Synthetic Heterocyclic Derivatives as Kinase Inhibitors Tested for the Treatment of Neuroblastoma

In the last few years, small molecules endowed with different heterocyclic scaffolds have been developed as kinase inhibitors. Some of them are being tested at preclinical or clinical levels for the potential treatment of neuroblastoma (NB). This disease is the most common extracranial solid tumor in childhood and is responsible for 10% to 15% of pediatric cancer deaths. Despite the availability of some treatments, including the use of very toxic cytotoxic chemotherapeutic agents, high-risk (HR)-NB patients still have a poor prognosis and a survival rate below 50%. For these reasons, new pharmacological options are urgently needed. This review focuses on synthetic heterocyclic compounds published in the last five years, which showed at least some activity on this severe disease and act as kinase inhibitors. The specific mechanism of action, selectivity, and biological activity of these drug candidates are described, when established. Moreover, the most remarkable clinical trials are reported. Importantly, kinase inhibitors approved for other diseases have shown to be active and endowed with lower toxicity compared to conventional cytotoxic agents. The data collected in this article can be particularly useful for the researchers working in this area.

Predicting amplification of MYCN using CpG methylation biomarkers in neuroblastoma

Background: Neuroblastoma is the most common extracranial solid tumor in childhood. Amplification of MYCN in neuroblastoma is a predictor of poor prognosis. Materials and methods: DNA methylation data from the TARGET data matrix were stratified into MYCN amplified and non-amplified groups. Differential methylation analysis, clustering, recursive feature elimination (RFE), machine learning (ML), Cox regression analysis and Kaplan–Meier estimates were performed. Results and Conclusion: 663 CpGs were differentially methylated between the two groups. A total of 25 CpGs were selected by RFE for clustering and ML, and a 100% clustering accuracy was obtained. ML validation on three external datasets produced high accuracy scores of 100%, 97% and 93%. Eight survival-associated CpGs were also identified. Therapeutic interventions may need to be targeted to patient subgroups.

EPIDEMIOLOGICAL PATTERNS OF PAEDIATRIC BRAIN TUMORS IN COIMBATORE

Background: Tumors of the nervous system are the second most common childhood tumors after leukemia,constituting approximately 35% of all childhood malignancies and remain the leading cause of cancer related deaths in children. In India,in the absence of a comprehensive population based national cancer registry,we depend on local hospital based registries for assessing the incidence of pediatric brain tumor.Hence,more and more institutional data are required to assess the actual disease load in India. Objective: The main objective of the present study is to assess the epidemiological patterns of brain tumors in children presenting in CMCH. Materials and Methods: Data regarding age,gender,topography and histopathology of 22 pediatric patients (0-18years)with brain tumors operated inCMCH over a period of 5 years(January 2015 to December 2019)was collected retrospectively and analysed. The results obtained were compared with available Indiandata and western literature. Results: Of 22 cases, males(63.6%) outnumbered females. In the present study, the most common anatomical site for brain tumors was cerebellum(45.5%) followed by cerebral hemispheres(36.2%), ventricles(13.6%) and sellar region(4.5%). The present study showed that Infratentorial tumors were more common (54.5%) as compared to Supratentorial tumors (45.5%).Thepresent study revealed that astrocytoma(36.4%) is the most common brain tumor in childhood. other common tumors include medulloblastoma(27.2%), followed by ependymoma(13.6%), oligodendroglioma(9%),pineal gland tumor(4.5%),craniopharyngioma(4.5%) and meningeal tumor(4.5%). Conclusion: From the present series, we conclude that, the frequencies of major histologic types of brain tumors found in the study do not differ substantially from that found in other developed and developing countries. Medulloblastomas and astrocytomas, which form the major histologic types in pediatric patients need special attention.

Phosphoinositide Signal Transduction Pathway and Osteosarcoma Metastases

: Metastasis spreading confers a worse prognosis to the clinical outcome among patients suffering from osteosarcoma, the most common primary bone tumor in childhood and adolescence. The detection of molecules involved in metastasis spreading might contribute to understanding tumor dissemination mechanisms, thereby opening the way to novel therapeutic strategies. The Ezrin-radixin-moesin (ERM) family proteins are activated after interacting with molecules belonging to the phosphoinositide signal transduction pathway. The phosphatydil inositol (4,5) bisphosphate (PIP2), a crucial molecule in the PI pathway, stabilizes the ERM proteins or a more efficient receptor binding. The PIP2 levels in the pathway are a critical element for regulating several cell events. The PIP2 levels are regulated using enzymes, including the PI-specific Phospholipase C family. A decrease in the PIP2 levels induces the dissociation of the ERM protein from the membrane. In this regard, the PI-PLC enzymes regulate this event. In this paper, the role of the PI signal transduction molecules in osteosarcoma metastases is discussed.

The Role of Biopsy in the Workup of Patients with Neuroblastoma: Comparison of the Incidence of Surgical Complications and the Diagnostic Reliability of Diverse Techniques

Neuroblastoma (NB) is the most common extracranial solid tumor in childhood, accounting for approximately 15% of all cancer-related deaths in the pediatric population. The overall survival of children with high-risk disease is around 40–50% despite the aggressive treatment protocols. In accordance with the most recent guidelines, a complete classification of the primary tumor, including its histopathological and molecular analysis, is necessary. In this regard, the biopsy of the primary tumor is an important diagnostic procedure adopted not only to confirm the diagnosis but also for staging and risk stratification of the disease. In this study, the authors describe their unicentric experience with four different approaches adopted for sampling NB tumors: (i) the open incisional biopsy; (ii) the minimally invasive thoracoscopic/laparoscopic incisional biopsy; (iii) the ultrasound-guided core needle biopsy; (iv) the laparoscopic-assisted core needle biopsy. The benefits of each technique are analyzed along with their contraindications.

Advances and Problems in Preclinical Models for Childhood Cancer

Microblogging today has gotten an acclaimed specific instrument amongNeuroblastoma is a sympathetic nervous system disease in children and is themost prevalent solid tumor in childhood, accounting for 15% of all pediatriconcology deaths. Nearly 80% of patients with this clinically active condition donot react to current treatments in the long run. The precise portrayal of tumorbiology and diversity is the key obstacle in the discovery and evaluation ofnovel agents for pediatric drug growth. In addition to this restriction, the lowprevalence of neuroblastoma renders it difficult to enroll qualifying patientsfor early phase clinical trials, emphasizing the importance of thoroughpreclinical studies to ensure that the right drugs are chosen. To address theseissues, researchers need new preclinical models, technologies, and principles.Tissue engineering provides appealing methods for developing threedimensional(3D) cell models utilizing different biomaterials andmanufacturing techniques that replicate the geometry, dynamics,heterogeneity, metabolic gradients, and cell connectivity of the native tumormicroenvironment. We address existing laboratory models and evaluate theirability to reflect the systemic organization and physiological conditions of thehuman body, as well as current and emerging strategies to recapitulate thetumor niche utilizing tissue-engineered platforms in this study. Finally, we'lltalk about how innovative 3Din vitroculture systems might be used to answerunanswered questions in neuroblastoma biology.

Synergistic Effect of Statins and Abiraterone Acetate on the Growth Inhibition of Neuroblastoma via Targeting Androgen Receptor

Neuroblastoma is the most common extracranial neuroendocrine tumor in childhood. Although many studies have tried to find effective treatments, there are still numerous limitations in current clinical targeted therapy. So, it is important to find new therapeutic targets and strategies from a new perspective. Our previous study reported that the androgen receptor (AR) promotes the growth of neuroblastoma in vitro and in vivo. Based on documentary investigation, we postulated that the AR–SCAP–SREBPs-CYP17/HMGCR axis may regulate cholesterol and androgens synthesis and form a positive enhancement loop promoting NB progression. Clinical samples and Oncomine database analysis proved the activation of AR–SCAP–SREBPs-CYP17/HMGCR axis in neuroblastoma. The combination of inhibitors of HMGCR (statins) and CYP17A1 (abiraterone acetate) showed synergistic effect that significantly inhibited the proliferation and migration with decreased expression of related genes detected in vitro and in vivo suggesting the dual-targeted therapy had the potential to inhibit the progression of neuroblastoma in spite of its MYCN status. This study provides new ideas for clinical treatment of neuroblastoma with efficacy and reduced toxicity.

The Role of Extracellular Vesicles in the Progression of Human Neuroblastoma

The long-underestimated role of extracellular vesicles in cancer is now reconsidered worldwide by basic and clinical scientists, who recently highlighted novel and crucial activities of these moieties. Extracellular vesicles are now considered as king transporters of specific cargoes, including molecular components of parent cells, thus mediating a wide variety of cellular activities both in normal and neoplastic tissues. Here, we discuss the multifunctional activities and underlying mechanisms of extracellular vesicles in neuroblastoma, the most frequent common extra-cranial tumor in childhood. The ability of extracellular vesicles to cross-talk with different cells in the tumor microenvironment and to modulate an anti-tumor immune response, tumorigenesis, tumor growth, metastasis and drug resistance will be pinpointed in detail. The results obtained on the role of extracellular vesicles may represent a panel of suggestions potentially useful in practice, due to their involvement in the response to chemotherapy, and, moreover, their ability to predict resistance to standard therapies—all issues of clinical relevance.