Abstract In most, if not all health systems, dementia is underdiagnosed, and when diagnosis occurs, it is typically at a relatively late stage in the disease process despite mounting evidence showing that a timely diagnosis would result in numerous benefits for patients, families, and society. Moving toward earlier diagnoses in Alzheimer's disease (AD) requires a conscientious and collective effort to implement a global strategy addressing the multiple causes hindering patient engagement at different levels of society. This article describes the design of the Models of Patient Engagement for Alzheimer's Disease project, an ongoing EU‐funded public‐private multinational initiative that will compare four innovative patient engagement strategies across five European countries regarding their ability to identify individuals with prodromal AD and mild AD dementia, which are “hidden” in their communities and traditionally not found in the typical memory clinic setting. The strategies include an online AD citizen science platform, an open house initiative at the memory clinics, and patient engagement at primary care and diabetologist clinics.
Abstract Cancer represents a leading cause of death by disease in childhood. Pediatric tumors exhibit a high intertumoral heterogeneity, as different tumor types and subtypes have emerged with peculiar molecular and clinical features; however, compared to cancer in adults, pediatric tumors are rare and mostly present with lower mutational burden. The lack of specific therapeutic options represents the main current challenge; systematic, multi-disciplinary approaches are required to accelerate drug development and ultimately to find cures for all children with cancer. The EU funded “Innovative Therapies for Children with Cancer–Pediatric Preclinical Proof-of-Concept Project” (ITCC-P4; www.itccp4.eu) consortium consists of a public-private partnership including academic and industrial partners with the goal of developing a large-scale platform comprising >400 patient-derived xenograft (PDX) models representing high-risk pediatric cancers. Currently, this collection of PDX models includes the most common types of pediatric tumors, such as leukemia (n=28), bone and soft-tissue sarcomas (n=154), CNS tumors (n=96) and neuroblastomas (n=38), as well as other rare childhood cancers, such as hepatoblastomas (n=20) and malignant rhabdoid tumors (n=18); PDX models have been generated either from primary (n=206) or relapse (n=118) disease. In order to: a) investigate the biology of the pediatric PDX models in a high-throughput and systematic fashion, b) assess whether they accurately reflect the molecular features of the corresponding primary tumor and, c) identify potential new suitable biomarkers, we performed a comprehensive molecular characterization (whole-exome and low-coverage whole-genome sequencing; DNA methylation profiling; RNAseq and gene expression profiling) of the PDX models, as well as their matching human tumors and germline samples. These data contributed to the stratification of the PDX models based on their mutational status and emerging molecular vulnerabilities to inform in vivo drug testing in all these PDX models. This proof-of-concept drug testing has been conducted defining, for each group of models, a panel of single compounds (SOC n=3; novel targeted therapies, n=6) or combinations (with each other or with chemo- or radiotherapy). All processed molecular and drug-testing data are collected in the consortium´s centralized data repository (https://r2.amc.nl) allowing data downstream analysis, visualization and interpretation. Taken together, the ITCC-P4 sustainable platform represents a validated and powerful tool to investigate the biology of pediatric cancer based on the establishment, characterization and preclinical testing of pediatric cancer PDX models, ultimately envisaged to contribute the development of innovative therapeutic options for childhood cancer patients. Citation Format: Aniello Federico, Apurva Gopisetty, Didier Surdez, Yasmine Iddir, Alexandra Saint-Charles, Justyna Wierzbinska, Andreas Schlicker, Richard Volckmann, Danny Zwijnenburg, Sara Colombetti, Olaf Heidenreich, Fatima Iradier, Heinrich Kovar, Jan-Henning Klusmann, Klaus-Michael Debatin, Simon Bomken, Christina Guttke, Maureen M. Hattersley, Frédéric Colland, Ashley Strougo, María José Guillén, Louis Chesler, Chris Jones, Maria Eugénia Marques da Costa, Katia Scotlandi, Massimo Moro, Beat Schäfer, Marco Wachtel, Johannes Gojo, Walter Berger, Ángel Montero Carcaboso, Dennis Gürgen, Jens Hoffmann, Emilie Indersie, Stefano Cairo, Julia Schueler, Nicole Huebener, Johannes H. Schulte, Jan J. Molenaar, Birgit Geoerger, David J. Shields, Hubert N. Caron, Gilles Vassal, Lou F. Stancato, Lou F. Stancato, Stefan M. Pfister, Natalie Jäger, Jan Koster, Marcel Kool, Gudrun Schleiermacher. The ITCC-P4 sustainable platform of fully characterized PDXs supports the preclinical proof-of-concept drug testing of high-risk pediatric tumor models. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 3571.
Abstract Cancer remains the main cause of disease-related death in childhood. Pediatric tumors are characterized by a low mutational burden and high intertumoral heterogeneity, with multiple subtypes compared to their adult counterparts. The lack of access to many innovative therapies remains one of the main challenges in the pediatric oncology, especially for the 25% of patients who experience relapses. In this context, the need for the development of a well characterized collection of pediatric models, to provide large scale preclinical testing, is capital for the subsequent identification and prioritization of promising novel therapeutic options. The EU funded “Innovative Therapies for Children with Cancer-Pediatric Preclinical Proof-of-Concept Platform” (ITCC-P4) consortium is a unique public-private collaborative project consisting of academic and industrial partners that aimed at establishing a collection of >400 patient-derived xenograft (PDX) models representing the most common high-risk pediatric cancers. The project involved various aspects of model development including the thorough molecular and pharmacological characterization. XenTech’s participation was focused on the development and preclinical in vivo drug testing of Ewing sarcoma (n=17), hepatoblastoma (n=10), rhabdoid tumors (n=6), synovial sarcoma (n=2), rhabdomyosarcoma (n=2) and other tumors (n=6), as part of overall cohort. PDXs were obtained by transplantation of post-surgery tumor specimens, either by grafting tumor fragments into the interscapular region or subcutaneously in the right flank of nude, NOD-Scid or NOD-Scid gamma mice. Tumor xenografts were amplified by serial transplantation, and tissue samples were retained at early passages for molecular characterization. Fragments from established PDX models where frozen to generate a revivable ITCC-P4 PDX collection. Then, proof-of-concept drug testing was conducted, in a single mouse trial format: each tumor type (n=X PDX models) was treated with a dedicated panel of Standard-of-Care (SoC;n=3) and novel targeted therapies (n=6), or combinations of 2 or 3 novel targeted therapies; for each PDX model n=1 mouse being included per treatment. All molecular and drug-testing data obtained by the different partners are being centralized in the R2 repository (https://r2.amc.nl), providing a powerful tool for data integration, visualization and interpretation of the results. A unique collection of well characterized pediatric PDX models derived from the most relevant pediatric tumor types was enabled by a strong public-private collaborative project. This large cohort is now available for preclinical testing of novel therapeutic agents within a non-for-profit spinoff company, ITCC-P4 gGmbH (www.itccp4.com), offering new perspectives to the identification of promising treatment options for children with cancer. Citation Format: Emilie Indersie, Sophie Branchereau, Brice Fresneau, Christophe Chardot, Didier Surdez, Alexandra Saint-Charles, Maria Eugénia Marques da Costa, Ángel M. Carcaboso, Katia Scotlandi, Massimo Moro, Heinrich Kovar, Jan-Henning Klusmann, Klaus-Michael Debatin, Simon Bomken, Louis Chesler, Chris Jones, Beat Schäfer, Marco Wachtel, Johannes Gojo, Walter Berger, Christina Guttke, Maureen Hattersley, Frédéric Colland, Ashley Strougo, Dennis Gürgen, Jens Hoffmann, Julia Schueler, Pablo M. Aviles, María José Guillén, Aniello Federico, Apurva Gopisetty, Justyna Anna Wierzbinska, Andreas Schlicker, Sara Colombetti, Olaf Heidenreich, Fatima Iradier, Nicole Huebener, Natalie Jäger, Jan Koster, Marcel Kool, Gudrun Schleiermacher, Jan J. Molenaar, Birgit Geoerger, David J. Shields, Hubert N. Caron, Louis F. Stancato, Stefan M. Pfister, Gilles Vassal, Eva-Maria Rief, Olivier Déas. ITCC-P4, a preclinical proof-of-concept drug testing platform as a tool for pharmacological screening in pediatric tumor models [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 5469.
Abstract Introduction The Models of Patient Engagement for Alzheimer's Disease (MOPEAD) project was conceived to explore innovative complementary strategies to uncover hidden prodromal and mild Alzheimer's disease (AD) dementia cases and to raise awareness both in the general public and among health professionals about the importance of early diagnosis. Methods Four different strategies or RUNs were used: (a) a web‐based (WB) prescreening tool, (2) an open house initiative (OHI), (3) a primary care–based protocol for early detection of cognitive decline (PC), and (4) a tertiary care–based pre‐screening at diabetologist clinics (DC). Results A total of 1129 patients at high risk of having prodromal AD or dementia were identified of 2847 pre‐screened individuals (39.7%). The corresponding proportion for the different initiatives were 36.8% (WB), 35.6% (OHI), 44.4% (PC), and 58.3% (DC). Conclusion These four complementary pre‐screening strategies were useful for identifying individuals at high risk of having prodromal or mild AD.
Abstract Advancements in state-of-the-art molecular profiling techniques have resulted in better understanding of pediatric cancers and driver events. It has become apparent that pediatric cancers are significantly more heterogeneous than previously thought as evidenced by the number of novel entities and subtypes that have been identified with distinct molecular and clinical characteristics. For most of these newly recognized entities there are extremely limited treatment options available. The ITCC-P4 consortium is an international collaboration between several European academic centers and pharmaceutical companies, with the overall aim to establish a sustainable platform of >400 molecularly well-characterized PDX models of high-risk pediatric cancers, their tumors and matching controls and to use the PDX models for in vivo testing of novel mechanism-of-action based treatments. Currently, 251 models are fully characterized, including 182 brain and 69 non-brain PDX models, representing 112 primary models, 92 relapse, 42 metastasis and 4 progressions under treatment models. Using low coverage whole-genome and whole exome sequencing, somatic mutation calling, DNA copy number and methylation analysis we aim to define genetic features in our PDX models and estimate the molecular fidelity of PDX models compared to their patient tumor. Based on DNA methylation profiling we identified 43 different tumor subgroups within 18 cancer entities. Mutational landscape analysis identified key somatic and germline oncogenic drivers. Ependymoma PDX models displayed the C11orf95-RELA fusion event, YAP1, C11orf95 and RELA structural variants. Medulloblastoma models were driven by MYCN, TP53, GLI2, SUFU and PTEN. High-grade glioma samples showed TP53, ATRX, MYCN and PIK3CA somatic SNVs, along with focal deletions in CDKN2A in chromosome 9. Neuroblastoma models were enriched for ALK SNVs and/or MYCN focal amplification, ATRX SNVs and CDKN2A/B deletions. Tumor mutational burden across entities and copy number analysis was performed to identify allele-specific copy number detection in tumor-normal pairs. Large chromosomal aberrations (deletions, duplications) detected in the PDX models were concurrent with molecular alterations frequently observed in each tumor type -isochromosome 17 was detected in 5 medulloblastoma models, while deletion of chromosome arm 1p or gain of parts of 17q in neuroblastomas which correlate with tumor progression. We observe clonal evolution of somatic variants not only in certain PDX-tumor pairs but also between disease states. The multi-omics approach in this study provides insight into the mutational landscape and patterns of the PDX models thus providing an overview of molecular mechanisms facilitating the identification and prioritization of oncogenic drivers and potential biomarkers for optimal treatment therapies. Citation Format: Apurva Gopisetty, Aniello Federico, Didier Surdez, Yasmine Iddir, Sakina Zaidi, Alexandra Saint-Charles, Joshua Waterfall, Elnaz Saberi-Ansari, Justyna Wierzbinska, Andreas Schlicker, Norman Mack, Benjamin Schwalm, Christopher Previti, Lena Weiser, Ivo Buchhalter, Anna-Lisa Böttcher, Martin Sill, Robert Autry, Frank Estermann, David Jones, Richard Volckmann, Danny Zwijnenburg, Angelika Eggert, Olaf Heidenreich, Fatima Iradier, Irmela Jeremias, Heinrich Kovar, Jan-Henning Klusmann, Klaus-Michael Debatin, Simon Bomken, Petra Hamerlik, Maureen Hattersley, Olaf Witt, Louis Chesler, Alan Mackay, Johannes Gojo, Stefano Cairo, Julia Schueler, Johannes Schulte, Birgit Geoerger, Jan J. Molenaar, David J. Shields, Hubert N. Caron, Gilles Vassal, Louis F. Stancato, Stefan M. Pfister, Natalie Jaeger, Jan Koster, Marcel Kool, Gudrun Schleiermacher. ITCC-P4: Genomic profiling and analyses of pediatric patient tumor and patient-derived xenograft (PDX) models for high throughput in vivo testing [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 234.
