RBM39 degrader invigorates natural killer cells to eradicate neuroblastoma despite cancer cell plasticity.

The cellular plasticity of neuroblastoma is defined by a mixture of two major cell states, adrenergic (ADRN) and mesenchymal (MES), which may contribute to therapy resistance. However, how neuroblastoma cells switch cellular states during therapy remains largely unknown and how to eradicate neuroblastoma regardless of their cell states is a clinical challenge. To better understand the lineage switch of neuroblastoma in chemoresistance, we comprehensively defined the transcriptomic and epigenetic map of ADRN and MES types of neuroblastomas using human and murine models treated with indisulam, a selective RBM39 degrader. We showed that cancer cells not only undergo a bidirectional switch between ADRN and MES states, but also acquire additional cellular states, reminiscent of the developmental pliancy of neural crest cells. The lineage alterations are coupled with epigenetic reprogramming and dependency switch of lineage-specific transcription factors, epigenetic modifiers and targetable kinases. Through targeting RNA splicing, indisulam induces an inflammatory tumor microenvironment and enhances anticancer activity of natural killer cells. The combination of indisulam with anti-GD2 immunotherapy results in a durable, complete response in high-risk transgenic neuroblastoma models, providing an innovative, rational therapeutic approach to eradicate tumor cells regardless of their potential to switch cell states.

Targeting TRIP13 in favorable histology Wilms tumor with nuclear export inhibitors synergizes with doxorubicin.

Wilms tumor (WT) is the most common renal malignancy of childhood. Despite improvements in the overall survival, relapse occurs in ~15% of patients with favorable histology WT (FHWT). Half of these patients will succumb to their disease. Identifying novel targeted therapies remains challenging in part due to the lack of faithful preclinical in vitro models. Here we establish twelve patient-derived WT cell lines and demonstrate that these models faithfully recapitulate WT biology using genomic and transcriptomic techniques. We then perform loss-of-function screens to identify the nuclear export gene, XPO1, as a vulnerability. We find that the FDA approved XPO1 inhibitor, KPT-330, suppresses TRIP13 expression, which is required for survival. We further identify synergy between KPT-330 and doxorubicin, a chemotherapy used in high-risk FHWT. Taken together, we identify XPO1 inhibition with KPT-330 as a potential therapeutic option to treat FHWTs and in combination with doxorubicin, leads to durable remissions in vivo.

Lemierre syndrome with pulmonary empyema caused by Prevotella intermedia.

Lemierre syndrome is a rare disease that is most often caused by Fusobacterium necrophorum We present a case caused by Prevotella intermedia in a young, healthy man, complicated by multiple cavitary lung lesions, loculated pleural effusions requiring chest tube placement and trapezius abscess. Our case highlights (a) P. intermedia as a rare cause of Lemierre syndrome and (b) clinical response to appropriate antimicrobial therapy may be protracted.

Pre-Existing Immunity to a Nucleic Acid Contaminant-Derived Antigen Mediates Transaminitis and Resultant Diminished Transgene Expression in a Mouse Model of Hepatic Recombinant Adeno-Associated Virus-Mediated Gene Transfer.

Liver injury with concomitant loss of therapeutic transgene expression can be a clinical sequela of systemic administration of recombinant adeno-associated virus (rAAV) when used for gene therapy, and a significant barrier to treatment efficacy. Despite this, it has been difficult to replicate this phenotype in preclinical models, thereby limiting the field's ability to systematically investigate underlying biological mechanisms and develop interventions. Prior animal models have focused on capsid and transgene-related immunogenicity, but the impact of concurrently present nontransgene or vector antigens on therapeutic efficacy, such as those derived from contaminating nucleic acids within rAAV preps, has yet to be investigated. In this study, using Ad5-CMV_GFP-immunized immunocompetent BALB/cJ mice, and a coagulation factor VIII expressing rAAV preparation that contains green flourescent protein (GFP) cDNA packaged as P5-associated contaminants, we establish a model to induce transaminitis and observe concomitant therapeutic efficacy reduction after rAAV administration. We observed strong epitope-specific anti-GFP responses in splenic CD8+ T cells when GFP cDNA was delivered as a P5-associated contaminant of rAAV, which coincided and correlated with alanine and aspartate aminotransferase elevations. Furthermore, we report a significant reduction in detectable circulating FVIII protein, as compared with control mice. Lastly, we observed an elevation in the detection of AAV8 capsid-specific T cells when GFP was delivered either as a contaminant or transgene to Ad5-CMV_GFP-immunized mice. We present this model as a potential tool to study the underlying biology of post-AAV hepatotoxicity and demonstrate the potential for T cell responses against proteins produced from AAV encapsidated nontherapeutic nucleic acids, to interfere with efficacious gene transfer.

Oncogenic Cells of Renal Embryonic Lineage Sensitive to the Small-Molecule Inhibitor QC6352 Display Depletion of KDM4 Levels and Disruption of Ribosome Biogenesis.

The histone lysine demethylases KDM4A-C are involved in physiologic processes including stem cell identity and self-renewal during development, DNA damage repair, and cell-cycle progression. KDM4A-C are overexpressed and associated with malignant cell behavior in multiple human cancers and are therefore potential therapeutic targets. Given the role of KDM4A-C in development and cancer, we aimed to test the potent, selective KDM4A-C inhibitor QC6352 on oncogenic cells of renal embryonic lineage. The anaplastic Wilms tumor cell line WiT49 and the tumor-forming human embryonic kidney cell line HEK293 demonstrated low nanomolar QC6352 sensitivity. The cytostatic response to QC6352 in WiT49 and HEK293 cells was marked by induction of DNA damage, a DNA repair-associated protein checkpoint response, S-phase cell-cycle arrest, profound reduction of ribosomal protein gene and rRNA transcription, and blockade of newly synthesized proteins. QC6352 caused reduction of KDM4A-C levels by a proteasome-associated mechanism. The cellular phenotype caused by QC6352 treatment of reduced migration, proliferation, tumor spheroid growth, DNA damage, and S-phase cell-cycle arrest was most closely mirrored by knockdown of KDM4A as determined by siRNA knockdown of KDM4A-C. QC6352 sensitivity correlated with high basal levels of ribosomal gene transcription in more than 900 human cancer cell lines. Targeting KDM4A may be of future therapeutic interest in oncogenic cells of embryonic renal lineage or cells with high basal expression of ribosomal protein genes.

Genetic and epigenetic features of bilateral Wilms tumor predisposition in patients from the Children's Oncology Group AREN18B5-Q.

Developing synchronous bilateral Wilms tumor suggests an underlying (epi)genetic predisposition. Here, we evaluate this predisposition in 68 patients using whole exome or genome sequencing (n = 85 tumors from 61 patients with matched germline blood DNA), RNA-seq (n = 99 tumors), and DNA methylation analysis (n = 61 peripheral blood, n = 29 non-diseased kidney, n = 99 tumors). We determine the predominant events for bilateral Wilms tumor predisposition: 1)pre-zygotic germline genetic variants readily detectable in blood DNA [WT1 (14.8%), NYNRIN (6.6%), TRIM28 (5%), and BRCA-related genes (5%)] or 2)post-zygotic epigenetic hypermethylation at 11p15.5 H19/ICR1 that may require analysis of multiple tissue types for diagnosis. Of 99 total tumor specimens, 16 (16.1%) have 11p15.5 normal retention of imprinting, 25 (25.2%) have 11p15.5 copy neutral loss of heterozygosity, and 58 (58.6%) have 11p15.5 H19/ICR1 epigenetic hypermethylation (loss of imprinting). Here, we ascertain the epigenetic and genetic modes of bilateral Wilms tumor predisposition.

The Genetic and Epigenetic Features of Bilateral Wilms Tumor Predisposition: A Report from the Children's Oncology Group AREN18B5-Q Study.

This study comprehensively evaluated the landscape of genetic and epigenetic events that predispose to synchronous bilateral Wilms tumor (BWT). We performed whole exome or whole genome sequencing, total-strand RNA-seq, and DNA methylation analysis using germline and/or tumor samples from 68 patients with BWT from St. Jude Children's Research Hospital and the Children's Oncology Group. We found that 25/61 (41%) of patients evaluated harbored pathogenic or likely pathogenic germline variants, with WT1 (14.8%), NYNRIN (6.6%), TRIM28 (5%) and the BRCA-related genes (5%) BRCA1, BRCA2, and PALB2 being most common. Germline WT1 variants were strongly associated with somatic paternal uniparental disomy encompassing the 11p15.5 and 11p13/WT1 loci and subsequent acquired pathogenic CTNNB1 variants. Somatic coding variants or genome-wide copy number alterations were almost never shared between paired synchronous BWT, suggesting that the acquisition of independent somatic variants leads to tumor formation in the context of germline or early embryonic, post-zygotic initiating events. In contrast, 11p15.5 status (loss of heterozygosity, loss or retention of imprinting) was shared among paired synchronous BWT in all but one case. The predominant molecular events for BWT predisposition include pathogenic germline variants or post-zygotic epigenetic hypermethylation at the 11p15.5 H19/ICR1 locus (loss of imprinting). This study demonstrates that post-zygotic somatic mosaicism for 11p15.5 hypermethylation/loss of imprinting is the single most common initiating molecular event predisposing to BWT. Evidence of somatic mosaicism for 11p15.5 loss of imprinting was detected in leukocytes of a cohort of BWT patients and long-term survivors, but not in unilateral Wilms tumor patients and long-term survivors or controls, further supporting the hypothesis that post-zygotic 11p15.5 alterations occurred in the mesoderm of patients who go on to develop BWT. Due to the preponderance of BWT patients with demonstrable germline or early embryonic tumor predisposition, BWT exhibits a unique biology when compared to unilateral Wilms tumor and therefore warrants continued refinement of its own treatment-relevant biomarkers which in turn may inform directed treatment strategies in the future.

Tracheostomy Is Associated With a Decrease in Delirium and Sedation for Intubated COVID-19 Patients.

BACKGROUND: Patients with coronavirus disease 2019 (COVID-19) acute respiratory distress syndrome can experience prolonged periods of ventilation, high incidence of delirium, and require high amounts of sedation. Tracheostomy has been associated with earlier ventilator liberation, decreased sedation needs, and lower rates of delirium but optimal timing of tracheostomy remains unknown. Is tracheostomy associated with lower sedation requirements and lower incidence of delirium in patients with COVID-19 that are intubated? METHODS: We retrospectively reviewed the first 32 patients at a large urban tertiary referral center that underwent tracheostomy for prolonged respiratory failure. We obtained Richmond Agitation Sedation-Scale scores and Confusion Assessment Method for Intensive Care Unit data along with amount(s) and type(s) of sedating medications given, in the 7 days before and after tracheostomy. Proportion of days delirious and sedating medications were compared in the 7 days before and after tracheostomy. RESULTS: There was a significant decrease in the amount of opioids and benzodiazepines in the 7-day period following tracheostomy. Opioid dosing decreased by 157.5 morphine equivalents (SD=339, P =0.01) and benzodiazepine dosing decreased by 18 mg lorazepam equivalents (SD=34, P =0.01). There was no significant difference in antipsychotic or other sedative-hyponotic drug doses. There was a significant decrease in the proportion of days of coma or delirium (mean decrease in proportion=0.16, SD=0.32, P =0.008) following tracheostomy. CONCLUSION: Tracheostomy was associated with a significant decrease amount of sedating medications and with a decrease in proportion of days delirious following tracheostomy.

Relationship between BMI, CT-derived body composition and colorectal neoplasia in a bowel screening population.

INTRODUCTION: Obesity is associated with an increased risk of colorectal cancer (CRC). Unlike the indirect measures such as BMI, CT-Body composition (CT-BC) allows for the assessment of both volume and distribution of adipose tissue. Therefore, the aim of this study was to examine the relationship between host characteristics, BMI, CT-BC measurements and the incidence of colorectal neoplasia. METHODS: Patients undergoing CT Colonography (CTC) as part of the Scottish Bowel Screening Programme, between July 2009 and February 2016, were eligible for inclusion. Data were collected including demographic data, clinicopathological variables and CT-BC measurements including skeletal muscle index (SMI), subcutaneous fat index (SFI) and visceral fat area (VFA). CTC, colonoscopy, and pathology reports were used to identify CRC incidence. Associations between demographic data, clinicopathological variables, CT-BC measurements, colorectal neoplasia and advanced colorectal neoplasia were analysed using univariate and multivariate binary logistics regression. RESULTS: 286 patients met the inclusion criteria. Neoplasia was detected in 105 (37%) of the patients with advanced neoplasia being detected in 72 (69%) of patients. On multivariate analysis sex (p < 0.05) and high VFA (p < 0.001) remained independently associated with colorectal neoplasia. On multivariate analysis a high SFI (p < 0.01) remained independently associated with advanced colorectal neoplasia. BMI was not associated with either colorectal neoplasia or advanced colorectal neoplasia. CONCLUSION: When directly compared to BMI, CT derived fat measurements were more closely associated with the degree of neoplasia in patients undergoing colorectal cancer screening. In patients investigated with CT colonography, CT adipose measures may stratify the risk and grade of neoplasia.

Study protocol: MyoFit46-the cardiac sub-study of the MRC National Survey of Health and Development.

BACKGROUND: The life course accumulation of overt and subclinical myocardial dysfunction contributes to older age mortality, frailty, disability and loss of independence. The Medical Research Council National Survey of Health and Development (NSHD) is the world's longest running continued surveillance birth cohort providing a unique opportunity to understand life course determinants of myocardial dysfunction as part of MyoFit46-the cardiac sub-study of the NSHD. METHODS: We aim to recruit 550 NSHD participants of approximately 75 years+ to undertake high-density surface electrocardiographic imaging (ECGI) and stress perfusion cardiovascular magnetic resonance (CMR). Through comprehensive myocardial tissue characterization and 4-dimensional flow we hope to better understand the burden of clinical and subclinical cardiovascular disease. Supercomputers will be used to combine the multi-scale ECGI and CMR datasets per participant. Rarely available, prospectively collected whole-of-life data on exposures, traditional risk factors and multimorbidity will be studied to identify risk trajectories, critical change periods, mediators and cumulative impacts on the myocardium. DISCUSSION: By combining well curated, prospectively acquired longitudinal data of the NSHD with novel CMR-ECGI data and sharing these results and associated pipelines with the CMR community, MyoFit46 seeks to transform our understanding of how early, mid and later-life risk factor trajectories interact to determine the state of cardiovascular health in older age. TRIAL REGISTRATION: Prospectively registered on ClinicalTrials.gov with trial ID: 19/LO/1774 Multimorbidity Life-Course Approach to Myocardial Health- A Cardiac Sub-Study of the MCRC National Survey of Health and Development (NSHD).

Approaches to identifying drug resistance mechanisms to clinically relevant treatments in childhood rhabdomyosarcoma.

Aim: Despite aggressive multiagent protocols, patients with metastatic rhabdomyosarcoma (RMS) have poor prognosis. In a recent high-risk trial (ARST0431), 25% of patients failed within the first year, while on therapy and 80% had tumor progression within 24 months. However, the mechanisms for tumor resistance are essentially unknown. Here we explore the use of preclinical models to develop resistance to complex chemotherapy regimens used in ARST0431. Methods: A Single Mouse Testing (SMT) protocol was used to evaluate the sensitivity of 34 RMS xenograft models to one cycle of vincristine, actinomycin D, cyclophosphamide (VAC) treatment. Tumor response was determined by caliper measurement, and tumor regression and event-free survival (EFS) were used as endpoints for evaluation. Treated tumors at regrowth were transplanted into recipient mice, and the treatment was repeated until tumors progressed during the treatment period (i.e., became resistant). At transplant, tumor tissue was stored for biochemical and omics analysis. Results: The sensitivity to VAC of 34 RMS models was determined. EFS varied from 3 weeks to > 20 weeks. Tumor models were classified as having intrinsic resistance, intermediate sensitivity, or high sensitivity to VAC therapy. Resistance to VAC was developed in multiple models after 2-5 cycles of therapy; however, there were examples where sensitivity remained unchanged after 3 cycles of treatment. Conclusion: The SMT approach allows for in vivo assessment of drug sensitivity and development of drug resistance in a large number of RMS models. As such, it provides a platform for assessing in vivo drug resistance mechanisms at a "population" level, simulating conditions in vivo that lead to clinical resistance. These VAC-resistant models represent "high-risk" tumors that mimic a preclinical phase 2 population and will be valuable for identifying novel agents active against VAC-resistant disease.

TERT Expression in Wilms Tumor Is Regulated by Promoter Mutation or Hypermethylation, WT1, and N-MYC.

Increased TERT mRNA is associated with disease relapse in favorable histology Wilms tumor (WT). This study sought to understand the mechanism of increased TERT expression by determining the association between TERT and WT1 and N-MYC, two proteins important in Wilms tumor pathogenesis that have been shown to regulate TERT expression. Three out of 45 (6.7%) WTs and the corresponding patient-derived xenografts harbored canonical gain-of-function mutations in the TERT promoter. This study identified near ubiquitous hypermethylation of the TERT promoter region in WT compared to normal kidney. WTs with biallelic inactivating mutations in WT1 (7/45, 15.6%) were found to have lower TERT expression by RNA-seq and qRT-PCR and lower telomerase activity determined by the telomerase repeat amplification protocol. Anaplastic histology and increased percentage of blastema were positively correlated with higher TERT expression and telomerase activity. In vitro shRNA knockdown of WT1 resulted in decreased expression of TERT, reduced colony formation, and decreased proliferation of WiT49, an anaplastic WT cell line with wild-type WT1. CRISPR-Cas9-mediated knockout of WT1 resulted in decreased expression of telomere-related gene pathways. However, an inducible Wt1-knockout mouse model showed no relationship between Wt1 knockout and Tert expression in normal murine nephrogenesis, suggesting that WT1 and TERT are coupled in transformed cells but not in normal kidney tissues. N-MYC overexpression resulted in increased TERT promoter activity and TERT transcription. Thus, multiple mechanisms of TERT activation are involved in WT and are associated with anaplastic histology and increased blastema. This study is novel because it identifies potential mechanisms of TERT activation in Wilms tumor that could be of therapeutic interests.

Preventing packaging of translatable P5-associated DNA contaminants in recombinant AAV vector preps.

Recombinant adeno-associated virus (rAAV) vectors are increasingly being used for clinical gene transfer and have shown great potential for the treatment of several monogenic disorders. However, contaminant DNA from producer plasmids can be packaged into rAAV alongside the intended expression cassette-containing vector genome. The consequences of this are unknown. Our analysis of rAAV preps revealed abundant contaminant sequences upstream of the AAV replication (Rep) protein driving promoter, P5, on the Rep-Cap producer plasmid. Characterization of P5-associated contaminants after infection showed transfer, persistence, and transcriptional activity in AAV-transduced murine hepatocytes, in addition to in vitro evidence suggestive of integration. These contaminants can also be efficiently translated and immunogenic, revealing previously unrecognized side effects of rAAV-mediated gene transfer. P5-associated contaminant packaging and activity were independent of an inverted terminal repeat (ITR)-flanked vector genome. To prevent incorporation of these potentially harmful sequences, we constructed a modified P5-promoter (P5-HS), inserting a DNA spacer between an Rep binding site and an Rep nicking site in P5. This prevented upstream DNA contamination regardless of transgene or AAV serotype, while maintaining vector yield. Thus, we have constructed an rAAV production plasmid that improves vector purity and can be implemented across clinical rAAV applications. These findings represent new vector safety and production considerations for rAAV gene therapy.

Comparison of the Filtration Efficiency of Different Face Masks Against Aerosols.

Background: The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) pandemic can spread through virus-containing aerosols ( ≤ 5 µm) and larger airborne droplets. Quantifying filtration efficiency of different kinds of masks and linings for aerosols that fall within the most penetrating particle size (80-400 nm) is critical to limiting viral transmission. The objective of our experiment was to compare the "real-world" filtering efficiency of different face masks for fine aerosols (350 nm) in laboratory simulations. Methods: We performed a simulated bench test that measured the filtering efficiency of N95 vs. N99 masks with elastomeric lining in relation to baseline ("background") aerosol generation. A mannequin head was placed within a chamber and was attached to an artificial lung simulator. Particles of known size (350 ± 6 nm aerodynamic diameter) were aerosolized into the chamber while simulating breathing at physiological settings of tidal volume, respiratory rate, and airflow. Particle counts were measured between the mannequin head and the lung simulator at the tracheal airway location. Results: Baseline particle counts without a filter (background) were 2,935 ± 555 (SD) cm-3, while the N95 (1348 ± 92 cm-3) and N99 mask with elastomeric lining (279 ± 164 cm-3; p <0.0001) exhibit lower counts due to filtration. Conclusion: The filtration efficiency of the N95 (54.1%) and N99 (90.5%) masks were lower than the filtration efficiency rating. N99 masks with elastomeric lining exhibit greater filtration efficiency than N95 masks without elastomeric lining and may be preferred to contain the spread of SARS-CoV-2 infection.

Effect of wearables on sleep in healthy individuals: a randomized crossover trial and validation study.

STUDY OBJECTIVES: The purpose of this study was to determine whether a wearable sleep-tracker improves perceived sleep quality in healthy participants and to test whether wearables reliably measure sleep quantity and quality compared with polysomnography. METHODS: This study included a single-center randomized crossover trial of community-based participants without medical conditions or sleep disorders. A wearable device (WHOOP, Inc.) was used that provided feedback regarding sleep information to the participant for 1 week and maintained sleep logs versus 1 week of maintained sleep logs alone. Self-reported daily sleep behaviors were documented in sleep logs. Polysomnography was performed on 1 night when wearing the wearable. The Patient-Reported Outcomes Measurement Information System sleep disturbance sleep scale was measured at baseline, day 7 and day 14 of study participation. RESULTS: In 32 participants (21 women; 23.8 ± 5 years), wearables improved nighttime sleep quality (Patient-Reported Outcomes Measurement Information System sleep disturbance: B = -1.69; 95% confidence interval, -3.11 to -0.27; P = .021) after adjusting for age, sex, baseline, and order effect. There was a small increase in self-reported daytime naps when wearing the device (B = 3.2; SE, 1.4; P = .023), but total daily sleep remained unchanged (P = .43). The wearable had low bias (13.8 minutes) and precision (17.8 minutes) errors for measuring sleep duration and measured dream sleep and slow wave sleep accurately (intraclass coefficient, 0.74 ± 0.28 and 0.85 ± 0.15, respectively). Bias and precision error for heart rate (bias, -0.17%; precision, 1.5%) and respiratory rate (bias, 1.8%; precision, 6.7%) were very low compared with that measured by electrocardiogram and inductance plethysmography during polysomnography. CONCLUSIONS: In healthy people, wearables can improve sleep quality and accurately measure sleep and cardiorespiratory variables. CLINICAL TRIAL REGISTRATION: Registry: ClinicalTrials.gov; Name: Assessment of Sleep by WHOOP in Ambulatory Subjects; Identifier: NCT03692195.

An 80-Year-Old Man With a 24-Hour History of Epigastric Pain.

CASE PRESENTATION: An 80-year-old man was admitted to our hospital with 24 hours of epigastric pain. The pain was described as sharp, episodic, nonradiating, and without an identifiable provoking factor. Associated symptoms included nausea and nonbloody vomiting. He denied dyspnea, angina, fevers, chills, dysphagia, diarrhea, melena, or hematochezia. He had taken less than 2 g of acetaminophen earlier in the day without symptomatic relief. He had a 30-pack-year smoking history but quit over 25 years ago. He did not drink alcohol or use illicit drugs. He had a medical history of end-stage renal disease, for which he had undergone hemodialysis; hypertension; metastatic prostate cancer, for which he had received androgen deprivation therapy; and abdominal aortic aneurysm. His surgical history included a remote endovascular repair of the abdominal aortic aneurysm. His medications included amlodipine, losartan, carvedilol, sevelamer, and leuprolide.

Forty-five patient-derived xenografts capture the clinical and biological heterogeneity of Wilms tumor.

The lack of model systems has limited the preclinical discovery and testing of therapies for Wilms tumor (WT) patients who have poor outcomes. Herein, we establish 45 heterotopic WT patient-derived xenografts (WTPDX) in CB17 scid-/- mice that capture the biological heterogeneity of Wilms tumor (WT). Among these 45 total WTPDX, 6 from patients with diffuse anaplastic tumors, 9 from patients who experienced disease relapse, and 13 from patients with bilateral disease are included. Early passage WTPDX show evidence of clonal selection, clonal evolution and enrichment of blastemal gene expression. Favorable histology WTPDX are sensitive, whereas unfavorable histology WTPDX are resistant to conventional chemotherapy with vincristine, actinomycin-D, and doxorubicin given singly or in combination. This WTPDX library is a unique scientific resource that retains the spectrum of biological heterogeneity present in WT and provides an essential tool to test targeted therapies for WT patient groups with poor outcomes.

Genomic Profiling of Childhood Tumor Patient-Derived Xenograft Models to Enable Rational Clinical Trial Design.

Accelerating cures for children with cancer remains an immediate challenge as a result of extensive oncogenic heterogeneity between and within histologies, distinct molecular mechanisms evolving between diagnosis and relapsed disease, and limited therapeutic options. To systematically prioritize and rationally test novel agents in preclinical murine models, researchers within the Pediatric Preclinical Testing Consortium are continuously developing patient-derived xenografts (PDXs)-many of which are refractory to current standard-of-care treatments-from high-risk childhood cancers. Here, we genomically characterize 261 PDX models from 37 unique pediatric cancers; demonstrate faithful recapitulation of histologies and subtypes; and refine our understanding of relapsed disease. In addition, we use expression signatures to classify tumors for TP53 and NF1 pathway inactivation. We anticipate that these data will serve as a resource for pediatric oncology drug development and will guide rational clinical trial design for children with cancer.