Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UNIPROT:P04637 (p53)
 77,613 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

A number of childhood cancer survivors develop adverse, late onset side effects of earlier cancer treatments, known as the late effects of cancer therapy. As the number of survivors continues to increase, this growing population is at increased risk for a number of health-related problems. In the present study, we have examined the effect of aspirin on the late effects of chemotherapy by treating juvenile mice with doxorubicin (DOX). This novel mouse model produced various long-term adverse effects, some of which resemble premature aging phenotypes. DOX also resulted in the tissue accumulation of senescent cells and up-regulation of cyclooxygenase-2 (COX2) expression. However, treatment with aspirin following juvenile exposure to DOX improved body weight gain, ameliorated the long-term adverse effects, and reduced the levels of senescence markers. Moreover, aspirin reduced p53 and p21 accumulation in DOX-treated human and mouse fibroblasts. However, the suppressive effect of aspirin on DOX-induced p53 accumulation was significantly decreased in COX2 knockout mouse embryonic fibroblasts. Additionally, treatment of senescent fibroblasts with aspirin or celecoxib, a COX2 specific inhibitor, reduced cell viability and decreased the levels of Bcl-xL protein. Taken together, these studies suggest that aspirin may be able to reduce the late effects of chemotherapy through the suppression of cellular senescence.
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PMID:Aspirin ameliorates the long-term adverse effects of doxorubicin through suppression of cellular senescence. 3212 52

Pineoblastoma is a rare pediatric cancer induced by germline mutations in the tumor suppressors RB1 or DICER1. Presence of leptomeningeal metastases is indicative of poor prognosis. Here we report that inactivation of Rb plus p53 via a WAP-Cre transgene, commonly used to target the mammary gland during pregnancy, induces metastatic pineoblastoma resembling the human disease with 100% penetrance. A stabilizing mutation rather than deletion of p53 accelerates metastatic dissemination. Deletion of Dicer1 plus p53 via WAP-Cre also predisposes to pineoblastoma, albeit with lower penetrance. In silico analysis predicts tricyclic antidepressants such as nortriptyline as potential therapeutics for both pineoblastoma models. Nortriptyline disrupts the lysosome, leading to accumulation of non-functional autophagosome, cathepsin B release and pineoblastoma cell death. Nortriptyline further synergizes with the antineoplastic drug gemcitabine to effectively suppress pineoblastoma in our preclinical models, offering new modality for this lethal childhood malignancy.
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PMID:Modeling germline mutations in pineoblastoma uncovers lysosome disruption-based therapy. 3228 80

Local intravitreal or intra-arterial chemotherapy has improved therapeutic success for the pediatric cancer retinoblastoma (RB), but toxicity remains a major caveat. RB initiates primarily with RB1 loss or, rarely, MYCN amplification, but the critical downstream networks are incompletely understood. We set out to uncover perturbed molecular hubs, identify synergistic drug combinations to target these vulnerabilities, and expose and overcome drug resistance. We applied dynamic transcriptomic analysis to identify network hubs perturbed in RB versus normal fetal retina, and performed in vivo RNAi screens in RB1null and RB1wt;MYCNamp orthotopic xenografts to pinpoint essential hubs. We employed in vitro and in vivo studies to validate hits, define mechanism, develop new therapeutic modalities, and understand drug resistance. We identified BRCA1 and RAD51 as essential for RB cell survival. Their oncogenic activity was independent of BRCA1 functions in centrosome, heterochromatin, or ROS regulation, and instead linked to DNA repair. RAD51 depletion or inhibition with the small molecule inhibitor, B02, killed RB cells in a Chk1/Chk2/p53-dependent manner. B02 further synergized with clinically relevant topotecan (TPT) to engage this pathway, activating p53-BAX mediated killing of RB but not human retinal progenitor cells. Paradoxically, a B02/TPT-resistant tumor exhibited more DNA damage than sensitive RB cells. Resistance reflected dominance of the p53-p21 axis, which mediated cell cycle arrest instead of death. Deleting p21 or applying the BCL2/BCL2L1 inhibitor Navitoclax re-engaged the p53-BAX axis, and synergized with B02, TPT or both to override resistance. These data expose new synergistic therapies to trigger p53-induced killing in diverse RB subtypes.
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PMID:Functional genomics identifies new synergistic therapies for retinoblastoma. 3257 60

Genetic predisposition is a major cause of childhood cancer. Multiple cancer-predisposing syndromes have been identified, including Li-Fraumeni syndrome (LFS), neurofibromatosis type 1, APC-related adenomatous polyposis, Beckwith-Wiedemann syndrome, multiple endocrine neoplasia 1, ataxia telangiectasia, RUNX1 deficiency, Fanconi anemia, Bloom syndrome, and PTEN hamartoma tumor syndrome. LFS is a prototypical genetically predisposing condition. Accordingly, individualized therapy, surveillance, risk reduction, and family counseling are needed when a patient is diagnosed with LFS. More ethically important problems are encountered in a pediatric LFS patient, including the identification of patients requiring screening, the age at screening, the process of obtaining informed consent from children, and the responsibility of following a pediatric patient with a genetic predisposition. Therefore, it is crucial to determine whether planned genetic testing has direct benefits for pediatric patients. In this context, TP53 testing may be justified in a pediatric cancer patient with suspected LFS, given the importance of decisions such as the use of radiotherapy and the screening of family members as hematopoietic stem cell transplantation donors, the surveillance of subsequent cancers, and counseling for family members. In this review article, I have discussed these issues and indicated some consensus among various clinicians, including adult hematologists.
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PMID:[Challenges of screening germline predispositions in children]. 3262 43

TP53 p.R337H germline mutation is highly prevalent in the Southern region of Brazil. We sought to investigate TP53 p.R337H mutation in pediatric tumor samples from a population settled in a geographic area of high prevalence for this variant. Mutation assessment and genetic counseling for carriers/relatives were provided. 6/57 tumor samples were heterozygous for TP53 p.R337H. As expected, a high frequency was observed within adrenocortical tumors (3/3) and choroid plexus carcinomas (2/2). Interestingly, the TP53 R337H mutation was found in one case of pediatric rhabdomyosarcoma with Li-Fraumeni pedigree. Our finding expands the spectrum of childhood cancer associated with this germline mutation.
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PMID:Frequency of the TP53 p.R337H mutation in a Brazilian cohort of pediatric patients with solid tumors. 3267 23

Acute myeloid leukemia (AML) accounts for ~20% of pediatric leukemia cases. The prognosis of pediatric AML has been improved in recent decades, but it trails that of most other types of pediatric cancer, with mortality rates of 30-40%. Consequently, newer more targeted drugs are required for incorporation into treatment plans. These newer drugs selectively target AML cells with specific gene alterations. However, there are significant differences in genetic alterations between adult and pediatric patients with AML. In the present study, inexpensive and rapid next-generation sequencing (NGS) of >150 cancer-related genes was performed for matched diagnostic, remission and relapse (if any) samples from 27 pediatric patients with AML. In this analysis, seven genes were recurrently mutated. KRAS was mutated in seven patients, NRAS was mutated in three patients, and KIT, GATA1, WT1, PTPN11, JAK3 and FLT3 were each mutated in two patients. Among patients with relapsed AML, six harbored KRAS mutations at diagnosis; however, four of these patients lost these mutations at relapse. Additionally, two genetic alterations (FLT3-ITD and TP53 alterations) were detected among patients who eventually relapsed, and these mutations are reported to be adverse prognostic factors for adult patients with AML. This panel-based, targeted sequencing approach may be useful in determining the genetic background of pediatric AML and improving the prediction of treatment response and detection of potentially targetable gene alterations. RAS pathway mutations were highly unstable at relapse; therefore, these mutations should be chosen as a target with caution. Incorporating this panel-based NGS approach into the clinical setting may allow for a patient-oriented strategy of precision treatment for childhood AML.
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PMID:Panel-based next-generation sequencing facilitates the characterization of childhood acute myeloid leukemia in clinical settings. 3293 18

Anthracyclines are the critical component in a majority of pediatric chemotherapy regimens due to their broad anticancer efficacy. Unfortunately, the vast majority of long-term childhood cancer survivors will develop a chronic health condition caused by their successful treatments and severe cardiac disease is a common life-threatening outcome that is unequivocally linked to previous anthracycline exposure. The intricacies of how anthracyclines such as doxorubicin, damage the heart and initiate a disease process that progresses over multiple decades is not fully understood. One area left largely unstudied is the role of the cardiac fibroblast, a key cell type in cardiac maturation and injury response. In this study, we demonstrate the effect of doxorubicin on cardiac fibroblast function in the presence and absence of the critical DNA damage response protein p53. In wildtype cardiac fibroblasts, doxorubicin-induced damage correlated with decreased proliferation and migration, cell cycle arrest, and a dilated cardiomyopathy gene expression profile. Interestingly, these doxorubicin-induced changes were completely or partially restored in p53-/- cardiac fibroblasts. Moreover, in wildtype cardiac fibroblasts, doxorubicin produced DNA damage and mitochondrial dysfunction, both of which are well-characterized cell stress responses induced by cytotoxic chemotherapy and varied forms of heart injury. A 3-fold increase in p53 (p = 0.004) prevented the completion of mitophagy (p = 0.032) through sequestration of Parkin. Interactions between p53 and Parkin increased in doxorubicin-treated cardiac fibroblasts (p = 0.0003). Finally, Parkin was unable to localize to the mitochondria in wildtype cardiac fibroblasts, but mitochondrial localization was restored in p53-/- cardiac fibroblasts. These findings strongly suggest that cardiac fibroblasts are an important myocardial cell type that merits further study in the context of doxorubicin treatment. A more robust knowledge of the role cardiac fibroblasts play in the development of doxorubicin-induced cardiotoxicity will lead to novel clinical strategies that will improve the quality of life of cancer survivors.
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PMID:Doxorubicin-induced p53 interferes with mitophagy in cardiac fibroblasts. 3296 Sep 2

Objectives: Secondary mucoepidermoid carcinoma (MEC) of the head and neck is occasionally observed in childhood cancer survivors. The goal of this research was to compare the demographic and pathologic characteristics, as well as survival between primary and secondary MEC in children and adolescent patients. Methods: Pediatric patients (younger than 19 years old) with surgically treated MEC of the head and neck were retrospectively enrolled at the Affiliated Children's Hospital of Zhengzhou University and divided into two groups based on their cancer history. Demographic, pathologic, and survival characteristics between the two groups were compared. The main study interests were recurrence-free survival (RFS), overall survival (OS), and disease-specific survival (DSS). Results: The primary and secondary groups consisted of 63 and 15 patients, respectively. The two groups had similar distributions in terms of age, sex, tumor stage, neck lymph node stage, perineural invasion, lymphovascular invasion, p53, Bcl-2, proliferating cell nuclear antigen, carcinoembryonic antigen, and Ki-67 index. The 10-year RFS rates for the primary group and secondary group were 80 and 71%, respectively, and this difference was not significant (p = 0.464). The 10-year DSS rates for the primary group and secondary group were 83 and 82%, respectively, and this difference was also not significant (p = 0.649). The 10-year OS rates for the primary group and secondary group were 74 and 51%, respectively; this difference was significant (p = 0.023). Further Cox model analysis confirmed the independence of a previous cancer history (p = 0.043) in decreasing OS. Conclusions: Pediatric patients with secondary MEC exhibit similar demographic, pathologic, and molecular characteristics as primary patients but worse OS. These findings indicate that special disease management approaches might be needed for secondary patients.
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PMID:Comparison Between Primary and Secondary Pediatric Mucoepidermoid Carcinoma of the Head and Neck. 3297 45

Subsequent malignant neoplasms (SMNs) are one of the most serious late complications in pediatric patients with cancer, with more than 10% of long-term cancer survivors developing SMNs. Germline mutations in cancer predisposition genes have been recently highlighted as a risk factor. For example, germline mutations in the TP53 gene were reported to be a risk factor for SMNs. A comprehensive genomic analysis for a large cohort of long-term survivors of childhood cancer showed that variants in cancer predisposition genes were correlated with the higher cumulative incidence of SMNs. As another genetic risk, previous reports suggested that polymorphisms in genes regulating thiopurine pathway such as TPMT gene might contribute to SMN development after acute lymphoblastic leukemia treatment. Considering improved survival probability, attention should be paid for late complications. Thus, therapeutic strategy should be optimized based on a risk for SMNs of each individual.
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PMID:[Genetic basis of subsequent malignant neoplasms]. 3316 13

Approximately 10% of pediatric cancer patients possess germline pathogenic/likely pathogenic variants (PV/LPV) in known tumor predisposition genes. Predictive testing is the optimal approach to identify asymptomatic at-risk relatives to guide gene-directed surveillance for early cancer detection and/or risk-reducing strategies. However, the uptake rate for predictive testing remains low in Asian countries. We aim to evaluate the uptake rate of predictive testing in a pediatric population (aged under 21-years-old) in a multi-ethnic Asian cancer center. Our retrospective analysis included families with PV/LPVs identified in genes associated with pediatric tumor predisposition. Of the 83 pediatric first-degree relatives (FDRs) from 49 unrelated families, 20 FDRs (24.1%) originating from 13 families (26.6%) underwent predictive testing. Genes tested in pediatric FDRs were APC, RB1, SBDS, SDHA, SDHB, SDHD, and TP53. All pediatric FDRs of probands with PV/LPVs in RB1 and biallelic PVs in SBDS underwent predictive testing, while <45% of pediatric FDRs had predictive testing for familial PV/LPVs identified in the APC, SDHA, SDHB, SDHD, and TP53 genes. Amongst the 13 families who underwent pre-test counseling, 80% of pediatric FDRs in these families proceeded with predictive testing. Malay pediatric FDRs and siblings of probands were more likely to undergo predictive testing. We conclude that the predictive testing rate in pediatric FDRs is higher than that of adult FDRs in Asia, but still below the global average. We postulate factors that may influence predictive testing uptake in pediatric FDRs includes a lack of genetics awareness, concerns regarding insurance, and genetic discrimination.
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PMID:Predictive Testing for Tumor Predisposition Syndromes in Pediatric Relatives: An Asian Experience. 3319 95


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