Germline predisposition to pediatric Ewing sarcoma is uniquely characterized by inherited pathogenic variants in DNA damage repair genes

More knowledge is needed around the role and importance of specific genes in germline predisposition to Ewing sarcoma to inform biological investigation and clinical practice. In this study, we evaluated the enrichment of pathogenic germline variants in Ewing sarcoma relative to other pediatric sarcoma subtypes, as well as patterns of inheritance of these variants. We carried out an ancestry-matched case-control analysis to screen for enrichment of pathogenic germline variants in 141 established cancer predisposition genes in 1138 individuals with pediatric sarcoma diagnoses (222 Ewing sarcoma cases) relative to identically processed cancer-free controls. Findings in Ewing sarcoma were validated with an additional cohort of 425 individuals, and 301 Ewing sarcoma parent-proband trios were analyzed for inheritance patterns of identified pathogenic variants. A distinct pattern of pathogenic germline variants was seen in Ewing sarcoma relative to other sarcoma subtypes. FANCC was the only gene with an enrichment signal for heterozygous pathogenic variants in the discovery Ewing sarcoma cohort (OR 14.4, 95% CI 3.5 - 51.2, p = 0.002, FDR = 0.28). This enrichment in FANCC heterozygous pathogenic variants was seen again in the Ewing sarcoma validation cohort (OR 5.1, 95% CI 1.2 - 18.5, p = 0.03, single hypothesis), representing a broader importance of genes involved in DNA damage repair, which were also nominally enriched in Ewing sarcoma cases. Pathogenic variants in DNA damage repair genes were acquired through autosomal inheritance. Our study provides new insight into germline risk factors contributing to Ewing sarcoma pathogenesis.

Inactivation of the CIC-DUX4 oncogene through P300/CBP inhibition, a therapeutic approach for CIC-DUX4 sarcoma

CIC-DUX4 sarcoma (CDS) is a highly aggressive and metastatic small round type of predominantly pediatric sarcoma driven by a fusion oncoprotein comprising the transcriptional repressor Capicua (CIC) fused to the C-terminal transcriptional activation domain of DUX4. CDS rapidly develops resistance to chemotherapy, thus novel specific therapies are greatly needed. We demonstrate that CIC-DUX4 requires P300/CBP to induce histone H3 acetylation, activate its targets, and drive oncogenesis. We describe the synthetic route to a selective and highly potent P300/CBP inhibitor named iP300w and related stereoisomers, and find that iP300w efficiently suppresses CIC-DUX4 transcriptional activity and reverses CIC-DUX4 induced acetylation. iP300w is active at 100-fold lower concentrations than related stereoisomers or A-485. At low doses, iP300w shows specificity to CDS cancer cell lines, rapidly inducing cell cycle arrest and preventing growth of established CDS xenograft tumors when delivered in vivo. The effectiveness of iP300w to inactivate CIC-DUX4 highlights a promising therapeutic opportunity for CDS.

Chimeric Antigen Receptor T Cell Therapy and the Immunosuppressive Tumor Microenvironment in Pediatric Sarcoma

Sarcomas are a diverse group of bone and soft tissue tumors that account for over 10% of childhood cancers. Outcomes are particularly poor for children with refractory, relapsed, or metastatic disease. Chimeric antigen receptor T (CAR T) cells are an exciting form of adoptive cell therapy that potentially offers new hope for these children. In early trials, promising outcomes have been achieved in some pediatric patients with sarcoma. However, many children do not derive benefit despite significant expression of the targeted tumor antigen. The success of CAR T cell therapy in sarcomas and other solid tumors is limited by the immunosuppressive tumor microenvironment (TME). In this review, we provide an update of the CAR T cell therapies that are currently being tested in pediatric sarcoma clinical trials, including those targeting tumors that express HER2, NY-ESO, GD2, EGFR, GPC3, B7-H3, and MAGE-A4. We also outline promising new CAR T cells that are in pre-clinical development. Finally, we discuss strategies that are being used to overcome tumor-mediated immunosuppression in solid tumors; these strategies have the potential to improve clinical outcomes of CAR T cell therapy for children with sarcoma.

Cell-surface vimentin positive circulating tumor cells as a diagnostic and prognostic indicator in pediatric sarcoma patients.

e15022 Background: Despite advances in care, the 5 year overall survival for patients with relapsed and or metastatic sarcoma remains as low as < 35%. Currently, there are no biomarkers available to assess disease status in patients with sarcomas and as such, disease surveillance remains only reliant on serial imaging which increases the risk of secondary malignancies and heightens patient anxiety. Methods: Here, we enumerated the cell surface vimentin (CSV+) CTCs in the blood of 92 sarcoma pediatric and adolescent and young adult (AYA) patients. Results: We discovered the CSV+CTC could serve as a possible biomarker of disease with sensitivity of 85.3% and specificity of 75%. Significantly, patients who were deemed to be CSV+ CTC positive were found to have a worse overall survival compared to those who were CSV+ CTC negative (773 days vs 2622 days). Addition of readily available genetic analyses improved the sensitivity in both diagnostic and prognostic tests. Conclusions: Our findings indicate that CSV+ CTCs have both diagnostic and prognostic value and can possibly serve as a measure of disease burden.

Infectious Morbidity in Pediatric Patients Receiving Neoadjuvant Chemotherapy for Sarcoma

The purpose of this retrospective, single-center cohort study was to assess the infectious burden in pediatric sarcoma patients during neoadjuvant chemotherapy. The review included all patients with a new diagnosis of Ewing sarcoma, osteosarcoma or soft tissue sarcoma between September 2009 and December 2018 who were enrolled in the EWING 2008, CWS SoTiSaR and EURAMOS clinical trial or registry. Primary endpoints were the occurrence of febrile neutropenia (FN) and microbiologically documented infection (MDI). Parameters with a potential impact on FN and MDI were also analyzed. A total of 170 sarcoma patients (median age: 13 years, range: 0–21; 96 m/74 f) received 948 chemotherapy courses (median: 6; range: 2–8). Of these patients, 58.8% had ≥1 FN episode and 20.6% ≥ 1 MDI. FN occurred in 272/948 courses (28.7%) with fever of unknown origin (FUO) in 231 courses and 45 MDI and 19 clinically documented infections (CDI) occurring in a total of 57 courses. Patients enrolled in EWING 2008 had significantly more FN (p < 0.001), infections (p = 0.02) and MDI (p = 0.035). No infection-related deaths were observed. Younger age, tumor type and localization, and higher median and maximum mucositis grades were significantly associated with higher numbers of FN (p < 0.001), and younger age (p = 0.024) and higher median mucositis grade (p = 0.017) with MDI. The study shows substantial infectious morbidity in sarcoma patients during neoadjuvant chemotherapy treatment and opportunities to improve prevention and management.

Pediatric sarcoma survivorship: A call for a developmental cascades approach

Survivors of pediatric sarcomas often experience greater psychological and psychosocial difficulties than their non-afflicted peers. We consider findings related to poorer outcomes from a developmental cascade perspective. Specifically, we discuss how physical, neurocognitive, psychological, and psychosocial costs associated with pediatric sarcomas and their treatment function transactionally to degrade well-being in long-term pediatric sarcoma survivors. We situate the sarcoma experience as a broad developmental threat – one stemming from both the presence and treatment of a life-imperiling disease, and the absence of typical childhood experiences. Ways in which degradation in one developmental domain spills over and effects other domains are highlighted. We argue that the aggregate effect of these cascades is two-fold: first, it adds to the typical stress involved in meeting developmental milestones and navigating developmental transitions; and second, it deprives survivors of crucial coping strategies that mitigate these stressors. This position suggests specific moments of intervention and raises specific hypotheses for investigators to explore.

Preclinical In Vivo Modeling of Pediatric Sarcoma—Promises and Limitations

Pediatric sarcomas are an extremely heterogeneous group of genetically distinct diseases. Despite the increasing knowledge on their molecular makeup in recent years, true therapeutic advancements are largely lacking and prognosis often remains dim, particularly for relapsed and metastasized patients. Since this is largely due to the lack of suitable model systems as a prerequisite to develop and assess novel therapeutics, we here review the available approaches to model sarcoma in vivo. We focused on genetically engineered and patient-derived mouse models, compared strengths and weaknesses, and finally explored possibilities and limitations to utilize these models to advance both biological understanding as well as clinical diagnosis and therapy.