Search

Survival outcomes for patients with neuroblastoma vary markedly and reliable prognostic markers and risk stratification tools are lacking. We sought to identify and validate a transcriptomic signature capable of predicting risk of mortality in patients with neuroblastoma. The TARGET NBL dataset (n = 243) was used to develop the model and two independent cohorts, E-MTAB-179 (n = 478) and GSE85047 (n = 240) were used as validation sets. EFS was the primary outcome and OS was the secondary outcome of interest for all analysis. We identified a 21-gene signature capable of stratifying neuroblastoma patients into high and low risk groups in the E-MTAB-179 (HR 5.87 [3.83–9.01], p < 0.0001, 5 year AUC 0.827) and GSE85047 (HR 3.74 [2.36–5.92], p < 0.0001, 5 year AUC 0.815) validation cohorts. Moreover, the signature remained independent of known clinicopathological variables, and remained prognostic within clinically important subgroups. Further, the signature was effectively incorporated into a risk model with clinicopathological variables to improve prognostic performance across validation cohorts (Pooled Validation HR 6.93 [4.89–9.83], p < 0.0001, 5 year AUC 0.839). Similar prognostic utility was also demonstrated with OS. The identified signature is a robust independent predictor of EFS and OS outcomes in neuroblastoma patients and can be combined with clinically utilized clinicopathological variables to improve prognostic performance. [ABSTRACT FROM AUTHOR]

Summary: High-risk, relapsed and refractory neuroblastoma are associated with poor 5-years survival rates, demonstrating the need for investigational therapeutic agents to treat this disease. Taurolidine is derived from the aminosulfoacid taurine and has known anti-microbial and anti-inflammatory properties. Taurolidine has also demonstrated anti-neoplastic effects in a range of cancers, providing the rationale to investigate the activity of taurolidine against neuroblastoma in preclinical studies. We investigated the in vitro activity of taurolidine against neuroblastoma using the alamar blue cytotoxicity assay, phase-contrast light microscopy, western blotting and analysis of global gene expression by RNA-Seq. In vivo activity of taurolidine was evaluated using mouse xenograft models. In vitro pre-clinical data show that taurolidine is cytotoxic to neuroblastoma cell lines, inducing cell death by apoptosis. Analysis of global gene expression and determination of signaling pathway activation scores using the in silico Pathway Activation Network Decomposition Analysis (iPANDA) platform indicates that taurolidine has an effect on the Notch, mitogen-activated protein kinase (MAPK) and interleukin-10 (IL-10) signaling pathways. In vivo experiments in xenograft mouse models show that taurolidine decreases tumor growth and improves survival. These results provide supportive pre-clinical data on the activity of taurolidine against neuroblastoma. The findings support the rationale for further evaluation of taurolidine for the treatment of relapsed/refractory neuroblastoma patients in an early phase clinical trial. [ABSTRACT FROM AUTHOR]

Background: Rhabdomyosarcoma (RMS) is the most common soft-tissue sarcoma in children. Pathogenesis of RMS is associated with aggressive growth pattern and increased risk of morbidity and mortality. There are two main subtypes or RMS: embryonal and alveolar. The embryonal type is characterized by distinct molecular aberrations, including alterations in the activity of certain protein kinases. Focal adhesion kinase (FAK) is a non-receptor tyrosine kinase that plays a vital role in focal adhesion (FA) assembly to promote cytoskeleton dynamics and regulation of cell motility. It is regulated by multiple phosphorylation sites: tyrosine 397, Tyr 576/577, and Tyr 925. Tyrosine 397 is the autophosphorylation site that regulates FAK localization at the cell periphery to facilitate the assembly and formation of the FA complex. The kinase activity of FAK is mediated by the phosphorylation of Tyr 576/577 within the kinase domain activation loop. Aberrations of FAK phosphorylation have been linked to the pathogenesis of different types of cancers. In this regard, pY397 upregulation is linked to increase ERMS cell motility, invasion, and tumorigenesis. Methods: In this study, we have used an established human embryonal muscle rhabdomyosarcoma cell line RD as a model to examine FAK phosphorylation profiles to characterize its role in the pathogenies of RMS. Results: Our findings revealed a significant increase of FAK phosphorylation at pY397 in RD cells compared to control cells (hTERT). On the other hand, Tyr 576/577 phosphorylation levels in RD cells displayed a pronounced reduction. Our data showed that Y925 residue exhibited no detectable change. The in vitro analysis showed that the FAK inhibitor, PF-562271 led to G1 cell-cycle arrest induced cell death (IC50, ~ 12 µM) compared to controls. Importantly, immunostaining analyses displayed a noticeable reduction of Y397 phosphorylation following PF-562271 treatment. Our data also showed that PF-562271 suppressed RD cell migration in a dose-dependent manner associated with a reduction in Y397 phosphorylation. Conclusions: The data presented herein indicate that targeting FAK phosphorylation at distinct sites is a promising strategy in future treatment approaches for defined subgroups of rhabdomyosarcoma. [ABSTRACT FROM AUTHOR]

Background: Leukemia accounts for 30% of all childhood cancers and although the survival rate for pediatric leukemia has greatly improved, relapse is a major cause of treatment failure. Therefore, the development and introduction of novel therapeutics to treat relapsed pediatric leukemia is urgently needed. The proteasome inhibitor bortezomib has been shown to be effective against adult hematological malignancies such as multiple myeloma and lymphoma, but is frequently associated with the development of resistance. Carfilzomib is a next-generation proteasome inhibitor that has shown promising results against refractory adult hematological malignancies.Objective: Carfilzomib has been extensively studied in adult hematological malignancies, providing the rationale for evaluating proof-of-concept activity of carfilzomib in pediatric leukemia.Methods: The effects of carfilzomib on pediatric leukemia cell lines and primary pediatric leukemia patient samples were investigated in vitro using the alamar blue cytotoxicity assay, western blotting, and a proteasome activity assay. Synergy with commonly used anticancer drugs was determined by calculation of combination indices.Results: In vitro preclinical data show pharmacologically relevant concentrations of carfilzomib are cytotoxic to pediatric leukemia cell lines and primary pediatric leukemia cells. Target modulation studies validate the effective inhibition of the proteasome and induction of apoptosis. We also identify agents that have effective synergy with carfilzomib in these cells.Conclusions: Our data provide pre-clinical information that can be incorporated into future early-phase clinical trials for the assessment of carfilzomib as a treatment for children with refractory hematological malignancies. [ABSTRACT FROM AUTHOR]

Over the past 50 years, numerous advances in treatment have produced dramatic increases in the cure rates of pediatric leukemias. Despite this progress, the majority of children with relapsed leukemia are not expected to survive. With current chemotherapy regimens, approximately 15 % of children with acute lymphoblastic leukemia and 45 % of children with acute myeloid leukemia will have refractory disease or experience a relapse. Advances in the treatment of pediatric relapsed leukemia have not mirrored the successes of upfront therapy, and newer treatments are desperately needed in order to improve survival in these challenging patients. Recent improvements in our knowledge of cancer biology have revealed an extensive number of targets that have the potential to be exploited for anticancer therapy. These advances have led to the development of a number of new treatments that are now being explored in children with relapsed or refractory leukemia. Novel agents seek to exploit the same molecular aberrations that contribute to leukemia development and resistance to therapy. Newer classes of drugs, including monoclonal antibodies, tyrosine kinase inhibitors and epigenetic modifiers are transforming the treatment of patients who are not cured with conventional therapies. As the side effects of many new agents are distinct from those seen with conventional chemotherapy, these treatments are often explored in combination with each other or combined with conventional treatment regimens. This review discusses the biological rationale for the most promising new agents and the results of recent studies conducted in pediatric patients with relapsed leukemia. [ABSTRACT FROM AUTHOR]

Anemia frequently accompanies the diagnosis of acute lymphoblastic leukemia (ALL) in children and is considered to be one of the most common clinical complications of the disease. In addition, a low hemoglobin (Hb) level is often responsible for fatigue and other associated symptoms that cause a decline in the quality of life of these children. Traditionally, a number of contributing factors such as overcrowding of the marrow, coexisting infections, and nutritional deficits have been used to explain this phenomenon. However, recent advances in in vivo modeling and real-time ultrastructural analytical techniques have enabled researchers to examine leukemic bone marrow (BM) microenvironment more closely and helped to build mechanistic models of this process. Importantly, data from these studies show that in the majority of cases, the required stem cell populations and the erythropoietic growth mechanisms remain intact in leukemia. In this report, we aim to review the current state of knowledge regarding the cellular and molecular mechanisms implicated in the altered erythropoiesis at the time of diagnosis of leukemia. We propose that further understanding of the mechanisms of anemia in leukemia may help to manage some of its clinical consequences more effectively as well as to yield key insight into the process of leukemogenesis itself. [ABSTRACT FROM AUTHOR]

The central nervous system Atypical Teratoid/Rhabdoid Tumor (CNS AT/RT) is a highly malignant neoplasm that commonly affects infants and young children, and has an extremely poor prognosis. Recently, a small subset of ion channels have been found to be over-expressed in a variety of malignant cells, thus emerging as potential therapeutic targets for difficult to treat tumors. We have studied the electrophysiological properties of AT/RT cell lines with particular attention to cell volume sensitive ion channels (VSC). This class of membrane proteins can play a fundamental role in cellular processes relevant to tumor development. We have found that chloride selective VSCs are particularly active in AT/RT cell lines, compared to non-tumor cells. We evaluated specific inhibitors for activity against chloride selective VSCs and consequently for their ability to inhibit the growth and survival of AT/RT cells in vitro. The results demonstrated that the extent of volume sensitive membrane current inhibition by these agents was correlated with their potency in AT/RT cell growth inhibition in vitro. In addition, we showed that ion channel inhibition enhanced the activity of certain anti-neoplastic agents, suggesting its value in effective drug combination protocols. Results presented provide preliminary in vitro data for possible evaluation of distinct ion channels as plausible therapeutic targets in the treatment of AT/RT. [ABSTRACT FROM AUTHOR]

The preferential metastasis of breast cancer cells to bone is a complex set of events including homing and preferential growth which may include unique factors produced by bone cells in the immediate microenvironment. In this study, we evaluated the suitability of bone cells derived from orthoplastic surgeries for use in an in vitro co-culture system representing a model of the bone microenvironment. Using a limiting dilution assay we determined the relative survival and proliferation potentials of breast cancer cell lines co-cultured on bone-derived cells or on Hs68 fibroblasts. The comparison of bone and skin fibroblastic substrata indicates that MCF-7 cells preferentially survive and grow in a bone microenvironment ( P < 0.001). Overall, we show that bone-derived cells enhance survival, proliferation, and migration of breast cancer cells, where migration is in part mediated by bone cell-produced osteopontin. Our in vitro co-culture model system provides a robust cost-effective method to study the various factors that mediate cancer/bone-derived cell interactions. [ABSTRACT FROM AUTHOR]

Wilms' tumour (WT) is the most common malignant renal tumour of childhood. During the past two decades or so, molecular studies carried out on biopsy specimens and tumour-derived cell lines have identified a multitude of chromosomal and epigenetic alterations in WT. In addition, a significant amount of evidence has been gathered to identify the genes and signalling pathways that play a defining role in its genesis, growth, survival and treatment responsiveness. As such, these molecules and mechanisms constitute potential targets for novel therapeutic strategies for refractory WT. In this report we aim to review some of the many candidate genes and intersecting pathways that underlie the complexities of WT biology. [ABSTRACT FROM AUTHOR]

Sarcomas, or tumors of connective tissue, represent roughly 20%of childhood cancers. Although the cure rate for sarcomas in general has significantly improved in the last 10 years, there continue to be subgroups that are difficult to treat. High-grade or metastatic soft-tissue sarcomas and rhabdomyosarcomas (RMS) of the extremities remain therapeutic challenges and their prognosis is often poor. The future of sarcoma therapy will likely include molecular approaches including gene/protein expression profiling and gene-based therapy. Most sarcomas harbor defects in the p53 or pRb pathways. The tumor suppressor p53 is central to regulation of cell growth and tumor suppression and restoring wild-type p53 function in pediatric sarcomas may be of therapeutic benefit. Studies with adenoviral-mediated p53 gene transfer have been conducted in many cancer types including cervical, ovarian, prostatic and head and neck tumors. Studies of this approach, however, remain limited in pediatric cancers, including sarcomas. Using three viral constructs containing cDNA for wild-type p53, mutant p53 (C135S) and lacZ, we studied the effect of adenoviral-mediated gene therapy in four pediatric sarcoma cell lines, RD and Rh4 (RMS), Rh1 (Ewing's sarcoma) and A204 (undifferentiated sarcoma). Using the MTT (3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl tetrazolium bromide) assay, we have shown a dose-dependent decrease in cell viability 72?h post-treatment that occurs with Ad-wtp53 but not with Ad-mutp53. Cells treated with Ad-wtp53 show upregulation of the p53 downstream targets, p21CIP1/WAF1 and bax. Growth curves demonstrate suppression of cell growth over a period of 4 days and cells treated with Ad-wtp53 demonstrate a significant increase in sensitivity to the chemotherapeutic agents, cisplatin and doxorubicin. Our results indicate that restoration of wild-type p53 function in pediatric sarcoma cells could provide a basis for novel approaches to treatment of this disease.Cancer Gene Therapy (2005) 12, 397-406. doi:10.1038/sj.cgt.7700798 Published online 24 December 2004 [ABSTRACT FROM AUTHOR]