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  • American Association for Cancer Research (AACR)  (24)
  • 1
    In: Blood Cancer Discovery, American Association for Cancer Research (AACR), Vol. 3, No. 5 ( 2022-09-06), p. 385-393
    Kurzfassung: To explore the role of clonal hematopoiesis (CH) in chimeric antigen receptor (CAR) T-cell therapy outcomes, we performed targeted deep sequencing on buffy coats collected during the 21 days before lymphodepleting chemotherapy from 114 large B-cell lymphoma patients treated with anti-CD19 CAR T cells. We detected CH in 42 (36.8%) pretreatment samples, most frequently in PPM1D (19/114) and TP53 (13/114) genes. Grade ≥3 immune effector cell-associated neurotoxicity syndrome (ICANS) incidence was higher in CH-positive patients than CH-negative patients (45.2% vs. 25.0%, P = 0.038). Higher toxicities with CH were primarily associated with DNMT3A, TET2, and ASXL1 genes (DTA mutations). Grade ≥3 ICANS (58.9% vs. 25%, P = 0.02) and ≥3 cytokine release syndrome (17.7% vs. 4.2%, P = 0.08) incidences were higher in DTA-positive than in CH-negative patients. The estimated 24-month cumulative incidence of therapy-related myeloid neoplasms after CAR T-cell therapy was higher in CH-positive than CH-negative patients [19% (95% CI, 5.5–38.7) vs. 4.2% (95% CI, 0.3–18.4), P = 0.028]. Significance: Our study reveals that CH mutations, especially those associated with inflammation (DNMT3A, TET2, and ASXL1), are associated with severe-grade neurotoxicities in lymphoma patients receiving anti-CD19 CAR T-cell therapy. Further studies to investigate the mechanisms and interventions to improve toxicities in the context of CH are warranted. See related content by Uslu and June, p. 382. This article is highlighted in the In This Issue feature, p. 369
    Materialart: Online-Ressource
    ISSN: 2643-3230 , 2643-3249
    Sprache: Englisch
    Verlag: American Association for Cancer Research (AACR)
    Publikationsdatum: 2022
    Standort Signatur Einschränkungen Verfügbarkeit
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  • 2
    In: Clinical Cancer Research, American Association for Cancer Research (AACR), Vol. 21, No. 2 ( 2015-01-15), p. 365-372
    Kurzfassung: Purpose: VEGF receptor (VEGFR) kinases are important drug targets in oncology that affect function of systemic endothelial cells. To discover genetic markers that affect VEGFR inhibitor pharmacodynamics, we performed a genome-wide association study of serum soluble vascular VEGFR2 concentrations [sVEGFR2], a pharmacodynamic biomarker for VEGFR2 inhibitors. Experimental Design: We conducted a genome-wide association study (GWAS) of [sVEGFR2] in 736 healthy Old Order Amish volunteers. Gene variants identified from the GWAS were genotyped serially in a cohort of 128 patients with advanced solid tumor with baseline [sVEGFR2] measurements, and in 121 patients with renal carcinoma with [sVEGFR2] measured before and during pazopanib therapy. Results: rs34231037 (C482R) in KDR, the gene encoding sVEGFR2 was found to be highly associated with [sVEGFR2], explaining 23% of the variance (P = 2.7 × 10−37). Association of rs34231037 with [sVEGFR2] was replicated in 128 patients with cancer with comparable effect size (P = 0.025). Furthermore, rs34231037 was a significant predictor of changes in [sVEGFR2] in response to pazopanib (P = 0.01). Conclusion: Our findings suggest that genome-wide analysis of phenotypes in healthy populations can expedite identification of candidate pharmacogenetic markers. Genotyping for germline variants in KDR may have clinical utility in identifying patients with cancer with unusual sensitivity to effects of VEGFR2 kinase inhibitors. Clin Cancer Res; 21(2); 365–72. ©2014 AACR.
    Materialart: Online-Ressource
    ISSN: 1078-0432 , 1557-3265
    RVK:
    Sprache: Englisch
    Verlag: American Association for Cancer Research (AACR)
    Publikationsdatum: 2015
    ZDB Id: 1225457-5
    ZDB Id: 2036787-9
    Standort Signatur Einschränkungen Verfügbarkeit
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  • 3
    In: Cancer Research, American Association for Cancer Research (AACR), Vol. 82, No. 12_Supplement ( 2022-06-15), p. 1661-1661
    Kurzfassung: An important obstacle to translating promising drug treatments against glioblastoma (GBM) to the clinic is lack of resistant GBM animal models that more accurately parallel the clinical course of GBM drug resistance found in patients. In this project, a recurrent patient derived intracranial GBM tumor model (GB10) was developed for the first time in the novel Rag2 Null transgenic rat to establish a reproducible preclinical brain tumor model. Histologic characterization confirmed markers of high nuclear proliferation (30% Ki67) and presence of neovascularity (3% Von Willebrand Factor VIII) in all tumors. Serial in vivo imaging was performed to determine a clinically relevant late stage of tumor across all rats before initiation of treatment, accounting for heterogeneity of tumor size and growth rate characteristics. Overall survival was measured following oral administration of control, Temozolomide (TMZ), or combination therapy with TMZ and Idasanutlin. Eighteen Rag2 Null rats were intracranially implanted with GB10, a well characterized, recurrent cell line from the Mayo Clinic Brain Tumor Patient-Derived Xenograft National Resource. Bi-weekly high resolution, 2-dimensional T2 magnetic resonance imaging (2DT2 MRI) was performed on a Bruker 9.4 tesla scanner until tumor volume reached 30 µL. 14 days later, simultaneous positron emission tomography and magnetic resonance imaging (PET MRI) was performed on each rat with three dimensional T1 post-contrast (3DT1 CE), amino acid-based 18F-Flouroethyltyrosine (18F-FET), and amide proton transfer-chemical exchange saturation transfer (amide-CEST). Measured tumor parameters included volumetry (3DT1 CE), metabolic activity (18F-FET), and mobile phase intracellular protein content (amide-CEST), to confirm late-stage viable tumors of similar size (15.3 mm^2 +/-1.38 based on SEM, N=16) and metabolism (2:1 ratio of activity of tumor relative to contralateral control brain tissue). Two rats were removed: 1 died prematurely of infection and 1 had extra-axial tumor location. Oral treatment groups were as follows: Control (N= 5), TMZ (N=6) or TMZ + Idasanutlin (N=5). Kaplan Meier survival curves for the TMZ treated group (80.2+/-4.1 days) and combined TMZ + Idasanutlin group (93.8+/-6.2 days) were both significantly increased (P & lt;0.001) compared to control (67.4+/-4.5 days). Survival for the TMZ + Idasanutlin treated group was also significantly increased (P & lt;0.001) relative to TMZ treated group indicating efficacy of combination therapy. In conclusion, a robust, resistant, patient derived GBM animal model was developed using serial, high field, non-invasive, multimodality, molecular imaging along with histopathologic analysis. Feasibility of assessing treatment response was also demonstrated with both a standard of care and experimental combination therapy, in the late stage of GBM growth. Citation Format: Luke R. Jackson, Megan R. Masi, Hamideh zarrinmayeh, Sudip K. Das, Mark A. Green, Scott E. Snyder, Nian Wang, Karen Pollok, Gary D. Hutchins, Elizabeth R. Butch, Michael C. Veronesi. Development of a patient-derived glioblastoma model in the transgenic Rag2 Null rat: In vivo imaging, histology, and combination therapy assessment [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 1661.
    Materialart: Online-Ressource
    ISSN: 1538-7445
    Sprache: Englisch
    Verlag: American Association for Cancer Research (AACR)
    Publikationsdatum: 2022
    ZDB Id: 2036785-5
    ZDB Id: 1432-1
    ZDB Id: 410466-3
    Standort Signatur Einschränkungen Verfügbarkeit
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  • 4
    In: Cancer Research, American Association for Cancer Research (AACR), Vol. 82, No. 12_Supplement ( 2022-06-15), p. 820-820
    Kurzfassung: The primary purpose of our work was to characterize the effects of the nuclear receptor TLX (NR2E1) in triple-negative breast cancer (TNBC) in order to evaluate its potential therapeutic value in a subtype of breast cancer that has proven particularly challenging to treat, primarily due to the lack of targeted modes of intervention. Unfortunately, breast cancer continues to be the second deadliest form of cancer among women in the United States. Considering the substantial public health implications, development of new therapeutic strategies for highly aggressive breast cancer subtypes, such as TNBC, is imperative. While the function of nuclear receptors such as the estrogen and androgen receptors has been extensively characterized in cancers of the breast and prostate respectively, due in part to their amenable nature to ligand modulation, it is likely that other nuclear receptors may represent therapeutic targets for these malignancies. Indeed, probing of available clinical datasets demonstrated that nuclear receptor TLX is most highly expressed in basal and estrogen receptor (ER)-negative breast cancer patients, and that ER-negative patients with higher TLX expression had increased relapse-free and overall survival. Therefore, we hypothesized that TLX could influence the pathophysiology of TNBC. Utilizing a stable overexpression model in the TNBC cell lines, MDA-MB-231 and MDA-MB-468, we have shown that TLX can inhibit critical oncogenic properties in the in vitro setting, including proliferation, migration and invasion. Furthermore, xenograft and lung colonization studies demonstrated that TLX continued to exert anti-oncogenic effects in the in vivo environment. In agreement with these results, transcriptomic analysis of TLX-overexpressing cells and xenograft tumors showed that TLX can regulate genes and pathways that are known to play crucial roles in the growth and metastatic dissemination of cancer. As previously published works have identified several putative TLX ligands, our findings demonstrating that TLX functions as an anti-cancer factor in TNBC provides a strong rationale for future research aimed at therapeutically targeting this nuclear receptor. Citation Format: Adam T. Nelczyk, Hashni E. Vidana Gamage, Liqian Ma, Michael T. McHenry, Madeline A. Henn, Mohammed Kadiri, Yu Wang, Anasuya Das Gupta, Natalia Krawczynska, Sisi He, Michael J. Spinella, Erik R. Nelson. Nuclear receptor TLX inhibits cancer cell intrinsic properties required for triple-negative breast cancer progression [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 820.
    Materialart: Online-Ressource
    ISSN: 1538-7445
    Sprache: Englisch
    Verlag: American Association for Cancer Research (AACR)
    Publikationsdatum: 2022
    ZDB Id: 2036785-5
    ZDB Id: 1432-1
    ZDB Id: 410466-3
    Standort Signatur Einschränkungen Verfügbarkeit
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  • 5
    In: Cancer Research, American Association for Cancer Research (AACR), Vol. 80, No. 16_Supplement ( 2020-08-15), p. 3916-3916
    Kurzfassung: Background: The National Cancer Institute (NCI) has developed a Patient-Derived Models Repository (PDMR; https://pdmr.cancer.gov) of preclinical models including patient-derived xenografts (PDX), organoids (PDOrg) and patient-derived cell cultures (PDC). Extensive clinical annotation and genomic datasets are available for these preclinical models. However, it is unclear if the molecular profiles of the corresponding patient tumors are stably propagated in these models. We have previously demonstrated that PDX models from the NCI PDMR faithfully represent the patient tumors both in terms of genomic stability and tumor heterogeneity. Here, we conduct an in-depth investigation of genomic representation of patient tumors in the PDOrgs and PDCs. Methods: PDOrgs (n=64) and PDCs (n=94) were established from tumor fragments (i.e., initiator specimens) obtained either from patient specimens or from PDX specimens of early passage. For some models (n=19), both PDOrgs and PDCs were generated from the same tumor tissue; in fewer cases (n=4), PDCs were established from organoids derived from patient specimens. Whole Exome Sequencing and RNA-Seq were performed on all PDCs and PDOrgs, and data were compared with patient specimens or early passage PDXs. Results: A majority of the PDOrgs and PDCs have stably inherited the genome of the corresponding patient specimens based on the following observations: (1) & gt;87% of PDOrgs and PDCs maintained similar copy number alteration profiles compared with the initiator specimens of the preclinical model; (2) the variant allele frequency (VAF) of clinically relevant mutations remained consistent between the PDOrgs, PDCs, and the initiator specimens, with none of the PDCs or PDOrgs deviating by & gt;15% VAF; and (3) clinically relevant biomarkers (e.g., MSI, LOH, mutational signatures etc.) are concordant amongst the PDOrgs, PDCs, and the initiator specimens. We observed that the majority of SNVs and indels present in the initiator specimens were also found in the PDOrgs and PDCs, suggesting almost all the tumor heterogeneity was preserved in these preclinical models. Conclusions: This large and histologically diverse set of PDOrgs and PDCs from the NCI PDMR exhibited genomic stability and faithfully represented the tumor heterogeneity observed in corresponding patient specimens. These preclinical models thus represent a valuable resource for researchers interested in pre-clinical drug or other studies. Citation Format: Biswajit Das, Yvonne A. Evrard, Li Chen, Rajesh Patidar, 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, Carrie A. Bonomi, Kelly M. Dougherty, Joseph P. Geraghty, Marion V. Gibson, Savanna S. Styers, Abigail J. Walke, Jenna E. Moyer, Anna Wade, Mariah L. Baldwin, Kaitlyn A. Arthur, Kevin J. Plater, Luke Stockwin, Matthew R. Murphy, Michael E. Mullendore, Dianne L. Newton, Melinda G. Hollingshead, Chris A. Karlovich, Paul M. Williams, James H. Doroshow. Patient-derived organoid and cell culture models from the NCI Patient-Derived Models Repository (NCI PDMR) preserve genomic stability and heterogeneity of patient tumor specimens [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 3916.
    Materialart: Online-Ressource
    ISSN: 0008-5472 , 1538-7445
    RVK:
    RVK:
    Sprache: Englisch
    Verlag: American Association for Cancer Research (AACR)
    Publikationsdatum: 2020
    ZDB Id: 2036785-5
    ZDB Id: 1432-1
    ZDB Id: 410466-3
    Standort Signatur Einschränkungen Verfügbarkeit
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  • 6
    In: Cancer Immunology Research, American Association for Cancer Research (AACR), Vol. 10, No. 12_Supplement ( 2022-12-01), p. A08-A08
    Kurzfassung: Active immunotherapy approaches for neuroblastoma (NB), a pediatric cancer of the sympathetic nervous system, has met with limited success. Especially challenging is the genetic heterogeneity of NB which makes it difficult to identify factors that consistently indicate the likelihood of an effective immune response and thereby select patients who are most likely to benefit from immunotherapy. Hence, we undertook an unbiased analysis of gene expression signatures from & gt;500 well-annotated primary NBs representing diverse clinical and genetic subtypes to identify of predictors of immune response. Using clustering analysis of bulk transcriptomic signatures from these tumors, we identified a subset of NBs that was notable for the high expression of genes associated with anti-tumor immune response. These “immunogenic” tumors showed a predominance of gene expression signatures derived from malignant cells with primitive neural crest-like or mesenchymal properties, one of the two cell states that shape intratumoral heterogeneity in NB. In contrast, tumors that expressed committed, adrenergic neuron-like signatures were less immunogenic. Single-cell (sc) RNA-seq and immunohistochemistry analysis further confirmed that NBs comprise both adrenergic and mesenchymal tumor cells, and that the presence of mesenchymal cells positively associated with immune cell infiltration into the TME. scRNA-seq also revealed that mesenchymal NB cells were enriched for inflammatory gene signature. Gene expression analysis of isogenic pairs of adrenergic and mesenchymal cells showed that mesenchymal NBs differentially upregulate genes involved in regulating antigen processing and presentation, MHC class I expression, type-I interferon and TLR3 signaling, and NK cell activation. This is achieved through a permissive chromatin landscape at the promoters of these immune regulatory genes that support their high expression in mesenchymal cells. By contrast, in adrenergic cells, tumor-intrinsic immune genes are epigenetically silenced by the PRC2 complex and PRC2 inhibition leads to increased immune cell activation. Remarkably, induction of the mesenchymal state in adrenergic cells through transcriptional reprogramming by PRRX1 or therapy resistance is accompanied by the epigenetic activation of innate and adaptive immune response genes. Functionally, the inherent immunogenicity of mesenchymal cells promotes T cell infiltration by secreting inflammatory cytokines, enables efficient targeting by antigen-specific cytotoxic T and NK cells, and imparts responsiveness to immune checkpoint blockade in a syngeneic NB model. In conclusion, our study uncovers an unappreciated link between immunogenicity and tumor lineage state in NB, and rationalizes future interrogations into (i) avenues through which the vulnerability of mesenchymal cells to immune-mediated targeting could be harnessed clinically and (ii) how perturbation of epigenetically-regulated cell states could be harnessed to promote anti-tumor immune response. Citation Format: Satyaki Sengupta, Sanjukta Das, Angela C. Crespo, Annelisa M. Cornel, Anand G. Patel, Navin R. Mahadevan, Marco Campisi, Alaa K. Ali, Bandana Sharma, Jared H. Rowe, Rogier Versteeg, Rudolf Jaenisch, Stefani Spranger, Rizwan Romee, Brian C. Miller, David A. Barbie, Stefan Nierkens, Michael A. Dyer, Judy Lieberman, Rani E. George. Divergent tumor cell states in neuroblastoma possess distinct immunogenic phenotypes [abstract]. In: Proceedings of the AACR Special Conference: Tumor Immunology and Immunotherapy; 2022 Oct 21-24; Boston, MA. Philadelphia (PA): AACR; Cancer Immunol Res 2022;10(12 Suppl):Abstract nr A08.
    Materialart: Online-Ressource
    ISSN: 2326-6074
    Sprache: Englisch
    Verlag: American Association for Cancer Research (AACR)
    Publikationsdatum: 2022
    ZDB Id: 2732517-9
    Standort Signatur Einschränkungen Verfügbarkeit
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  • 7
    In: Cancer Research, American Association for Cancer Research (AACR), Vol. 81, No. 13_Supplement ( 2021-07-01), p. 3012-3012
    Kurzfassung: 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.
    Materialart: Online-Ressource
    ISSN: 0008-5472 , 1538-7445
    RVK:
    RVK:
    Sprache: Englisch
    Verlag: American Association for Cancer Research (AACR)
    Publikationsdatum: 2021
    ZDB Id: 2036785-5
    ZDB Id: 1432-1
    ZDB Id: 410466-3
    Standort Signatur Einschränkungen Verfügbarkeit
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  • 8
    In: Cancer Research, American Association for Cancer Research (AACR), Vol. 83, No. 7_Supplement ( 2023-04-04), p. 36-36
    Kurzfassung: The National Cancer Institute has developed a Patient-Derived Models Repository (NCI PDMR; https://pdmr.cancer.gov) comprised of quality-controlled, early passage, and clinically-annotated patient-derived tumor xenografts (PDXs), organoids (PDOrgs), cell cultures (PDCs), and cancer associated fibroblasts (CAFs) available with genomic data to the extramural community for research use. Models are developed by the NCI PDMR in decreasing order of complexity, specifically 1) patient material can be used to develop PDXs, PDOrgs, PDCs, and CAFs, 2) PDX material for PDOrgs and PDCs, and 3) PDOrg material for PDCs, but a PDC is never used to develop a PDOrg or PDX. Eleven pairs of 22 matched PDCs have been developed in parallel from either patient, PDX, patient-derived organoid, or PDX-derived organoid tumor material and sequenced by WES and RNASeq. Genetic stability was assessed using multiple approaches including microsatellite instability (MSI) generated from MSISensor2, percentage of genomic loss of heterozygosity (LOH) using a set of ~800k heterozygous SNPs from a population level genomic database (gnomAD), pairwise Spearman correlation based on BIN level copy number (CN)/RNA expression profiles, and OncoKB annotated oncogenic/likely oncogenic variants. No systematic differences were observed within PDC pairs derived from different origins or compared to their patient and/or PDX material in MSI, LOH% and RNA expression profile but pairwise Spearman correlation (0.66-0.88) in CNV profiles were somewhat variable, likely due to low sequencing depth. In one PDC pair (299254), 3 out of 12 OncoKB annotated Indels and CNV showed opposite level of variant allele frequencies/CN when comparing a model derived from patient material to one developed from a PDX-derived organoid, possibly driven by a lineage-specific subclonal outgrowth when compared to patient and PDX data. Phenotypic characteristics of matched PDCs also overall show no major differences, though variability in growth rates and the ability to form spheroids in serum-free medium were noted. In one pair (919269), the PDC derived from patient material was able to form a cell line xenograft (CLX) in NSG mice but not the PDC developed from a patient-derived organoid. Overall, these models demonstrate a high degree of concordance at the genetic and phenotypic level when compared to the originating patient and/or PDX tumor. Though further characterization (e.g., preclinical drug testing) may be needed to define differences between matched PDC pairs, lack of access to patient tissue or failure to generate tumor cell cultures from one source of material should not hamper development of preclinical in vitro models from other patient-derived model types as long as the source-of-origin is clearly defined. Funded by NCI Contract No. HHSN261200800001E Citation Format: Cindy R. Timme, Ting-Chia Chang, Sergio Y. Alcoser, Gareth Bliss, Carrie Bonomi, Suzanne Borgel, John Carter, Alice Chen, Li Chen, Kevin Cooper, Biswajit Das, Kelly Dougherty, Lindsay Dutko, Marion Gibson, Michelle M. Gottholm-Ahalt, Tara Grinnage-Pulley, Shahanawaz Jiwani, Keegan Kalmbach, Chris Karlovich, Kimberly Klarmann, Tiffanie Chase, Michael Mullendore, Matthew Murphy, Kevin Plater, Gloryvee Rivera, Jessica Steed, Luke Stockwin, Yvonne A. Evrard, Mickey Williams, Dianne L. Newton, Melinda G. Hollingshead, James H. Doroshow. Comparing twenty-two matched patient-derived cell lines developed from either patient, PDX, or organoid tumor cell material [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 36.
    Materialart: Online-Ressource
    ISSN: 1538-7445
    Sprache: Englisch
    Verlag: American Association for Cancer Research (AACR)
    Publikationsdatum: 2023
    ZDB Id: 2036785-5
    ZDB Id: 1432-1
    ZDB Id: 410466-3
    Standort Signatur Einschränkungen Verfügbarkeit
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  • 9
    In: Cancer Research, American Association for Cancer Research (AACR), Vol. 65, No. 15 ( 2005-08-01), p. 6692-6700
    Kurzfassung: The cells' ability to proliferate in response to growth factor stimulation is significantly altered during cancer progression. To investigate the mechanisms underlying these alterations in prostate cancer, the role and expression of β1A integrin and type 1 insulin-like growth factor receptor (IGF-IR), known to contribute to cell proliferation and transformation, were analyzed. Using small interfering RNA oligonucleotides to down-regulate β1A, we show that β1A expression is required for IGF-IR–mediated prostate cancer cell proliferation and anchorage-independent growth. In vivo, using age-matched transgenic adenocarcinoma of mouse prostate (TRAMP) mice at different stages of prostate cancer [prostatic intraepithelial neoplasia, PIN; well-differentiated adenocarcinoma, WD; and poorly differentiated adenocarcinoma, PD], the expression of β1A and of IGF-IR was studied. β1A and IGF-IR expression levels were concurrently up-regulated in high PIN and WD, whereas their expression did not correlate in late-stage PD. In contrast to the up-regulated expression of β1A, the levels of β1C, a β1 cytoplasmic variant that inhibits cell proliferation, were down-regulated in all stages of prostate cancer. A similar expression pattern was observed for a β1C downstream effector, Grb2-associated binder-1 (Gab1) which is known to inhibit IGF-IR phosphorylation. To analyze in vitro the mechanistic implications of β1A, β1C, and Gab1 deregulation in prostate cancer, we investigated whether expression of either β1 variant in β1-null cells affected IGF-IR localization. We found that IGF-IR and β1A were colocalized in highly specialized integrin signaling compartments, designated focal contacts. However, in the presence of β1C, IGF-IR remained diffuse on the cell surface and did not localize to focal contacts. The findings that β1 integrins and IGF-IR are concurrently deregulated and that expression of β1 integrins is necessary to achieve appropriate IGF-IR intracellular distribution point to the important role that the cross-talk between these receptors may have during prostate cancer progression and will be helpful in formulating new therapeutic strategies.
    Materialart: Online-Ressource
    ISSN: 0008-5472 , 1538-7445
    RVK:
    RVK:
    Sprache: Englisch
    Verlag: American Association for Cancer Research (AACR)
    Publikationsdatum: 2005
    ZDB Id: 2036785-5
    ZDB Id: 1432-1
    ZDB Id: 410466-3
    Standort Signatur Einschränkungen Verfügbarkeit
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  • 10
    In: Cancer Research, American Association for Cancer Research (AACR), Vol. 78, No. 13_Supplement ( 2018-07-01), p. 986-986
    Kurzfassung: The National Cancer Institute (NCI) has developed a Patient-Derived Models Repository (PDMR) comprised of quality-controlled, early-passage, clinically-annotated patient-derived xenografts (PDXs) to serve as a resource for public-private partnerships and academic drug discovery efforts. 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, RNASeq), which is available in a publicly accessible database. The PDMR was established by NCI at the Frederick National Laboratory for Cancer Research (FNLCR) in direct response to discussions with academia and industry; the oncology community's highest priority need was preclinical models that more faithfully reflect the patient's tumor and are associated with the patient's treatment history. NCI has focused on generating models to complement existing PDX collections and address unmet needs in the preclinical model space. The PDMR generates the majority of its PDXs by subcutaneous implantation except for those histologies having better success rates in either orthotopic or alternate implant sites. All SOPs and quality-control standards developed by the PDMR as well as those shared by collaborators are posted to a public web site that houses the PDMR database. In May 2017, the public website (https://pdmr.cancer.gov/) went live with its first 100 models from histologies including pancreatic, colorectal, renal, head and neck, and lung squamous cell cancers as well as melanoma and adult soft tissue sarcomas. In early 2018, the PDMR will begin releasing models from gynecological cancers, small cell lung cancer, chondro/osteo sarcomas, lung adenocarcinoma, and squamous cell skin and Merkel cell carcinomas. In addition, wherever available germline sequence and somatic variant calls will be added to the existing molecular characterization data for each model. NCI has also increased its focus on creating PDXs from racial and ethnic minorities through several funding opportunities. The overall goal of NCI is to create a long-term home for at least 1000 models such that sufficient biological and clinical diversity is represented to allow researchers to ask questions regarding the impact of tumor heterogeneity on target qualification or clinical response, whether PDXs more faithfully represent the human tumor for pharmacodynamic assay and predictive marker development, or if adequately powered preclinical PDX clinical trials can lead to better evaluation of therapies for future clinical use. Moving forward the PDMR plans to distribute in vitro, early-passage tumor cell cultures and cancer-associated fibroblasts as well as releasing PDX drug response data for a panel of FNA-approved therapeutic agents. Funded by NCI Contract No. HHSN261200800001E Citation Format: Yvonne A. Evrard, Michelle M. Gottholm Ahalt, Sergio . Y. Alcoser, Kaitlyn Arthur, Mariah Baldwin, Linda L. Blumenauer, Carrie Bonomi, Suzanne Borgel, Elizabeth Bradtke, Corinne Camalier, John Carter, Tiffanie Chase, Alice Chen, Lily Chen, Donna W. Coakley, Nicole E. Craig, Biswajit Das, Vivekananda Datta, Jordyn Davidson, Margaret R. DeFreytas, Emily Delaney, Michelle A. Eugeni, Raymond Divelbiss, Palmer Fliss, Thomas Forbes, Marion Gibson, Tara Grinnage-Pulley, Sierra Hoffman, Lilia Ileva, Paula Jacobs, Franklyn Jimenez, Joseph Kalen, Catherine Karangwa, Chris Karlovich, Candace Mallow, Chelsea McGlynn, Jenna E. Moyer, Michael Mullendore, Dianne L. Newton, Nimit Patel, Rajesh Patidar, Kevin Plater, Marianne Radzyminski, Lisa Riffle, Larry Rubinstein, Luke H. Stockwin, Mickey Williams, Melinda G. Hollingshead, James H. Doroshow. The National Cancer Institute's patient-derived models repository (PDMR) [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 986.
    Materialart: Online-Ressource
    ISSN: 0008-5472 , 1538-7445
    RVK:
    RVK:
    Sprache: Englisch
    Verlag: American Association for Cancer Research (AACR)
    Publikationsdatum: 2018
    ZDB Id: 2036785-5
    ZDB Id: 1432-1
    ZDB Id: 410466-3
    Standort Signatur Einschränkungen Verfügbarkeit
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