/imunologia , Pulmão/patologia , Transplante de Células-Tronco Mesenquimais , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Endogâmicos C57BL , Camundongos Knockout , Células Th2/imunologia , Transplante Homólogo , Transplante Isogênico
14.
Anal Biochem ; 425(1): 54-61, 2012 Jun 01.
Artigo em Inglês | MEDLINE | ID: mdl-22406431

RESUMO

Rapid presymptomatic diagnosis of Bacillus anthracis at early stages of infection plays a crucial role in prompt medical intervention to prevent rapid disease progression and accumulation of lethal levels of toxin. To detect low levels of the anthrax protective antigen (PA) exotoxin in biological fluids, we have developed a metal-enhanced fluorescence (MEF)-PA assay using a combination of the MEF effect and microwave-accelerated PA protein surface absorption. The assay is based on a modified version of our "rapid catch and signal" (RCS) technology previously designed for the ultra-fast and sensitive analysis of genomic DNA sequences. Technologically, the proposed MEF-PA assay uses standard 96-well plastic plates modified with silver island films (SiFs) grown within the wells. It is shown that the fluorescent probe, covalently attached to the secondary antibody, plays a crucial role of indicating complex formation (i.e., shows a strong MEF response to the recognition event). Microwave irradiation rapidly accelerates PA deposition onto the surface ("rapid catch"), significantly speeding up the MEF-PA assay and resulting in a total assay run time of less than 40 min with an analytical sensitivity of less than 1 pg/ml PA.


Assuntos
Antígenos de Bactérias/análise , Toxinas Bacterianas/análise , Fluorescência , Micro-Ondas , Prata/química , Antígenos de Bactérias/química , Bacillus anthracis/imunologia , Bacillus anthracis/isolamento & purificação , Toxinas Bacterianas/química , Metais/química
16.
Clin Transl Sci ; 15(7): 1713-1722, 2022 07.
Artigo em Inglês | MEDLINE | ID: mdl-35620969

RESUMO

WNT974 is a potent, selective, and orally bioavailable first-in-class inhibitor of Porcupine, a membrane-bound O-acyltransferase required for Wnt secretion, currently under clinical development in oncology. A phase I clinical trial is being conducted in patients with advanced solid tumors. During the dose-escalation part, various dosing regimens, including once or twice daily continuous and intermittent dosing at a dose range of 5-45 mg WNT974 were studied, however, the protocol-defined maximum tolerated dose (MTD) was not established based on dose-limiting toxicity. To assist in the selection of the recommended dose for expansion (RDE), a model-based approach was utilized. It integrated population pharmacokinetic (PK) modeling and exposure-response analyses of a target-inhibition biomarker, skin AXIN2 mRNA expression, and the occurrence of the adverse event, dysgeusia. The target exposure range of WNT974 that would provide a balance between target inhibition and tolerability was estimated based on exposure-response analyses. The dose that was predicted to yield an exposure within the target exposure range was selected as RDE. This model-based approach integrated PK, biomarker, and safety data to determine the RDE and represented an alternative as opposed to the conventional MTD approach for selecting an optimal biological dose. The strategy can be broadly applied to select doses in early oncology trials and inform translational clinical oncology drug development.


Assuntos
Antineoplásicos , Neoplasias , Antineoplásicos/uso terapêutico , Relação Dose-Resposta a Droga , Humanos , Dose Máxima Tolerável , Neoplasias/tratamento farmacológico , Neoplasias/genética , Pirazinas/uso terapêutico , Piridinas/uso terapêutico , Resultado do Tratamento
17.
CPT Pharmacometrics Syst Pharmacol ; 11(8): 1122-1134, 2022 08.
Artigo em Inglês | MEDLINE | ID: mdl-35728123

RESUMO

Machine learning (ML) opens new perspectives in identifying predictive factors of efficacy among a large number of patients' characteristics in oncology studies. The objective of this work was to combine ML with population pharmacokinetic/pharmacodynamic (PK/PD) modeling of tumor growth inhibition to understand the sources of variability between patients and therefore improve model predictions to support drug development decisions. Data from 127 patients with hepatocellular carcinoma enrolled in a phase I/II study evaluating once-daily oral doses of the fibroblast growth factor receptor FGFR4 kinase inhibitor, Roblitinib (FGF401), were used. Roblitinib  PKs was best described by a two-compartment model with a delayed zero-order absorption and linear elimination. Clinical efficacy using the longitudinal sum of the longest lesion diameter data was described with a population PK/PD model of tumor growth inhibition including resistance to treatment. ML, applying elastic net modeling of time to progression data, was associated with cross-validation, and allowed to derive a composite predictive risk score from a set of 75 patients' baseline characteristics. The two approaches were combined by testing the inclusion of the continuous risk score as a covariate on PD model parameters. The score was found as a significant covariate on the resistance parameter and resulted in 19% reduction of its variability, and 32% variability reduction on the average dose for stasis. The final PK/PD model was used to simulate effect of patients' characteristics on tumor growth inhibition profiles. The proposed methodology can be used to support drug development decisions, especially when large interpatient variability is observed.


Assuntos
Carcinoma Hepatocelular , Neoplasias Hepáticas , Carcinoma Hepatocelular/tratamento farmacológico , Humanos , Neoplasias Hepáticas/tratamento farmacológico , Aprendizado de Máquina , Modelos Biológicos , Piperazinas , Inibidores de Proteínas Quinases/farmacologia , Inibidores de Proteínas Quinases/uso terapêutico , Piridinas/farmacologia
18.
Clin Pharmacol Ther ; 112(6): 1329-1339, 2022 12.
Artigo em Inglês | MEDLINE | ID: mdl-36131557

RESUMO

Model-informed dose selection has been drawing increasing interest in oncology early clinical development. The current paper describes the example of FGF401, a selective fibroblast growth factor receptor 4 (FGFR4) inhibitor, in which a comprehensive modeling and simulation (M&S) framework, using both pharmacometrics and statistical methods, was established during its first-in-human clinical development using the totality of pharmacokinetics (PK), pharmacodynamic (PD) biomarkers, and safety and efficacy data in patients with cancer. These M&S results were used to inform FGF401 dose selection for future development. A two-compartment population PK (PopPK) model with a delayed 0-order absorption and linear elimination adequately described FGF401 PK. Indirect PopPK/PD models including a precursor compartment were independently established for two biomarkers: circulating FGF19 and 7α-hydroxy-4-cholesten-3-one (C4). Model simulations indicated a close-to-maximal PD effect achieved at the clinical exposure range. Time-to-progression was analyzed by Kaplan-Meier method which favored a trough concentration (Ctrough )-driven efficacy requiring Ctrough above a threshold close to the drug concentration producing 90% inhibition of phospho-FGFR4. Clinical tumor growth inhibition was described by a PopPK/PD model that reproduced the dose-dependent effect on tumor growth. Exposure-safety analyses on the expected on-target adverse events, including elevation of aspartate aminotransferase and diarrhea, indicated a lack of clinically relevant relationship with FGF401 exposure. Simulations from an indirect PopPK/PD model established for alanine aminotransferase, including a chain of three precursor compartments, further supported that maximal target inhibition was achieved and there was a lack of safety-exposure relationship. This M&S framework supported a dose selection of 120 mg once daily fasted or with a low-fat meal and provides a practical example that might be applied broadly in oncology early clinical development.


Assuntos
Piperazinas , Piridinas , Humanos , Piperazinas/farmacologia , Simulação por Computador , Alanina Transaminase , Modelos Biológicos , Relação Dose-Resposta a Droga
19.
Gynecol Oncol Rep ; 40: 100974, 2022 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-35434236

RESUMO

Uterine serous carcinoma (USC) is an uncommon subtype of endometrial cancer with a poor prognosis. USCs have genomic alterations in the PI3K pathway. A prior phase II study of AKT inhibitor MK-2206 (an allosteric AKT inhibitor, primarily affecting AKT1 and AKT2) in endometrial cancers resulted in progression-free survival (PFS) of ≥6 months in five out of seven patients with USC. To further assess the activity of MK-2206 in USC, we designed a phase II, single-stage assessment of MK-2206 in patients with advanced or recurrent high-grade serous endometrial cancer, who had received up to two lines of prior therapy. MK-2206 (135 mg) was administered orally once per week, in continuous 28-day cycles. Fourteen patients received treatment. The most common treatment-related adverse events were diarrhea (36%), acneiform rash (36%), nausea (29%), fatigue (29%), and hyperglycemia (21%); most events were grade 1-2. One confirmed partial response was observed in a patient who was also alive and progression-free at 6 months. One additional patient was alive and progression-free at 6 months. The clinical benefit rate was 14.3% (95% CI: 1.8 to 42.8). Five patients had stable disease (35.7%) and seven had progressive disease (50%); one was unevaluable. Median PFS was 2 months (95% CI: 1.6 to 4.4) and median overall survival was 6.4 months (95% CI: 5.1 to not reached). In summary, MK-2206 had limited activity in USC, although a few patients achieved sustained progression-free intervals in this study and in the previously reported phase II trial of MK-2206. Further investigations are needed to identify features associated with response.

20.
J Exp Clin Cancer Res ; 41(1): 189, 2022 Jun 02.
Artigo em Inglês | MEDLINE | ID: mdl-35655320

RESUMO

BACKGROUND: Deregulation of FGF19-FGFR4 signaling is found in several cancers, including hepatocellular carcinoma (HCC), nominating it for therapeutic targeting. FGF401 is a potent, selective FGFR4 inhibitor with antitumor activity in preclinical models. This study was designed to determine the recommended phase 2 dose (RP2D), characterize PK/PD, and evaluate the safety and efficacy of FGF401 alone and combined with the anti-PD-1 antibody, spartalizumab. METHODS: Patients with HCC or other FGFR4/KLB expressing tumors were enrolled. Dose-escalation was guided by a Bayesian model. Phase 2 dose-expansion enrolled patients with HCC from Asian countries (group1), non-Asian countries (group2), and patients with other solid tumors expressing FGFR4 and KLB (group3). FGF401 and spartalizumab combination was evaluated in patients with HCC. RESULTS: Seventy-four patients were treated in the phase I with single-agent FGF401 at 50 to 150 mg. FGF401 displayed favorable PK characteristics and no food effect when dosed with low-fat meals. The RP2D was established as 120 mg qd. Six of 70 patients experienced grade 3 dose-limiting toxicities: increase in transaminases (n = 4) or blood bilirubin (n = 2). In phase 2, 30 patients in group 1, 36 in group 2, and 20 in group 3 received FGF401. In total, 8 patients experienced objective responses (1 CR, 7 PR; 4 each in phase I and phase II, respectively). Frequent adverse events (AEs) were diarrhea (73.8%), increased AST (47.5%), and ALT (43.8%). Increase in levels of C4, total bile acid, and circulating FGF19, confirmed effective FGFR4 inhibition. Twelve patients received FGF401 plus spartalizumab. RP2D was established as FGF401 120 mg qd and spartalizumab 300 mg Q3W; 2 patients reported PR. CONCLUSIONS: At biologically active doses, FGF401 alone or combined with spartalizumab was safe in patients with FGFR4/KLB-positive tumors including HCC. Preliminary clinical efficacy was observed. Further clinical evaluation of FGF401 using a refined biomarker strategy is warranted. TRIAL REGISTRATION: NCT02325739 .


Assuntos
Carcinoma Hepatocelular , Neoplasias Hepáticas , Anticorpos Monoclonais Humanizados , Teorema de Bayes , Biomarcadores , Carcinoma Hepatocelular/tratamento farmacológico , Humanos , Neoplasias Hepáticas/tratamento farmacológico , Piperazinas , Piridinas
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