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For over a century, early researchers sought to study biological organisms in a laboratory setting, leading to the generation of both in vitro and in vivo model systems. Patient-derived models of cancer (PDMCs) have more recently come to the forefront of preclinical cancer models and are even finding their way into clinical practice as part of functional precision medicine programs. The PDMC Consortium, supported by the Division of Cancer Biology in the National Cancer Institute of the National Institutes of Health, seeks to understand the biological principles that govern the various PDMC behaviors, particularly in response to perturbagens, such as cancer therapeutics. Based on collective experience from the consortium groups, we provide insight regarding PDMCs established both in vitro and in vivo, with a focus on practical matters related to developing and maintaining key cancer models through a series of vignettes. Although every model has the potential to offer valuable insights, the choice of the right model should be guided by the research question. However, recognizing the inherent constraints in each model is crucial. Our objective here is to delineate the strengths and limitations of each model as established by individual vignettes. Further advances in PDMCs and the development of novel model systems will enable us to better understand human biology and improve the study of human pathology in the lab.

Medulloblastoma is among the most common malignant brain tumors in children. Recent studies have identified at least four subgroups of the disease that differ in terms of molecular characteristics and patient outcomes. Despite this heterogeneity, most patients with medulloblastoma receive similar therapies, including surgery, radiation, and intensive chemotherapy. Although these treatments prolong survival, many patients still die from the disease and survivors suffer severe long-term side effects from therapy. We hypothesize that each patient with medulloblastoma is sensitive to different therapies and that tailoring therapy based on the molecular and cellular characteristics of patients' tumors will improve outcomes. To test this, we assembled a panel of orthotopic patient-derived xenografts (PDX) and subjected them to DNA sequencing, gene expression profiling, and high-throughput drug screening. Analysis of DNA sequencing revealed that most medulloblastomas do not have actionable mutations that point to effective therapies. In contrast, gene expression and drug response data provided valuable information about potential therapies for every tumor. For example, drug screening demonstrated that actinomycin D, which is used for treatment of sarcoma but rarely for medulloblastoma, was active against PDXs representing Group 3 medulloblastoma, the most aggressive form of the disease. Functional analysis of tumor cells was successfully used in a clinical setting to identify more treatment options than sequencing alone. These studies suggest that it should be possible to move away from a one-size-fits-all approach and begin to treat each patient with therapies that are effective against their specific tumor. SIGNIFICANCE: These findings show that high-throughput drug screening identifies therapies for medulloblastoma that cannot be predicted by genomic or transcriptomic analysis.

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.

Embryonal tumors with multilayered rosettes (ETMRs) are highly lethal infant brain cancers with characteristic amplification of Chr19q13.41 miRNA cluster (C19MC) and enrichment of pluripotency factor LIN28A. Here we investigated C19MC oncogenic mechanisms and discovered a C19MC-LIN28A-MYCN circuit fueled by multiple complex regulatory loops including an MYCN core transcriptional network and super-enhancers resulting from long-range MYCN DNA interactions and C19MC gene fusions. Our data show that this powerful oncogenic circuit, which entraps an early neural lineage network, is potently abrogated by bromodomain inhibitor JQ1, leading to ETMR cell death.

Existing knowledge graph completion models learn a single static feature representation for entities and relationships by integrating multi-source information.But they can't represent the subtle meaning and dynamic attributes of entities and relationships that appear in different contexts.That is,entities and relationships will show different attributes,because they have different roles and meanings when they are involved in different triples.To solve above problems,an adaptive attention network for knowledge graph completion is proposed,which uses adaptive attention to model the contribution of each task-specified feature dimension,and generates dynamic and variable embedding representations for target entities and relationships.Specifically,the proposed model defines the neighbor encoder and the path aggregator to process two structures in the entity neighborhood subgraph,adaptively learn the attention weights to capture the most logically related features of the task,and to give the entities and relationships with fine-grained semantics in line with the current task.Experimental results in link prediction task show that,the MeanRank of the proposed model on FB15K-237 dataset is 6.9% lower than PathCon,and Hits@1 is 2.3% higher than PathCon.For the sparse datasets NELL-995 and DDB14,its Hits@1 reaches 87.9% and 98% respectively.Therefore,it proves that the introduction of adaptive attention mechanism can effectively extract the dynamic attributes of entities and relationships to generate a more comprehensive embedding representation,and improves the accuracy of knowledge graph completion.

A major limitation of targeted cancer therapy is the rapid emergence of drug resistance, which often arises through mutations at or downstream of the drug target or through intrinsic resistance of subpopulations of tumor cells. Medulloblastoma (MB), the most common pediatric brain tumor, is no exception, and MBs that are driven by sonic hedgehog (SHH) signaling are particularly aggressive and drug-resistant. To find new drug targets and therapeutics for MB that may be less susceptible to common resistance mechanisms, we used a developmental phosphoproteomics approach in murine granule neuron precursors (GNPs), the developmental cell of origin of MB. The protein kinase CK2 emerged as a driver of hundreds of phosphorylation events during the proliferative, MB-like stage of GNP growth, including the phosphorylation of three of the eight proteins commonly amplified in MB. CK2 was critical to the stabilization and activity of the transcription factor GLI2, a late downstream effector in SHH signaling. CK2 inhibitors decreased the viability of primary SHH-type MB patient cells in culture and blocked the growth of murine MB tumors that were resistant to currently available Hh inhibitors, thereby extending the survival of tumor-bearing mice. Because of structural interactions, one CK2 inhibitor (CX-4945) inhibited both wild-type and mutant CK2, indicating that this drug may avoid at least one common mode of acquired resistance. These findings suggest that CK2 inhibitors may be effective for treating patients with MB and show how phosphoproteomics may be used to gain insight into developmental biology and pathology.

High-grade gliomas in children are different from those that arise in adults. Recent collaborative molecular analyses of these rare cancers have revealed previously unappreciated connections among chromatin regulation, developmental signaling, and tumorigenesis. As we begin to unravel the unique developmental origins and distinct biological drivers of this heterogeneous group of tumors, clinical trials need to keep pace. It is important to avoid therapeutic strategies developed purely using data obtained from studies on adult glioblastoma. This approach has resulted in repetitive trials and ineffective treatments being applied to these children, with limited improvement in clinical outcome. The authors of this perspective, comprising biology and clinical expertise in the disease, recently convened to discuss the most effective ways to translate the emerging molecular insights into patient benefit. This article reviews our current understanding of pediatric high-grade glioma and suggests approaches for innovative clinical management.

Medulloblastoma (MB) is a highly malignant pediatric brain tumor. Despite aggressive therapy, many patients succumb to the disease, and survivors experience severe side effects from treatment. MYC-driven MB has a particularly poor prognosis and would greatly benefit from more effective therapies. We used an animal model of MYC-driven MB to screen for drugs that decrease viability of tumor cells. Among the most effective compounds were histone deacetylase inhibitors (HDACIs). HDACIs potently inhibit survival of MYC-driven MB cells in vitro, in part by inducing expression of the FOXO1 tumor suppressor gene. HDACIs also synergize with phosphatidylinositol 3-kinase inhibitors to inhibit tumor growth in vivo. These studies identify an effective combination therapy for the most aggressive form of MB.

The development of targeted anti-cancer therapies through the study of cancer genomes is intended to increase survival rates and decrease treatment-related toxicity. We treated a transposon-driven, functional genomic mouse model of medulloblastoma with 'humanized' in vivo therapy (microneurosurgical tumour resection followed by multi-fractionated, image-guided radiotherapy). Genetic events in recurrent murine medulloblastoma exhibit a very poor overlap with those in matched murine diagnostic samples (

BACKGROUND: LMD in children with recurrent medulloblastoma and other PNETs carries a poor prognosis and novel therapies are urgently needed to improve disease control. Somatostatin receptor-2 (SSR-2)is overexpressed in medulloblastoma and other central PNETs and can serve as a target for radionuclide tagged somatostatin analogues like 177Lu-DOTA-TATE that has shown considerable efficacy in adults with SSR-2 positive neuro-endocrine tumors. As a preliminary step prior to testing this agent in children with LMD, we performed an efficacy study of i.t. 177Lu-DOTA-TATE in athymic rats bearing LMD from MBL. METHODS: The subarachnoid space was accessed through the animal's cervical spine and a catheter was threaded along the dorsal aspect of spinal cord to the lumbar region and injected with 1 x 107 D341 human MBL cells and treatment initiated 3 days later. Groups of 10 animals received a single i.t. dose of 2, 3, or 5 mCi of 177Lu- DOTA-TATE or saline control. Animals were followed 300 days for survival. RESULTS: Treatment with 2 mCi resulted in an increase in median survival of 58.3% compared with saline control (p < 0.001). Treatment with 5.0 mCi of 177Lu-DOTA-TATE increased median survival by 75.0% compared with the saline control group while a single dose of 3.0 mCi 177Lu-DOTA-TATE increased median survival compared with saline controls by 519.4%. Long-term survivors were seen in 0 of 10 animals treated with saline, 4 of 11 treated with 3 mCi, and 3 of 12 treated with 5.0 mCi. CONCLUSION: Intrathecal 177Lu- DOTA TATE is efficacious in controlling LMD from medulloblastoma in athymic rats. A phase I trial of this agent is being planned in children with LMD from recurrent MBL and other CNS PNETs. INTRODUCTION: Medulloblastoma/PNET is the most common malignant brain tumor in children. For children older than 3 years, the treatment of high risk group includes surgery, craniospinal (CSI) radiation therapy (30-36 Gy) plus local boost radiotherapy (54-56 Gy) and adjuvant chemotherapy, such as cisplatinum, carboplatin, lomustine, cyclophosphamide, and vincristine. The results have demonstrated 5-year overall survival (OS) of 40-60%. This study aimed to evaluate the outcomes of high risk medulloblastoma/PNET patients who were treated with radiation and adjuvant chemotherapy. METHODS: Patients were diagnosed with high risk medulloblastoma/PNET according to the histopathology, medulloblastoma risk classification by an evidence of metastasis or the residual tumor more than 1.5 cm2 and evidence of residual tumor after surgery in PNET. Treatment protocol was CSI RT 36 Gy with local boost at tumor 54-56 Gy. Two to four weeks after RT, patients received 8 courses of chemotherapy consisting of cyclophosphamide 800 mg/m2, day 1-3 and vincristine 2 mg/m2, week 1-3, alternated with carboplatin 200 mg/m2, day 1-3 and etoposide 150 mg/m2, day 1-3. RESULTS: Total of 25 patients, male: female of 2.6:1 and mean ± SD for age of 9.7± 3.0 years, were enrolled. The 5-year progression free survival and OS were 41.6± 11.7% and 61.5± 12.9%,respectively. The age and sex did not determine the difference in outcomes. The hematotoxic side effect, according to the National Cancer Institute's Common Terminology Criteria, were grade 4 leucopenia 60%, grade 4 neutropenia 60%, grade 4 anemia 20%, grade 4 thrombocytopenia 16%, grade 3 leucopenia 20%, grade 3 neutropenia 20%, grade 3 anemia 40%, and grade 3 thrombocytopenia 36%. Febrile neutropenia was found in 11 patients (44%). CONCLUSION: The present study demonstrated the similar outcomes of high risk medulloblastoma/PNET with the previous studies. Although, the grade 3 and 4 hematologic toxicity was high, no treatment related death was found. OBJECTIVE: Recent investigations revealed an association between transcriptional subtypes and morphological features in medulloblastoma. Since both characteristics are of prognostic significance, a precise correlation between them should be well established. Therefore we re-examined paediatric nodular medulloblastoma tumours for correlation with molecular subtypes of disease. METHODS: Paediatric patients with previously diagnosed desmoplastic/nodular (D/N) or medulloblastoma with extensive nodularity (MBEN) histopathology were re-analysed by two neuropathologists. In addition to H&E-stained slides, reticulin preparations were simultaneously analysed from the same FFPE blocks. For identification of transcriptional subtypes of tumours immunohistopathological analyses were performed using a panel of representative antibodies. MYCC amplification was detected by FISH. RESULTS: Altogether 28 tumours with original MBEN or D/N diagnosis where molecular subtypes could be determined were identified. All tumours with MBEN histology belonged to SHH group and displayed distinctive reticulin-positive internodular reaction. However, only ∼60% of tumours with original D/N diagnosis were reticulin-positive. They belonged to SHH type, were mainly infantile and patients are still alive. Among reticulin-negative tumours only two were of the SHH type and were subsequently reclassified as classic and anaplastic tumours with pseudonodules. Importantly, all remaining reticulin-negative tumours with a presence of nodules in H&E staining belonged to the non-WNT,SHH type. Therefore the original diagnosis was again reclassified as classic or anaplastic tumours with pseudonodules. Patients from this group were only males, with median age 14 years old, one had MYCC amplification and two of them died because of disease. Therefore, non-WNT,SHH tumours did not display typical desmoplastic/nodular histology accompanied by reticulin positive reaction as opposite to truly D/N tumours being typical for SHH molecular group (p < 0.001). CONCLUSION: Reticulin staining is necessary to distinguish two different biologically and clinically group of nodular tumours which appear morphologically similar under H&E staining alone. BACKGROUND: In the PNET4 European randomised controlled trial, children with standard risk medulloblastoma were allocated to HFRT or to STRT. All received maintenance chemotherapy. Event-free survival was similar between the two treatment arms. HFRT was associated with worse growth and better questionnaire-based executive function 6.1 years post-diagnosis, especially in children aged 8 years at diagnosis. In children aged .10); WMI (5.20 [-2.07 to 12.47], p > .10), PSI (10.91 [-1.54 to 23.36], p = .08; FSIQ (5.28 [-4.23 to 14.79], p > .10). CONCLUSION: HFRT was associated with higher verbal IQ in children aged

Two photochromic Cd(II)-CPs were obtained based on the viologen ligand using different synthetic routes, named {[Cd4(p-BDC)4(CPB)2(H2O)2]·2H2O·EtOH}n (1) and {[Cd(p-BDC)(CPB)(H2O)]·(L)·DMF}n (2) (p-H2BDC = 1,4-benzene-dicarboxylate, HCPB·Cl = 1-(4-carboxyphenyl)-4,4′-bipyridinium·Cl, L = 2,4-dinitrochlorobenzene, and DMF = N,N-dimethylformamide), respectively. Due to different coordination modes, the two Cd(II)-CPs show different structures. Compound 1 exhibits a three-dimensional (3D) framework with bimetallic nodes, while compound 2 displays a 2-fold interpenetrated (4,4) net topology. Notably, the two Cd(II)-CPs exhibit substantial disparities in photo/thermochromism, which can be attributed to variations in donor–acceptor (D–A) distances arising from structural differences. Compound 1 showed visually sensitive photo- and thermochromic behavior due to multi-pathway electron transfer and short D–A distances, which is relatively rare in electron-transfer type photochromic systems. In contrast, 2 only demonstrates insensitive photochromic behavior, with a slight deepening of the color observed after 2 hours of UV light, which is due to the mono-pathway electron transfer and long D–A distance. Moreover, we first combined Cd(II)-viologen CPs with polydimethylsiloxane (PDMS) to prepare a 1@PDMS flexible UV imaging film. 1@PDMS exhibits excellent bendability and stretchability and maintains good photochromic properties after 100 bending cycles. To demonstrate the rapid color response and distinct color contrast of 1, its application in anti-counterfeiting is also demonstrated. [ABSTRACT FROM AUTHOR]