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1.
Cancer ; 127(6): 894-904, 2021 03 15.
Artículo en Inglés | MEDLINE | ID: mdl-33231866

RESUMEN

BACKGROUND: Therapeutic options for patients with advanced soft-tissue sarcoma (STS) are limited. The goal of the current phase 2 study was to examine the clinical activity and safety of the combination of gemcitabine plus pazopanib, a multityrosine kinase inhibitor with activity in STS. METHODS: The current randomized, phase 2 trial enrolled patients with advanced nonadipocytic STS who had received prior anthracycline-based therapy. Patients were assigned 1:1 to receive gemcitabine at a dose of 1000 mg/m2 on days 1 and 8 with pazopanib at a dose of 800 mg daily (G+P) or gemcitabine at a dose of 900 mg/m2 on days 1 and 8 and docetaxel at a dose of 100 mg/m2 on day 8 (G+T) every 3 weeks. Crossover was allowed at the time of disease progression. The study used a noncomparative statistical design based on the precision of 95% confidence intervals for reporting the primary endpoints of median progression-free survival (PFS) and rate of grade ≥3 adverse events (AEs) for these 2 regimens based on the intent-to-treat patient population (AEs were graded using version 4.0 of the National Cancer Institute Common Terminology Criteria for Adverse Events). RESULTS: A total of 90 patients were enrolled: 45 patients on each treatment arm. The median PFS was 4.1 months for each arm (P = .3, log-rank test). The best overall response of stable disease or better (complete response + partial response + stable disease) was the same for both treatment arms (64% for both the G+T and G+P arms). The rate of related grade ≥3 AEs was 82% for the G+T arm and 78% for the G+P arm. Related grade ≥3 AEs occurring in ≥10% of patients in the G+T and G+P arms were anemia (36% and 20%, respectively), fatigue (29% and 13%, respectively), thrombocytopenia (53% and 49%, respectively), neutropenia (20% and 49%, respectively), lymphopenia (13% and 11%, respectively), and hypertension (2% and 20%, respectively). CONCLUSIONS: The data from the current study have demonstrated the safety and efficacy of G+P as an alternative to G+T for patients with nonadipocytic STS.


Asunto(s)
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Desoxicitidina/análogos & derivados , Docetaxel/administración & dosificación , Indazoles/administración & dosificación , Pirimidinas/administración & dosificación , Neoplasias de los Tejidos Blandos/tratamiento farmacológico , Sulfonamidas/administración & dosificación , Adulto , Anciano , Anciano de 80 o más Años , Estudios Cruzados , Desoxicitidina/administración & dosificación , Desoxicitidina/efectos adversos , Docetaxel/efectos adversos , Femenino , Humanos , Indazoles/efectos adversos , Masculino , Persona de Mediana Edad , Pirimidinas/efectos adversos , Neoplasias de los Tejidos Blandos/mortalidad , Sulfonamidas/efectos adversos , Adulto Joven , Gemcitabina
2.
Curr Probl Cancer ; 43(4): 273-282, 2019 08.
Artículo en Inglés | MEDLINE | ID: mdl-31221500

RESUMEN

The optimal management of localized soft tissue sarcomas of the extremities and retroperitoneum involves a high volume multidisciplinary team with expertise in sarcoma. In this review, we will highlight the importance of the sarcoma pathologist and imaging techniques prior to surgery and radiation. In addition, the data on neoadjuvant and adjuvant chemotherapy will be discussed. Finally, consideration is given to the importance of identifying genetic cancer predispositions, multidisciplinary management, long-term survivorship, and the current clinical trials for patients undergoing curative intent management.


Asunto(s)
Extremidades/patología , Neoplasias Retroperitoneales/terapia , Sarcoma/terapia , Terapia Combinada , Manejo de la Enfermedad , Humanos , Pronóstico , Neoplasias Retroperitoneales/patología , Sarcoma/patología
3.
J Clin Oncol ; 36(2): 180-187, 2018 01 10.
Artículo en Inglés | MEDLINE | ID: mdl-29220290

RESUMEN

Synovial sarcoma (SS) is a rare sarcoma driven by a translocation between SS18 and SSX 1, 2, or 4. With approximately 800 to 1,000 cases a year in the United States, it most commonly affects young adults between the ages of 15 and 30 years. The resultant tumors are either monophasic (pure sarcomas), biphasic (a combination or epithelioid and sarcomatous components), or poorly differentiated. The hybrid transcription factor SS18:SSX alters SWItch/Sucrose Non-Fermentable (SWI/SNF) chromatin remodeling and global methylation patterns that may allow for future therapeutic opportunities. In this review, we focus on the pharmacologic management of SS, both in the curative setting, where the standard approach is wide surgical excision combined with radiotherapy and/or (neo)adjuvant chemotherapy as appropriate, and in the palliative setting. In advanced disease, chemotherapy with anthracyclines and/or ifosfamide, trabectedin, or pazopanib has been demonstrated to be more active compared with other soft tissue sarcomas. In addition, a better understanding of the molecular and immunologic characteristics of SS has allowed for the identification of new potential targets and the development of novel biology-driven therapies that are all at different stages of testing. There include targeted agents, immunotherapy, and metabolic therapies. Because the impact of these strategies for improving SS outcome is still limited, current and future research is strongly needed to better understand the tumor biology, to identify predictive biomarkers, and to improve the outcomes for patients with SS.


Asunto(s)
Biomarcadores de Tumor/genética , Sarcoma Sinovial/genética , Neoplasias de los Tejidos Blandos/genética , Translocación Genética , Adolescente , Adulto , Quimioradioterapia , Humanos , Proteínas de Fusión Oncogénica/genética , Sarcoma Sinovial/cirugía , Sarcoma Sinovial/terapia , Neoplasias de los Tejidos Blandos/cirugía , Neoplasias de los Tejidos Blandos/terapia , Adulto Joven
4.
Theranostics ; 8(8): 2107-2116, 2018.
Artículo en Inglés | MEDLINE | ID: mdl-29721066

RESUMEN

Rational: In a subset of cancers, arginine auxotrophy occurs due to the loss of expression of argininosuccinate synthetase 1 (ASS1). This loss of ASS1 expression makes cancers sensitive to arginine starvation that is induced by PEGylated arginine deiminase (ADI-PEG20). Although ADI-PEG20 treatment is effective, it does have important limitations. Arginine starvation is only beneficial in patients with cancers that are ASS1-deficient. Also, these tumors may metabolically reprogram to express ASS1, transforming them from an auxotrophic phenotype to a prototrophic phenotype and thus rendering ADI-PEG20 ineffective. Due to these limitations of ADI-PEG20 treatment and the potential for developing resistance, non-invasive tools to monitor sensitivity to arginine starvation are needed. Methods: Within this study, we assess the utility of a novel positron emission tomography (PET) tracer to determine sarcomas reliant on extracellular arginine for survival by measuring changes in amino acid transport in arginine auxotrophic sarcoma cells treated with ADI-PEG20. The uptake of the 18F-labeled histidine analogue, (S)-2-amino-3-[1-(2-[18F]fluoroethyl)-1H-[1,2,3]triazol-4-yl]propanoic acid (AFETP), was assessed in vitro and in vivo using human-derived sarcoma cell lines. In addition, we examined the expression and localization of cationic amino acid transporters in response to arginine starvation with ADI-PEG20. Results: In vitro studies revealed that in response to ADI-PEG20 treatment, arginine auxotrophs increase the uptake of L-[3H]arginine and [18F]AFETP due to an increase in the expression and localization to the plasma membrane of the cationic amino acid transporter CAT-1. Furthermore, in vivo PET imaging studies in mice with arginine-dependent osteosarcoma xenografts showed increased [18F]AFETP uptake in tumors 4 days after ADI-PEG20 treatment compared to baseline. Conclusion: CAT-1 transporters localizes to the plasma membrane as a result of arginine starvation with ADI-PEG20 in ASS1-deficient tumor cells and provides a mechanism for using cationic amino acid transport substrates such as [18F]AFETP for identifying tumors susceptible to ADI-PEG20 treatment though non-invasive PET imaging techniques. These findings indicate that [18F]AFETP-PET may be suitable for the early detection of tumor response to arginine depletion due to ADI-PEG20 treatment.


Asunto(s)
Aminoácidos/metabolismo , Arginina/deficiencia , Argininosuccinato Sintasa/deficiencia , Radioisótopos de Flúor/química , Sarcoma/enzimología , Sistema de Transporte de Aminoácidos y+/metabolismo , Argininosuccinato Sintasa/metabolismo , Línea Celular Tumoral , Membrana Celular/efectos de los fármacos , Membrana Celular/metabolismo , Humanos , Hidrolasas/farmacología , Modelos Biológicos , Polietilenglicoles/farmacología , Tomografía de Emisión de Positrones , Sarcoma/patología
5.
Cell Rep ; 18(4): 991-1004, 2017 01 24.
Artículo en Inglés | MEDLINE | ID: mdl-28122247

RESUMEN

Targeting defects in metabolism is an underutilized strategy for the treatment of cancer. Arginine auxotrophy resulting from the silencing of argininosuccinate synthetase 1 (ASS1) is a common metabolic alteration reported in a broad range of aggressive cancers. To assess the metabolic effects that arise from acute and chronic arginine starvation in ASS1-deficient cell lines, we performed metabolite profiling. We found that pharmacologically induced arginine depletion causes increased serine biosynthesis, glutamine anaplerosis, oxidative phosphorylation, and decreased aerobic glycolysis, effectively inhibiting the Warburg effect. The reduction of glycolysis in cells otherwise dependent on aerobic glycolysis is correlated with reduced PKM2 expression and phosphorylation and upregulation of PHGDH. Concurrent arginine deprivation and glutaminase inhibition was found to be synthetic lethal across a spectrum of ASS1-deficient tumor cell lines and is sufficient to cause in vivo tumor regression in mice. These results identify two synthetic lethal therapeutic strategies exploiting metabolic vulnerabilities of ASS1-negative cancers.


Asunto(s)
Argininosuccinato Sintasa/genética , Glutamina/metabolismo , Serina/biosíntesis , Animales , Arginina/química , Argininosuccinato Sintasa/metabolismo , Proteínas Portadoras/metabolismo , Línea Celular Tumoral , Proliferación Celular/efectos de los fármacos , Ciclo del Ácido Cítrico/efectos de los fármacos , Medios de Cultivo/química , Medios de Cultivo/farmacología , Glucosa/metabolismo , Glucosa/farmacología , Glutaminasa/antagonistas & inhibidores , Glutaminasa/genética , Glutaminasa/metabolismo , Glutamina/farmacología , Glucólisis/efectos de los fármacos , Humanos , Hidrolasas/farmacología , Proteínas de la Membrana/metabolismo , Metabolómica , Ratones , Fosfoglicerato-Deshidrogenasa/genética , Fosfoglicerato-Deshidrogenasa/metabolismo , Fosforilación/efectos de los fármacos , Polietilenglicoles/farmacología , Interferencia de ARN , Hormonas Tiroideas/metabolismo , Regulación hacia Arriba/efectos de los fármacos , Proteínas de Unión a Hormona Tiroide
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