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There is an unmet need for preclinical models of rare cancers and rare disease sub-types. The National Cancer Institute's Patient-Derived Models Repository (NCI PDMR; https://pdmr.cancer.gov) is developing quality-controlled, early-passage, clinically-annotated patient-derived tumor xenografts (PDXs), in vitro tumor cell cultures (PDCs), cancer associated fibroblasts (CAFs), and patient-derived organoids (PDOrg) and has focused on addressing unmet needs in the preclinical model space including developing models from adult and pediatric patients with rare cancers. To date, NCI has created and molecularly characterized over 150 preclinical models of rare cancer including indications such as Hurthle cell carcinoma, osteosarcomas, Merkel cell carcinomas, salivary gland cancers, synovial sarcomas, and carcinosarcomas. Rare cancer models developed to date will be reviewed and their histopathologic and molecular characteristics compared to that reported in the clinical setting. A pipeline to identify fusion proteins in these rare cancers such as the Ewing sarcoma EWSR1-FLI1 fusion and NAB2-STAT6 fusions in solitary fibrous tumors (SFT) has been implemented. Four malignant peripheral nerve sheath tumors (MPNST) PDX models are available for researches; these models were developed from patients diagnosed between the ages of 37-68. At the time of model development, two patients were treatment naïve and two had prior radiotherapy. Two of the MPNST PDX models have NF1 oncogenic mutations, three have deep deletions in CDKN2A/B, and three have a mutation in either EED or SUZ12 consistent with the reported molecular characteristics of patients with MPNST. Also of clinical relevance, of two mesothelioma models available, one carries an NF2 driver mutation and the other BAP1 and LATS2 and a PDX model for Hurthle cell carcinoma has wide-spread loss of heterozygosity (LOH 80%). Models for other rare cancers are in development, including four cholangiocarcinoma PDXs with histopathologic confirmation that are currently being expanded for molecular characterization and distribution. Funded by NCI Contract No. HHSN261200800001E Citation Format: Cindy R. Timme, Sergio Y. Alcoser, Devynn Breen, John Carter, Ting-Chia Chang, Alice Chen, Li Chen, Kristen Cooley, Biswajit Das, Emily Delaney, Michelle A. Eugeni, Michelle M. Gottholm-Ahalt, Tara Grinnage-Polley, Jenna Hull, Chris Karlovich, Kimberly Klarmann, Shahanawaz Jiwani, Candace Mallow, Chelsea McGlynn, Justine Mills, Malorie Morris, Michael Mullendore, Dianne Newton, Tia Shearer, Jesse Stottlemyer, Shannon Uzelac, Thomas Walsh, P. Mickey Williams, Yvonne A. Evrard, Melinda G. Hollingshead, James H. Doroshow. Patient-derived models of rare cancers in the National Cancer Institute's patient-derived models repository [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 3012.

Background: Acquired Uniparental Disomy (aUPD) is relatively common in cancer. Occurrence of aUPD is more frequent in some tumor histologies (e.g., serous ovarian, colorectal) and may be relevant for choice of therapy. The Patient-Derived Models Repository (PDMR; https://pdmr.cancer.gov) developed by The National Cancer Institute (NCI) includes patient-derived xenograft (PDX) models from multiple tumor histologies with different passages and lineages. The associated clinical annotation and genomic data make it possible to assess the prevalence of aUPD in the PDMR cohort and the stability of aUPD in different passages and lineages within a PDX model. Methods: High tumor purity in the PDX specimens (after removal of mouse reads representing the stroma) enabled highly accurate assessment of loss of heterozygosity (LOH). Variants called by GATK Haplotype caller from whole exome sequencing (WES) data were used to identify segments of homozygosity using BCFtools/RoH (runs of homozygosity). The RoH segments were then intersected with the bed file for chromosome arms to get %LOH at the arm level. If %LOH on a chromosome arm was >90%, we considered the sample to have aUPD at the arm level. WES was also used to look for associations between DNA damage repair (DDR) pathway alterations and aUPD. Results: We made the following observations: a) aUPD was observed most frequently in chr18q (75/427, 17.6%) and chr3p (69/427, 16%) of PDX models; b) aUPD was observed more frequently in certain tumor histologies, e.g., clear cell renal cell carcinoma (6/8), small cell lung cancer (3/4) and non-small cell lung cancer (25/38); c) extensive aUPD was observed in 4 PDMR models (>50% of evaluated chromosome arms in these models have aUPD); d) aUPD was not observed in some tumor histologies, i.e., synovial sarcoma, uterine endometrioid carcinoma; e) in the vast majority of PDMR models (>90%), aUPD is maintained faithfully across lineages and through multiple passaging; f) subclonal aUPD events were observed in some models across different lineages; g) significant enrichment of double strand DNA break repair (DSBR) pathway alterations was observed in PDMR models without aUPD (p=0.0007, Fisher's exact test) suggesting defects in DSBR are not associated with aUPD; and h) aUPD was rarely observed in MSI-high models (1/30) suggesting mutual exclusivity of mismatch repair (MMR) pathway defects and aUPD. Conclusion: We observed a relatively high frequency of UPD in the PDMR models (at least 1 arm of a chromosome). UPD was more frequently observed in specific chromosomal arms. The frequency of aUPD was higher in some tumor histologies and absent in others. aUPD was stably maintained across passages and lineages, although some heterogeneity was observed. Our data suggest aUPD is not associated with defects in DSBR and MMR pathways. Preclinical drug studies using NCI PDMR models may suggest appropriate therapeutic options for cancers with aUPD. Citation Format: Rajesh Patidar, Li Chen, Chris A. Karlovich, Biswajit Das, Yvonne A. Evrard, Tomas Vilimas, Justine N. McCutcheon, Amanda L. Peach, Nikitha V. Nair, Thomas D. Forbes, Brandie A. Fullmer, Anna J. Lee Fong, Luis E. Romero, Alyssa K. Chapman, Kelsey A. Conley, Robin D. Harrington, Shahanawaz S. Jiwani, Peng Wang, Michelle M. Gottholm Ahalt, Erin N. Cantu, Gloryvee Rivera, Lindsay M. Dutko, Kelly M. Benauer, Vishnuprabha R. Kannan, Suzanne D. Borgel, John P. Carter, Jesse M. Stottlemyer, Tiffanie L. Miner, Devynn R. Breen, Emily T. Delaney, Chelsea A. McGlynn, Candace N. Mallow, Marianne Radzyminski, Shannon N. Uzelac, Sergio Y. Alcoser, Tara L. Grinnage-Pulley, Michelle A. Eugeni, Dianne L. Newton, Melinda G. Hollingshead, Paul M. Williams, James H. Doroshow. Genomic landscape of acquired uniparental disomy in NCI PDMR patient derived xenograft models [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 3554.

The National Cancer Institute's Patient-Derived Models Repository (NCI PDMR; https://pdmr.cancer.gov) is performing a large-scale multi-year preclinical study with 39 PDX models of rare cancers (mesothelioma, MPNST, osteosarcoma, Merkel cell carcinoma, etc) treated with 56 novel therapeutic combinations in an exploratory, n-of-4 arm, study design. Combinations that show promising responses (e.g., regression or durable inhibition of tumor growth) will be repeated along with the single agent arms to determine if the response is driven by the combination or only one of the agents. In order to do this in a timely fashion, relatively speaking, the PDX tumors are serially passaged and each passage is treated with a set of 8 combinations plus relevant vehicle control(s) while in parallel enough PDXs are retained to be expanded for the next passage and drug set. Every serial passage undergoes several quality control assessments that serve as go/no-go criteria including pathology assessment, human:mouse DNA content assessment, and low pass whole genome sequencing to determine the average fraction of genome changed compared to the original donor material. If there is a QC failure, the PDX model is restarted from early passage cryo-material (passage 1-2). An additional quality control effort is to bookend the combination studies with the first set of agents to see if tumor response is similar across passages. To date, most of the models have demonstrated a high degree of stability, though a couple of models have moved toward murine content and have been restarted from early passage material so all drug combinations can be tested. DNA and RNA are retained from all passages so a full NGS evaluation can be performed at a later date. This effort has been ongoing for over a year and the first bookend studies are beginning to be tested to determine if response at first and last passage of the study are consistent with each other, given the constraints of the inherent heterogeneity of the models themselves. Single agent studies of drug combinations that demonstrated a response in 30%-50% of the models tested are also underway to determine which combinations have a more than additive effect compared to the single agents. Promising combinations will be moved forward to early phase clinical trials for these rare cancers. Funded by NCI Contract No. HHSN261200800001E Citation Format: Yvonne A. Evrard, Biswajit Das, Sergio Y. Alcoser, Suzanne Borgel, Devynn Breen, John Carter, Tiffanie Chase, Alice Chen, Lily Chen, Kristen Cooley, Emily Delaney, Raymond Divelbiss, Lyndsay Dutko, Thomas Forbes, Kyle Georgius, Michelle Gottholm-Ahalt, Tara Grinnage-Pulley, Sierra Hoffman, Chris Karlovich, Shahanawaz Jiwani, Justine Mills, Malorie Morris, Michael Mullendore, Dianne Newton, Rajesh Patidar, Gloryvee Rivera, Howard Stotler, Jesse Stottlemyer, Savanna Styers, Debbie Trail, Shannon Uzelac, Thomas Vilimas, Abigail Walke, Thomas Walsh, Nicole Walters, Peng Wang, P. Mickey Williams, Melinda Hollingshead, James H. Doroshow. Quality control efforts in a large-scale, preclinical trial of rare cancer PDXs by the National Cancer Institute's patient-derived models repository (NCI PDMR) [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 5056.

The National Cancer Institute (NCI) has developed a Patient-Derived Models Repository (PDMR) comprised of quality-controlled, early-passage, clinically-annotated patient-derived tumor xenografts (PDXs), in vitro tumor cell cultures (PDCs), cancer associated fibroblasts (CAFs), and patient-derived organoids (PDOrg). NCI has focused on generating models to complement existing PDX collections and address unmet needs in the preclinical model space. These models are offered to the extramural community for research use (https://pdmr.cancer.gov), along with clinical annotation and molecular information (whole exome sequence, gene expression using RNASeq), via a publicly accessible database. Currently, over 200 PDX models, 50 PDC models, and 100 CAF models are available for distribution to the US research community. Approximately 50 PDOrg models will be released in early 2019. As part of its rare cancer initiative, the NCI is also targeting the collection of infrequently-observed tumor histologies to advance both biological investigations and drug development efforts for under-studied malignancies. Comparison of matched models, models where more than one model type are available (e.g., PDX and PDC), demonstrate a high degree of concordance across the model types. Genetic stability across the models is assessed using multiple criteria including genetic assessment of CNVs and presence of driver mutations. Optimal CNV assessment uses whole exome sequence data corrected for cellularity in the patient specimen using germline reads and corrected for cellularity in the PDX specimens by subtraction of the mouse reads. Histomorphologic comparison of PDXs and cell line xenografts (CLX) generated from in vitro PDCs and PDOrgs also overall show a high degree of concordance, though loss of features and dedifferentiation can be observed in some models. Overall these models demonstrate a high degree of conservation at the genetic and pathologic level when compared to the patient tumor. These models can provide researchers the ability to perform high- or mid-throughput screening in 2D or 3D culture followed by targeted selection of PDX models for in vivo studies. Funded by NCI Contract No. HHSN261200800001E Citation Format: Yvonne A. Evrard, Dianne Newton, Biswajit Das, Sergio Y. Alcoser, Kaitlyn Arthur, Mariah Baldwin, Carrie Bonomi, Suzanne Borgel, John Carter, Tiffany Chase, Alice Chen, Lily Chen, Nikki E. Craig, Vivekananda Datta, Emily Delaney, Raymond Divelbiss, Kelly Dougherty, Thomas Forbes, Kyle Georgius, Joe Geraghty, Marion Gibson, Michelle M. Gottholm-Ahalt, Tara Grinnage-Pulley, Kelly Hedger, Sierra Hoffman, Chris Karlovich, Wiem Lassoued, Shahanawaz Jiwani, Candace Mallow, Chelsea McGlynn, Mallorie Morris, Jenna Moyer, Mike Mullendore, Matt Murphy, Rajesh Patidar, Kevin Plater, Marianne Radzyminski, Nicki Scott, Luke H. Stockwin, Howard Stotler, Jesse Stottlemyer, Savanna Styers, Debbie Trail, Tomas Vilimas, Anna Wade, Abigail Walke, Thomas Walsh, P. Mickey Williams, Melinda G. Hollingshead, James H. Doroshow. Comparison of PDX, PDC, and PDOrg models from the National Cancer Institute’s Patient-Derived Models Repository (PDMR) [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 4524.

Background: Patient-derived tumor xenografts (PDX) are powerful tools to study cancer biology, cancer genomics and developmental therapeutics. A common problem in the development of PDX models is proliferation of atypical lymphocytes at the implant site, which often overtake or limit the growth of the original tumor. This atypical proliferation has been described as Xenograft-Associated B cell Lymphoproliferative Disease (XABLD) in our PDX models. In this study, we characterized XABLD cases by morphology, immunophenotyping and genomic profiling. We hypothesize that XABLD tumors are morphologically and phenotypically similar to EBV-driven lymphoma of the elderly and may function as a surrogate model for that lymphoma. Materials and Methods: Models were generated from patient tissue collected under NCI Tissue Procurement Protocol (clincialtrials.gov: NCT00900198) and CIRB Tissue Procurement Protocol 9846 for development of models for NCI's Patient-Derived Models Repository (https://pdmr.cancer.gov). Specimens were implanted subcutaneously in NOD/SCID/IL2Rg null (NSG) mice and animal health was monitored throughout the study. Tumors in mice with suspected XABLD were harvested and reviewed by histology and immunohistochemical analysis for CD45, B and T cell markers and EBV status. All samples in this study were classified by the Lymph2Cx NanoString cell of origin assay and transcriptome profiling. Results: XABLD-associated mice had rapidly growing CD45-positive tumors at the implantation site. Histopathological features were consistent with EBV-driven diffuse large B-cell lymphoma (DLBCL) primarily of polymorphous subtype. All XABLD specimens were diffusely positive for CD20 and EBNA, and most cases contained tumor infiltrating CD8-positive T-cells. Out of 42 cases, 36 were PD-L1-positive and 26 were PD-1-positive by IHC. 39 cases exhibited an activated B cell (ABC) phenotype, which is predominant in EBV-positive DLBCL. Conclusion: XABLD development has been seen across multiple patient histologies from both solid tumor and circulating tumor cells tissues of origin. The clinical presentation, morphology and molecular characteristics of XABLD cases were similar to EBV-driven DLBCL. As DLBCL is an aggressive disease with limited treatment options, our early-passage XABLD models may be useful in the preclinical evaluation of new therapies for EBV-positive DLBCL. Grant Support: This project has been funded in part with federal funds from the National Cancer Institute, National Institutes of Health, under Contract No. HHSN261200800001E. The content of this publication does not necessarily reflect the views or policies of the Department of Health and Human Services, nor does mention of trade names, commercial products, or organizations imply endorsement by the U.S. Government. Citation Format: Tomas Vilimas, Gloryvee Rivera, Brandie Fullmer, Wiem Lassoued, Lindsay Dutko, William Walsh, Amanda Peach, Corinne Camalier, Li Chen, Rajesh Patidar, Suzanne Borgel, John Carter, Howard Stotler, Raymond Divelbiss, Jesse Stottlemyer, Margaret Defreytas, Michelle M. Gottholm-Ahalt, Michelle A. Crespo-Eugeni, Sean McDermott, Yvonne A. Evrard, Melinda G. Hollingshead, Biswajit Das, Chris Karlovich, Vivekananda Datta, James H. Doroshow, P. Mickey Williams. Xenograft-associated B cell lymphoproliferative disease as a surrogate model to study Epstein-Barr virus (EBV) driven lymphoma of the elderly [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 1038.