Pediatric Kidney Tumors Research Articles

Characterization of malignant kidney tumors in childhood by 18F-FDG PET/CT.

To evaluate the role of semiquantitative parameters derived from 18F-FDG PET/CT in characterizing pediatric malignant kidney tumors. 54 children with pathologically confirmed renal malignancies who underwent pretreatment 18F-FDG PET/CT were retrospectively reviewed. Association between PET-derived semiquantitative parameters, including maximum standardized uptake value (SUVmax), mean standardized uptake value (SUVmean), metabolic tumor volume (MTV) and total lesion glycolysis (TLG), and tumor histology, disease stage, and loss of heterozygosity were analyzed. Of the 54 patients, 43 had Wilms tumor (WT), 4 had clear cell sarcoma of the kidney (CCSK), 3 had rhabdoid tumor of kidney, 2 had renal cell carcinoma, and 2 had congenital mesoblastic nephroma. 18F-FDG PET/CT detected all primary renal tumors, with SUVmax ranging from 1.2 to 14.5. PET-derived parameters showed no significant differences among different tumor types, except for CCSK, which exhibited lower FDG uptake compared to WT (SUVmax 3.60 ± 1.02 vs. 6.10 ± 2.25, p = 0.034). Higher MTV, TLG, and lactate dehydrogenase were associated with stage IV disease. ROC analysis showed that TLG had the highest AUC (0.931) for predicting stage IV disease in the whole cohort, while SUVmax had the highest AUC (0.867) for predicting stage IV and V in WT. Furthermore, Children with 1q gain exhibited higher MTV in WT (447 ± 354 vs. 207 ± 189, p = 0.041). PET-derived semiquantitative parameters highly associated with disease stage both in the overall cohort of renal malignancies and specifically in the WT group. Additionally, volumetric metabolic indices might provide further insights into loss of heterozygosity in children with WT.

Navigating the complexity of Wilms tumors in pediatrics: diagnostic challenges for better treatment

AbstractMost pediatric kidney tumors clinically present as an abdominal mass, typically detected by the child’s caregivers and later confirmed through imaging tests. Malignant renal cancers account for approximately 5% of childhood kidney neoplasms, with Wilms tumors (WT) being the most common diagnosis in this category (90% of cases). Patients are treated according to two main protocols: the American protocol of the Children’s Oncology Group (COG) or the protocol from the Société Internationale d’Oncologie Pédiatrique (SIOP), which differ in terms of the timing of surgery (before or after chemotherapy). Grossly, pediatric kidney tumors are neoplasms that can vary significantly in size. After a correct histological diagnosis, the child will be treated according to the guidelines for that specific neoplasm. Therefore, the accurate diagnosis of the histological subtype is crucial for determining the appropriate treatment that can improve survival rates in children. Consequently, it is extremely important to recognize neoplasms that require differentiation from WT.

Cytokine Signaling in Pediatric Kidney Tumor Cell Lines WT-CLS1, WT-3ab and G-401.

Renal tumors comprise ~7% of all malignant pediatric tumors. Approximately 90% of pediatric kidney tumors comprise Wilms tumors, and the remaining 10% include clear cell sarcoma of the kidney, malignant rhabdoid tumor of the kidney, renal cell carcinoma and other rare renal tumors. Over the last 30 years, the role of cytokines and their receptors has been considerably investigated in both cancer progression and anti-cancer therapy. However, more effective immunotherapies require the cytokine profiling of each tumor type and comprehensive understanding of tumor biology. In this study, we aimed to investigate the activation of signaling pathways in response to cytokines in three pediatric kidney tumor cell lines, in WT-CLS1 and WT-3ab cells (both are Wilms tumors), and in G-401 cells (a rhabdoid kidney tumor, formerly classified as Wilms tumor). We observed that interferon-alpha (IFN-α) and interferon-gamma (IFN-γ) very strongly induced the activation of the STAT1 protein, whereas IL-6 and IFN-α activated STAT3 and IL-4 activated STAT6 in all examined tumor cell lines. STAT protein activation was examined by flow cytometry and Western blot using phospho-specific anti-STAT antibodies which recognize only activated (phosphorylated) STAT proteins. Nuclear translocation of phospho-STAT proteins upon activation with specific cytokines was furthermore confirmed by immunofluorescence. Our results also showed that both IFN-α and IFN-γ caused upregulation of major histocompatibility complex (MHC) class I proteins, however, these cytokines did not have any effect on the expression of MHC class II proteins. We also observed that pediatric kidney tumor cell lines exhibit the functional expression of an additional cytokine signaling pathway, the tumor necrosis factor (TNF)-α-mediated activation of nuclear factor kappa B (NF-κB). In summary, our data show that human pediatric renal tumor cell lines are responsive to stimulation with various human cytokines and could be used as in vitro models for profiling cytokine signaling pathways.

Hypertension in Wilms tumor.

Wilms tumor (WT) represents over 90% of all pediatric kidney tumors. Children with WT often present acutely with hypertension which resolves in the short term after nephrectomy. However, WT survivors have increased long-term risk of hypertension, primarily due to decreased nephron mass after nephrectomy, with additional insults from possible exposure to abdominal radiation and nephrotoxic therapies. The diagnosis of hypertension may be improved by ambulatory blood pressure monitoring (ABPM), as several recent single-center studies have shown a substantial proportion of WT survivors with masked hypertension. Current gaps in knowledge include determining which WT patients may benefit from routine screening with ABPM, correlation of casual and ABPM parameters with cardiac abnormalities, and longitudinal assessment of cardiovascular and kidney parameters in relation to appropriate treatment of hypertension. This review aims to summarize the most recent literature on hypertension presentation and management at the time of WT diagnosis as well as the long-term hypertension risk and impact on kidney and cardiovascular outcomes in WT survivors.

Appropriate Amounts and Activity of the Wilms' Tumor Suppressor Gene, wt1, Are Required for Normal Pronephros Development of Xenopus Embryos.

The Wilms' tumor suppressor gene, wt1, encodes a zinc finger-containing transcription factor that binds to a GC-rich motif and regulates the transcription of target genes. wt1 was first identified as a tumor suppressor gene in Wilms' tumor, a pediatric kidney tumor, and has been implicated in normal kidney development. The WT1 protein has transcriptional activation and repression domains and acts as a transcriptional activator or repressor, depending on the target gene and context. In Xenopus, an ortholog of wt1 has been isolated and shown to be expressed in the developing embryonic pronephros. To investigate the role of wt1 in pronephros development in Xenopus embryos, we mutated wt1 by CRISPR/Cas9 and found that the expression of pronephros marker genes was reduced. In reporter assays in which known WT1 binding sequences were placed upstream of the luciferase gene, WT1 activated transcription of the luciferase gene. The injection of wild-type or artificially altered transcriptional activity of wt1 mRNA disrupted the expression of pronephros marker genes in the embryos. These results suggest that the appropriate amounts and activity of WT1 protein are required for normal pronephros development in Xenopus embryos.

The functions of Wt1 in mouse gonad development and somatic cells differentiation†.

Wilms' tumor 1 (Wt1) encodes a zinc finger nuclear transcription factor which is mutated in 15-20% of Wilms' tumor, a pediatric kidney tumor. Wt1 has been found to be involved in the development of many organs. In gonads, Wt1 is expressed in genital ridge somatic cells before sex determination, and its expression is maintained in Sertoli cells and granulosa cells after sex determination. It has been demonstrated that Wt1 is required for the survival of the genital ridge cells. Homozygous mutation of Wt1 causes gonad agenesis. Recent studies find that Wt1 plays important roles in lineage specification and maintenance of gonad somatic cells. In this review, we will summarize the recent research works about Wt1 in gonadal somatic cell differentiation.

POS-409 IDENTIFICATION OF IMPORTANT PATHOLOGICAL mRNA and microRNA TRANSCRIPTS INVOLVED IN WILMS TUMOR AND RHABDOID TUMOR OF THE KIDNEY USING ASSOCIATION RULE MINING

Wilms tumor (WT) and rhabdoid tumor of the kidney (RT) are respectively the most and less common types of pediatric kidney tumors. Due to the presence of overlapping histologic patterns and similar cell types across these tumors, their differential diagnosis solely based on histologic study can be challenging. To this end, this study aimed to apply machine learning and deep learning algorithms to identify the most important mRNAs and microRNAs panels that can be involved in the pathogenesis of the WT and RT.

Bladder cancer-associated transcript 2 contributes to nephroblastoma progression.

Nephroblastoma is a common pediatric kidney tumor. Existing evidence has indicated that long non-coding RNAs (lncRNAs) may be associated with tumorigenesis such as nephroblastoma. However, the contribution of lncRNA bladder cancer-associated transcript 2 (BLACAT2) to tumorigenesis and the postoperative nephroblastoma prognosis remains unknown. In total, 50 pairs of patient nephroblastoma and corresponding adjacent non-tumorous tissues were analyzed for BLACAT2 expression. The underlying roles of BLACAT2 in nephroblastoma cells were also investigated. The BLACAT2 level was detected in four nephroblastoma cell lines and normal cell line NGC-407 using a quantitative real-time polymerase chain reaction. The potential influence of BLACAT2 on nephroblastoma cells was explored based on RNA interference technology in vitro and in vivo. Moreover, the microRNA targeted by BLACAT2 and its target gene were predicted and verified. BLACAT2 silencing suppressed cell proliferation, colony formation and tumor growth in vivo and promoted cell apoptosis in vitro. Furthermore, BLACAT2 could directly bind to miR-504-3p, thereby decreasing miR-504-3p expression. In addition, the impact of miR-504-3p on proliferation, colony formation and nephroblastoma cell apoptosis was reversed by BLACAT2. Wnt11 was identified as a target of miR-504-3p. The present study revealed that a novel BLACAT2/miR-504-3p/Wnt11 axis is associated with nephroblastoma, where BLACAT2 is able to sponge miR-504-3p to down-regulate Wnt11.

The Clinical Characteristics and Survival Profiles of Wilms Tumor in the United Arab Emirates: A Single-center Retrospective Analysis

Background: Wilms Tumor (WT) is the most common pediatric kidney tumor, yet the disease has variable clinical characteristics and prognostic outcomes across different populations. Objectives: This study aims to review the clinical characteristics and survival outcomes of children with WT who have received treatment at Dubai Hospital, UAE. Methods: A retrospective study was conducted involving the medical records of confirmed WT children (aged < 14 years) who had received treatment between 2013 and 2018. Diagnosis should have been established based on the histopathological examination of operable tumors and needle biopsy for inoperable tumors. The Société Internationale d’Oncologie Pédiatrique (SIOP) WT 2001 protocol was used for patient management, and the UMBRELLA SIOP–RTSG 2016 Wilms tumor pathology and molecular biology protocol was used for histopathologic classification and clinical staging. The presenting sign and symptoms, the findings of diagnostic imaging techniques, histological grading, the received treatments, and follow-up outcomes were collected and analyzed. Kaplan-Meier survival analysis was used to carry out the survival analysis. Results: Ten children were diagnosed with WT (median age of 3.40 years, 60% males). All patients presented with abdominal masses without prominent pain. Synchronous bilateral lesions were found at diagnosis in one patient and metastatic lesions in three patients. Four children were discharged against medical advice; five received treatment according to the SIOP WT 2001 regimen, while the remaining patient was managed in the United States according to the National Wilms Tumor Study Group (NWTSG) protocol. The overall 6-year and relapse-free survival rates were 90% and 80%, respectively. Conclusion: The clinical characteristics and managemental outcomes of children presenting with WT are promising, possibly owing to adopting the SIOP protocol. Considering the small sample size, more large-scale, nation-wide studies are warranted.

Structure and Role of BCOR PUFD in Noncanonical PRC1 Assembly and Disease.

Polycomb repression complex 1 (PRC1) is a multiprotein assembly that regulates transcription. The Polycomb group ring finger 1 protein (PCGF1) is central in the assembly of the noncanonical PRC1 variant called PRC1.1 through its direct interaction with BCOR (BCL-6-interacting corepressor) or its paralog, BCOR-like 1 (BCORL1). Previous structural studies revealed that the C-terminal PUFD domain of BCORL1 is necessary and sufficient to heterodimerize with the RAWUL domain of PCGF1 and, together, form a new protein-protein binding interface that associates with the histone demethylase KDM2B. Here, we show that the PUFD of BCOR and BCORL1 differ in their abilities to assemble with KDM2B. Unlike BCORL1, the PUFD of BCOR alone does not stably assemble with KDM2B. Rather, additional residues N-terminal to the BCOR PUFD are necessary for stable association. Nuclear magnetic resonance (NMR) structure determination and 15N T2 relaxation time measurements of the BCOR PUFD alone indicate that the termini of the BCOR PUFD, which are critical for binding PCGF1 and KDM2B, are disordered. This suggests a hierarchical mode of assembly whereby BCOR PUFD termini become structurally ordered upon binding PCGF1, which then allows stable association with KDM2B. Notably, BCOR internal tandem duplications (ITDs) leading to pediatric kidney and brain tumors map to the PUFD termini. Binding studies with the BCOR ITD indicate the ITD would disrupt PRC1.1 assembly, suggesting loss of the ability to assemble PRC1.1 is a critical molecular event driving tumorigenesis.

Rare childhood kidney tumors

Pediatric kidney tumors are rare and account for about 6% of all childhood malignancies. By far the most common tumors are nephroblastomas. This review presents rare childhood renal tumors. Mesoblastic nephroma, as tumors of the low risk group, as well as the clear-cell sarcomas of the kidney and malignant rhabdoid tumors, as tumors of the high-risk group, and the so-called anaplastic sarcomas of the kidney will be discussed.Due to the significantly divergent therapy, acorrect diagnosis is important. Due to the often overlapping morphology, pathologic diagnosis is often difficult. In addition to the typical morphologic features, the specific immunohistochemical aspects as well as the known molecular changes will be presented.

The role of TCF3 as potential master regulator in blastemal Wilms tumors.

Wilms tumors are the most common type of pediatric kidney tumors. While the overall prognosis for patients is favorable, especially tumors that exhibit a blastemal subtype after preoperative chemotherapy have a poor prognosis. For an improved risk assessment and therapy stratification, it is essential to identify the driving factors that are distinctive for this aggressive subtype. In our study, we compared gene expression profiles of 33 tumor biopsies (17 blastemal and 16 other tumors) after neoadjuvant chemotherapy. The analysis of this dataset using the Regulator Gene Association Enrichment algorithm successfully identified several biomarkers and associated molecular mechanisms that distinguish between blastemal and nonblastemal Wilms tumors. Specifically, regulators involved in embryonic development and epigenetic processes like chromatin remodeling and histone modification play an essential role in blastemal tumors. In this context, we especially identified TCF3 as the central regulatory element. Furthermore, the comparison of ChIP-Seq data of Wilms tumor cell cultures from a blastemal mouse xenograft and a stromal tumor provided further evidence that the chromatin states of blastemal cells share characteristics with embryonic stem cells that are not present in the stromal tumor cell line. These stem-cell like characteristics could potentially add to the increased malignancy and chemoresistance of the blastemal subtype. Along with TCF3, we detected several additional biomarkers that are distinctive for blastemal Wilms tumors after neoadjuvant chemotherapy and that may provide leads for new therapeutic regimens.

Circulating tumor DNA analysis enables molecular characterization of pediatric renal tumors at diagnosis.

Circulating tumor DNA (ctDNA) is a powerful tool for the molecular characterization of cancer. The most frequent pediatric kidney tumors (KT) are Wilms' tumors (WT), but other diagnoses may occur. According to the SIOP strategy, in most countries pediatric KT have a presumptive diagnosis of WT if they are clinically and radiologically compatible. The histologic confirmation is established after post-chemotherapy nephrectomy. Thus, there is a risk for a small fraction of patients to receive neoadjuvant chemotherapy that is not adapted to the disease. The aim of this work is to perform molecular diagnosis of pediatric KT by tumor genetic characterization based on the analysis of ctDNA. We analyzed ctDNA extracted from plasma samples of 18 pediatric patients with KT by whole-exome sequencing and compared the results to their matched tumor and germline DNA. Copy number alterations (CNAs) and single nucleotide variations (SNVs) were analyzed. We were able to detect tumor cell specific genetic alterations-CNAs, SNVs or both-in ctDNA in all patients except in one (for whom the plasma sample was obtained long after nephrectomy). These results open the door to new applications for the study of ctDNA with regards to the molecular diagnosis of KT, with a possibility of its usefulness for adapting the treatment early after diagnosis, but also for disease monitoring and follow up.

Pediatric and adult kidney tumors differ

Kidney Cancer Understanding tumor origins and the similarities and differences between organ-specific cancers is important for determining treatment options. Young et al. generated more than 72,000 single-cell transcriptomes from healthy and cancerous human kidneys. From these data, they determined that Wilms tumor, a pediatric kidney cancer, originates from aberrant fetal cells, whereas adult kidney cancers are likely derived from a specific subtype of proximal convoluted tubular cell. Science , this issue p. [594][1] [1]: /lookup/doi/10.1126/science.aat1699

The unique characteristics of intussusception after renal tumor surgery in children

Abstract Introduction To further optimize survival rates as well as quality of cure for pediatric kidney tumors, attention for treatment related morbidity and mortality has become increasingly important. Intussusception is a rare but important complication after tumornephrectomy in children, causing morbidity, mortality and prolonged hospitalization. In this study, we describe two recent cases in our institute and provide a comprehensive review of the literature. Methods For our narrative review, we searched for all reported cases of post tumor nephrectomy intussusception published until November 2016, using Pubmed and Embase libraries. Results A total of 52 pediatric renal tumor cases who developed intussusception after tumor nephrectomy were identified. Median age was 23 months (range 3–84). Median time of onset was postoperative day 6 (range 1–18). Of 41 patients described in detail, only 4/41 were ileocolic, the others suffered from a small bowel intussusception. Most frequent presenting symptom was bilious vomiting. Preceding treatment approach was documented in 47 cases; i.e. preoperative chemotherapy had been administered to 10/47 patients. In 29 of 30 well documented cases, successful manually reduction during re-laparotomy was described and only 1 patient needed resection. All patients survived without recurrence of intussusception. Conclusion In pediatric renal tumor patients, small bowel obstruction seems to reflect mostly post nephrectomy intussusception cases in contrast to the ileocolic idiopathic intussusceptions that are observed in healthy children. Symptoms of intussusception mimic chemotherapy related toxicity and general post-surgical symptoms, thereby initiating a significant delay in diagnosis. Awareness of intussusception after renal tumor surgery is warranted.

Over-Expression of miR-21 and Lower PTEN Levels in Wilms' Tumor with Aggressive Behavior.

Wilms' tumor (WT) is the most common pediatric kidney tumor. MiR-21 is one of the most frequently overexpressed microRNAs in solid tumors, while phosphatase and tensin homolog deleted from chromosome 10 (PTEN) is the most highly mutated tumor suppressor gene. The aim of this study was to investigate the relationship between miR-21 and PTEN in WT. The expression levels of miR-21 and the PTEN protein were determined by qRT-PCR and Western blot analyses in WT specimens, respectively. In WT tissues, the miR-21 expression levels were significantly higher and the PTEN protein levels were significantly lower, compared to the adjacent non-tumorous renal tissues. The higher levels of miR-21 and lower levels of PTEN were correlated with age (> 24 months), late clinical stage, unfavorable histopathological type and lymphatic metastasis. A univariate linear regression analysis indicated a significant correlation between higher miR-21 levels and lower PTEN levels. Using the SK-NEP-1 WT cell line, we showed that the decreased expression levels of miR-21 promoted cell proliferation and invasion, but inhibited apoptosis. Importantly, lowered expression levels of miR-21 increased the expression levels of PTEN protein and decreased the expression levels of phosphoinositide 3-kinase (PI3K) and phosphorylated protein kinase B (p-AKT), each of which functions in the downstream signaling pathway. Dual luciferase-reporter assays indicated that PTEN mRNA was a direct target of miR-21. In conclusion, higher miR-21 levels and lower PTEN protein levels are predictive biomarkers for poor prognosis of WT patients. Over-expression of miR-21 promotes aggressive behavior of WT by targeting PTEN.

KDM2B Recruitment of the Polycomb Group Complex, PRC1.1, Requires Cooperation between PCGF1 and BCORL1

KDM2B recruits H2A-ubiquitinating activity of a non-canonical Polycomb Repression Complex 1 (PRC1.1) to CpG islands, facilitating gene repression. We investigated the molecular basis of recruitment using invitro assembly assays to identify minimal components, subcomplexes, and domains required for recruitment. A minimal four-component PRC1.1 complex can be assembled by combining two separately isolated subcomplexes: the DNA-binding KDM2B/SKP1 heterodimer and the heterodimer of BCORL1 and PCGF1, a core component of PRC1.1. The crystal structure of the KDM2B/SKP1/BCORL1/PCGF1 complex illustrates the crucial role played by the PCGF1/BCORL1 heterodimer. The BCORL1 PUFD domain positions residues preceding the RAWUL domain of PCGF1 to create an extended interface for interaction with KDM2B, which is unique to the PCGF1-containing PRC1.1 complex. The structure also suggests how KDM2B might simultaneously function in PRC1.1 and an SCF ubiquitin ligase complex and the possible molecular consequences of BCOR PUFD internal tandem duplications found in pediatric kidney and brain tumors.

Integration of Cistromic and Transcriptomic Analyses Identifies Nphs2, Mafb, and Magi2 as Wilms' Tumor 1 Target Genes in Podocyte Differentiation and Maintenance.

The Wilms' tumor suppressor gene 1 (WT1) encodes a zinc finger transcription factor. Mutation of WT1 in humans leads to Wilms' tumor, a pediatric kidney tumor, or other kidney diseases, such as Denys-Drash and Frasier syndromes. We showed previously that inactivation of WT1 in podocytes of adult mice results in proteinuria, foot process effacement, and glomerulosclerosis. However, the WT1-dependent transcriptional network regulating podocyte development and maintenance in vivo remains unknown. Here, we performed chromatin immunoprecipitation followed by high-throughput sequencing with glomeruli from wild-type mice. Additionally, we performed a cDNA microarray screen on an inducible podocyte-specific WT1 knockout mouse model. By integration of cistromic and transcriptomic analyses, we identified the WT1 targetome in mature podocytes. To further analyze the function and targets of WT1 in podocyte maturation, we used an Nphs2-Cre model, in which WT1 is deleted during podocyte differentiation. These mice display anuria and kidney hemorrhage and die within 24 hours after birth. To address the evolutionary conservation of WT1 targets, we performed functional assays using zebrafish as a model and identified Nphs2, Mafb, and Magi2 as novel WT1 target genes required for podocyte development. Our data also show that both Mafb and Magi2 are required for normal development of the embryonic zebrafish kidney. Collectively, our work provides insights into the transcriptional networks controlled by WT1 and identifies novel WT1 target genes that mediate the function of WT1 in podocyte differentiation and maintenance.

FAK Inhibition Abrogates the Malignant Phenotype in Aggressive Pediatric Renal Tumors

Despite the tremendous advances in the treatment of childhood kidney tumors, there remain subsets of pediatric renal tumors that continue to pose a therapeutic challenge, mainly malignant rhabdoid kidney tumors and nonosseous renal Ewing sarcoma. Children with advanced, metastatic, or relapsed disease have a poor disease-free survival rate. Focal adhesion kinase (FAK) is a nonreceptor tyrosine kinase that is important in many facets of tumor development and progression. FAK has been found in other pediatric solid tumors and in adult renal cellular carcinoma, leading to the hypothesis that FAK contributes to pediatric kidney tumors and would affect cellular survival. In the current study, FAK was present and phosphorylated in pediatric kidney tumor specimens. Moreover, the effects of FAK inhibition upon G401 and SK-NEP-1 cell lines were examined using a number of parallel approaches to block FAK, including RNA interference and small-molecule FAK inhibitors. FAK inhibition resulted in decreased cellular survival, invasion and migration, and increased apoptosis. Furthermore, small-molecule inhibition of FAK led to decreased SK-NEP-1 xenograft growth in vivo. These data deepen the knowledge of the tumorigenic process in pediatric renal tumors, and provide desperately needed therapeutic strategies and targets for these rare, but difficult to treat, malignancies. This study provides a fundamental understanding of tumorigenesis in difficult to treat renal tumors and provides an impetus for new avenues of research and potential for novel, targeted therapies.

Preclinical Evaluation of Engineered Oncolytic Herpes Simplex Virus for the Treatment of Pediatric Solid Tumors

Recently, investigators showed that mice with syngeneic murine gliomas that were treated with a neuroattenuated oncolytic herpes simplex virus-1 (oHSV), M002, had a significant increase in survival. M002 has deletions in both copies of the γ134.5 gene, enabling replication in tumor cells but precluding infection of normal cells. Previous studies have shown antitumor effects of other oHSV against a number of adult tumors including hepatocellular carcinoma and renal cell carcinoma. The purpose of the current study was to investigate the oncolytic potential of M002 against difficult to treat pediatric liver and kidney tumors. We showed that the oHSV, M002, infected, replicated, and decreased cell survival in hepatoblastoma, malignant rhabdoid kidney tumor, and renal sarcoma cell lines. In addition, we showed that in murine xenografts, treatment with M002 significantly increased survival and decreased tumor growth. Finally, these studies showed that the primary entry protein for oHSV, CD111 (nectin-1) was present in human hepatoblastoma and malignant rhabdoid kidney tumor specimens. We concluded that M002 effectively targeted these rare aggressive tumor types and that M002 may have potential for use in children with unresponsive or relapsed pediatric solid tumors.