scholarly journals Accelerating development of high-risk neuroblastoma patient-derived xenograft models for preclinical testing and personalised therapy

2020 ◽  
Vol 122 (5) ◽  
pp. 680-691 ◽  
Author(s):  
Alvin Kamili ◽  
Andrew J. Gifford ◽  
Nancy Li ◽  
Chelsea Mayoh ◽  
Shu-Oi Chow ◽  
...  
Keyword(s):  
Bone Marrow ◽  
High Risk ◽  
Pleural Fluid ◽  
Personalised Medicine ◽  
Model Development ◽  
Treatment Strategies ◽  
Nsg Mice ◽  
Patient Derived Xenograft ◽  
New Treatment ◽  
Pdx Models

Abstract Background Predictive preclinical models play an important role in the assessment of new treatment strategies and as avatar models for personalised medicine; however, reliable and timely model generation is challenging. We investigated the feasibility of establishing patient-derived xenograft (PDX) models of high-risk neuroblastoma from a range of tumour-bearing patient materials and assessed approaches to improve engraftment efficiency. Methods PDX model development was attempted in NSG mice by using tumour materials from 12 patients, including primary and metastatic solid tumour samples, bone marrow, pleural fluid and residual cells from cytogenetic analysis. Subcutaneous, intramuscular and orthotopic engraftment were directly compared for three patients. Results PDX models were established for 44% (4/9) of patients at diagnosis and 100% (5/5) at relapse. In one case, attempted engraftment from pleural fluid resulted in an EBV-associated atypical lymphoid proliferation. Xenogeneic graft versus host disease was observed with attempted engraftment from lymph node and bone marrow tumour samples but could be prevented by T-cell depletion. Orthotopic engraftment was more efficient than subcutaneous or intramuscular engraftment. Conclusions High-risk neuroblastoma PDX models can be reliably established from diverse sample types. Orthotopic implantation allows more rapid model development, increasing the likelihood of developing an avatar model within a clinically useful timeframe.

Disease Propagating Blasts in Standard and High Risk Acute Lymphoblastic Leukemia Are Frequent and of Diverse Immunophenotype.

Blood ◽  
2009 ◽  
Vol 114 (22) ◽  
pp. 1421-1421 ◽  
Author(s):  
Klaus Rehe ◽  
Kerrie Wilson ◽  
Hesta McNeill ◽  
Martin Schrappe ◽  
Julie Irving ◽  
...  
Keyword(s):  
Stem Cells ◽  
Bone Marrow ◽  
Stem Cell ◽  
High Risk ◽  
Cancer Stem Cells ◽  
Conflicts Of Interest ◽  
Lymphoblastic Leukemia ◽  
Color Flow ◽  
Nsg Mice ◽  
Limiting Dilution

Abstract Abstract 1421 Poster Board I-444 Conflicting results in the field of cancer stem cells have reignited debate regarding the frequency and identity of cells with the ability to self renew and to propagate the complete phenotype of the malignancy. Initially it was suggested by different studies that cancer stem cells represent only a small minority of the malignant population and that the immunophenotypes of these cells resemble a rather immature type in the cell hierarchy. More recent data from our own and other groups have challenged these findings by demonstrating that cells at different maturity levels within the leukemic hierarchy have cancer stem cell abilities and that the frequency of the leukemia maintaining cell is higher than previously thought (Cancer Cell 2008, 14(1), p47-58). We use an in vivo NOD/scid IL2Rγnull (NSG) mouse intra-femoral transplant model to determine the clonogenicity of sorted candidate leukemic stem cell populations, characterized by specific immunophenotypes. We selected the surface markers CD10 and CD20, in order to differentiate between rather immature and more mature cells. Furthermore we carried out limiting dilution experiments on sorted (CD20) and unsorted leukemic blasts to investigate the frequency of the proposed leukemic stem cells. Flow sorted ALL blasts of CD19+CD20low and CD19+CD20high as well as of CD19+CD10low and CD19+CD10high immunophenotype were transplanted into NSG mice. Sorts were performed on primary patient material and on leukemic blasts that had been harvested following prior passage in mice. Different subtypes of ALL were included (high risk: BCR/ABL (t9;22) positive (patients L4967, L4951, L49101, L8849, L2510), high hyperdiploid/MRD positive high risk (L754, L835), intermediate risk: high WBC/MRD negative (L736, L784), age >10 years (L803)). CD20 sorts were performed on primary patient material (L4951, L49101, L754, L835 and L776), on secondary samples harvested from engrafted primary mice (L4967, L4951, L2510, L736 and L754) and on tertiary samples harvested from engrafted secondary mice (L4967 and L736). In total 151 mice were transplanted, with 122 showing engraftment in consecutive bone marrow punctures or in bone marrow harvests. CD10 sorts were performed on primary patient material (L784 and L49101) and on secondary samples harvested from engrafted primary mice (L4951, L8849, L2510 and L803) with 31 out of 52 mice transplanted with sorted material showing engraftment as seen with CD20 sorted cells. Blasts of all selected immunophenotypes were able to engraft the leukemia in unconditioned NSG mice as determined by 5 color flow cytometry. In particular, sorted cells of both fractions were able to reconstitute the complete phenotype of the leukemia. Harvested cells from engrafted mice could then be re-sorted into high and low antigen expressing fractions and successfully re-engrafted on secondary and tertiary mice. Cell purities of transplanted cells were usually higher than 90% (range 67-100%). The ability of all populations to serially engraft mice demonstrates long-term self-renewal capacity. Two additional patients were used in the limiting dilution assays (high WBC/t(4;11) high risk (L826); low WBC/MRD negative low risk (L792)) and experiments were performed on primary unsorted and secondary sorted material. Cell numbers necessary for ALL engraftment differed between individual leukemias but as little as 100 cells proved to be sufficient in one unsorted and in both the CD19+CD20low and CD19+CD20high fractions (Table 1). Mice transplanted with 10 cells only are still under observation. Table 1 Patient Transplant Population Cell dose Mice engrafted/transplanted L4951 Secondary CD20 high 500 3/3 CD20 low 3/3 CD20 high 100 3/3 CD20 low 3/3 L2510 Secondary CD20 high 3,000 2/4 CD20 low 4/4 CD20 high 300 0/4 CD20 low 1/4 L49101 Primary Unsorted 500 3/4 100 0/4 L792 Primary Unsorted 1,000 5/5 100 1/5 L826 Primary Unsorted 1,000 3/4 100 0/4 In conclusion we present strong evidence that leukemia-propagating cells are much more prevalent than previously thought and that blasts of diverse immunophenotype are able to serially reconstitute the complete leukemia in immune-deficient mice. Disclosures: No relevant conflicts of interest to declare.

An Enhanced International Prognostic Index (IPI) for Patients with Diffuse Large B-Cell Lymphoma (DLBCL) in the Rituximab Era Using the National Comprehensive Cancer Network (NCCN) Database.

Blood ◽  
2012 ◽  
Vol 120 (21) ◽  
pp. 2656-2656
Author(s):  
Zheng Zhou ◽  
Alfred W. Rademaker ◽  
Leo I. Gordon ◽  
Ann S. LaCasce ◽  
Ann Vanderplas ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Overall Survival ◽  
High Risk ◽  
International Prognostic Index ◽  
Model Development ◽  
Prognostic Index ◽  
Risk Groups ◽  
Ratio Test ◽  
Validation Sample ◽  
Gi Tract

Abstract Abstract 2656 Introduction: The International Prognostic Index (IPI) was first developed in 1993 to risk stratify patients with aggressive Non-Hodgkin's lymphoma (NHL) for outcome prediction (Shipp, NEJM, 1993). Since the addition of rituximab to conventional CHOP chemotherapy for the treatment of DLBCL, there have been many efforts to validate the IPI as well as to improve upon the model's capacity to distinguish subgroups with discrete clinical outcomes, especially high-risk patients. Previous studies have focused on adding clinical or biologic prognostic factor(s) to the original model or regrouping the original IPI score (R-IPI; Sehn, Blood, 2007). We, therefore, built anew a modern IPI based solely on clinical factors available in the real world NCCN clinical database. Methods: Using the nationwide population-based NHL lymphoma database from NCCN, patients with newly diagnosed DLBCL enrolled between June 2000 and Dec. 2010 at 7 NCCN cancer centers were included with at least 1 year and up to 5 years of follow-up. Clinical characteristics including age, Ann Arbor stage, ECOG performance status, disease in extranodal sites (including positivity in bone marrow, CNS, liver/GI tract, lung, other sites and spleen), LDH, presence of bulky disease (>10 cm) as well as B symptoms were studied as potential predictors for model development using COX proportional hazards regression. IPI scores were assigned proportionally based on parameter estimates of the statistically significant predictors in the final COX model. Model selection and its comparison to the original IPI model were made based on Akaike Criteria (AIC) and the likelihood ratio test. Categorization of age and LDH was decided by testing the linearity assumption and Martingale residuals. Kaplan-Meier curves were plotted for stratified risk groups per the new and original IPI. Finally, both IPI models were compared using the initial randomly selected 15% validation sample. Results: There were 1,650 DLBCL patients with complete clinical information included for model development. The new IPI model consisted of similar component predictors but used a maximum of 8 scoring points by further categorizing age group into >40–60 (score of 1), >60–75 (score of 2) and >75 yrs (score of 3), and normalized LDH between >1–3 times (score of 1) and 33 times (score of 2) upper limit of normal. These categorizations minimized the Martingale residuals. Age effect was linear and 20-year increments fit the model best, whereas the effect of normalized LDH was not linear and reached plateau at a ratio of 3. Lymphomatous involvement either of bone marrow, CNS, Liver/GI tract or lung appeared as a stronger predictor (p<0.001) than number of extranodal sites (p=0.91). Four risk groups (Low, Low-intermediate, High-intermediate and High) were identified using the current IPI (Table 1) with enhanced discrimination power when compared with the original IPI and better global model fitting statistics, i.e. smaller AIC and significant likelihood ratio test (p<0.001). It was possible to identify a high risk group (score 3 6) with 5-year overall survival of 33% (95% CI: 22%–45%). Better model prediction was also shown in the validation sample. Conclusions: We were able to develop an enhanced IPI model for clinical prediction among previously untreated DLBCL cases by using patient level data from the NCCN NHL database. The NCCN-IPI demonstrates better risk stratification and identifies a poor risk subgroup with <50% 5-year overall survival in the current real-world clinical setting as compared to the original IPI model developed for aggressive lymphoma prior to the rituximab era. Disclosures: No relevant conflicts of interest to declare.

scholarly journals Imetelstat Significantly Reduces Leukemia Stem Cells in Patient-Derived Xenograft Models of Pediatric AML

Blood ◽  
2021 ◽  
Vol 138 (Supplement 1) ◽  
pp. 3352-3352
Author(s):  
Sonali P. Barwe ◽  
Fei Huang ◽  
E. Anders Kolb ◽  
Anilkumar Gopalakrishnapillai
Keyword(s):  
Stem Cells ◽  
Bone Marrow ◽  
Research Funding ◽  
Annexin V ◽  
Telomerase Activity ◽  
Leukemia Stem Cells ◽  
Patient Derived Xenograft ◽  
Pediatric Aml ◽  
Pdx Models

Abstract Introduction Acute myeloid leukemia (AML) is the deadliest malignancy in children. Despite the use of maximally intensive therapy, 20% of patients experience recurrent disease. These patients are also burdened with significant treatment-related toxicities. To improve survival in pediatric AML, novel targeted therapies that are more effective and less toxic are needed. Telomerase inhibition has been shown to be effective in reducing leukemic burden and eradicating leukemia stem cells (LSCs) in syngeneic mouse models of AML and in patient-derived xenograft (PDX) models of adult AML (Bruedigam et al., 2014). Recent transcriptome analyses demonstrate that the genomic landscape of pediatric AML is distinct from adult AML (Bolouri et al., 2018). In fact, mutations in the telomerase complex components are infrequent in pediatric AML unlike adult AML patients (Aalbers et al., 2013). However, similar to what is seen in adult patients, Aalbers et al. identified that telomere lengths in pediatric AML cells were shortened compared to normal leukocytes, and pediatric AML patients with the shortest telomere length tend to have shorter overall survival. Furthermore, the 5-year survival rate was 88% for pediatric AML patients who had lower telomerase activity, and 43% for those patients with higher telomerase activity, suggesting telomerase activity could be an important prognostic factor in pediatric AML patients (Verstovsek et al., 2003). Imetelstat is an oligonucleotide that specifically binds with high affinity to the RNA template of telomerase and is a potent, competitive inhibitor of telomerase enzymatic activity (Asai et al., 2003; Herbert et al., 2005). In this study, we evaluated if imetelstat has anti-leukemia activity in pediatric AML PDX models. Results The PDX lines tested in this study were derived using samples from pediatric AML patients who were 1-14 years old, representing different FAB subtypes. Mouse passaged pediatric AML PDX lines (n=6) were treated ex vivo with imetelstat or mismatch oligo control and the viability of LSC (CD34+CD38low population) was determined at 48 or 96 h by staining with BV785-human CD45, APC-human CD34, Pacific blue-human CD38, FITC conjugated annexin V and propidium iodide (PI). Imetelstat treatment significantly increased apoptosis/death (PI+/annexin V+) of the LSC population in a dose-dependent manner in all PDX lines evaluated (Fig. 1A, B), while it had limited activity on LSCs in normal pediatric bone marrow samples (n=4). The efficacy of imetelstat either alone or in combination with chemotherapy or azacitidine was evaluated in two distinct PDX models of pediatric AML in vivo. Mice engrafted with both NTPL-377 and DF-2 lived longer when treated with imetelstat than the untreated mice (Fig. 1C, D, n=5 each, P&lt;0.05). Mice receiving standard chemotherapy consisting of cytarabine and daunorubicin or azacitidine showed prolonged survival compared to the untreated mice. Interestingly, sequential administration of imetelstat following chemotherapy treatment provided additional benefit over chemotherapy alone (P&lt;0.01). Concurrent treatment of azacitidine and imetelstat further extended survival of these mice compared to azacitidine alone (P&lt;0.05). At the end of the in vivo studies, the percentage of LSC population was evaluated in the bone marrow of mice post euthanasia. There was a significant reduction of LSC population in mice treated with imetelstat compared to those treated with the mismatch oligo (Fig. 1E, F, P&lt;0.05). Neither chemotherapy nor azacitidine alone affected LSC population compared to untreated mice. However, imetelstat significantly reduced the LSC population when combined with chemotherapy or azacitidine compared to single agent (P&lt;0.05). These results were confirmed by secondary transplantation in mice, which showed delayed engraftment of cells isolated from imetelstat treated mice (Fig. 1G, H). Conclusions Imetelstat treatment of pediatric AML PDX samples showed significant dose- and time-dependent effects on the viability of the LSCs to induce cell apoptosis/death. These results were corroborated in vivo in two distinct PDX models which showed reduced LSC population and increased median survival in mice with imetelstat treatment. Combining imetelstat with chemotherapy or azacitidine further enhanced activity against LSCs, suggesting imetelstat could represent an effective therapeutic strategy for pediatric AML. Figure 1 Figure 1. Disclosures Barwe: Prelude Therapeutics: Research Funding. Huang: Geron Corp: Current Employment, Current equity holder in publicly-traded company. Gopalakrishnapillai: Geron: Research Funding.

scholarly journals Influence of metformin on HIF-1 pathway in multiple myeloma

2020 ◽  
Vol 72 (5) ◽  
pp. 1407-1417
Author(s):  
Kinga A. Kocemba-Pilarczyk ◽  
Sonia Trojan ◽  
Barbara Ostrowska ◽  
Małgorzata Lasota ◽  
Paulina Dudzik ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Bone Marrow ◽  
Plasma Cells ◽  
Treatment Strategies ◽  
Annexin V ◽  
Growth And Survival ◽  
Hypoxic Conditions ◽  
New Treatment ◽  
First Time ◽  
Pcr Techniques

Abstract Background Multiple myeloma (MM) is defined as plasma cells malignancy, developing in the bone marrow. At the beginning of the disease, the malignant plasma cells are dependent on bone marrow microenvironment, providing growth and survival factors. Importantly, the recent studies pointed hypoxia as an important factor promoting progression of MM. In particular, hypoxia-triggered HIF-1 signaling was shown to promote chemoresistance, angiogenesis, invasiveness and induction of immature phenotype, suggesting that strategies targeting HIF-1 may contribute to improvement of anti-myeloma therapies. Methods The Western Blot and RT-PCR techniques were applied to analyze the influence of metformin on HIF-1 pathway in MM cells. To evaluate the effect of metformin on the growth of MM cell lines in normoxic and hypoxic conditions the MTT assay was used. The apoptosis induction in metformin treated hypoxic and normoxic cells was verified by Annexin V/PI staining followed by FACS analysis. Results Our results showed, for the first time, that metformin inhibits HIF-1 signaling in MM cells. Moreover, we demonstrated the effect of metformin to be mainly oxygen dependent, since the HIF-1 pathway was not significantly affected by metformin in anoxic conditions as well as after application of hypoxic mimicking compound, CoCl2. Our data also revealed that metformin triggers the growth arrest without inducing apoptosis in either normoxic or hypoxic conditions. Conclusions Taken together, our study indicates metformin as a promising candidate for developing new treatment strategies exploiting HIF-1 signaling inhibition to enhance the overall anti-MM effect of currently used therapies, that may considerably benefit MM patients.

scholarly journals Improved Patient-Derived Xenograft Model for Acute Myeloid Leukemia

Blood ◽  
2014 ◽  
Vol 124 (21) ◽  
pp. 3491-3491 ◽  
Author(s):  
Xiaochuan Shan ◽  
Cedric Dos Santos ◽  
Chenghui Zhou ◽  
Georges Habineza Ndikuyeze ◽  
Anthony Secreto ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Research Funding ◽  
Xenograft Model ◽  
Mouse Strains ◽  
Mouse Bone Marrow ◽  
Tissue Samples ◽  
Hematopoietic Stem ◽  
Gm Csf ◽  
Nsg Mice ◽  
Patient Derived Xenograft

Abstract We previously demonstrated that the NSG (NOD-Scid-IL2Rgcnull) xenotransplantation is an improved model for human AML samples, allowing us to better understand and characterize AML biology, especially in the context of drug therapy studies (Sanchez et al., Leukemia 2009). However, we observed that approximately half of AML patients’ samples either did not engraft in NSG mice (based on <0.1% human blasts in mouse bone marrow) or showed low (0.1 to 1% blasts) and highly variable engraftment. Recently, NSG mice expressing human SCF, GM-CSF and IL-3 transgenes (NSG-S) have been reported to enhance the engraftment of normal hematopoietic stem cells and primary AML cells, although only a few AML patients were evaluated (Wunderlich M et al, Leukemia 2010). This report describes a comprehensive paired analysis of engraftment of AML samples in NSG and NSG-S mice. T-cell depleted AML cells (5 -10 x 106 per mouse) were injected intravenously in sub-lethally irradiated mice (n=5/AML sample). Leukemia engraftment was assessed up to 16 weeks after injection in peripheral blood (PB), spleen (SPL) and bone marrow (BM) based on the percentage and absolute number of human leukemic blasts (huCD45+CD33+/-CD3-) in each tissue. Samples from 71 AML patients, representing all FAB and prognosis groups, were injected in NSG mice and only 35 samples (49%) engrafted based on human blasts >0.5% in mouse BM. From these 35 NSG-engrafting samples, 14 were also injected in NSG-S mice and all of them engrafted. Leukemic burden was significantly (p ≤ 0.05) increased in NSG-S versus NSG mice: 39±21% vs 22±23% BM blasts, 21±15% vs 7±10% SPL blasts, 2,732±6,488 vs 141±221 blasts/ml PB. Interestingly, the dramatic increase in peripheral blast count observed in NSG-S mice provides new opportunities to use PB to monitor drug response for the many patient samples that show no or very low peripheral engraftment in NSG mice. However, for 7 of these 14 NSG-engrafting AML samples, the use of NSG-S mice as recipients was associated with rapid engraftment, excessive leukemic burden, anemia, weight loss and lethargy requiring early sacrifice and leading to shorter overall survival (54±26 days in NSG-S vs >90 days in NSG). Out of the 36 patients’ samples that failed to engraft in NSG mice, 19 were tested for engraftment in NSG-S mice. Remarkably, 14 out 19 (74%) samples engrafted (17±16% BM blasts, 8±12% SPL, and 1,418±4,609/ml PB blasts at Day 77 post-transplant) and the kinetics of engraftment were slower compared to AML samples that can engraft in both mouse strains. These results suggest that the presence of human SCF, GM-CSF and IL-3 in NSG-S is sufficient to rescue leukemia-initiating cells for most AML samples that fail to engraft in NSG mice. Only 5 out of 33 samples (15%) failed to engraft in NSG and NSG-S mice, indicating that the NSG-S BM microenvironment remains suboptimal for a small minority of AML samples. We are investigating if NSG-S engraftment is correlated to CD116, CD117, CD123 expression, cytogenetics, mutations, and prognosis. Overall, our results show that NSG-S mice represent a significant improvement over previous patient-derived xenograft models since they can (1) accelerate and enhance leukemic engraftment compared to NSG mice, and (2) support engraftment for 85% of our AML patients, making this model particularly useful for pre-clinical studies. Disclosures Dos Santos: Janssen R&D: Research Funding. Danet-Desnoyers:Janssen R&D: Research Funding.

scholarly journals Development of an Easily Accessible Patient-Derived Xenograft (PDX) Mouse Model in Multiple Myeloma

Blood ◽  
2019 ◽  
Vol 134 (Supplement_1) ◽  
pp. 5538-5538
Author(s):  
Can Li ◽  
Yogesh Jethava ◽  
Ivana Frech ◽  
Fenghuang Zhan
Keyword(s):  
Multiple Myeloma ◽  
Bone Marrow ◽  
Flow Cytometry ◽  
Mouse Model ◽  
Mouse Models ◽  
Mononuclear Cells ◽  
Plasma Cells ◽  
M Protein ◽  
Nsg Mice ◽  
Patient Derived Xenograft

Preclinical mouse models are important tools to recapitulate human multiple myeloma (MM) disease. Different preclinical models allow for specific hypothesis-driven research and enables researchers to address multiple questions. Though the SCID-Hu and SCID-synth-hu mice, and a recently established humanized mouse model containing the knock-in of human cytokine genes permit the growth of primary pre-neoplastic and malignant plasma cells, the high-cost, long-term workflow, lack of access to genetically engineered mice are overwhelming disadvantages of these current humanized MM mouse models. Our objective is to establish a unique patient-derived-xenograft (PDX) MM mouse model as an easily accessible approach for prevention and therapy of human MM disease. Bone marrow aspirates from MM patients upon diagnosis were obtained from the Multiple Myeloma Molecular Epidemiology Resource (University of Iowa) and mononuclear cells were isolated. Groups of 7-8 weeks old NOD/SCID/IL2RΥgnull (NSG) mice were administrated with sub-lethal irradiation. 3-5×106 unsorted MM patient-derived bone marrow mononuclear cells were intravenously injected into each recipient NSG mouse after irradiation. In order to monitor engraftment, recipient mice were bled weekly from week 2 after inoculation and serial Serum Protein Electrophoresis (SPEP) tests of recipient mice were performed. Detection of distinct M-protein band by the SPEP test with weight loss and/or limited mobility of injected recipient mice were indicative of successful MM engraftment and the endpoint of this study. M protein was found in all 30 mice after 3 ~ 5 weeks of injection human MM mononuclear cells. To further confirm that the M protein was secreted from human MM cells, we performed flow cytometry to determine human MM cells using anti-human CD138 antibody from mouse tissues. About 10% human CD138+ MM cells were detected in spleen and bone marrow from these PDX-NSG mice by flow cytometry, whereas human CD138+ cells were absent in irradiated control mice without injection of human MM cells. We also performed immunohistochemistry on bone marrow sections of PDX-NSG mice. Human CD138 protein and human light chain protein were positively stained on these samples. We next examined MM related organ damage, which is part of the defining criteria of human MM disease. Elevated blood urea nitrogen (BUN) was detected in xenograft mouse serum compared to control mice, suggesting renal insufficiency rendered by MM engraftment. Meanwhile, xenograft mouse kidney sections were stained with PAS (Periodic acid-Schiff), which demonstrated protein and cellular cast nephropathy and inflammatory infiltration. We also performed TRAP staining on representative xenograft mouse bone sections. TRAP positive osteoclasts were increased in the distal portions of the femur bones derived from these PDX-NSG mice. We present robust data that a newly developed PDX-NSG model can grow primary human MM cells. Our hypothesis holds that cells from the same patient bone marrow microenvironment support tumor plasma cells survival and growth. These factors enables this new model to recapitulate more accurately the features of human MM. We will further investigate whether this new humanized PDX-NSG model provides a better tool for understanding MM development and for a personalized medicine. Disclosures Zhan: BIPHARM LLC: Consultancy, Other: % Allocation of Profit.

scholarly journals Establishment and characterisation of testicular cancer patient-derived xenograft models for preclinical evaluation of novel therapeutic strategies

2020 ◽  
Vol 10 (1) ◽  
Author(s):  
Gerda de Vries ◽  
Ximena Rosas-Plaza ◽  
Gert Jan Meersma ◽  
Vincent C. Leeuwenburgh ◽  
Klaas Kok ◽  
...  
Keyword(s):  
Testicular Cancer ◽  
Therapeutic Strategies ◽  
Ki 67 ◽  
Nsg Mice ◽  
Molecular Features ◽  
Patient Derived Xenograft ◽  
Cisplatin Sensitivity ◽  
Novel Therapeutic Strategies ◽  
Pdx Models ◽  
Novel Therapeutic

Abstract Testicular cancer (TC) is the most common solid tumour in young men. While cisplatin-based chemotherapy is highly effective in TC patients, chemoresistance still accounts for 10% of disease-related deaths. Pre-clinical models that faithfully reflect patient tumours are needed to assist in target discovery and drug development. Tumour pieces from eight TC patients were subcutaneously implanted in NOD scid gamma (NSG) mice. Three patient-derived xenograft (PDX) models of TC, including one chemoresistant model, were established containing yolk sac tumour and teratoma components. PDX models and corresponding patient tumours were characterised by H&E, Ki-67 and cyclophilin A immunohistochemistry, showing retention of histological subtypes over several passages. Whole-exome sequencing, copy number variation analysis and RNA-sequencing was performed on these TP53 wild type PDX tumours to assess the effects of passaging, showing high concordance of molecular features between passages. Cisplatin sensitivity of PDX models corresponded with patients’ response to cisplatin-based chemotherapy. MDM2 and mTORC1/2 targeted drugs showed efficacy in the cisplatin sensitive PDX models. In conclusion, we describe three PDX models faithfully reflecting chemosensitivity of TC patients. These models can be used for mechanistic studies and pre-clinical validation of novel therapeutic strategies in testicular cancer.

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