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1.
Cancer ; 130(2): 232-243, 2024 01.
Artículo en Inglés | MEDLINE | ID: mdl-37776537

RESUMEN

BACKGROUND: Resistance to BRAF and MEK inhibitors in BRAF V600-mutant melanoma is common. Multiple resistance mechanisms involve heat-shock protein 90 (HSP90) clients, and a phase 1 study of vemurafenib with the HSP90 inhibitor XL888 in patients with advanced melanoma showed activity equivalent to that of BRAF and MEK inhibitors. METHODS: Vemurafenib (960 mg orally twice daily) and cobimetinib (60 mg orally once daily for 21 of 28 days) with escalating dose cohorts of XL888 (30, 45, 60, or 90 mg orally twice weekly) was investigated in a phase 1 trial of advanced melanoma, with a modified Ji dose-escalation design. RESULTS: Twenty-five patients were enrolled. After two dose-limiting toxicities (DLTs) (rash and acute kidney injury) in the first cohort, lower doses of vemurafenib (720 mg) and cobimetinib (40 mg) were investigated with the same XL888 doses. Three DLTs (rash) were observed in 12 patients in the XL888 60-mg cohort, and this was determined as the maximum tolerated dose. Objective responses were observed in 19 patients (76%), and the median progression-free survival was 7.6 months, with a 5-year progression-free survival rate of 20%. The median overall survival was 41.7 months, with a 5-year overall survival rate of 37%. Single-cell RNA sequencing was performed on baseline and on-treatment biopsies; treatment was associated with increased immune cell influx (CD4-positive and CD8-positive T cells) and decreased melanoma cells. CONCLUSIONS: Combined vemurafenib and cobimetinib plus XL888 had significant toxicity, requiring frequent dose reductions, which may have contributed to the relatively low progression-free survival despite a high tumor response rate. Given overlapping toxicities, caution must be used when combining HSP90 inhibitors with BRAF and MEK inhibitors.


Asunto(s)
Exantema , Melanoma , Neoplasias Cutáneas , Humanos , Melanoma/tratamiento farmacológico , Melanoma/genética , Melanoma/patología , Vemurafenib , Proteínas Proto-Oncogénicas B-raf , Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , Inhibidores de Proteínas Quinasas/efectos adversos , Exantema/inducido químicamente , Exantema/tratamiento farmacológico , Proteínas de Choque Térmico/genética , Proteínas de Choque Térmico/uso terapéutico , Quinasas de Proteína Quinasa Activadas por Mitógenos/genética , Mutación , Neoplasias Cutáneas/tratamiento farmacológico , Neoplasias Cutáneas/genética , Neoplasias Cutáneas/patología
2.
Support Care Cancer ; 32(6): 330, 2024 May 06.
Artículo en Inglés | MEDLINE | ID: mdl-38709312

RESUMEN

PURPOSE: Little is known about late and long-term patient-reported outcomes (PROs) of immune checkpoint modulators (ICMs) outside clinical trials. We conducted a cross-sectional, mixed-methods study to describe long-term PROs among advanced melanoma patients who began standard of care treatment with ICMs at least 1 year previously. METHODS: All participants completed the Functional Assessment of Cancer Therapy-Immune Checkpoint Modulator (FACT-ICM), assessing 46 immune-related side effects on a 5-point Likert scale, and a subset completed individual interviews. Descriptive statistics were computed for quantitative data and applied thematic analysis was used to examine qualitative data. RESULTS: Participants (N = 80) had a mean age of 67 years, and the majority were male (66%), non-Hispanic White (96%), and college graduates (61%). Single-agent nivolumab was the most common first (47%) and current/recent ICM (64%). On the FACT-ICM, 98% of participants reported at least one side effect, and 78% reported moderate or severe side effects. The most common moderate or severe side effects were aching joints (43%) and fatigue (38%). In interviews (n = 20), we identified five themes regarding patients' longer-term experiences after ICMs: lasting fatigue or decline in functioning, minimal side effects, manageable thyroid and pituitary dysfunction, skin conditions can be difficult to manage, and treating the cancer is worth the side effects. CONCLUSIONS: Nearly all patients reported side effects of ICMs at least 1 year after starting treatment. Our findings suggest that ICM side effect screening and management-especially for aching joints and fatigue-are indicated during long-term care of people living with advanced melanoma.


Asunto(s)
Inhibidores de Puntos de Control Inmunológico , Melanoma , Medición de Resultados Informados por el Paciente , Humanos , Melanoma/tratamiento farmacológico , Masculino , Femenino , Anciano , Inhibidores de Puntos de Control Inmunológico/efectos adversos , Inhibidores de Puntos de Control Inmunológico/uso terapéutico , Estudios Transversales , Persona de Mediana Edad , Recurrencia Local de Neoplasia , Adulto , Anciano de 80 o más Años , Neoplasias Cutáneas/tratamiento farmacológico , Calidad de Vida
3.
Cancer ; 129(11): 1723-1734, 2023 06 01.
Artículo en Inglés | MEDLINE | ID: mdl-36869646

RESUMEN

BACKGROUND: Immune checkpoint inhibitors (ICIs) have substantially improved overall survival in patients with advanced melanoma; however, the lack of biomarkers to monitor treatment response and relapse remains an important clinical challenge. Thus, a reliable biomarker is needed that can risk-stratify patients for disease recurrence and predict response to treatment. METHODS: A retrospective analysis using a personalized, tumor-informed circulating tumor DNA (ctDNA) assay on prospectively collected plasma samples (n = 555) from 69 patients with advanced melanoma was performed. Patients were divided into three cohorts: cohort A (N = 30), stage III patients receiving adjuvant ICI/observation; cohort B (N = 29), unresectable stage III/IV patients receiving ICI therapy; and cohort C (N = 10), stage III/IV patients on surveillance after planned completion of ICI therapy for metastatic disease. RESULTS: In cohort A, compared to molecular residual disease (MRD)-negative patients, MRD-positivity was associated with significantly shorter distant metastasis-free survival (DMFS; hazard ratio [HR], 10.77; p = .01). Increasing ctDNA levels from the post-surgical or pre-treatment time point to after 6 weeks of ICI were predictive of shorter DMFS in cohort A (HR, 34.54; p < .0001) and shorter progression-free survival (PFS) in cohort B (HR, 22; p = .006). In cohort C, all ctDNA-negative patients remained progression-free for a median follow-up of 14.67 months, whereas ctDNA-positive patients experienced disease progression. CONCLUSION: Personalized and tumor-informed longitudinal ctDNA monitoring is a valuable prognostic and predictive tool that may be used throughout the clinical course of patients with advanced melanoma.


Asunto(s)
ADN Tumoral Circulante , Melanoma , Humanos , ADN Tumoral Circulante/genética , Estudios Retrospectivos , Recurrencia Local de Neoplasia , Melanoma/tratamiento farmacológico , Melanoma/genética , Melanoma/patología , Pronóstico , ADN de Neoplasias , Biomarcadores de Tumor/genética
4.
Lancet ; 400(10357): 1008-1019, 2022 09 24.
Artículo en Inglés | MEDLINE | ID: mdl-36108657

RESUMEN

BACKGROUND: Merkel cell carcinoma is among the most aggressive and lethal of primary skin cancers, with a high rate of distant metastasis. Anti-programmed death receptor 1 (anti-PD-1) and programmed death ligand 1 (PD-L1) monotherapy is currently standard of care for unresectable, recurrent, or metastatic Merkel cell carcinoma. We assessed treatment with combined nivolumab plus ipilimumab, with or without stereotactic body radiotherapy (SBRT) in patients with advanced Merkel cell carcinoma as a first-line therapy or following previous treatment with anti-PD-1 and PD-L1 monotherapy. METHODS: In this randomised, open label, phase 2 trial, we randomly assigned adults from two cancer sites in the USA (one in Florida and one in Ohio) to group A (combined nivolumab and ipilimumab) or group B (combined nivolumab and ipilimumab plus SBRT) in a 1:1 ratio. Eligible patients were aged at least 18 years with histologically proven advanced stage (unresectable, recurrent, or stage IV) Merkel cell carcinoma, a minimum of two tumour lesions measureable by CT, MRI or clinical exam, and tumour tissue available for exploratory biomarker analysis. Patients were stratified by previous immune-checkpoint inhibitor (ICI) status to receive nivolumab 240 mg intravenously every 2 weeks plus ipilimumab 1 mg/kg intravenously every 6 weeks (group A) or the same schedule of combined nivolumab and ipilimumab with the addition of SBRT to at least one tumour site (24 Gy in three fractions at week 2; group B). Patients had to have at least two measurable sites of disease so one non-irradiated site could be followed for response. The primary endpoint was objective response rate (ORR) in all randomly assigned patients who received at least one dose of combined nivolumab and ipilimumab. ORR was defined as the proportion of patients with a complete response or partial response per immune-related Response Evaluation Criteria in Solid Tumours. Response was assessed every 12 weeks. Safety was assessed in all patients. This trial is registered with ClinicalTrials.gov, NCT03071406. FINDINGS: 50 patients (25 in both group A and group B) were enrolled between March 14, 2017, and Dec 21, 2021, including 24 ICI-naive patients (13 [52%] of 25 group A patients and 11 [44%] of 25 group B patients]) and 26 patients with previous ICI (12 [48%] of 25 group A patients and 14 [56%] of 25 group B patients]). One patient in group B did not receive SBRT due to concerns about excess toxicity. Median follow-up was 14·6 months (IQR 9·1-26·5). Two patients in group B were excluded from the analysis of the primary endpoint because the target lesions were irradiated and so the patients were deemed non-evaluable. Of the ICI-naive patients, 22 (100%) of 22 (95% CI 82-100) had an objective response, including nine (41% [95% CI 21-63]) with complete response. Of the patients who had previously had ICI exposure, eight (31%) of 26 patients (95% CI 15-52) had an objective response and four (15% [5-36]) had a complete response. No significant differences in ORR were observed between groups A (18 [72%] of 25 patients) and B (12 [52%] of 23 patients; p=0·26). Grade 3 or 4 treatment-related adverse events were observed in 10 (40%) of 25 patients in group A and 8 (32%) of 25 patients in group B. INTERPRETATION: First-line combined nivolumab and ipilimumab in patients with advanced Merkel cell carcinoma showed a high ORR with durable responses and an expected safety profile. Combined nivolumab and ipilimumab also showed clinical benefit in patients with previous anti-PD-1 and PD-L1 treatment. Addition of SBRT did not improve efficacy of combined nivolumab and ipilimumab. The combination of nivolumab and ipilimumab represents a new first-line and salvage therapeutic option for advanced Merkel cell carcinoma. FUNDING: Bristol Myers Squibb Rare Population Malignancy Program.


Asunto(s)
Carcinoma de Células de Merkel , Radiocirugia , Neoplasias Cutáneas , Adolescente , Adulto , Protocolos de Quimioterapia Combinada Antineoplásica , Antígeno B7-H1 , Biomarcadores , Carcinoma de Células de Merkel/tratamiento farmacológico , Carcinoma de Células de Merkel/radioterapia , Humanos , Inhibidores de Puntos de Control Inmunológico , Ipilimumab , Nivolumab , Receptores de Muerte Celular , Neoplasias Cutáneas/tratamiento farmacológico , Neoplasias Cutáneas/radioterapia
5.
Mol Ther ; 30(6): 2315-2326, 2022 06 01.
Artículo en Inglés | MEDLINE | ID: mdl-35150889

RESUMEN

We have reported previously that CD33hi myeloid-derived suppressor cells (MDSCs) play a direct role in the pathogenesis of myelodysplastic syndromes (MDSs) and that their sustained activation contributes to hematopoietic and immune impairment, including modulation of PD1/PDL1. MDSCs can also limit the clinical activity of immune checkpoint inhibition in solid malignancies. We hypothesized that depletion of MDSCs may ameliorate resistance to checkpoint inhibitors and, hence, targeted them with AMV564 combined with anti-PD1 in MDS bone marrow (BM) mononuclear cells (MNCs) enhanced activation of cytotoxic T cells. AMV564 was active in vivo in a leukemia xenograft model when co-administered with healthy donor peripheral blood MNCs (PBMCs). Our findings provide a strong rationale for clinical investigation of AMV564 as a single agent or in combination with an anti-PD1 antibody and in particular for treatment of cancers resistant to checkpoint inhibitors.


Asunto(s)
Anticuerpos Biespecíficos , Antineoplásicos , Melanoma , Síndromes Mielodisplásicos , Células Supresoras de Origen Mieloide , Animales , Anticuerpos Biespecíficos/farmacología , Antineoplásicos/farmacología , Humanos , Melanoma/tratamiento farmacológico , Síndromes Mielodisplásicos/tratamiento farmacológico , Lectina 3 Similar a Ig de Unión al Ácido Siálico , Linfocitos T
6.
Bioinformatics ; 37(23): 4584-4586, 2021 12 07.
Artículo en Inglés | MEDLINE | ID: mdl-34734969

RESUMEN

SUMMARY: Multiplex immunofluorescence (mIF) staining combined with quantitative digital image analysis is a novel and increasingly used technique that allows for the characterization of the tumor immune microenvironment (TIME). Generally, mIF data is used to examine the abundance of immune cells in the TIME; however, this does not capture spatial patterns of immune cells throughout the TIME, a metric increasingly recognized as important for prognosis. To address this gap, we developed an R package spatialTIME that enables spatial analysis of mIF data, as well as the iTIME web application that provides a robust but simplified user interface for describing both abundance and spatial architecture of the TIME. The spatialTIME package calculates univariate and bivariate spatial statistics (e.g. Ripley's K, Besag's L, Macron's M and G or nearest neighbor distance) and creates publication quality plots for spatial organization of the cells in each tissue sample. The iTIME web application allows users to statistically compare the abundance measures with patient clinical features along with visualization of the TIME for one tissue sample at a time. AVAILABILITY AND IMPLEMENTATION: spatialTIME is implemented in R and can be downloaded from GitHub (https://github.com/FridleyLab/spatialTIME) or CRAN. An extensive vignette for using spatialTIME can also be found at https://cran.r-project.org/web/packages/spatialTIME/index.html. iTIME is implemented within a R Shiny application and can be accessed online (http://itime.moffitt.org/), with code available on GitHub (https://github.com/FridleyLab/iTIME). SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online.


Asunto(s)
Programas Informáticos , Humanos , Análisis por Conglomerados , Técnica del Anticuerpo Fluorescente
7.
Cancer Immunol Immunother ; 69(12): 2465-2476, 2020 Dec.
Artículo en Inglés | MEDLINE | ID: mdl-32556443

RESUMEN

Emm55 is a bacterial gene derived from Streptococcus pyogenes (S. pyogenes) that was cloned into a plasmid DNA vaccine (pAc/emm55). In this study, we investigated the anti-tumor efficacy of pAc/emm55 in a B16 murine melanoma model. Intralesional (IL) injections of pAc/emm55 significantly delayed tumor growth compared to the pAc/Empty group. There was a significant increase in the CD8+ T cells infiltrating into the tumors after pAc/emm55 treatment compared to the control group. In addition, we observed that IL injection of pAc/emm55 increased antigen-specific T cell infiltration into tumors. Depletion of CD4+ or CD8+ T cells abrogated the anti-tumor effect of pAc/emm55. Combination treatment of IL injection of pAc/emm55 with anti-PD-1 antibody significantly delayed tumor growth compared to either monotherapy. pAc/emm55 treatment combined with PD-1 blockade enhanced anti-tumor immune response and improved systemic anti-tumor immunity. Together, these strategies may lead to improvements in the treatment of patients with melanoma.


Asunto(s)
Antígenos Bacterianos/inmunología , Antineoplásicos Inmunológicos/administración & dosificación , Proteínas de la Membrana Bacteriana Externa/inmunología , Inmunoterapia/métodos , Melanoma Experimental/terapia , Animales , Antígenos Bacterianos/genética , Proteínas de la Membrana Bacteriana Externa/genética , Linfocitos T CD8-positivos/inmunología , Línea Celular Tumoral/trasplante , Terapia Combinada/métodos , Femenino , Humanos , Inyecciones Intralesiones , Linfocitos Infiltrantes de Tumor/inmunología , Melanoma Experimental/inmunología , Ratones , Plásmidos/administración & dosificación , Plásmidos/genética , Receptor de Muerte Celular Programada 1/antagonistas & inhibidores , Receptor de Muerte Celular Programada 1/inmunología
8.
Biochim Biophys Acta Rev Cancer ; 1868(2): 500-509, 2017 Dec.
Artículo en Inglés | MEDLINE | ID: mdl-28963068

RESUMEN

Nitric oxide (NO) is a small gaseous signaling molecule that mediates its effects in melanoma through free radical formation and enzymatic processes. Investigations have demonstrated multiple roles for NO in melanoma pathology via immune surveillance, apoptosis, angiogenesis, melanogenesis, and on the melanoma cell itself. In general, elevated levels of NO prognosticate a poor outcome for melanoma patients. However, there are processes where the relative concentration of NO in different environments may also serve to limit melanoma proliferation. This review serves to outline the roles of NO in melanoma development and proliferation. As demonstrated by multiple in vivo murine models and observations from human tissue, NO may promote melanoma formation and proliferation through its interaction via inhibitory immune cells, inhibition of apoptosis, stimulation of pro-tumorigenic cytokines, activation of tumor associated macrophages, alteration of angiogenic processes, and stimulation of melanoma formation itself.


Asunto(s)
Melanoma/etiología , Óxido Nítrico/fisiología , Animales , Apoptosis , Proliferación Celular , Citocinas/biosíntesis , Humanos , Activación de Macrófagos , Melanoma/inmunología , Melanoma/metabolismo , Melanoma/patología , Células Supresoras de Origen Mieloide/fisiología , Neovascularización Fisiológica , Óxido Nítrico Sintasa de Tipo II/fisiología
9.
World J Surg ; 44(4): 1283-1293, 2020 04.
Artículo en Inglés | MEDLINE | ID: mdl-31811340

RESUMEN

BACKGROUND: Traditional chemotherapy agents adversely affect wound healing and need to be held prior to or after surgery. Immune checkpoint inhibitors (ICIs) and targeted agents are now standard of care for the several treatment cancers. We hypothesize that ICI and targeted therapy do not have similar adverse effects on perioperative outcomes. METHODS: We performed a review of melanoma patients undergoing surgery at an academic hospital between 2011 and 2019. All patients received ICI or targeted therapy ≤ 60 days prior to surgery, including palliative procedures. Preoperative performance status was assessed using Eastern Cooperative Oncology Group score and American Society of Anesthesiologists Classification System. Thirty-day complications were classified by Clavien-Dindo grade. No statistical comparisons were performed. RESULTS: Of 63 patients included in the analysis, 29 (46%) patients received ICI and 34 (54%) received targeted therapy with median of 14 days (IQR 5-27 days) between the last preoperative dose and day of surgery (ICI, median 18 days [IQR 13-34.5]; targeted therapy, median 7 days [IQR 3-22.25]). There were no perioperative mortalities. Among patients treated with ICI, 22 patients (76%) had no complications. Four patients had wound infections (2 readmitted), 1 had reoperation (hematoma) and 2 readmitted for other reasons (fever; volvulus). Among patients treated with targeted therapy, 25 patients (74%) had no complications. Seven patients had wound infections (none readmitted), 1 had reoperation (flap failure) and 1 had dehiscence (not treated). CONCLUSIONS: Patients undergoing treatment with ICI or targeted therapies can safely undergo surgery without substantially increased risk of serious intraoperative and postoperative complications.


Asunto(s)
Inhibidores de Puntos de Control Inmunológico/uso terapéutico , Melanoma/cirugía , Terapia Molecular Dirigida , Adolescente , Adulto , Anciano , Anciano de 80 o más Años , Niño , Terapia Combinada , Femenino , Humanos , Masculino , Melanoma/tratamiento farmacológico , Persona de Mediana Edad , Complicaciones Posoperatorias/etiología , Reoperación , Estudios Retrospectivos , Adulto Joven
10.
J Surg Oncol ; 118(3): 501-509, 2018 Sep.
Artículo en Inglés | MEDLINE | ID: mdl-30132912

RESUMEN

BACKGROUND AND OBJECTIVES: MicroRNAs (miRs) are noncoding RNAs that regulate protein translation and melanoma progression. Changes in plasma miR expression following surgical resection of metastatic melanoma are under-investigated. We hypothesize differences in miR expression exist following complete surgical resection of metastatic melanoma. METHODS: Blood collection pre- and post-surgical resection was performed in six individuals with solitary melanoma metastases. miR expression in extracted RNA was quantified using the NanoString nCounter Digital Analyzer. RESULTS: Pre- and post-surgical plasma samples contained 216 miRs with expression above baseline. Comparison of postsurgical to preresection samples revealed differential expression of 25 miRs: miR-let-7a, miR-let7g, miR-15a, miR-16, miR-22, miR-30b, miR-126, miR-140, miR-145, miR-148a, miR-150-5p, miR-191, miR-378i, miR-449c, miR-494, miR-513b, miR-548aa, miR-571, miR-587, miR-891b, miR-1260a, miR 1268a, miR-1976, miR-4268, miR-4454 (P < 0.05). Utilizing P < 0.0046 as a cutoff to control for one false positive among the 216 miRs revealed that postsurgical melanoma plasma samples had upregulation of miR-1260a (P = 0.0007) and downregulation of miR-150-5p (P = 0.0026) relative to pre-surgical samples. CONCLUSIONS: Differential expression of miR-150-5p and miR-1260a is present in plasma following surgical resection of metastatic melanoma in this small sample (n = 6) of melanoma patients. Therefore, further investigation of these plasma miRs as noninvasive biomarkers for melanoma is warranted.


Asunto(s)
Regulación Neoplásica de la Expresión Génica , Melanoma/genética , MicroARNs/genética , Recurrencia Local de Neoplasia/genética , Anciano , Biomarcadores de Tumor , Femenino , Estudios de Seguimiento , Perfilación de la Expresión Génica , Humanos , Metástasis Linfática , Masculino , Melanoma/secundario , Melanoma/cirugía , Persona de Mediana Edad , Recurrencia Local de Neoplasia/patología , Recurrencia Local de Neoplasia/cirugía , Pronóstico , Tasa de Supervivencia
11.
J Immunol ; 197(4): 1489-97, 2016 08 15.
Artículo en Inglés | MEDLINE | ID: mdl-27385779

RESUMEN

CD200 is a cell surface glycoprotein that functions through engaging CD200R on cells of the myeloid lineage and inhibits their functions. Expression of CD200 was implicated in a variety of human cancer cells, including melanoma cells; however, its roles in tumor growth and immunity are not clearly understood. In this study, we used CD200R-deficient mice and the B16 tumor model to evaluate this issue. We found that CD200R-deficient mice exhibited accelerated growth of CD200(+), but not CD200(-), B16 tumors. Strikingly, CD200R-deficient mice receiving CD200(+) B16 cells i.v. exhibited massive tumor growth in multiple organs, including liver, lung, kidney, and peritoneal cavity, whereas the growth of the same tumors in wild-type mice was limited. CD200(+) tumors grown in CD200R-deficient mice contained higher numbers of CD11b(+)Ly6C(+) myeloid cells, exhibited increased expression of VEGF and HIF1α genes with increased angiogenesis, and showed significantly reduced infiltration of CD4(+) and CD8(+) T cells, presumably as the result of reduced expression of T cell chemokines, such as CXCL9 and CXCL16. The liver from CD200R-deficient mice, under metastatic growth of CD200(+) tumors, contained significantly increased numbers of CD11b(+)Gr1(-) myeloid cells and Foxp3(+) regulatory T cells and reduced numbers of NK cells. Liver T cells also had a reduced capacity to produce IFN-γ or TNF-α. Taken together, we revealed a critical role for CD200R signaling in limiting the growth and metastasis of CD200(+) tumors. Thus, targeting CD200R signaling may potentially interfere with the metastatic growth of CD200(+) tumors, like melanoma.


Asunto(s)
Antígenos CD/metabolismo , Melanoma Experimental/patología , Invasividad Neoplásica/patología , Transducción de Señal/fisiología , Animales , Antígenos CD/inmunología , Citometría de Flujo , Técnica del Anticuerpo Fluorescente , Técnicas de Inactivación de Genes , Humanos , Inmunohistoquímica , Linfocitos Infiltrantes de Tumor/patología , Melanoma Experimental/inmunología , Melanoma Experimental/metabolismo , Ratones , Ratones Endogámicos C57BL , Invasividad Neoplásica/inmunología , Neovascularización Patológica/inmunología , Neovascularización Patológica/metabolismo , Reacción en Cadena en Tiempo Real de la Polimerasa , Microambiente Tumoral/fisiología
12.
Proc Natl Acad Sci U S A ; 112(49): E6744-51, 2015 Dec 08.
Artículo en Inglés | MEDLINE | ID: mdl-26582795

RESUMEN

The B-Raf proto-oncogene serine/threonine kinase (BRAF) gene is the most frequently mutated gene in malignant melanoma (MM) and papillary thyroid cancer (PTC) and is causally involved in malignant cell transformation. Mutated BRAF is associated with an aggressive disease phenotype, thus making it a top candidate for targeted treatment strategies in MM and PTC. We show that BRAF mutations in both MM and PTC drive increased expression of oncomiR-3151, which is coactivated by the SP1/NF-κB complex. Knockdown of microRNA-3151 (miR-3151) with short hairpin RNAs reduces cell proliferation and increases apoptosis of MM and PTC cells. Using a targeted RNA sequencing approach, we mechanistically determined that miR-3151 directly targets TP53 and other members of the TP53 pathway. Reducing miR-3151's abundance increases TP53's mRNA and protein expression and favors its nuclear localization. Consequently, knockdown of miR-3151 also leads to caspase-3-dependent apoptosis. Simultaneous inhibition of aberrantly activated BRAF and knockdown of miR-3151 potentiates the effects of sole BRAF inhibition with the BRAF inhibitor vemurafenib and may provide a novel targeted therapeutic approach in BRAF-mutated MM and PTC patients. In conclusion, we identify miR-3151 as a previously unidentified player in MM and PTC pathogenesis, which is driven by BRAF-dependent and BRAF-independent mechanisms. Characterization of TP53 as a downstream effector of miR-3151 provides evidence for a causal link between BRAF mutations and TP53 inactivation.


Asunto(s)
Carcinoma/genética , Melanoma/genética , MicroARNs/fisiología , Mutación , Proteínas Proto-Oncogénicas B-raf/genética , Neoplasias de la Tiroides/genética , Proteína p53 Supresora de Tumor/fisiología , Transporte Activo de Núcleo Celular , Carcinoma Papilar , Humanos , Indoles/uso terapéutico , Melanoma/tratamiento farmacológico , FN-kappa B/fisiología , Proto-Oncogenes Mas , Sulfonamidas/uso terapéutico , Cáncer Papilar Tiroideo , Vemurafenib
13.
Cancer Immunol Immunother ; 66(11): 1437-1447, 2017 Nov.
Artículo en Inglés | MEDLINE | ID: mdl-28688082

RESUMEN

This study sought to evaluate whether myeloid-derived suppressor cells (MDSC) could be affected by chemotherapy and correlate with pathologic complete response (pCR) in breast cancer patients receiving neo-adjuvant chemotherapy. Peripheral blood levels of granulocytic (G-MDSC) and monocytic (M-MDSC) MDSC were measured by flow cytometry prior to cycle 1 and 2 of doxorubicin and cyclophosphamide and 1st and last administration of paclitaxel or paclitaxel/anti-HER2 therapy. Of 24 patients, 11, 6 and 7 patients were triple negative, HER2+ and hormone receptor+, respectively. 45.8% had pCR. Mean M-MDSC% were <1. Mean G-MDSC% and 95% confidence intervals were 0.88 (0.23-1.54), 5.07 (2.45-7.69), 9.32 (4.02-14.61) and 1.97 (0.53-3.41) at draws 1-4. The increase in G-MDSC by draw 3 was significant (p < 0.0001) in all breast cancer types. G-MDSC levels at the last draw were numerically lower in patients with pCR (1.15; 95% CI 0.14-2.16) versus patients with no pCR (2.71; 95% CI 0-5.47). There was no significant rise in G-MDSC from draw 1 to 3 in African American patients, and at draw 3 G-MDSC levels were significantly lower in African Americans versus Caucasians (p < 0.05). It was concluded that G-MDSC% increased during doxorubicin and cyclophosphamide therapy, but did not significantly differ between patients based on pathologic complete response.


Asunto(s)
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Neoplasias de la Mama/sangre , Neoplasias de la Mama/tratamiento farmacológico , Células Supresoras de Origen Mieloide/efectos de los fármacos , Adulto , Negro o Afroamericano , Anciano , Neoplasias de la Mama/etnología , Recuento de Células , Quimioterapia Adyuvante , Ciclofosfamida/administración & dosificación , Citocinas/sangre , Doxorrubicina/administración & dosificación , Femenino , Granulocitos/efectos de los fármacos , Granulocitos/patología , Humanos , Persona de Mediana Edad , Monocitos/efectos de los fármacos , Monocitos/patología , Células Supresoras de Origen Mieloide/patología , Terapia Neoadyuvante , Paclitaxel/administración & dosificación , Proyectos Piloto , Resultado del Tratamiento , Población Blanca
14.
J Immunol ; 195(5): 1995-2005, 2015 Sep 01.
Artículo en Inglés | MEDLINE | ID: mdl-26238487

RESUMEN

Sorafenib is an oral multikinase inhibitor that was originally developed as a Raf kinase inhibitor. We hypothesized that sorafenib would also have inhibitory effects on cytokine signaling pathways in immune cells. PBMCs from normal donors were treated with varying concentrations of sorafenib and stimulated with IFN-α or IL-2. Phosphorylation of STAT1 and STAT5 was measured by flow cytometry and confirmed by immunoblot analysis. Changes in IFN-α- and IL-2-stimulated gene expression were measured by quantitative PCR, and changes in cytokine production were evaluated by ELISA. Cryopreserved PBMCs were obtained from cancer patients before and after receiving 400 mg sorafenib twice daily. Patient PBMCs were thawed, stimulated with IL-2 or IFN-α, and evaluated for phosphorylation of STAT1 and STAT5. Pretreatment of PBMCs with 10 µM sorafenib decreased STAT1 and STAT5 phosphorylation after treatment with IFN-α or IL-2. This inhibitory effect was observed in PBMCs from healthy donors over a range of concentrations of sorafenib (5-20 µM), IL-2 (2-24 nM), and IFN-α (10(1)-10(6) U/ml). This effect was observed in immune cell subsets, including T cells, B cells, NK cells, regulatory T cells, and myeloid-derived suppressor cells. Pretreatment with sorafenib also inhibited PBMC expression of IFN-α- and IL-2-regulated genes and inhibited NK cell production of IFN-γ, RANTES, MIP1-α, and MIG in response to IFN-α stimulation. PBMCs from patients receiving sorafenib therapy showed decreased responsiveness to IL-2 and IFN-α treatment. Sorafenib is a Raf kinase inhibitor that could have off-target effects on cytokine-induced signal transduction in immune effector cells.


Asunto(s)
Janus Quinasa 1/metabolismo , Leucocitos Mononucleares/efectos de los fármacos , Inhibidores de Proteínas Quinasas/farmacología , Factor de Transcripción STAT1/metabolismo , Factor de Transcripción STAT5/metabolismo , Transducción de Señal/efectos de los fármacos , Animales , Línea Celular Tumoral , Células Cultivadas , Relación Dosis-Respuesta a Droga , Citometría de Flujo , Expresión Génica/efectos de los fármacos , Humanos , Immunoblotting , Interferón-alfa/farmacología , Interleucina-2/farmacología , Células K562 , Leucocitos Mononucleares/inmunología , Leucocitos Mononucleares/metabolismo , Linfocitos/efectos de los fármacos , Linfocitos/metabolismo , Ratones Endogámicos BALB C , Niacinamida/análogos & derivados , Niacinamida/farmacología , Compuestos de Fenilurea/farmacología , Fosforilación/efectos de los fármacos , Reacción en Cadena de la Polimerasa de Transcriptasa Inversa , Sorafenib , Neoplasias de la Tiroides/sangre , Neoplasias de la Tiroides/tratamiento farmacológico , Quinasas raf/antagonistas & inhibidores , Quinasas raf/metabolismo
15.
Proc Natl Acad Sci U S A ; 111(11): 4179-84, 2014 Mar 18.
Artículo en Inglés | MEDLINE | ID: mdl-24586049

RESUMEN

Neuroblastoma rat sarcoma (RAS) viral oncogene homolog (NRAS), a small GTPase, is one of the most thoroughly studied oncogenes that controls cell growth, differentiation, and survival by facilitating signal transduction. Here, we identify four novel naturally occurring NRAS isoforms (isoforms 2-5) in addition to the canonical isoform (isoform 1). Expression analyses performed on a panel of several different human malignancies and matching normal tissue revealed distinct isoform expression patterns. Two of the novel isoforms were found in the nucleus and cytoplasm, whereas the others were exclusively cytoplasmic. The isoforms varied in their binding affinities to known downstream targets and differentially regulated the RAS signaling pathway. Strikingly, forced expression of isoform 5, which encodes only a 20-aa peptide, led to increased cell proliferation and to transformation by activation of known NRAS targets. These discoveries open new avenues in the study of NRAS.


Asunto(s)
Carcinoma de Pulmón de Células no Pequeñas/genética , Transformación Celular Neoplásica/genética , GTP Fosfohidrolasas/genética , Regulación Neoplásica de la Expresión Génica/genética , Proteínas de la Membrana/genética , Isoformas de Proteínas/genética , Transducción de Señal/genética , Animales , Secuencia de Bases , Western Blotting , Células COS , Chlorocebus aethiops , Clonación Molecular , Cartilla de ADN/genética , Humanos , Inmunoprecipitación , Ratones , Microscopía Confocal , Datos de Secuencia Molecular , Células 3T3 NIH , Análisis de Secuencia de ADN , Estadísticas no Paramétricas
16.
Cancer Immunol Immunother ; 64(2): 149-59, 2015 Feb.
Artículo en Inglés | MEDLINE | ID: mdl-25305035

RESUMEN

Elevated levels of myeloid-derived suppressor cells (MDSCs) induced by tumor-derived factors are associated with inhibition of immune responses in patients with gastrointestinal malignancies. We hypothesized that pro-MDSC cytokines and levels of MDSC in the peripheral blood would be elevated in pancreatic adenocarcinoma patients with progressive disease. Peripheral blood mononuclear cells (PBMCs) were isolated from 16 pancreatic cancer patients undergoing chemotherapy and phenotyped for MDSC using a five antigen panel (CD33, HLA-DR, CD11b, CD14, CD15). Patients with stable disease had significantly lower MDSC levels in the peripheral blood than those with progressive disease (1.41 ± 1.12 vs. 5.14 ± 4.58 %, p = 0.013, Wilcoxon test). A cutoff of 2.5 % MDSC identified patients with progressive disease. Patients with ECOG performance status ≥2 had a weaker association with increased levels of MDSC. Plasma was obtained from 15 chemonaive patients, 13 patients undergoing chemotherapy and 9 normal donors. Increases in the levels of pro-MDSC cytokines were observed for pancreatic cancer patients versus controls, and the pro-MDSC cytokine IL-6 was increased in those patients undergoing chemotherapy. This study suggests that MDSC in peripheral blood may be a predictive biomarker of chemotherapy failure in pancreatic cancer patients.


Asunto(s)
Adenocarcinoma/inmunología , Adenocarcinoma/patología , Células Mieloides/inmunología , Neoplasias Pancreáticas/inmunología , Neoplasias Pancreáticas/patología , Adenocarcinoma/tratamiento farmacológico , Adenocarcinoma/metabolismo , Anciano , Anciano de 80 o más Años , Antígenos de Superficie/metabolismo , Recuento de Células , Factores Quimiotácticos/sangre , Factores Quimiotácticos/metabolismo , Citocinas/sangre , Citocinas/metabolismo , Progresión de la Enfermedad , Femenino , Antígenos HLA-DR/inmunología , Antígenos HLA-DR/metabolismo , Humanos , Inmunofenotipificación , Masculino , Persona de Mediana Edad , Células Mieloides/metabolismo , Estadificación de Neoplasias , Neoplasias Pancreáticas/tratamiento farmacológico , Neoplasias Pancreáticas/metabolismo , Transducción de Señal
17.
Biochim Biophys Acta ; 1835(1): 100-9, 2013 Jan.
Artículo en Inglés | MEDLINE | ID: mdl-23123827

RESUMEN

S100A9 is a calcium binding protein with multiple ligands and post-translation modifications that is involved in inflammatory events and the initial development of the cancer cell through to the development of metastatic disease. This review has a threefold purpose: 1) describe the S100A9 structural elements important for its biological activity, 2) describe the S100A9 biology in the context of the immune system, and 3) illustrate the role of S100A9 in the development of malignancy via interactions with the immune system and other cellular processes.


Asunto(s)
Calgranulina B/metabolismo , Neoplasias/metabolismo , Animales , Calgranulina B/química , Humanos
19.
Biopolymers ; 102(4): 344-58, 2014 Jul.
Artículo en Inglés | MEDLINE | ID: mdl-24839139

RESUMEN

Protein-protein interactions are part of a large number of signaling networks and potential targets for drug development. However, discovering molecules that can specifically inhibit such interactions is a major challenge. S100B, a calcium-regulated protein, plays a crucial role in the proliferation of melanoma cells through protein-protein interactions. In this article, we report the design and development of a bidentate conformationally constrained peptide against dimeric S100B based on a natural tight-binding peptide, TRTK-12. The helical conformation of the peptide was constrained by the substitution of α-amino isobutyric acid--an amino acid having high helical propensity--in positions which do not interact with S100B. A branched bidentate version of the peptide was bound to S100B tightly with a dissociation constant of 8 nM. When conjugated to a cell-penetrating peptide, it caused growth inhibition and rapid apoptosis in melanoma cells. The molecule exerts antiproliferative action through simultaneous inhibition of key growth pathways, including reactivation of wild-type p53 and inhibition of Akt and STAT3 phosphorylation. The apoptosis induced by the bidentate constrained helix is caused by direct migration of p53 to mitochondria. At moderate intravenous dose, the peptide completely inhibits melanoma growth in a mouse model without any significant observable toxicity. The specificity was shown by lack of ability of a double mutant peptide to cause tumor regression at the same dose level. The methodology described here for direct protein-protein interaction inhibition may be effective for rapid development of inhibitors against relatively weak protein-protein interactions for de novo drug development.


Asunto(s)
Proteína CapZ/química , Proteína CapZ/farmacología , Melanoma/patología , Fragmentos de Péptidos/química , Fragmentos de Péptidos/farmacología , Secuencia de Aminoácidos , Animales , Western Blotting , Línea Celular Tumoral , Proliferación Celular/efectos de los fármacos , Supervivencia Celular , Modelos Animales de Enfermedad , Humanos , Ratones , Microscopía de Contraste de Fase , Datos de Secuencia Molecular , Unión Proteica , Estructura Secundaria de Proteína , Inducción de Remisión , Transducción de Señal/efectos de los fármacos , Temperatura , Proteína p53 Supresora de Tumor/metabolismo
20.
Biochim Biophys Acta Rev Cancer ; 1879(1): 189038, 2024 01.
Artículo en Inglés | MEDLINE | ID: mdl-38061664

RESUMEN

Nitric oxide (NO) generated from nitric oxide synthase (NOS) exerts a dichotomous effect in melanoma, suppressing or promoting tumor progression. This dichotomy is thought to depend on the intracellular NO concentration and the cell type in which it is generated. Due to its central role in the metabolism of multiple critical constituents involved in signaling and stress, it is crucial to explore NO's contribution to the metabolic dysfunction of melanoma. This review will discuss many known metabolites linked to NO production in melanoma. We discuss the synthesis of these metabolites, their role in biochemical pathways, and how they alter the biological processes observed in the melanoma tumor microenvironment. The metabolic pathways altered by NO and the corresponding metabolites reinforce its dual role in melanoma and support investigating this effect for potential avenues of therapeutic intervention.


Asunto(s)
Melanoma , Óxido Nítrico , Humanos , Óxido Nítrico Sintasa/metabolismo , Transducción de Señal , Microambiente Tumoral
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