TRIB3 silencing promotes the downregulation of Akt pathway and PAX3-FOXO1 in high-risk rhabdomyosarcoma.

Rhabdomyosarcoma (RMS), such as other childhood tumors, has witnessed treatment advancements in recent years. However, high-risk patients continue to face poor survival rates, often attributed to the presence of the PAX3/7-FOXO1 fusion proteins, which has been associated with metastasis and treatment resistance. Despite efforts to directly target these chimeric proteins, clinical success remains elusive. In this study, the main aim was to address this challenge by investigating regulators of FOXO1. Specifically, we focused on TRIB3, a potential regulator of the fusion protein in RMS. Our findings revealed a prominent TRIB3 expression in RMS tumors, highlighting its correlation with the presence of fusion protein. By conducting TRIB3 genetic inhibition experiments, we observed an impairment on cell proliferation. Notably, the knockdown of TRIB3 led to a decrease in PAX3-FOXO1 and its target genes at protein level, accompanied by a reduction in the activity of the Akt signaling pathway. Additionally, inducible silencing of TRIB3 significantly delayed tumor growth and improved overall survival in vivo. Based on our analysis, we propose that TRIB3 holds therapeutic potential for treating the most aggressive subtype of RMS. The findings herein reported contribute to our understanding of the underlying molecular mechanisms driving RMS progression and provide novel insights into the potential use of TRIB3 as a therapeutic intervention for high-risk RMS patients.

Analysis of Cancer Genomic Amplifications Identifies Druggable Collateral Dependencies within the Amplicon.

The identification of novel therapeutic targets for specific cancer molecular subtypes is crucial for the development of precision oncology. In the last few years, CRISPR/Cas9 screens have accelerated the discovery and validation of new targets associated with different tumor types, mutations, and fusions. However, there are still many cancer vulnerabilities associated with specific molecular features that remain to be explored. Here, we used data from CRISPR/Cas9 screens in 954 cancer cell lines to identify gene dependencies associated with 16 common cancer genomic amplifications. We found that high-copy-number genomic amplifications generate multiple collateral dependencies within the amplified region in most cases. Further, to prioritize candidate targets for each chromosomal region amplified, we integrated gene dependency parameters with both druggability data and subcellular location. Finally, analysis of the relationship between gene expression and gene dependency led to the identification of genes, the expression of which may constitute predictive biomarkers of dependency. In conclusion, our study provides a set of druggable targets specific for each amplification, opening the possibility to specifically target amplified tumors on this basis.

Targeting the Hedgehog Pathway in Rhabdomyosarcoma.

Aberrant activation of the Hedgehog (Hh) signalling pathway is known to play an oncogenic role in a wide range of cancers; in the particular case of rhabdomyosarcoma, this pathway has been demonstrated to be an important player for both oncogenesis and cancer progression. In this review, after a brief description of the pathway and the characteristics of its molecular components, we describe, in detail, the main activation mechanisms that have been found in cancer, including ligand-dependent, ligand-independent and non-canonical activation. In this context, the most studied inhibitors, i.e., SMO inhibitors, have shown encouraging results for the treatment of basal cell carcinoma and medulloblastoma, both tumour types often associated with mutations that lead to the activation of the pathway. Conversely, SMO inhibitors have not fulfilled expectations in tumours-among them sarcomas-mostly associated with ligand-dependent Hh pathway activation. Despite the controversy existing regarding the results obtained with SMO inhibitors in these types of tumours, several compounds have been (or are currently being) evaluated in sarcoma patients. Finally, we discuss some of the reasons that could explain why, in some cases, encouraging preclinical data turned into disappointing results in the clinical setting.

Integrin alpha9 emerges as a key therapeutic target to reduce metastasis in rhabdomyosarcoma and neuroblastoma.

The majority of current cancer therapies are aimed at reducing tumour growth, but there is lack of viable pharmacological options to reduce the formation of metastasis. This is a paradox, since more than 90% of cancer deaths are attributable to metastatic progression. Integrin alpha9 (ITGA9) has been previously described as playing an essential role in metastasis; however, little is known about the mechanism that links this protein to this process, being one of the less studied integrins. We have now deciphered the importance of ITGA9 in metastasis and provide evidence demonstrating its essentiality for metastatic dissemination in rhabdomyosarcoma and neuroblastoma. However, the most translational advance of this study is to reveal, for the first time, the possibility of reducing metastasis by pharmacological inhibition of ITGA9 with a synthetic peptide simulating a key interaction domain of ADAM proteins, in experimental metastasis models, not only in childhood cancers but also in a breast cancer model.

Dickkopf-1 Inhibition Reactivates Wnt/ß-Catenin Signaling in Rhabdomyosarcoma, Induces Myogenic Markers In Vitro and Impairs Tumor Cell Survival In Vivo.

The Wnt/ß-catenin signaling pathway plays a pivotal role during embryogenesis and its deregulation is a key mechanism in the origin and progression of several tumors. Wnt antagonists have been described as key modulators of Wnt/ß-catenin signaling in cancer, with Dickkopf-1 (DKK-1) being the most studied member of the DKK family. Although the therapeutic potential of DKK-1 inhibition has been evaluated in several diseases and malignancies, little is known in pediatric tumors. Only a few works have studied the genetic inhibition and function of DKK-1 in rhabdomyosarcoma. Here, for the first time, we report the analysis of the therapeutic potential of DKK-1 pharmaceutical inhibition in rhabdomyosarcoma, the most common soft tissue sarcoma in children. We performed DKK-1 inhibition via shRNA technology and via the chemical inhibitor WAY-2626211. Its inhibition led to ß-catenin activation and the modulation of focal adhesion kinase (FAK), with positive effects on in vitro expression of myogenic markers and a reduction in proliferation and invasion. In addition, WAY-262611 was able to impair survival of tumor cells in vivo. Therefore, DKK-1 could constitute a molecular target, which could lead to novel therapeutic strategies in RMS, especially in those patients with high DKK-1 expression.

Dickkopf Proteins and Their Role in Cancer: A Family of Wnt Antagonists with a Dual Role.

The Wnt signaling pathway regulates crucial aspects such as cell fate determination, cell polarity and organogenesis during embryonic development. Wnt pathway deregulation is a hallmark of several cancers such as lung, gastric and liver cancer, and has been reported to be altered in others. Despite the general agreement reached by the scientific community on the oncogenic potential of the central components of the pathway, the role of the antagonist proteins remains less clear. Deregulation of the pathway may be caused by overexpression or downregulation of a wide range of antagonist proteins. Although there is growing information related to function and regulation of Dickkopf (DKK) proteins, their pharmacological potential as cancer therapeutics still has not been fully developed. This review provides an update on the role of DKK proteins in cancer and possible potential as therapeutic targets for the treatment of cancer; available compounds in pre-clinical or clinical trials are also reviewed.

A Mechanism-Based Sphingosine-1-phosphate Lyase Inhibitor.

The synthesis of a series of vinylated analogues of sphingosine-1-phosphate together with their unambiguous configurational assignment by VCD methods is reported. Among them, compound RBM10-8 can irreversibly inhibit human sphingosine-1-phosphate lyase (hS1PL) while behaving also as an enzyme substrate. These findings, together with the postulated mechanism for S1PL activity, reinforce the role of RBM10-8 as a new mechanism-based hS1PL inhibitor.

One-Year Results of Bioresorbable Vascular Scaffolds for Coronary Chronic Total Occlusions.

The potential of bioresorbable vascular scaffold (BVS) technology has been demonstrated in first-in-man studies with up to 5-year follow-up. This study sought to investigate the 1-year outcomes of the BVS, for the treatment of chronic total occlusions (CTOs), using various imaging techniques. Thirty-five true CTO lesions treated with BVS were included in this prospective study. Scaffolds were deployed after mandatory predilation and intravascular ultrasound analysis. Optical coherence tomography was performed after BVS implantation and at 10 to 12 months. Multislice computed tomography was performed at baseline and at 6 to 8 months. Mean patient age was 61 ± 10 years. The most frequent vessel treated was the right coronary artery (46%). Lesions were classified as intermediate (49%) or difficult/very difficult (26%) according to the Japanese CTO complexity score. Predilation was performed in 100% of lesions, using cutting balloons in 71% of these. The total scaffold length implanted per lesion was of 52 ± 23 mm. All scaffolds were delivered and deployed successfully. Postdilation was undertaken in 63%. By multislice computed tomography at 6 months, we observed 2 cases of asymptomatic scaffold restenosis, subsequently confirmed by angiography. At 12 months, no scaffold thrombosis or major adverse cardiac events were reported. The optical coherence tomography at follow-up showed that 94% of struts were well apposed and covered (5% of uncovered struts and 1% of nonapposed struts), and only 0.6% of struts were nonapposed and uncovered. In conclusion, 1-year results suggest that BVS for CTO is associated with excellent clinical and imaging outcomes. Accurate percutaneous coronary BVS technique might have enabled these promising results.

Determinantes del éxito de la revascularización de las oclusiones coronarias crónicas: estudio mediante tomografía computarizada con multidetectores / Factors determining success in percutaneous revascularization of chronic total coronary occlusion: multidetector computed tomography análisis

Introducción y objetivos. La revascularización percutánea de las oclusiones crónicas totales supone un desafío técnico, y tiene una tasa de éxito menor que las demás angioplastias. Conocer los predictores de fracaso permitiría mejorar la selección de pacientes con mayores posibilidades de éxito. Diseñamos un estudio para identificar los datos de la tomografía computarizada con multidetectores que podrían asociarse al fracaso del tratamiento percutáneo de las oclusiones crónicas totales. Métodos. Estudio prospectivo monocéntrico sobre 69 pacientes consecutivos, portadores de una oclusión crónica total, a los que se realizó una tomografía computarizada con multidetectores previa a la revascularización. Resultados. Se analizaron 77 lesiones, con una longitud ocluida media de 19,9±14,3 mm y una duración de la oclusión de 47±62 meses. El único factor predictor angiográfico independiente del fracaso de la revascularización fue la presencia de una fuerte curva entre la placa y el vaso proximal permeable (odds ratio=3,8; intervalo de confianza del 95%, 1,2-12; p=0,02). El único factor derivado de la tomografía computarizada con multidetectores asociado significativamente con fracaso fue la presencia de un arco de calcio que afectase a más del 50% de la circunferencia del segmento ocluido en la porción proximal (p=0,04) y media (p=0,03). Conclusiones. La tomografía computarizada con multidetectores identifica una variable no cuantificable por angiografía como predictora del fracaso de la revascularización de las oclusiones crónicas totales. En casos seleccionados podría ser útil para el cribado antes de la revascularización (AU)

Introduction and objectives. Percutaneous revascularization of chronic total coronary artery occlusion is a technical challenge and has a lower success rate than other angioplasty procedures. Identification of predictors of failure could lead to better selection of patients with the greatest possibility of success. In this study, we investigate the multidetector computed tomography features associated with failure of percutaneous treatment for chronic total coronary occlusion. Methods. This is a prospective, single-center study of 69 consecutive patients with chronic total occlusion in whom multidetector computed tomography study was performed before percutaneous coronary revascularization. Results. Seventy-seven lesions were analyzed. The mean length of the occlusion was 19.9 (14.3) mm and the estimated duration of occlusion was 47 (62) months. The only angiographic factor independently predictive of failure was a severe curve between the plaque and the proximal patent vessel (odds ratio 3.8, 95% confidence interval, 1.2-12; P=.02). On multidetector computed tomography, the only factor predictive of failure was an arc of calcium affecting more than 50% of the vessel circumference in the proximal (P=.04) and middle (P=.03) third of the occlusion. Conclusions. Multidetector computed tomography identified a variable that cannot be measured by angiography that can predict failure in percutaneous revascularization of chronic total coronary occlusions. In selected cases, this parameter could be useful for preprocedure screening (AU)

Factors determining success in percutaneous revascularization of chronic total coronary occlusion: multidetector computed tomography analysis.

INTRODUCTION AND OBJECTIVES: Percutaneous revascularization of chronic total coronary artery occlusion is a technical challenge and has a lower success rate than other angioplasty procedures. Identification of predictors of failure could lead to better selection of patients with the greatest possibility of success. In this study, we investigate the multidetector computed tomography features associated with failure of percutaneous treatment for chronic total coronary occlusion. METHODS: This is a prospective, single-center study of 69 consecutive patients with chronic total occlusion in whom multidetector computed tomography study was performed before percutaneous coronary revascularization. RESULTS: Seventy-seven lesions were analyzed. The mean length of the occlusion was 19.9 (14.3) mm and the estimated duration of occlusion was 47 (62) months. The only angiographic factor independently predictive of failure was a severe curve between the plaque and the proximal patent vessel (odds ratio 3.8, 95% confidence interval, 1.2-12; P=.02). On multidetector computed tomography, the only factor predictive of failure was an arc of calcium affecting more than 50% of the vessel circumference in the proximal (P=.04) and middle (P=.03) third of the occlusion. CONCLUSIONS: Multidetector computed tomography identified a variable that cannot be measured by angiography that can predict failure in percutaneous revascularization of chronic total coronary occlusions. In selected cases, this parameter could be useful for preprocedure screening.