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1.
Invest New Drugs ; 31(2): 425-34, 2013 Apr.
Artículo en Inglés | MEDLINE | ID: mdl-22864522

RESUMEN

Background Arginine deiminase (ADI) is an enzyme that degrades arginine, an amino acid that is important for growth and development of normal and neoplastic cells. Melanoma cells are auxotrophic for arginine, because they lack argininosuccinatesynthetase (ASS), a key enzyme required for the synthesis of arginine. Patients and methods Patients with advanced melanoma were treated with 40, 80 or 160 IU/m(2) ADI-PEG 20 i.m. weekly. Primary endpoints were toxicity and tumor response, secondary endpoints included metabolic response by (18)FDG-PET, pharmacodynamic (PD) effects upon circulating arginine levels, and argininosuccinate synthetase tumor expression by immunohistochemistry. Results 31 previously treated patients were enrolled. The main toxicities were grade 1 and 2 adverse events including injection site pain, rash, and fatigue. No objective responses were seen. Nine patients achieved stable disease (SD), with 2 of these durable for >6 months. Four of the 9 patients with SD had uveal melanoma. PD analysis showed complete plasma arginine depletion in 30/31 patients by day 8. Mean plasma levels of ADI-PEG 20 correlated inversely with ADI-PEG 20 antibody levels. Immunohistochemical ASS expression analysis in tumor tissue was negative in 24 patients, whereas 5 patients had <5 % cells positive. Conclusions ADI-PEG 20 is well tolerated in advanced melanoma patients and leads to consistent, but transient, arginine depletion. Although no RECIST responses were observed, the encouraging rate of SD in uveal melanoma patients indicates that it may be worthwhile to evaluate ADI-PEG 20 in this melanoma subgroup.


Asunto(s)
Hidrolasas/uso terapéutico , Melanoma/tratamiento farmacológico , Polietilenglicoles/uso terapéutico , Neoplasias Cutáneas/tratamiento farmacológico , Neoplasias de la Úvea/tratamiento farmacológico , Adulto , Anciano , Anciano de 80 o más Años , Estudios de Cohortes , Relación Dosis-Respuesta a Droga , Femenino , Estudios de Seguimiento , Humanos , Hidrolasas/farmacocinética , Técnicas para Inmunoenzimas , Masculino , Dosis Máxima Tolerada , Melanoma/metabolismo , Melanoma/patología , Persona de Mediana Edad , Estadificación de Neoplasias , Polietilenglicoles/farmacocinética , Pronóstico , Neoplasias Cutáneas/metabolismo , Neoplasias Cutáneas/secundario , Tasa de Supervivencia , Distribución Tisular , Neoplasias de la Úvea/metabolismo , Neoplasias de la Úvea/secundario
2.
Oncoimmunology ; 10(1): 1943253, 2021.
Artículo en Inglés | MEDLINE | ID: mdl-34290906

RESUMEN

Background: Pegylated arginine deiminase (ADI-PEG 20) is a metabolism-based strategy that depletes arginine, resulting in tumoral stress and cytotoxicity. Preclinically, ADI-PEG 20 modulates T-cell activity and enhances the therapeutic efficacy of programmed death-1 (PD-1) inhibition. Methods: A phase 1b study, including a dose-escalation cohort and an expansion cohort, was undertaken to explore the effects of ADI-PEG 20 in combination with pembrolizumab, an anti-PD-1 antibody, for safety, pharmacodynamics, and response. CD3 levels and programmed death-ligand 1 (PD-L1) expression were assessed in paired biopsies collected prior to and after ADI-PEG 20 treatment but before pembrolizumab. Results: Twenty-five patients, nine in the dose-escalation cohort and sixteen in the expansion cohort, were recruited. Treatment was feasible with adverse events consistent with those known for each agent, except for Grade 3/4 neutropenia which was higher than expected, occurring in 10/25 (40%) patients. Mean arginine levels were suppressed for 1-3 weeks, but increased gradually. CD3+ T cells increased in 10/12 (83.3%) subjects following ADI-PEG 20 treatment, including in three partial responders (p = .02). PD-L1 expression was low and increased in 3/10 (30%) of subjects. Partial responses occurred in 6/25 (24%) heavily pretreated patients, in both argininosuccinate synthetase 1 proficient and deficient subjects. Conclusions: The immunometabolic combination was safe with the caveat that the incidence of neutropenia might be increased compared with either agent alone. ADI-PEG 20 treatment increased T cell infiltration in the low PD-L1 tumor microenvironment. The recommended phase 2 doses are 36 mg/m2 weekly for ADI-PEG 20 and 200 mg every 3 weeks for pembrolizumab.


Asunto(s)
Protocolos de Quimioterapia Combinada Antineoplásica , Neoplasias , Anticuerpos Monoclonales Humanizados , Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , Humanos , Hidrolasas , Neoplasias/tratamiento farmacológico , Polietilenglicoles , Microambiente Tumoral
3.
Clin Cancer Res ; 25(9): 2708-2716, 2019 05 01.
Artículo en Inglés | MEDLINE | ID: mdl-30796035

RESUMEN

PURPOSE: Patients with recurrent high-grade gliomas (HGG) are usually managed with alkylating chemotherapy ± bevacizumab. However, prognosis remains very poor. Preclinically, we showed that HGGs are a target for arginine depletion with pegargiminase (ADI-PEG20) due to epimutations of argininosuccinate synthetase (ASS1) and/or argininosuccinate lyase (ASL). Moreover, ADI-PEG20 disrupts pyrimidine pools in ASS1-deficient HGGs, thereby impacting sensitivity to the antifolate, pemetrexed. PATIENTS AND METHODS: We expanded a phase I trial of ADI-PEG20 with pemetrexed and cisplatin (ADIPEMCIS) to patients with ASS1-deficient recurrent HGGs (NCT02029690). Patients were enrolled (01/16-06/17) to receive weekly ADI-PEG20 36 mg/m2 intramuscularly plus pemetrexed 500 mg/m2 and cisplatin 75 mg/m2 intravenously once every 3 weeks for up to 6 cycles. Patients with disease control were allowed ADI-PEG20 maintenance. The primary endpoints were safety, tolerability, and preliminary estimates of efficacy. RESULTS: Ten ASS1-deficient heavily pretreated patients were treated with ADIPEMCIS therapy. Treatment was well tolerated with the majority of adverse events being Common Terminology Criteria for Adverse Events v4.03 grade 1-2. The best overall response was stable disease in 8 patients (80%). Plasma arginine was suppressed significantly below baseline with a reciprocal increase in citrulline during the sampling period. The anti-ADI-PEG20 antibody titer rose during the first 4 weeks of treatment before reaching a plateau. Median progression-free survival (PFS) was 5.2 months (95% confidence interval (CI), 2.5-20.8) and overall survival was 6.3 months (95% CI, 1.8-9.7). CONCLUSIONS: In this recurrent HGG study, ADIPEMCIS was well tolerated and compares favorably to historical controls. Additional trials of ADI-PEG20 in HGG are planned.


Asunto(s)
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Arginina/metabolismo , Argininosuccinato Sintasa/deficiencia , Neoplasias Encefálicas/tratamiento farmacológico , Glioma/tratamiento farmacológico , Recurrencia Local de Neoplasia/tratamiento farmacológico , Adulto , Neoplasias Encefálicas/enzimología , Neoplasias Encefálicas/patología , Cisplatino/administración & dosificación , Femenino , Estudios de Seguimiento , Glioma/enzimología , Glioma/patología , Humanos , Hidrolasas/administración & dosificación , Masculino , Dosis Máxima Tolerada , Persona de Mediana Edad , Clasificación del Tumor , Recurrencia Local de Neoplasia/enzimología , Recurrencia Local de Neoplasia/patología , Pemetrexed/administración & dosificación , Polietilenglicoles/administración & dosificación , Estudios Retrospectivos , Distribución Tisular , Resultado del Tratamiento
4.
J Clin Oncol ; 35(16): 1778-1785, 2017 Jun 01.
Artículo en Inglés | MEDLINE | ID: mdl-28388291

RESUMEN

Purpose Pegylated arginine deiminase (ADI-PEG 20) depletes essential amino acid levels in argininosuccinate synthetase 1 (ASS1) -negative tumors by converting arginine to citrulline and ammonia. The main aim of this study was to determine the recommended dose, safety, and tolerability of ADI-PEG 20, cisplatin, and pemetrexed in patients with ASS1-deficient malignant pleural mesothelioma (MPM) or non-small-cell lung cancer (NSCLC). Patients and Methods Using a 3 + 3 + 3 dose-escalation study, nine chemotherapy-naïve patients (five MPM, four NSCLC) received weekly ADI-PEG 20 doses of 18 mg/m2, 27 mg/m2, or 36 mg/m2, together with pemetrexed 500 mg/m2 and cisplatin 75 mg/m2 which were given every three weeks (maximum of six cycles). Patients achieving stable disease or better could continue ADI-PEG 20 monotherapy until disease progression or withdrawal. Adverse events were assessed by Common Terminology Criteria for Adverse Events version 4.03, and pharmacodynamics and immunogenicity were also evaluated. Tumor response was assessed by Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1 for NSCLC and by modified RECIST criteria for MPM. Results No dose-limiting toxicities were reported; nine of 38 reported adverse events (all grade 1 or 2) were related to ADI-PEG 20. Circulating arginine concentrations declined rapidly, and citrulline levels increased; both changes persisted at 18 weeks. Partial responses were observed in seven of nine patients (78%), including three with either sarcomatoid or biphasic MPM. Conclusion Target engagement with depletion of arginine was maintained throughout treatment with no dose-limiting toxicities. In this biomarker-selected group of patients with ASS1-deficient cancers, clinical activity was observed in patients with poor-prognosis tumors. Therefore, we recommend a dose for future studies of weekly ADI-PEG 20 36 mg/m2 plus three-weekly cisplatin 75 mg/m2 and pemetrexed 500 mg/m2.


Asunto(s)
Protocolos de Quimioterapia Combinada Antineoplásica/administración & dosificación , Argininosuccinato Sintasa/deficiencia , Carcinoma de Pulmón de Células no Pequeñas/tratamiento farmacológico , Neoplasias Pulmonares/tratamiento farmacológico , Mesotelioma/tratamiento farmacológico , Neoplasias Pleurales/tratamiento farmacológico , Anciano , Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , Carcinoma de Pulmón de Células no Pequeñas/enzimología , Cisplatino/administración & dosificación , Cisplatino/efectos adversos , Relación Dosis-Respuesta a Droga , Femenino , Humanos , Hidrolasas/administración & dosificación , Hidrolasas/efectos adversos , Neoplasias Pulmonares/enzimología , Masculino , Mesotelioma/enzimología , Mesotelioma Maligno , Persona de Mediana Edad , Pemetrexed/administración & dosificación , Pemetrexed/efectos adversos , Neoplasias Pleurales/enzimología , Polietilenglicoles/administración & dosificación , Polietilenglicoles/efectos adversos
5.
JAMA Oncol ; 3(1): 58-66, 2017 Jan 01.
Artículo en Inglés | MEDLINE | ID: mdl-27584578

RESUMEN

IMPORTANCE: Preclinical studies show that arginine deprivation is synthetically lethal in argininosuccinate synthetase 1 (ASS1)-negative cancers, including mesothelioma. The role of the arginine-lowering agent pegylated arginine deiminase (ADI-PEG20) has not been evaluated in a randomized and biomarker-driven study among patients with cancer. OBJECTIVE: To assess the clinical impact of arginine depletion in patients with ASS1-deficient malignant pleural mesothelioma. DESIGN, SETTING, AND PARTICIPANTS: A multicenter phase 2 randomized clinical trial, the Arginine Deiminase and Mesothelioma (ADAM) study, was conducted between March 2, 2011, and May 21, 2013, at 8 academic cancer centers. Immunohistochemical screening of 201 patients (2011-2013) identified 68 with advanced ASS1-deficient malignant pleural mesothelioma. INTERVENTIONS: Randomization 2:1 to arginine deprivation (ADI-PEG20, 36.8 mg/m2, weekly intramuscular) plus best supportive care (BSC) or BSC alone. MAIN OUTCOMES AND MEASURES: The primary end point was progression-free survival (PFS) assessed by modified Response Evaluation Criteria in Solid Tumors (RECIST) (target hazard ratio, 0.60). Secondary end points were overall survival (OS), tumor response rate, safety, and quality of life, analyzed by intention to treat. We measured plasma arginine and citrulline levels, anti-ADI-PEG20 antibody titer, ASS1 methylation status, and metabolic response by 18F-fluorodeoxyglucose positron-emission tomography. RESULTS: Median (range) follow-up in 68 adults (median [range] age, 66 [48-83] years; 19% female) was 38 (2.5-39) months. The PFS hazard ratio was 0.56 (95% CI, 0.33-0.96), with a median of 3.2 months in the ADI-PEG20 group vs 2.0 months in the BSC group (P = .03) (absolute risk, 18% vs 0% at 6 months). Best response at 4 months (modified RECIST) was stable disease: 12 of 23 (52%) in the ADI-PEG20 group vs 2 of 9 (22%) in the BSC group (P = .23). The OS curves crossed, so life expectancy was used: 15.7 months in the ADI-PEG20 group vs 12.1 months in the BSC group (difference of 3.6 [95% CI, -1.0 to 8.1] months; P = .13). The incidence of symptomatic adverse events of grade at least 3 was 11 of 44 (25%) in the ADI-PEG20 group vs 4 of 24 (17%) in the BSC group (P = .43), the most common being immune related, nonfebrile neutropenia, gastrointestinal events, and fatigue. Differential ASS1 gene-body methylation correlated with ASS1 immunohistochemistry, and longer arginine deprivation correlated with improved PFS. CONCLUSIONS AND RELEVANCE: In this trial, arginine deprivation with ADI-PEG20 improved PFS in patients with ASS1-deficient mesothelioma. Targeting arginine is safe and warrants further clinical investigation in arginine-dependent cancers. TRIAL REGISTRATION: clinicaltrials.gov Identifier: NCT01279967.


Asunto(s)
Argininosuccinato Sintasa/sangre , Biomarcadores de Tumor/sangre , Citrulinemia/tratamiento farmacológico , Hidrolasas/administración & dosificación , Neoplasias Pulmonares/tratamiento farmacológico , Mesotelioma/tratamiento farmacológico , Polietilenglicoles/administración & dosificación , Anciano , Anciano de 80 o más Años , Arginina/metabolismo , Biomarcadores de Tumor/genética , Citrulinemia/sangre , Citrulinemia/genética , Citrulinemia/patología , Metilación de ADN/genética , Supervivencia sin Enfermedad , Determinación de Punto Final , Femenino , Humanos , Neoplasias Pulmonares/sangre , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/patología , Masculino , Mesotelioma/sangre , Mesotelioma/genética , Mesotelioma/patología , Mesotelioma Maligno , Persona de Mediana Edad , Resultado del Tratamiento
6.
Cancer Res ; 74(3): 896-907, 2014 Feb 01.
Artículo en Inglés | MEDLINE | ID: mdl-24285724

RESUMEN

Targeted therapies have yet to have significant impact on the survival of patients with bladder cancer. In this study, we focused on the urea cycle enzyme argininosuccinate synthetase 1 (ASS1) as a therapeutic target in bladder cancer, based on our discovery of the prognostic and functional import of ASS1 in this setting. ASS1 expression status in bladder tumors from 183 Caucasian and 295 Asian patients was analyzed, along with its hypothesized prognostic impact and association with clinicopathologic features, including tumor size and invasion. Furthermore, the genetics, biology, and therapeutic implications of ASS1 loss were investigated in urothelial cancer cells. We detected ASS1 negativity in 40% of bladder cancers, in which multivariate analysis indicated worse disease-specific and metastasis-free survival. ASS1 loss secondary to epigenetic silencing was accompanied by increased tumor cell proliferation and invasion, consistent with a tumor-suppressor role for ASS1. In developing a treatment approach, we identified a novel targeted antimetabolite strategy to exploit arginine deprivation with pegylated arginine deiminase (ADI-PEG20) as a therapeutic. ADI-PEG20 was synthetically lethal in ASS1-methylated bladder cells and its exposure was associated with a marked reduction in intracellular levels of thymidine, due to suppression of both uptake and de novo synthesis. We found that thymidine uptake correlated with thymidine kinase-1 protein levels and that thymidine levels were imageable with [(18)F]-fluoro-L-thymidine (FLT)-positron emission tomography (PET). In contrast, inhibition of de novo synthesis was linked to decreased expression of thymidylate synthase and dihydrofolate reductase. Notably, inhibition of de novo synthesis was associated with potentiation of ADI-PEG20 activity by the antifolate drug pemetrexed. Taken together, our findings argue that arginine deprivation combined with antifolates warrants clinical investigation in ASS1-negative urothelial and related cancers, using FLT-PET as an early surrogate marker of response.


Asunto(s)
Argininosuccinato Sintasa/metabolismo , Tomografía de Emisión de Positrones , Neoplasias de la Vejiga Urinaria/diagnóstico , Neoplasias de la Vejiga Urinaria/metabolismo , Animales , Antimetabolitos Antineoplásicos/farmacología , Argininosuccinato Sintasa/deficiencia , Argininosuccinato Sintasa/genética , Línea Celular Tumoral , Proliferación Celular , Metilación de ADN , Modelos Animales de Enfermedad , Sinergismo Farmacológico , Femenino , Glutamatos/farmacología , Guanina/análogos & derivados , Guanina/farmacología , Humanos , Hidrolasas/farmacología , Hidrolasas/toxicidad , Inmunohistoquímica , Ratones , Invasividad Neoplásica , Pemetrexed , Polietilenglicoles/farmacología , Polietilenglicoles/toxicidad , Pronóstico , Pirimidinas/metabolismo , Neoplasias de la Vejiga Urinaria/tratamiento farmacológico , Neoplasias de la Vejiga Urinaria/genética , Neoplasias de la Vejiga Urinaria/mortalidad , Microtomografía por Rayos X
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