Receptor Tyrosine Kinases as Therapeutic Targets in Rhabdomyosarcoma

Rhabdomyosarcomas (RMSs) are the most common soft tissue sarcomas of childhood and adolescence. To date, there are no effective treatments that target the genetic abnormalities in RMS, and current treatment options for high-risk groups are not adequate. Over the past two decades, research into the molecular mechanisms of RMS has identified key genes and signaling pathways involved in disease pathogenesis. In these studies, members of the receptor tyrosine kinase (RTK) family of cell surface receptors have been characterized as druggable targets for RMS. Through small molecule inhibitors, ligand-neutralizing agents, and monoclonal receptor-blocking antibodies, RTK activity can be manipulated to block oncogenic properties associated with RMS. Herein, we review the members of the RTK family that are implicated in RMS tumorigenesis and discuss both the problems and promise of targeting RTKs in RMS

Soft Tissue Sarcoma Cancer Stem Cells: An Overview

Soft tissue sarcomas (STSs) are an uncommon group of solid tumors that can arise throughout the human lifespan. Despite their commonality as non-bony cancers that develop from mesenchymal cell precursors, they are heterogeneous in their genetic profiles, histology, and clinical features. This has made it difficult to identify a single target or therapy specific to STSs. And while there is no one cell of origin ascribed to all STSs, the cancer stem cell (CSC) principle—that a subpopulation of tumor cells possesses stem cell-like properties underlying tumor initiation, therapeutic resistance, disease recurrence, and metastasis—predicts that ultimately it should be possible to identify a feature common to all STSs that could function as a therapeutic Achilles' heel. Here we review the published evidence for CSCs in each of the most common STSs, then focus on the methods used to study CSCs, the developmental signaling pathways usurped by CSCs, and the epigenetic alterations critical for CSC identity that may be useful for further study of STS biology. We conclude with discussion of some challenges to the field and future directions

Embryonic Signaling Pathways and Rhabdomyosarcoma: Contributions to Cancer Development and Opportunities for Therapeutic Targeting

Rhabdomyosarcoma is the most common soft tissue sarcoma of childhood and adolescence, accounting for approximately 7% of childhood cancers. Current therapies include nonspecific cytotoxic chemotherapy regimens, radiation therapy, and surgery; however, these multimodality strategies are unsuccessful in the majority of patients with high-risk disease. It is generally believed that these tumors represent arrested or aberrant skeletal muscle development, and, accordingly, developmental signaling pathways critical to myogenesis such as Notch, WNT, and Hedgehog may represent new therapeutic targets. In this paper, we summarize the current preclinical studies linking these embryonic pathways to rhabdomyosarcoma tumorigenesis and provide support for the investigation of targeted therapies in this embryonic cancer

The Third International Meeting on Genetic Disorders in the RAS/MAPK Pathway: Toward a Therapeutic Approach

The Third International Meeting on Genetic Disorders in the RAS/MAPK Pathway: Towards a Therapeutic Approach was held at the Renaissance Orlando at SeaWorld Hotel (August 2-4, 2013). Seventy-one physicians and scientists attended the meeting, and parallel meetings were held by patient advocacy groups (CFC International, Costello Syndrome Family Network, NF Network and Noonan Syndrome Foundation). Parent and patient advocates opened the meeting with a panel discussion to set the stage regarding their hopes and expectations for therapeutic advances. In keeping with the theme on therapeutic development, the sessions followed a progression from description of the phenotype and definition of therapeutic endpoints, to definition of genomic changes, to identification of therapeutic targets in the RAS/MAPK pathway, to preclinical drug development and testing, to clinical trials. These proceedings will review the major points of discussion

A Review: Molecular Aberrations within Hippo Signaling in Bone and Soft Tissue Sarcomas

The Hippo signaling pathway is an evolutionarily conserved developmental network vital for the regulation of organ size, tissue homeostasis, repair and regeneration, and cell fate. The Hippo pathway has also been shown to have tumor suppressor properties. Hippo transduction involves a series of kinases and scaffolding proteins that are intricately connected to proteins in developmental cascades and in the tissue microenvironment. This network governs the downstream Hippo transcriptional coactivators YAP and TAZ, which bind to and activate the output of TEADs, as well as other transcription factors responsible for cellular proliferation, self-renewal, differentiation, and survival. Surprisingly, there are few oncogenic mutations within the core components of the Hippo pathway. Instead, dysregulated Hippo signaling is a versatile accomplice to commonly mutated cancer pathways. For example, YAP and TAZ can be activated by oncogenic signaling from other pathways, or serve as coactivators for classical oncogenes. Emerging evidence suggests that Hippo signaling couples cell density and cytoskeletal structural changes to morphogenic signals, and conveys a mesenchymal phenotype. While much of Hippo biology has been described in epithelial cell systems, it is clear that dysregulated Hippo signaling also contributes to malignancies of mesenchymal origin. This review will summarize the known molecular alterations within the Hippo pathway in sarcomas, and highlight how several pharmacologic compounds have shown activity in modulating Hippo components, providing proof-of-principle that Hippo signaling may be harnessed for therapeutic application in sarcomas

Case Report Asparaginase-Induced Hypertriglyceridemia Presenting as Pseudohyponatremia during Leukemia Treatment

Asparaginase is a chemotherapeutic agent used to induce disease remission in children with acute lymphoblastic leukemia (ALL). We describe the cases of two females with ALL who developed pseudohyponatremia as a presentation of hypertriglyceridemia following asparaginase treatment. Nine similar published cases of asparaginase-induced hypertriglyceridemia and its complications are also discussed. Possible mechanisms of action include inhibition of lipoprotein lipase, decreased hepatic synthesis of lipoprotein, and increased synthesis of VLDL. Effects of asparaginase-induced hypertriglyceridemia range from asymptomatic to transaminasemia, pancreatitis, and life-threatening thrombosis or hyperviscosity syndrome. All cases of hypertriglyceridemia described resolved following cessation of asparaginase treatment ± further treatments

Modulation of cell growth and differentiation by ceramide

AbstractCeramide has been suggested as an intracellular modulator of cell growth and differentiation [Okazaki, T. el al. (1990) J. Biol. Chem. 265, 15823-15831]. In this study, parameters that modulate the effects of ceramide on HL-60 cell growth and differentiation were examined. A short-chain, cell-permeable analog of ceramide, C2-ceramide, induced differentiation of HL-60 human leukemia cells and inhibited HL-60 growth in a concentration-dependent manner. The potency of C2-ceramide was modulated by the starting cell density such that the concentration of C2-ceramide producing 50% inhibition of cell growth (IC50%) ranged from 2 μM (for cells suspended at 1 × 105 cells/ml) to 11 μM (for cells at 8 × 105 cells/ml). However, the IC50% showed little variation if the concentration of C2-ceramide was expressed as fmol of C2-ceramide per 105 cells. Therefore, the effectiveness of C2-ceramide appeared to be primarily determined by its cellular rather than molar concentration. Binding of C2-ceramide to serum proteins resulted in a 10-fold increase in the IC50%. These results demonstrate that the biologic activity of C2-ceramide is subject to surface dilution kinetics and is sensitive to the presence of lipid-binding proteins. In these properties, ceramide behaves as a prototypic lipid second messenger/intracellular mediator