PURPOSE: Pediatric sarcomas are bone and soft tissue tumors that often exhibit high metastatic potential and refractory stem-like phenotypes, resulting in poor outcomes. Aggressive sarcomas frequently harbor a disrupted p53 pathway. However, whether pediatric sarcoma stemness is associated with abrogated p53 function and might be attenuated via p53 reactivation remains unclear. METHODS: We utilized a unique panel of pediatric sarcoma models and tumor tissue cohorts to investigate the correlation between the expression of stemness-related transcription factors, p53 pathway dysregulations, tumorigenicity in vivo, and clinicopathological features. TP53 mutation status was assessed by next-generation sequencing. Major findings were validated via shRNA-mediated silencing and functional assays. The p53 pathway-targeting drugs were used to explore the effects and selectivity of p53 reactivation against sarcoma cells with stem-like traits. RESULTS: We found that highly tumorigenic stem-like sarcoma cells exhibit dysregulated p53, making them vulnerable to drugs that restore wild-type p53 activity. Immunohistochemistry of mouse xenografts and human tumor tissues revealed that p53 dysregulations, together with enhanced expression of the stemness-related transcription factors SOX2 or KLF4, are crucial features in pediatric osteosarcoma, rhabdomyosarcoma, and Ewing's sarcoma development. p53 dysregulation appears to be an important step for sarcoma cells to acquire a fully stem-like phenotype, and p53-positive pediatric sarcomas exhibit a high frequency of early metastasis. Importantly, reactivating p53 signaling via MDM2/MDMX inhibition selectively induces apoptosis in aggressive, stem-like Ewing's sarcoma cells while sparing healthy fibroblasts. CONCLUSIONS: Our results indicate that restoring canonical p53 activity provides a promising strategy for developing improved therapies for pediatric sarcomas with unfavorable stem-like traits.
- MeSH
- dítě MeSH
- Krüppel-like faktor 4 * MeSH
- lidé MeSH
- mladiství MeSH
- myši MeSH
- nádorové buněčné linie MeSH
- nádorové kmenové buňky * metabolismus patologie MeSH
- nádorový supresorový protein p53 * metabolismus genetika MeSH
- předškolní dítě MeSH
- regulace genové exprese u nádorů MeSH
- sarkom * genetika patologie metabolismus MeSH
- signální transdukce MeSH
- xenogenní modely - testy protinádorové aktivity MeSH
- zvířata MeSH
- Check Tag
- dítě MeSH
- lidé MeSH
- mladiství MeSH
- mužské pohlaví MeSH
- myši MeSH
- předškolní dítě MeSH
- ženské pohlaví MeSH
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
Despite significant improvement in the survival of pediatric patients with cancer, treatment outcomes for high-risk, relapsed, and refractory cancers remain unsatisfactory. Moreover, prolonged survival is frequently associated with long-term adverse effects due to intensive multimodal treatments. Accelerating the progress of pediatric oncology requires both therapeutic advances and strategies to mitigate the long-term cytotoxic side effects, potentially through targeting specific molecular drivers of pediatric malignancies. In this report, we present the results of integrative genomic and transcriptomic profiling of 230 patients with malignant solid tumors (the "primary cohort") and 18 patients with recurrent or otherwise difficult-to-treat nonmalignant conditions (the "secondary cohort"). The integrative workflow for the primary cohort enabled the identification of clinically significant single nucleotide variants, small insertions/deletions, and fusion genes, which were found in 55% and 28% of patients, respectively. For 38% of patients, molecularly informed treatment recommendations were made. In the secondary cohort, known or potentially driving alteration was detected in 89% of cases, including a suspected novel causal gene for patients with inclusion body infantile digital fibromatosis. Furthermore, 47% of findings also brought therapeutic implications for subsequent management. Across both cohorts, changes or refinements to the original histopathological diagnoses were achieved in 4% of cases. Our study demonstrates the efficacy of integrating advanced genomic and transcriptomic analyses to identify therapeutic targets, refine diagnoses, and optimize treatment strategies for challenging pediatric and young adult malignancies and underscores the need for broad implementation of precision oncology in clinical settings.
- MeSH
- dítě MeSH
- genomika * metody MeSH
- individualizovaná medicína * metody MeSH
- kohortové studie MeSH
- kojenec MeSH
- lékařská onkologie metody MeSH
- lidé MeSH
- mladiství MeSH
- mladý dospělý MeSH
- nádory * genetika terapie MeSH
- předškolní dítě MeSH
- stanovení celkové genové exprese MeSH
- Check Tag
- dítě MeSH
- kojenec MeSH
- lidé MeSH
- mladiství MeSH
- mladý dospělý MeSH
- mužské pohlaví MeSH
- předškolní dítě MeSH
- ženské pohlaví MeSH
- Publikační typ
- časopisecké články MeSH
A lot of hope for high-risk cancers is being pinned on immunotherapy but the evidence in children is lacking due to the rarity and limited efficacy of single-agent approaches. Here, we aim to assess the effectiveness of multimodal therapy comprising a personalized dendritic cell (DC) vaccine in children with relapsed and/or high-risk solid tumors using the N-of-1 approach in real-world scenario. A total of 160 evaluable events occurred in 48 patients during the 4-year follow-up. Overall survival of the cohort was 7.03 years. Disease control after vaccination was achieved in 53.8% patients. Comparative survival analysis showed the beneficial effect of DC vaccine beyond 2 years from initial diagnosis (HR = 0.53, P = .048) or in patients with disease control (HR = 0.16, P = .00053). A trend for synergistic effect with metronomic cyclophosphamide and/or vinblastine was indicated (HR = 0.60 P = .225). A strong synergistic effect was found for immune check-point inhibitors (ICIs) after priming with the DC vaccine (HR = 0.40, P = .0047). In conclusion, the personalized DC vaccine was an effective component in the multimodal individualized treatment. Personalized DC vaccine was effective in less burdened or more indolent diseases with a favorable safety profile and synergized with metronomic and/or immunomodulating agents.
- MeSH
- cyklofosfamid * terapeutické užití aplikace a dávkování MeSH
- dendritické buňky * imunologie MeSH
- dítě MeSH
- imunoterapie metody MeSH
- individualizovaná medicína * metody MeSH
- inhibitory kontrolních bodů terapeutické užití MeSH
- kojenec MeSH
- kombinovaná terapie MeSH
- lidé MeSH
- metronomické podávání léků MeSH
- mladiství MeSH
- nádory * mortalita imunologie terapie farmakoterapie MeSH
- následné studie MeSH
- předškolní dítě MeSH
- protinádorové vakcíny * aplikace a dávkování terapeutické užití MeSH
- vinblastin aplikace a dávkování terapeutické užití MeSH
- Check Tag
- dítě MeSH
- kojenec MeSH
- lidé MeSH
- mladiství MeSH
- mužské pohlaví MeSH
- předškolní dítě MeSH
- ženské pohlaví MeSH
- Publikační typ
- časopisecké články MeSH
Constitutional mismatch repair deficiency (CMMRD) is a rare syndrome characterized by an increased incidence of cancer. It is caused by biallelic germline mutations in one of the four mismatch repair genes (MMR) genes: MLH1, MSH2, MSH6, or PMS2. Accurate diagnosis accompanied by a proper molecular genetic examination plays a crucial role in cancer management and also has implications for other family members. In this report, we share the impact of the diagnosis and challenges during the clinical management of two brothers with CMMRD from a non-consanguineous family harbouring compound heterozygous variants in the PMS2 gene. Both brothers presented with different phenotypic manifestations and cancer spectrum. Treatment involving immune checkpoint inhibitors significantly contributed to prolonged survival in both patients affected by lethal gliomas. The uniform hypermutation also allowed immune-directed treatment using nivolumab for the B-cell lymphoma, thereby limiting the intensive chemotherapy exposure in this young patient who remains at risk for subsequent malignancies.
- Publikační typ
- časopisecké články MeSH
- MeSH
- aminopyridiny MeSH
- anaplastický velkobuněčný lymfom * farmakoterapie MeSH
- laktamy MeSH
- lidé MeSH
- makrocyklické laktamy MeSH
- pyrazoly terapeutické užití MeSH
- reziduální nádor MeSH
- Check Tag
- lidé MeSH
- Publikační typ
- časopisecké články MeSH
Koncept personalizované medicíny je jedním z hlavních léčebných směrů v pediatrické onkologii posledních přibližně 15 let. Potřeba individualizace léčby či její personalizace vyplynula z klinických zkušeností a léčebných výsledků dosažených na bázi léčby čistě podle klinických protokolů, které - jakkoli přinesly do klinické medicíny potřebný prvek standardizace - často nebyly schopny zohlednit faktor jedince. Mezi faktory jedince patří z těch základních věk, komorbidity, souběžná terapie a vývoj těchto aspektů v průběhu onemocnění. V dalším textu se zaměříme na stručný rozbor aspektů vlastního onemocnění, aspektů celkového kontextu organismu hostitele, tj. pacienta, kterého léčíme, a dále aspektů léčiv, resp. léčebné strategie, jíž pacienta léčíme.
For more then fifteen years a concept of personalized medicine has become a dominant treatment approach in pediatric oncology. A need for person-dependent therapy adjustment has emerged based on clinical experience and often unsatisfactory results obtained using treatment protocols that - despite bringing a much needed element of standardization to clinical practice - essentially failed to consider aspects of individuality. Basic aspects of individuality are age, comorbidities, co-medications and their time-dependent variations. In the following we discuss aspects of a disease in the context of a host/patient and elaborate on aspects of the medicinal products and treatment strategy.
