Targeting the p53 Pathway in Ewing Sarcoma

The p53 tumour suppressor plays a pivotal role in the prevention of oncogenic transformation. Cancers frequently evade the potent antitumour surveillance mechanisms of p53 through mutation of the TP53 gene, with approximately 50% of all human malignancies expressing dysfunctional, mutated p53 proteins. Interestingly, genetic lesions in the TP53 gene are only observed in 10% of Ewing Sarcomas, with the majority of these sarcomas expressing a functional wild-type p53. In addition, the p53 downstream signaling pathways and DNA-damage cell cycle checkpoints remain functionally intact in these sarcomas. This paper summarizes recent insights into the functional capabilities and regulation of p53 in Ewing Sarcoma, with a particular focus on the cross-talk between p53 and the EWS-FLI1 gene rearrangement frequently associated with this disease. The development of several activators of p53 is discussed, with recent evidence demonstrating the potential of small molecule p53 activators as a promising systemic therapeutic approach for the treatment of Ewing Sarcomas with wild-type p53

The utility of ETV1, ETV4 and ETV5 RNA inâ situ hybridization in the diagnosis of CICâ DUX sarcomas

Peer Reviewedhttps://deepblue.lib.umich.edu/bitstream/2027.42/136260/1/his13112_am.pdfhttps://deepblue.lib.umich.edu/bitstream/2027.42/136260/2/his13112.pd

MAPK/ERK Signaling in Osteosarcomas, Ewing Sarcomas and Chondrosarcomas: Therapeutic Implications and Future Directions

The introduction of cytotoxic chemotherapeutic drugs in the 1970's improved the survival rate of patients with bone sarcomas and allowed limb salvage surgeries. However, since the turn of the century, survival data has plateaued for a subset of metastatic, nonresponding osteo, and/or Ewing sarcomas. In addition, most high-grade chondrosarcoma does not respond to current chemotherapy. With an increased understanding of molecular pathways governing oncogenesis, modern targeted therapy regimens may enhance the efficacy of current therapeutic modalities. Mitogen-Activated Protein Kinases (MAPK)/Extracellular-Signal-Regulated Kinases (ERK) are key regulators of oncogenic phenotypes such as proliferation, invasion, angiogenesis, and inflammatory responses; which are the hallmarks of cancer. Consequently, MAPK/ERK inhibitors have emerged as promising therapeutic targets for certain types of cancers, but there have been sparse reports in bone sarcomas. Scattered papers suggest that MAPK targeting inhibits proliferation, local invasiveness, metastasis, and drug resistance in bone sarcomas. A recent clinical trial showed some clinical benefits in patients with unresectable or metastatic osteosarcomas following MAPK/ERK targeting therapy. Despite in vitro proof of therapeutic concept, there are no sufficient in vivo or clinical data available for Ewing sarcomas or chondrosarcomas. Further experimental and clinical trials are awaited in order to bring MAPK targeting into a clinical arena

Efficacy of ATR inhibitors as single agents in Ewing sarcoma

Ewing sarcomas (ES) are pediatric bone tumors that arise from a driver translocation, most frequently EWS/FLI1. Current ES treatment involves DNA damaging agents, yet the basis for the sensitivity to these therapies remains unknown. Oncogene-induced replication stress (RS) is a known source of endogenous DNA damage in cancer, which is suppressed by ATR and CHK1 kinases. We here show that ES suffer from high endogenous levels of RS, rendering them particularly dependent on the ATR pathway. Accordingly, two independent ATR inhibitors show in vitro toxicity in ES cell lines as well as in vivo efficacy in ES xenografts as single agents. Expression of EWS/FLI1 or EWS/ERG oncogenic translocations sensitizes non-ES cells to ATR inhibitors. Our data shed light onto the sensitivity of ES to genotoxic agents, and identify ATR inhibitors as a potential therapy for Ewing Sarcomas.We would want to thank Enrique de Alava for providing ES lines. Work in O.F. laboratory was supported by Fundación Botín, by Banco Santander through its Santander Universities Global Division and by grants from MINECO (SAF2014-57791-REDC and SAF2014-59498-R), Fundació La Marato de TV3, Howard Hughes Medical Institute and the European Research Council (ERC-617840). The A.N. laboratory was supported by the Intramural Research Program of the NIH, the National Cancer Institute, the Center for Cancer Research, an Ellison Medical Foundation Senior Scholar in Aging, and the Alex Lemonade Stand Foundation Award. J.A. laboratory is supported by Asociación Pablo Ugarte, ASION-La Hucha de Tomás, Fundación La Sonrisa de Alex and Instituto de Salud Carlos III (PI12/00816 and Spanish Cancer Network RTICC RD12/0036/0027). A.L. laboratory was supported by the Danish National Research Foundation (DNRF115), Danish Council for Independent Research (Sapere Aude, DFF-Starting Grant 2014) and Danish Cancer Society (KBVU-2014).S

Ewing sarcoma in a child with neurofibromatosis type 1.

We report here on a case of Ewing sarcoma (ES) occurring in a child with neurofibromatosis type 1. The sarcoma had an EWSR1-ERG translocation as well as loss of the remaining wild-type allele of NF1. Loss of the NF1 wild-type allele in the tumor suggests that activation of the Ras pathway contributed to its evolution. Review of available public data suggests that secondary mutations in the Ras pathway are found in ∼3% of ESs. This case suggests that Ras pathway activation may play a role in tumor progression in a subset of ESs

Ewing sarcoma of larynx: A rare case in a 5-year-old boy

Ewing Sarcoma of the head and neck region is an extremely rare entity. Treatment usually involves surgery, chemotherapy and radiotherapy in varying sequences. We present the third case to date of Ewing sarcoma of the larynx in a paediatric population. A 5-year-old boy presented to emergency room with acute respiratory distress. Computerized tomography scan showed a mass in the supraglottis; he was intubated using videolaryngoscope and tracheostomy was avoided, mass was removed by cold dissection. Final histopathologic examination revealed Ewing sarcoma. Further workup showed no systemic metastasis. Patient was advised adjuvant therapy which the family refused. Currently he is doing fine on 2 years of follow-up

Ewing-like Sarcoma – Hiding in PA view

Ewing-like sarcomas (ELS) are a heterogenous group of neoplasms that typically occur in the bone and soft tissue of pediatric and young adult patients. ELS share various degrees of morphological, immunohistochemical, molecular, and clinical similarity with Ewing sarcomas. However, these tumors lack the pathognomonic molecular hallmark of Ewing sarcoma, which is defined as translocation between a gene of the RNA-binding TET family (EWSR1 or FUS) with a gene of the ETS-transcription family (FLI1, ERG, ETV1, ETV4, or FEV). Accurate classification and distinction from classical Ewing sarcomas is important for patient management. A subset of ELS harboring the BCOR-CCNB3 fusion has been described recently – the majority of which that have been reported to date are bone-based tumors, though there have been cases of discrete soft tissue-based tumors. We herein present a case of ELS harboring the BCOR-CCNB3 translocation occurring in a pediatric patient presenting with a large abdominal mass discovered on chest CT after failed outpatient treatment for pneumonia with effusion. This patient was a 14-year-old Caucasian boy with a past medical history significant for obesity and three episodes of pneumonia since 6-years-old. Imaging showed a large heterogeneous mass at the posterior left upper quadrant of the abdomen protruding through the posterior aspect of the left hemidiaphragm causing atelectasis. The mass abuts the inferior leftward aspect of the descending thoracic aorta and also protrudes between the 11th and 12th posterior lateral left rib. Pathology revealed this mass to be an Ewing-like sarcoma with a BCOR-CCNB3 fusion. Patient was treated with chemotherapy and radiation. This case demonstrates the importance of determining an accurate diagnosis to provide specific management

Ewing Sarcoma of the Posterior Fossa in an Adolescent Girl

Medulloblastoma, astrocytoma, and ependymoma represent the most common infratentorial tumors in childhood, while Ewing sarcomas in that localization are extremely rare. A large left infratentorial space-occupying lesion was diagnosed in a 12-year-old girl with signs of increased intracranial pressure. Following total tumor resection, histological and molecular examination revealed Ewing sarcoma with rearranged EWSR-1 gene. The patient achieved complete remission following adjuvant chemotherapy and radiotherapy according to Euro-EWING 2008 treatment protocol. Intracranial Ewing sarcoma, although rare, should be an important differential diagnosis of intracranial tumors in childhood which requires aggressive multimodal treatment

Childhood cancer incidence and survival in Japan and England: A population-based study (1993-2010).

The present study aimed to compare cancer incidence and trends in survival for children diagnosed in Japan and England, using population-based cancer registry data. The analysis was based on 5192 children with cancer (age 0-14 years) from 6 prefectural cancer registries in Japan and 21 295 children diagnosed in England during 1993-2010. Differences in incidence rates between the 2 countries were measured with Poisson regression models. Overall survival was estimated using the Kaplan-Meier method. Incidence rates for Hodgkin lymphoma, renal tumors and Ewing sarcomas in England were more than twice as high as those in Japan. Incidence of germ cell tumors, hepatic tumors, neuroblastoma and acute myeloid leukemia (AML) was higher in Japan than in England. Incidence of all cancers combined decreased in Japan throughout the period 1993 to 2010, which was mainly explained by a decrease in registration of neuroblastoma in infants. For many cancers, 5-year survival improved in both countries. The improvement in survival in chronic myeloid leukemia (CML) was particularly dramatic in both countries. However, 5-year survival remained less than 80% in 2005-2008 in both countries for AML, brain tumors, soft tissue sarcomas, malignant bone tumors and neuroblastoma (age 1-14 years). There were significant differences in incidence of several cancers between countries, suggesting variation in genetic susceptibility and possibly environmental factors. The decrease in incidence for all cancers combined in Japan was related to the cessation of the national screening program for neuroblastoma. The large improvement in survival in CML coincided with the introduction of effective therapy (imatinib)