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Ewing and Rhabdomyosarcoma: The Present, The Problems and The Possibilities

Ewing and Rhabdomyosarcoma: The Present, The Problems and The Possibilities. Robin L Jones University of Washington / Fred Hutchinson Cancer Center Seattle USA. The Present. Multi modality management: improved survival Multi agent chemotherapy Surgical advances

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Ewing and Rhabdomyosarcoma: The Present, The Problems and The Possibilities

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  1. Ewing and Rhabdomyosarcoma:The Present, The Problems and The Possibilities Robin L Jones University of Washington / Fred Hutchinson Cancer Center Seattle USA

  2. The Present • Multi modality management: improved survival • Multi agent chemotherapy • Surgical advances • Standardized + centralized treatment • Childhood Oncology Centers • Ewing Sarcoma: Interval compressed chemotherapy • Traditional evaluation of novel agents Balamuth and Womer Lancet Oncol 11; 184-192: 2010 Gosiengfiao Y et al Pediatr Drugs 14; 389-400: 2012 Womer RB et al JCO 2012

  3. The Problems • Metastatic/ recurrent disease • Poor outcome • Need for • Improved therapies • Better selection • Evaluation of novel agents • Potential markers of response and outcome • Evaluation IGF1-R inhibitors in Ewing sarcoma • Why do only some patients have durable benefit? • Clinical trial design

  4. The Problems • Long-term adverse effects • Surveillance + follow-up important • Skeletal effects of radiation on long bones of children and adults with ES • Krasin MJ et al • N=37 • Maximum RT to adjacent bone predictor of fracture • Incidence of fracture • ≥60 Gy: 57% • <60 Gy: 15% • Physis closure significantly affected by increasing dose

  5. The Problems: Ewing • Older age as an independent prognostic factor in ES: • Albritton K et al • N=1244 • 161 > 17 years of age • Multivariate model • Why do older patients fare worse?

  6. The Possibilities: Ewing • Proton therapy of axial skeleton • Indelicato D et al • N=24 • Median follow-up 2 years: 22/ 24 disease-free • Allows highly conformal RT delivery • Proton therapy • Likely to change management tumors adjacent to sensitive structures

  7. The Possibilities: Ewing • Should the pre- or-post chemotherapy tumor volume be resected? • Beckingsale T et al • Exploratory study • Chemotherapy response incomplete • Microscopically positive or close margins • Local + distant failure according to mode of local control • Dubois SG et al • N=465 treated within 3 clinical trials • Definitive radiation • Higher risk of local failure • NOT distant failure • Is a randomized trial of local therapy possible?

  8. The Possibilities: Ewing • High-dose chemotherapy in relapsed disease • Dirksen U et al • Retrospective analysis of prospective database • N=239 with first relapse • N=73 high-dose chemotherapy • No randomized dataof high-dose chemotherapy

  9. The Possibilities: Ewing • CD99 triggering • Guerzoni C et al • MDM2 degradation + p53 reactivation • Upregulation IGF1-R + RAS • PARP-1 inhibition amplifies the effects of radiation • Schmidt B et al • Olaparib sensitized Ewing cell lines to RT • DNA damage persisted beyond 24 hours with PARP-1 inhibition • Potential to decrease RT dose in the clinical setting? • ERBB4 novel driver of metastasis • Mendoza-Naranjo A et al • Gene expression profiling/ PCR/ immunoblot: cell line • Immunohistochemistry paired biopsies primary + metastases • Therapeutic potential

  10. The Possibilities: Ewing • Nutrient deprivation • Airik M et al • More invasive + migratory phenotype • Up-regulate Rho-MKL transcriptional targets • Rho-MKL antagonist: inhibited cell migration • Foxo1 and Sirt1 • Niedan S et al • Xenograft model: Methyl selenic acid reactivate FOXO1 + reduce tumor growth • NOTCH suppression result in activation SIRT1: p53 activation • Sirtuin inhibitor: Induce apoptosis in Ewing cell lines • Clinical evaluation of novel targets and agents • Accompanying translational studies • Identify those most likely to benefit

  11. The Possibilities: Rhabdo • Metastatic disease (ARST0431 trial) • Weigel B et al • Single arm trial, n=109 • Interval compressed chemotherapy • Feasibility + toxicity vincristine/ irinotecan + radiation • FoxM1/ Bub1b: critical signaling pathway required for growth and survival • Wan X et al • Knockdown Bub1b: suppression xenograft growth • Correlation between FoxM1 and Bub1b • Suppression FoxM1 • Reduction Bub1b expression • Inhibition cell growth + survival

  12. Conclusions • Optimize present management • Minimize long-term complications • Outcome measures/ quality of life data • Identify potential novel targets • Clinical trials with translational studies • Potential markers of response • Trial recruitment of adolescents + young adults • Improve outcome for older patients • Factors responsible for poor outcome

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