RESUMEN
BACKGROUND: KRAS mutations are clinically important predictors of resistance to EGFR-directed therapies in colorectal cancer (CRC). Oncogenic activation of the RAS/RAF/MEK/ERK signaling cascade mediates proliferation independent of growth factor signaling. We hypothesized that targeting MEK with selumetinib could overcome resistance to cetuximab in KRAS mutant CRC. METHODS: A phase I study (NCT01287130) was undertaken to determine the tolerability, and pharmacokinetic profiles of the combination of selumetinib and cetuximab, with an expanded cohort in KRAS-mutant CRC. RESULTS: 15 patients were treated in the dose escalation cohort and 18 patients were treated in the expansion cohort. Two dose-limiting toxicities were observed. One grade 3 acneiform rash and one grade 4 hypomagnesemia occurred. The most common grade 1 and 2 adverse events included rash, nausea/vomiting, diarrhea, and fatigue. The maximum tolerated dose was established at selumetinib 75 mg p.o. BID and cetuximab 250 mg/m(2) weekly following a 400 mg/m(2) load. Best clinical response in the dose escalation group included 1 unconfirmed partial response in a patient with CRC and stable disease (SD) in 5 patients (1 squamous cell carcinoma of the tonsil, 1 non-small cell lung cancer, and 3 CRC), and in the KRAS-mutant CRC dose expansion cohort, of the 14 patients who were evaluable for response, 5 patients had SD and 9 patients had progressive disease. CONCLUSIONS: The combination of selumetinib and cetuximab is safe and well tolerated. Minimal anti-tumor activity was observed in KRAS-mutant refractory metastatic CRC. Further investigations might be warranted in other cancer subtypes.
Asunto(s)
Bencimidazoles/uso terapéutico , Cetuximab/uso terapéutico , Neoplasias Colorrectales/tratamiento farmacológico , Quinasas de Proteína Quinasa Activadas por Mitógenos/antagonistas & inhibidores , Mutación/genética , Inhibidores de Proteínas Quinasas/uso terapéutico , Proteínas Proto-Oncogénicas p21(ras)/genética , Adulto , Anciano , Anciano de 80 o más Años , Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/farmacocinética , Protocolos de Quimioterapia Combinada Antineoplásica/farmacología , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Bencimidazoles/efectos adversos , Bencimidazoles/farmacocinética , Bencimidazoles/farmacología , Cetuximab/efectos adversos , Cetuximab/farmacología , Neoplasias Colorrectales/sangre , Neoplasias Colorrectales/genética , Relación Dosis-Respuesta a Droga , Femenino , Humanos , Masculino , Dosis Máxima Tolerada , Persona de Mediana Edad , Quinasas de Proteína Quinasa Activadas por Mitógenos/metabolismo , Inhibidores de Proteínas Quinasas/farmacología , Resultado del TratamientoRESUMEN
AIM: Serum PSA screening for prostate cancer (PCa) is controversial. Here, we identify three urinary biomarkers - aHGF, IGFBP3 and OPN - for PCa screening and prognostication. METHODS: Urinary aHGF, OPN and IGFBP3 from healthy men (n = 19) and men with localized (n = 65) and metastatic (n = 36) PCa were quantified via ELISA. Mann-Whitney nonparametric t-test and the Search Tool for the Retrieval of Interacting Genes/Proteins (STRING) analyses were used to analyze associations. RESULTS: Mean aHGF and IGFBP3 levels were significantly elevated in PCa patients versus controls (p = 0.0006 and p = 0.0012, respectively), and the area under the curve of the receiver operating characteristic curve (indicator of diagnostic accuracy) for aHGF and IGFBP3 was 0.75 and 0.74, respectively. OPN levels were significantly higher in metastatic groups (p = 0.0060) versus localized and controls (area under the curve = 0.68). CONCLUSION: Urinary aHGF and IGFBP3 exhibit the capacity for diagnostic discrimination for PCa, whereas OPN may indicate presence of metastatic disease.
Asunto(s)
Biomarcadores de Tumor/orina , Neoplasias de la Próstata/diagnóstico , Área Bajo la Curva , Biomarcadores de Tumor/sangre , Ensayo de Inmunoadsorción Enzimática , Factor de Crecimiento de Hepatocito/orina , Humanos , Proteína 3 de Unión a Factor de Crecimiento Similar a la Insulina/orina , Masculino , Redes y Vías Metabólicas , Estadificación de Neoplasias , Osteopontina/orina , Pronóstico , Antígeno Prostático Específico/sangre , Neoplasias de la Próstata/sangre , Curva ROC , Sensibilidad y EspecificidadRESUMEN
Myeloid-derived suppressor cells (MDSC) are a heterogenous population of cells comprising myeloid progenitor cells and immature myeloid cells, which have the ability to suppress the effector immune response. In humans, MDSC have not been well characterized owing to the lack of specific markers, although it is possible to broadly classify the MDSC phenotypes described in the literature as being predominantly granulocytic (expressing markers such as CD15, CD66, CD33) or monocytic (expressing CD14). In this study, we set out to perform a direct comparative analysis across both granulocytic and monocytic MDSC subsets in terms of their frequency, absolute number, and function in the peripheral blood of patients with advanced GI cancer. We also set out to determine the optimal method of sample processing given that this is an additional source of heterogeneity. Our findings demonstrate consistent changes across sample processing methods for monocytic MDSC, suggesting that reliance upon cryopreserved PBMC is acceptable. Although we did not see an increase in the population of granulocytic MDSC, these cells were found to be more suppressive than their monocytic counterparts.