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  • L-Kynurenine Recent advances in microarray and next generati

    2019-07-11

    Recent advances in microarray [32] and next-generation sequencing [33] based technologies have led to tremendous increases in information about the molecular mechanisms that are responsible for malignant transformation of rare and poorly understood soft tissue sarcomas. However, data interpretation of such testing still remains a challenge. In this study, we assessed the clinical use of conventional cytogenetics, FISH, and RT-PCR testing in the diagnosis and management of patients with ES. By comparing the overall detection rate and concordance among these methods, we conclude that an integrated and multimodal approach [34] best facilitates accurate clinical diagnosis and also provides a detailed information regarding the tumor genetics, which eventually may lead to potential [35] disease monitoring or personalized therapy.
    Acknowledgment
    Background Ewing sarcoma (ES) is the third most common primary bone sarcoma after osteosarcoma and chondrosarcoma. However it is still rare with an overall incidence of 2.9 new cases/1,000,000 every year in the United States [1]. In children and adolescents ES is mainly localised in bone, with a peak incidence at 15 years of age [2]. In adults, ES localises more frequently primarily in soft tissue or organs. The tumour is diagnostically defined by a reciprocal translocation, causing a fusion of the EWSR1-gene on chromosome 22 with a member of the ETS (E26 transformation-specific) family of transcription factors [3]. The most common translocation (85%) is the t(11;22)(q24;q12), fusing EWSR1 to FLI1. Other rare ETS and non-ETS fusion partners have been described, and so far it is unclear whether the latter should be considered a separate entity [3]. The EWSR1-ETS translocation type does not influence the outcome or reaction on chemotherapy [4], [5]. Proven genetic prognostic factors are TP53 mutations [6], CDKN2A deletions [7], 1q gain [8] and Stag2 mutations [9], [10], [11], [12]. With current multimodal treatment options, including surgery, conventional chemotherapy and radiotherapy, the 5-year survival for localised disease is 60%. However, for patients that present with metastatic disease other than lung involvement only, the 5-year survival is below 20%. The outcome for patients with relapsed or refractory ES is even worse with a 5-year survival as low as 10% [13]. Therefore, new treatment strategies are urgently needed. Currently the insulin-like growth factor 1 L-Kynurenine (IGF-1R) pathway and the poly-ADP-ribose-polymerase (PARP) pathway are being investigated for potential targeted therapies. In our opinion these two pathways represent the main area of early clinical studies in ES in the recent years deserving an in-depth review. Therefore, here we summarise current knowledge in an attempt to stimulate further treatment development for ES.
    Insulin-like growth factor 1 receptor pathway in Ewing sarcoma
    Poly-ADP-ribose-polymerase pathway in Ewing sarcoma
    Discussion Regarding the IGF-1R pathway five pharmaceutical companies went in parallel to the niche indication ES for rapid approval in an orphan disease. Despite some durable responses the overall results of these studies were disappointing and as a result all companies stopped further development of IGF-1R pathway inhibitors for ES [75]. We think that this decision was made too fast and that IGF-1R antibodies can work in ES, but they should be tested in the right patient population. To find the right patient population it is very important to understand the biological rationale behind this treatment so that specific patients’ schedules and doses can be selected to reach positive results for the individual patients. Good non-heterogeneous biomarkers are needed to stratify patients to assess the right treatment schedule and to determine response during treatment [76], [77]. In preclinical studies the resistance mechanism for ES to IGF-1R has been studied. Resistant cells switch from IGF-1/IGF-1R signalling to IGF-2/IR-A signalling [39], [78], [79]. Therefore, one could postulate that ES patients should be treated with a dual IGF-1R and IR-A inhibitor, such as linsitinib (OSI-906). The EuroSarc consortium (www.eurosarc.eu) initiated the LINES (eurosarc trial of LINsitinib in advanced Ewing Sarcoma) study (ISRCTN 94236001), which is currently the only remaining open study for ES patients with a drug targeting the IGF-1R receptor. This is a phase II study in which refractory and/or relapsed ES patients are being treated with the dual IGF-1R and IR inhibitor linsitinib in a single arm Bayesian design. Patients will undergo mandatory tumour biopsies during the treatment for translational research and this will be compared to pre-treatment material to monitor response at the molecular level and to look for possible biomarkers. Pharmacokinetic assays will be conducted testing for IGF-1, IGF-2, IGFBP3 and insulin levels on blood samples. The tumour core biopsies will be used to test for phosphoproteome/kinase assays of pre-treatment kinome IGF-1R pathway activation. Quantitative immunoassays for IGF-1R, IRS1, pS6, FOXO and EGFR1 will be performed using multi-spectral confocal image segmentation and random forest analysis (LINES protocol Annex 1). This study will hopefully answer the question why inhibition of the IGF pathway may work in some patients and not in others.