PMCID string | Title string | Sentences string |
|---|---|---|
PMC12852540 | Choosing the right animal model for sarcoma research | The subsequent phase II trial confirmed that palbociclib achieved clinically meaningful disease stabilisation with a 12-week progression-free rate of approximately 60% in this molecularly selected population and more recent CDK4/CDKN2A-guided phase II work has extended this paradigm to additional sarcoma subtypes . |
PMC12852540 | Choosing the right animal model for sarcoma research | The primary advantages of CDXs are their reproducibility and ease of use, making them a fundamental tool for preclinical sarcoma research. |
PMC12852540 | Choosing the right animal model for sarcoma research | Using well-characterised human sarcoma cell lines, such as U-2 OS for osteosarcoma and SW872 for liposarcoma , CDX models provide consistent and predictable tumour growth in immunocompromised mice. |
PMC12852540 | Choosing the right animal model for sarcoma research | This reproducibility allows researchers to perform standardised experiments, compare therapeutic effects across studies, and reliably evaluate drug efficacy. |
PMC12852540 | Choosing the right animal model for sarcoma research | Moreover, compared to 2D or 3D cultures of the same cell lines, CDX adds vascular delivery, stromal crosstalk and in vivo pharmacokinetics. |
PMC12852540 | Choosing the right animal model for sarcoma research | These factors modify the ranking of responses and reveal effects dependent on schedule and exposure that are invisible in vitro. |
PMC12852540 | Choosing the right animal model for sarcoma research | For example, CDX models have been instrumental in testing chemotherapeutic agents, such as doxorubicin and ifosfamide , which remain the cornerstones of sarcoma treatment. |
PMC12852540 | Choosing the right animal model for sarcoma research | They have also been used to explore novel targeted therapies , such as CDK4/6 inhibitors, in dedifferentiated liposarcoma, demonstrating their utility in preclinical drug development . |
PMC12852540 | Choosing the right animal model for sarcoma research | The scalability of CDX systems enables high-throughput drug screening and combination therapy studies, in which multiple agents can be tested simultaneously to identify synergistic effects. |
PMC12852540 | Choosing the right animal model for sarcoma research | Notably, unlike syngeneic or chemically induced mouse tumours, CDX reproduces the aneuploidy, copy-number changes and fusion landscapes of human sarcomas to some extent because the malignant genome is human. |
PMC12852540 | Choosing the right animal model for sarcoma research | This improves construct validity for genotype-directed agents. |
PMC12852540 | Choosing the right animal model for sarcoma research | Imaging technologies, such as bioluminescence and MRI, further enhance CDX models by allowing real-time tracking of tumour growth and treatment response . |
PMC12852540 | Choosing the right animal model for sarcoma research | For example, VEGF inhibitors have been studied in CDX angiosarcoma models to investigate their impact on tumour angiogenesis . |
PMC12852540 | Choosing the right animal model for sarcoma research | In addition, the rapid tumour growth and cost-effectiveness of CDX models make them ideal starting points for hypothesis generation and initial therapeutic evaluation before moving on to more complex models such as patient-derived xenografts (PDXs). |
PMC12852540 | Choosing the right animal model for sarcoma research | The primary limitation of CDX models is their inability to recapitulate the complex microenvironment and immune-tumour interactions of human sarcomas. |
PMC12852540 | Choosing the right animal model for sarcoma research | Because host mice are immunocompromised, these models cannot be used to study the efficacy of immunotherapies such as checkpoint inhibitors targeting CTLA-4 or PD-1, which are increasingly being investigated in soft tissue sarcomas such as alveolar soft part sarcoma . |
PMC12852540 | Choosing the right animal model for sarcoma research | CDX can be established either subcutaneously or orthotopically . |
PMC12852540 | Choosing the right animal model for sarcoma research | The latter improves the fidelity of the microenvironment for bone and soft tissue niches as the subcuteneous implantation does not accurately simulate the native tissue environment of sarcomas such as the periosteal or bone marrow microenvironment critical for osteosarcoma or the retroperitoneal space relevant for liposarcoma . |
PMC12852540 | Choosing the right animal model for sarcoma research | These discrepancies reduce the ability of these models to study site-specific tumour behaviour or therapeutic responses. |
PMC12852540 | Choosing the right animal model for sarcoma research | Reliance on established cell lines also presents challenges as these lines often represent highly proliferative or aggressive subclones that lack the genetic heterogeneity of primary sarcomas. |
PMC12852540 | Choosing the right animal model for sarcoma research | For example, while CDX models are useful for studying general tumour biology, they do not effectively recapitulate key genetic fusions, such as FUS-DDIT3 in myxoid liposarcoma or NAB2-STAT6 in solitary fibrous tumours . |
PMC12852540 | Choosing the right animal model for sarcoma research | In addition, cell lines can undergo genetic drift during prolonged culture, which further diverges from the characteristics of the original tumour. |
PMC12852540 | Choosing the right animal model for sarcoma research | Although subcutaneous CDXs rarely metastasise, orthotopic and tail-vein or intracardiac models using luciferase-labelled sarcoma lines often produce lung or systemic metastases. |
PMC12852540 | Choosing the right animal model for sarcoma research | This makes longitudinal bioluminescent tracking possible. |
PMC12852540 | Choosing the right animal model for sarcoma research | To broaden the CDX perspective, luciferase-labelled metastatic models span osteosarcoma, host–genetic susceptibility, and fusion-driven soft-tissue sarcoma. |
PMC12852540 | Choosing the right animal model for sarcoma research | In osteosarcoma, intratibial implantation of luciferase-tagged Saos2 enabled derivation of a lung-metastasis–enriched subline (Saos2-l) with spontaneous pulmonary dissemination quantified by bioluminescence imaging; the study reports increased adhesion, migration and invasion in Saos2-l relative to parental cells In a host-genetics paradigm, tail-vein S180-Fluc yielded lung-restricted colonisation with marked strain effects – A/J mice develop high burden whereas BTBRT + tf/J clear disease – and resistance is diminished by supralethal irradiation and T-cell depletion, highlighting immune control . |
PMC12852540 | Choosing the right animal model for sarcoma research | Extending luciferase CDX to a translocation-positive entity, clear cell sarcoma (EWSR1–ATF1/CREB) CCS292-Luc produced multi-organ metastases after intravenous injection into NSG mice with weekly bioluminescence tracking, providing a fusion-driven metastasis model suitable for therapeutic testing . |
PMC12852540 | Choosing the right animal model for sarcoma research | Despite their utility for initial drug testing, the high failure rate of therapies that perform well in CDX models, but fail in clinical trials, underscores their limited predictive power. |
PMC12852540 | Choosing the right animal model for sarcoma research | These limitations necessitate complementing CDX models with more advanced systems, such as PDXs or genetically engineered mouse models (GEMMs), to achieve greater translational relevance. |
PMC12852540 | Choosing the right animal model for sarcoma research | An alternative to CDX is the transplantation of fresh tumour tissue from cancer patients into immunocompromised mice, creating PDX models. |
PMC12852540 | Choosing the right animal model for sarcoma research | Patient-derived xenografts (PDX) are mainly used to preserve patient-specific histology, genomic complexity and intra-tumour heterogeneity, enabling subtype-appropriate testing of targeted agents and combinations, co-clinical trial designs and exploratory biomarker validation in a setting that closely mirrors the treated human tumour . |
PMC12852540 | Choosing the right animal model for sarcoma research | Moreover, PDX resources are available for subtypes for which there are no reliable, shareable cell lines, such as EHE, DSRCT and MPNST. |
PMC12852540 | Choosing the right animal model for sarcoma research | This is a sarcoma-specific issue, and PDX is the only method that enables preclinical testing in this area. |
PMC12852540 | Choosing the right animal model for sarcoma research | Generation of established PDX models requires at least three consecutive transplantations of developed tumours in mice. |
PMC12852540 | Choosing the right animal model for sarcoma research | Tumor fragments are implanted subcutaneously into the flanks of nude mice under sterile conditions. |
PMC12852540 | Choosing the right animal model for sarcoma research | First-generation tumours (P1) are harvested when they reached a volume of 1500 mm³ and reimplanted into additional mice to generate second (P2) and third (P3) generations. |
PMC12852540 | Choosing the right animal model for sarcoma research | Numerous models have been successfully developed, achieving an engraftment success rate ranging from 32% to 69% and effectively replicating the genetic and phenotypic traits of the original tumour . |
PMC12852540 | Choosing the right animal model for sarcoma research | PDX models have gained prominence in sarcoma research due to their ability to mimic the complexity and heterogeneity of human tumours. |
PMC12852540 | Choosing the right animal model for sarcoma research | For example, Gebreyohannes and colleagues demonstrated that the tyrosine kinase inhibitor cabozantinib effectively reduced tumour growth in both imatinib-sensitive and resistant PDX models of GISTs . |
PMC12852540 | Choosing the right animal model for sarcoma research | Similarly, Van Looy’s team showed that combining PI3K inhibitors with imatinib reduced tumour volumes in GIST PDX models . |
PMC12852540 | Choosing the right animal model for sarcoma research | PDX models are particularly useful in predicting patient responses to therapies and are increasingly applied in personalised medicine . |
PMC12852540 | Choosing the right animal model for sarcoma research | For instance, in osteosarcoma, PDX models are particularly important due to the genetic complexity and heterogeneity of the disease . |
PMC12852540 | Choosing the right animal model for sarcoma research | Tumours from less aggressive sarcoma subtypes, such as low-grade chondrosarcoma, showed lower engraftment rates, as did samples with extensive necrosis or those collected after chemotherapy. |
PMC12852540 | Choosing the right animal model for sarcoma research | Nanni et al. . |
PMC12852540 | Choosing the right animal model for sarcoma research | highlighted the close resemblance between the original tumours and their PDX models by examining molecular markers such as SATB2 and P-glycoprotein in osteosarcoma (OS) and CD99 in Ewing sarcoma (EW). |
PMC12852540 | Choosing the right animal model for sarcoma research | These characteristics were maintained over multiple in vivo passages, demonstrating the stability of the models. |
PMC12852540 | Choosing the right animal model for sarcoma research | Gene expression profiling confirmed a high correlation between patient tumours and their corresponding PDX models (Pearson’s r = 0.94–0.96), which remained consistent over successive passages. |
PMC12852540 | Choosing the right animal model for sarcoma research | The study tested a novel therapeutic combination of anti-CD99 diabody (C7) and irinotecan in EW PDX models and demonstrated that this treatment significantly reduced tumour growth and, in some cases, eliminated metastases. |
PMC12852540 | Choosing the right animal model for sarcoma research | This finding highlights the utility of PDX models for the novel therapeutic strategies evaluation. |
PMC12852540 | Choosing the right animal model for sarcoma research | Compared to primary cell cultures derived from patient samples, PDX models more closely recapitulated the molecular and genetic characteristics of the original tumours. |
PMC12852540 | Choosing the right animal model for sarcoma research | In contrast, in vitro models exhibited significant genetic drift, making them less reliable for translational research. |
PMC12852540 | Choosing the right animal model for sarcoma research | The PDX models of OS showed faster tumour growth in early passages compared to EW models, but their growth rates stabilised in subsequent passages. |
PMC12852540 | Choosing the right animal model for sarcoma research | The study also showed that untreated OS samples had a higher engraftment success rate compared to post-chemotherapy samples, highlighting the influence of pre-treatment on the efficiency of PDX establishment. |
PMC12852540 | Choosing the right animal model for sarcoma research | In addition, the ability to generate PDX models often depended on the specific tumour sample rather than patient-related factors, as samples from the same patient occasionally gave inconsistent results. |
PMC12852540 | Choosing the right animal model for sarcoma research | By including both paediatric and adult bone sarcoma samples, the study created a valuable resource for investigating tumour biology in different age groups. |
PMC12852540 | Choosing the right animal model for sarcoma research | The authors ensured the reliability of the PDX models for long-term research by performing multiple in vivo passages and using bioinformatic analysis to confirm their molecular stability. |
PMC12852540 | Choosing the right animal model for sarcoma research | In addition, by avoiding enzymatic dissociation and using direct implantation, the structural and cellular integrity of the tumours was maintained, increasing the fidelity of the models to the original patient tumours. |
PMC12852540 | Choosing the right animal model for sarcoma research | Translational signal from PDX-guided decisions is quantifiable: in a 92-patient co-clinical series linking 129 PDX-tested regimens to matched therapies, sensitivity was 96% (80/83), specificity 70% (32/46), positive predictive value 85% (80/94), and negative predictive value 91% (32/35); performance was highest when the PDX screen informed the first post-resection treatment (PPV 94%, NPV 94%) . |
PMC12852540 | Choosing the right animal model for sarcoma research | Mechanism-anchored sarcoma exemplars underscore practical impact but also limits: CDK4/6 inhibition advanced from xenograft-supported preclinical work to phase II trials in CDK4-amplified WD/DD liposarcoma with 12-week PFS 66% and median PFS 18 weeks on 200 mg 14/21, and 12-week PFS 57.2% with median PFS 17.9 weeks on 125 mg 21/28 , while MDM2 antagonism informed by PDXs shows early activity (brigimadlin disease-control rate 75% in DDLPS) and is now in randomised testing ; together these data indicate that PDXs can enrich for clinical benefit and de-prioritise ineffective options, though predictive accuracy may fall with intervening therapies and the absence of an intact immune system necessitates humanised variants for immunotherapy questions . |
PMC12852540 | Choosing the right animal model for sarcoma research | Selinexor, a selective inhibitor of nuclear export targeting XPO1, has been evaluated in carefully characterised patient-derived xenograft models of dedifferentiated liposarcoma. |
PMC12852540 | Choosing the right animal model for sarcoma research | Three PDXs (LS-GD-1 with rhabdomyoblastic, LS-BZ-1 and LS-BP-1 with myogenic dedifferentiation) were established from the dedifferentiated component of primary, treatment-naïve, retroperitoneal FNCLCC grade 3 tumours harbouring amplification of MDM2, CDK4 and HMGA2; 3-mm³ fragments were implanted subcutaneously into CB17/SCID mice, serially passaged, then engrafted into nude mice for efficacy studies .When tumours reached about 150 mm³, mice (n = 8 per group) received selinexor 10 mg/kg orally twice weekly for eight doses versus doxorubicin 4 mg/kg intravenously every 7 days × 3, with selinexor achieving greater maximum tumour volume inhibition (46–80% vs. 37–60%) and longer growth delay, without excess weight loss or overt toxicity .Pharmacodynamic analyses showed reduced XPO1 and survivin expression, nuclear accumulation of p53 and p21, and increased cleaved caspase-3 and TUNEL positivity, indicating apoptosis driven by nuclear retention of tumour suppressors and depletion of cytoplasmic survivin .More recently, GIST PDX collections recapitulating specific primary and secondary KIT/PDGFRA mutations have been used prospectively to select mutation-specific inhibitor candidates – such as AZD3229 – and to define dose levels yielding sustained KIT blockade and regression in vivo before entry into first-in-human trials .illustrating how contemporary PDX platforms can provide a “ready-to-use” translational filter for next-generation TKIs . |
PMC12852540 | Choosing the right animal model for sarcoma research | Despite their advantages, PDX models have limitations. |
PMC12852540 | Choosing the right animal model for sarcoma research | The need for immunodeficient mice to prevent graft rejection means that critical immune-tumour interactions, such as those involving T cells or macrophages, can only be studied in combination with humanised immune systems . |
PMC12852540 | Choosing the right animal model for sarcoma research | In addition, establishing a PDX model can take several months and the success rate depends on factors such as tumour type, tissue quality and pre-treatment status. |
PMC12852540 | Choosing the right animal model for sarcoma research | Shimade et al. . |
PMC12852540 | Choosing the right animal model for sarcoma research | aimed to establish a PDX model for pleomorphic leiomyosarcoma (PLMS), a rare and aggressive subtype of leiomyosarcoma, using tissue obtained from a single patient. |
PMC12852540 | Choosing the right animal model for sarcoma research | Among the ten tumor samples transplanted into SCID mice, only one successfully proliferated, reflecting the significant challenges in establishing sarcoma PDX models due to variability in tumor biology and host compatibility. |
PMC12852540 | Choosing the right animal model for sarcoma research | The resulting PDX tumor retained the key histological features of primary PLMS, including spindle cell proliferation and marked nuclear pleomorphism. |
PMC12852540 | Choosing the right animal model for sarcoma research | Immunohistochemistry further confirmed the expression of smooth muscle markers such as SMA, caldesmon, and M-actin, demonstrating that the PDX model closely recapitulates the differentiation characteristics of PLMS. |
PMC12852540 | Choosing the right animal model for sarcoma research | Despite the low initial engraftment rate, the established PDX model exhibited stable growth across successive passages (P1 to P3), with its histological and immunohistochemical features remaining consistent. |
PMC12852540 | Choosing the right animal model for sarcoma research | Tumor growth rates increased with each passage, likely reflecting adaptation to the murine microenvironment. |
PMC12852540 | Choosing the right animal model for sarcoma research | This PDX model provides a valuable platform for studying the rare pathology of PLMS, offering insights into its aggressive growth behavior and distinct histological features. |
PMC12852540 | Choosing the right animal model for sarcoma research | While specific drug trials were not conducted in this study, the model was proposed as a potential tool for screening therapies for PLMS, a cancer with limited treatment options and poor prognosis. |
PMC12852540 | Choosing the right animal model for sarcoma research | The exceptionally low engraftment rate (10%) underscores the inherent difficulties in establishing sarcoma PDX models, particularly for rare and aggressive subtypes such as PLMS. |
PMC12852540 | Choosing the right animal model for sarcoma research | The authors speculated that high malignancy, rapid cell division, and eventual adaptation to the murine environment were key factors contributing to the ultimate success of the model. |
PMC12852540 | Choosing the right animal model for sarcoma research | The observation that only one of ten tumour fragments engrafted highlights the importance of spatial heterogeneity in terms of both biology and stromal content. |
PMC12852540 | Choosing the right animal model for sarcoma research | It also suggests that a single PDX may not capture the full range of subclonal, therapeutically relevant diversity. |
PMC12852540 | Choosing the right animal model for sarcoma research | In another study focusing on the generation of PDX models for challenging tumour types such as GISTs, a total of 185 tumour samples from 176 patients were used. |
PMC12852540 | Choosing the right animal model for sarcoma research | These samples were collected from patients both before (35.7%) and after (64.3%) tyrosine kinase inhibitor (TKI) treatment. |
PMC12852540 | Choosing the right animal model for sarcoma research | Tumour fragments were implanted subcutaneously into NSG mice shortly after surgical resection. |
PMC12852540 | Choosing the right animal model for sarcoma research | Successfully engrafted tumours were excised when they reached 1.5–2 cm in diameter and re-implanted in subsequent generations of mice (F1, F2). |
PMC12852540 | Choosing the right animal model for sarcoma research | Despite these efforts, only 31 PDX models were successfully established, resulting in a low overall success rate of 16.8%. |
PMC12852540 | Choosing the right animal model for sarcoma research | Interestingly, the success rate was significantly higher for tumours harvested after TKI treatment (25.2%) compared to untreated tumours (1.5%). |
PMC12852540 | Choosing the right animal model for sarcoma research | Several factors influenced the likelihood of successful transplantation. |
PMC12852540 | Choosing the right animal model for sarcoma research | Larger tumours (> 100 mm) had a much higher success rate (37.5%) compared to smaller tumours (6.5% for tumours ≤ 50 mm). |
PMC12852540 | Choosing the right animal model for sarcoma research | Tumours with high mitotic counts and a Ki-67 index of ≥ 1/3 had a 42.9% success rate, while those with lower Ki-67 indices had a success rate of only 5.4%. |
PMC12852540 | Choosing the right animal model for sarcoma research | High cellularity was another critical factor, with a success rate of 26.2% compared to only 4.9% for tumours with low cellularity. |
PMC12852540 | Choosing the right animal model for sarcoma research | The presence of necrosis was also associated with a higher engraftment rate (26.4% compared to 8.3% for tumours without necrosis). |
PMC12852540 | Choosing the right animal model for sarcoma research | In addition, samples with KIT exon 11 mutations had a higher engraftment rate (22.4%) than those with other mutations or wild-type tumours. |
PMC12852540 | Choosing the right animal model for sarcoma research | The resulting PDX tumours retained the histological characteristics of the original patient tumours, including cell morphology and mitotic activity. |
PMC12852540 | Choosing the right animal model for sarcoma research | Molecular stability over multiple passages was confirmed using Ki-67 staining and immunohistochemistry, further validating the reliability of the models for preclinical research. |
PMC12852540 | Choosing the right animal model for sarcoma research | Similarly, in alveolar rhabdomyosarcoma, PDX models have been used to study the role of the PAX3‒FOXO1 fusion in driving oncogenesis and resistance to chemotherapy .These models are particularly valuable for evaluating precision therapies because they can be used to test targeted agents in tumours with actionable mutations or amplifications, such as FGFR2 in myxofibrosarcoma or PDGFRA in gastrointestinal stromal tumours (GISTs) . |
PMC12852540 | Choosing the right animal model for sarcoma research | For example, they have been used to study how ALK mutations in inflammatory myofibroblastic tumours confer resistance to ALK inhibitors and to provide a platform for testing next-generation inhibitors. |
PMC12852540 | Choosing the right animal model for sarcoma research | Another key advantage is their use in personalised medicine; PDX models can serve as avatars for individual patients, allowing researchers to test multiple treatment regimens on a patient’s tumor to identify the most effective therapy. |
PMC12852540 | Choosing the right animal model for sarcoma research | For example, PDX models derived from dedifferentiated liposarcoma have been used to test novel combinations of CDK4/6 inhibitors with chemotherapy, providing critical insights for optimising therapeutic strategies. |
PMC12852540 | Choosing the right animal model for sarcoma research | Additional limitations of PDX models are their complexity, cost, and the time required to develop and maintain them. |
PMC12852540 | Choosing the right animal model for sarcoma research | Establishing a PDX model requires fresh patient tumour samples, often obtained through invasive surgery or biopsy, and the engraftment process can take several months. |
PMC12852540 | Choosing the right animal model for sarcoma research | Success rates vary by sarcoma subtype, with more aggressive tumours such as undifferentiated pleomorphic sarcoma having higher engraftment rates than indolent subtypes such as low-grade chondrosarcoma. |
PMC12852540 | Choosing the right animal model for sarcoma research | This variability limits their scalability to high-throughput drug screening and large-scale studies. |
PMC12852540 | Choosing the right animal model for sarcoma research | In addition, PDX models rely on immunocompromised mice that lack a functional immune system, making them unsuitable for studying immuno-oncology therapies, such as anti-CTLA-4 or PD-1/PD-L1 checkpoint inhibitors, which are gaining traction in sarcomas, such as deddifferentiated liposarcoma . |
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