%0 Journal Article %J Cell Rep %D 2019 %T Genomic Profiling of Childhood Tumor Patient-Derived Xenograft Models to Enable Rational Clinical Trial Design. %A Rokita, Jo Lynne %A Rathi, Komal S %A Cardenas, Maria F %A Upton, Kristen A %A Jayaseelan, Joy %A Cross, Katherine L %A Pfeil, Jacob %A Egolf, Laura E %A Way, Gregory P %A Farrel, Alvin %A Kendsersky, Nathan M %A Patel, Khushbu %A Gaonkar, Krutika S %A Modi, Apexa %A Berko, Esther R %A Lopez, Gonzalo %A Vaksman, Zalman %A Mayoh, Chelsea %A Nance, Jonas %A McCoy, Kristyn %A Haber, Michelle %A Evans, Kathryn %A McCalmont, Hannah %A Bendak, Katerina %A Böhm, Julia W %A Marshall, Glenn M %A Tyrrell, Vanessa %A Kalletla, Karthik %A Braun, Frank K %A Qi, Lin %A Du, Yunchen %A Zhang, Huiyuan %A Lindsay, Holly B %A Zhao, Sibo %A Shu, Jack %A Baxter, Patricia %A Morton, Christopher %A Kurmashev, Dias %A Zheng, Siyuan %A Chen, Yidong %A Bowen, Jay %A Bryan, Anthony C %A Leraas, Kristen M %A Coppens, Sara E %A Harshavardhan Doddapaneni %A Momin, Zeineen %A Zhang, Wendong %A Sacks, Gregory I %A Hart, Lori S %A Krytska, Kateryna %A Mosse, Yael P %A Gatto, Gregory J %A Sanchez, Yolanda %A Greene, Casey S %A Diskin, Sharon J %A Vaske, Olena Morozova %A Haussler, David %A Gastier-Foster, Julie M %A Kolb, E Anders %A Gorlick, Richard %A Li, Xiao-Nan %A Reynolds, C Patrick %A Kurmasheva, Raushan T %A Houghton, Peter J %A Smith, Malcolm A %A Lock, Richard B %A Raman, Pichai %A David A Wheeler %A Maris, John M %K Animals %K Cell Line, Tumor %K Central Nervous System Neoplasms %K Child %K Clinical Trials as Topic %K Disease Models, Animal %K Exome Sequencing %K Genomics %K Humans %K Mice %K Mutation %K Neuroblastoma %K Neurofibromin 1 %K Osteosarcoma %K Precursor Cell Lymphoblastic Leukemia-Lymphoma %K Recurrence %K Rhabdomyosarcoma %K Sarcoma, Ewing %K Tumor Suppressor Protein p53 %K Wilms Tumor %K Xenograft Model Antitumor Assays %X

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.

%B Cell Rep %V 29 %P 1675-1689.e9 %8 2019 Nov 05 %G eng %N 6 %1 https://www.ncbi.nlm.nih.gov/pubmed/31693904?dopt=Abstract %R 10.1016/j.celrep.2019.09.071 %0 Journal Article %J Cancer Res %D 2016 %T Genomic Profiling of Pediatric Acute Myeloid Leukemia Reveals a Changing Mutational Landscape from Disease Diagnosis to Relapse. %A Farrar, Jason E %A Schuback, Heather L %A Ries, Rhonda E %A Wai, Daniel %A Hampton, Oliver A %A Treviño, Lisa R %A Alonzo, Todd A %A Guidry Auvil, Jaime M %A Davidsen, Tanja M %A Gesuwan, Patee %A Hermida, Leandro %A Muzny, Donna M %A Dewal, Ninad %A Rustagi, Navin %A Lewis, Lora R %A Gamis, Alan S %A Wheeler, David A %A Smith, Malcolm A %A Gerhard, Daniela S %A Meshinchi, Soheil %K Adolescent %K Child %K Child, Preschool %K DNA Copy Number Variations %K Female %K Gene Expression Profiling %K Humans %K Infant %K Leukemia, Myeloid, Acute %K Male %K Mutation %K Recurrence %X

The genomic and clinical information used to develop and implement therapeutic approaches for acute myelogenous leukemia (AML) originated primarily from adult patients and has been generalized to patients with pediatric AML. However, age-specific molecular alterations are becoming more evident and may signify the need to age-stratify treatment regimens. The NCI/COG TARGET-AML initiative used whole exome capture sequencing (WXS) to interrogate the genomic landscape of matched trios representing specimens collected upon diagnosis, remission, and relapse from 20 cases of de novo childhood AML. One hundred forty-five somatic variants at diagnosis (median 6 mutations/patient) and 149 variants at relapse (median 6.5 mutations) were identified and verified by orthogonal methodologies. Recurrent somatic variants [in (greater than or equal to) 2 patients] were identified for 10 genes (FLT3, NRAS, PTPN11, WT1, TET2, DHX15, DHX30, KIT, ETV6, KRAS), with variable persistence at relapse. The variant allele fraction (VAF), used to measure the prevalence of somatic mutations, varied widely at diagnosis. Mutations that persisted from diagnosis to relapse had a significantly higher diagnostic VAF compared with those that resolved at relapse (median VAF 0.43 vs. 0.24, P < 0.001). Further analysis revealed that 90% of the diagnostic variants with VAF >0.4 persisted to relapse compared with 28% with VAF <0.2 (P < 0.001). This study demonstrates significant variability in the mutational profile and clonal evolution of pediatric AML from diagnosis to relapse. Furthermore, mutations with high VAF at diagnosis, representing variants shared across a leukemic clonal structure, may constrain the genomic landscape at relapse and help to define key pathways for therapeutic targeting. Cancer Res; 76(8); 2197-205. ©2016 AACR.

%B Cancer Res %V 76 %P 2197-205 %8 2016 Apr 15 %G eng %N 8 %1 https://www.ncbi.nlm.nih.gov/pubmed/26941285?dopt=Abstract %R 10.1158/0008-5472.CAN-15-1015 %0 Journal Article %J Pediatr Blood Cancer %D 2015 %T Initial testing (stage 1) of the PARP inhibitor BMN 673 by the pediatric preclinical testing program: PALB2 mutation predicts exceptional in vivo response to BMN 673. %A Smith, Malcolm A %A Hampton, Oliver A %A Reynolds, C Patrick %A Kang, Min H %A Maris, John M %A Gorlick, Richard %A Kolb, E Anders %A Lock, Richard %A Carol, Hernan %A Keir, Stephen T %A Wu, Jianrong %A Kurmasheva, Raushan T %A Wheeler, David A %A Houghton, Peter J %K Animals %K Bone Neoplasms %K Drug Evaluation, Preclinical %K Enzyme Inhibitors %K Fanconi Anemia Complementation Group N Protein %K Female %K Glioblastoma %K Humans %K Mice %K Mutation %K Neuroblastoma %K Nuclear Proteins %K Phthalazines %K Poly(ADP-ribose) Polymerase Inhibitors %K Rhabdomyosarcoma %K Sarcoma, Ewing %K Tumor Suppressor Proteins %X

BACKGROUND: BMN 673 is a potent inhibitor of poly-ADP ribose polymerase (PARP) that is in clinical testing with a primary focus on BRCA-mutated cancers. BMN 673 is active both through inhibiting PARP catalytic activity and by tightly trapping PARP to DNA at sites of single strand breaks.

PROCEDURE: BMN 673 was tested in vitro at concentrations ranging from 0.1 nM to 1 μM and in vivo at a daily dose of 0.33 mg/kg administered orally twice daily (Mon-Fri) and once daily on weekends (solid tumors) for 28 days.

RESULTS: The median relative IC50 (rIC50 ) concentration against the PPTP cell lines was 25.8 nM. The median rIC50 for the Ewing cell lines was lower than for the remaining cell lines (6.4 vs. 31.1 nM, respectively). In vivo BMN 673 induced statistically significant differences in EFS distribution in 17/43 (39.5%) xenograft models. Three objective regressions were observed: a complete response (CR) in a medulloblastoma line (BT-45), a maintained CR in a Wilms tumor line (KT-10), and a maintained CR in an ependymoma line (BT-41). BMN 673 maintained its high level of activity against KT-10 with a threefold reduction in dose. KT-10 possesses a truncating mutation in PALB2 analogous to PALB2 mutations associated with hereditary breast and ovarian cancer that abrogate homologous recombination (HR) repair.

CONCLUSIONS: The PPTP results suggest that single agent BMN 673 may have limited clinical activity against pediatric cancers. Single agent activity is more likely for patients whose tumors have defects in HR repair.

%B Pediatr Blood Cancer %V 62 %P 91-8 %8 2015 Jan %G eng %N 1 %1 https://www.ncbi.nlm.nih.gov/pubmed/25263539?dopt=Abstract %R 10.1002/pbc.25201 %0 Journal Article %J Cancer Cell %D 2015 %T Recurrent DGCR8, DROSHA, and SIX homeodomain mutations in favorable histology Wilms tumors. %A Walz, Amy L %A Ooms, Ariadne %A Gadd, Samantha %A Gerhard, Daniela S %A Smith, Malcolm A %A Guidry Auvil, Jaime M %A Meerzaman, Daoud %A Chen, Qing-Rong %A Hsu, Chih Hao %A Yan, Chunhua %A Nguyen, Cu %A Hu, Ying %A Bowlby, Reanne %A Brooks, Denise %A Ma, Yussanne %A Mungall, Andrew J %A Moore, Richard A %A Schein, Jacqueline %A Marra, Marco A %A Huff, Vicki %A Dome, Jeffrey S %A Chi, Yueh-Yun %A Mullighan, Charles G %A Ma, Jing %A Wheeler, David A %A Hampton, Oliver A %A Jafari, Nadereh %A Ross, Nicole %A Gastier-Foster, Julie M %A Perlman, Elizabeth J %K Gene Expression Regulation, Neoplastic %K Homeodomain Proteins %K Humans %K Loss of Heterozygosity %K MicroRNAs %K Mutation %K Neoplasm Recurrence, Local %K Nerve Tissue Proteins %K Polymorphism, Single Nucleotide %K Ribonuclease III %K RNA-Binding Proteins %K Wilms Tumor %X

We report the most common single-nucleotide substitution/deletion mutations in favorable histology Wilms tumors (FHWTs) to occur within SIX1/2 (7% of 534 tumors) and microRNA processing genes (miRNAPGs) DGCR8 and DROSHA (15% of 534 tumors). Comprehensive analysis of 77 FHWTs indicates that tumors with SIX1/2 and/or miRNAPG mutations show a pre-induction metanephric mesenchyme gene expression pattern and are significantly associated with both perilobar nephrogenic rests and 11p15 imprinting aberrations. Significantly decreased expression of mature Let-7a and the miR-200 family (responsible for mesenchymal-to-epithelial transition) in miRNAPG mutant tumors is associated with an undifferentiated blastemal histology. The combination of SIX and miRNAPG mutations in the same tumor is associated with evidence of RAS activation and a higher rate of relapse and death.

%B Cancer Cell %V 27 %P 286-97 %8 2015 Feb 09 %G eng %N 2 %1 https://www.ncbi.nlm.nih.gov/pubmed/25670082?dopt=Abstract %R 10.1016/j.ccell.2015.01.003 %0 Journal Article %J Nat Commun %D 2015 %T Rise and fall of subclones from diagnosis to relapse in pediatric B-acute lymphoblastic leukaemia. %A Ma, Xiaotu %A Edmonson, Michael %A Yergeau, Donald %A Muzny, Donna M %A Hampton, Oliver A %A Rusch, Michael %A Song, Guangchun %A Easton, John %A Harvey, Richard C %A Wheeler, David A %A Ma, Jing %A Doddapaneni, Harshavardhan %A Vadodaria, Bhavin %A Wu, Gang %A Nagahawatte, Panduka %A Carroll, William L %A Chen, I-Ming %A Gastier-Foster, Julie M %A Relling, Mary V %A Smith, Malcolm A %A Devidas, Meenakshi %A Guidry Auvil, Jaime M %A Downing, James R %A Loh, Mignon L %A Willman, Cheryl L %A Gerhard, Daniela S %A Mullighan, Charles G %A Hunger, Stephen P %A Zhang, Jinghui %K 5'-Nucleotidase %K Child %K Clonal Evolution %K Clone Cells %K CREB-Binding Protein %K Disease Progression %K DNA Copy Number Variations %K Exome %K Extracellular Matrix Proteins %K Female %K GTP Phosphohydrolases %K Histone-Lysine N-Methyltransferase %K Humans %K Ikaros Transcription Factor %K Male %K Membrane Proteins %K Mutation %K Neoplasm Recurrence, Local %K Precursor B-Cell Lymphoblastic Leukemia-Lymphoma %K Repressor Proteins %K Tumor Suppressor Protein p53 %X

There is incomplete understanding of genetic heterogeneity and clonal evolution during cancer progression. Here we use deep whole-exome sequencing to describe the clonal architecture and evolution of 20 pediatric B-acute lymphoblastic leukaemias from diagnosis to relapse. We show that clonal diversity is comparable at diagnosis and relapse and clonal survival from diagnosis to relapse is not associated with mutation burden. Six pathways were frequently mutated, with NT5C2, CREBBP, WHSC1, TP53, USH2A, NRAS and IKZF1 mutations enriched at relapse. Half of the leukaemias had multiple subclonal mutations in a pathway or gene at diagnosis, but mostly with only one, usually minor clone, surviving therapy to acquire additional mutations and become the relapse founder clone. Relapse-specific mutations in NT5C2 were found in nine cases, with mutations in four cases being in descendants of the relapse founder clone. These results provide important insights into the genetic basis of treatment failure in ALL and have implications for the early detection of mutations driving relapse.

%B Nat Commun %V 6 %P 6604 %8 2015 Mar 19 %G eng %1 https://www.ncbi.nlm.nih.gov/pubmed/25790293?dopt=Abstract %R 10.1038/ncomms7604