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1
Varticovski, L., M. G. Hollingshead, M. R. Anver, A. I. Robles, J. E. Green, K. W. Hunter, G. Merlino et al. "Preclinical testing using tumors from genetically engineered mouse mammary models". Journal of Clinical Oncology 24, n. 18_suppl (20 giugno 2006): 10067. http://dx.doi.org/10.1200/jco.2006.24.18_suppl.10067.
Abstract (sommario):
10067 Background: Mouse models have been used extensively in preclinical testing of anticancer drugs. However, few of these models reflect the progression of human disease, and even fewer predict the performance of these drugs in clinical trials. Testing anticancer therapies in genetically engineered mouse (GEM) holds the promise of improving preclinical models and guiding the design of clinical trials. Unfortunately, the use of tumor-bearing GEM is hampered by the difficulty in simultaneously obtaining sufficient numbers of animals with the same stage of tumor development. The additional complexity in testing breast cancer therapies in the mouse is that all 10 mammary glands can develop tumors, frequently at different times. Methods: To circumvent the variable tumor latency and lack of synchrony in GEM, we transplanted tumor fragments or cell suspensions from multiple mammary tumor-bearing GEM into the mammary fat pad or subcutaneously into naïve syngeneic, immunodeficient athymic nude, or scid mice. Results: Tumors transplanted as fragments or cell suspensions derived from anterior mammary gland grew faster than the posterior tumors for serial passages without any significant morphologic differences. Cell suspensions using fresh or frozen cells were equally effective in generating tumors, and increasing the numbers of transplanted cells resulted in faster tumor growth. The transplantation strategy was reproducible in multiple breast cancer mouse models, including MMTV-PyMT, -Her2/neu, -wnt1/p53, BRCA1/p53, and others. Metastatic disease in the lungs was evident after removing the primary tumors at different rates for each mouse model. The transplanted primary tumors and the tumors arising in the original GEM had similar morphologic appearance and sensitivity to several chemotherapeutic and novel molecular targeted agents. Conclusions: We have established transplantable synchronous mammary tumors from GEM which also develop metastatic disease. These valuable mouse models are suitable for studying tumor-host interactions, tumor progression, and preclinical testing in a well-characterized molecular and genetic background. Testing these GEM tumors for conventional and novel molecular targeted therapies will be discussed. No significant financial relationships to disclose.
2
Klenner, Marbod, Pia Freidel, Mariella G. Filbin e Alexander Beck. "DIPG-39. New preclinical models for Diffuse Midline Glioma". Neuro-Oncology 24, Supplement_1 (1 giugno 2022): i27. http://dx.doi.org/10.1093/neuonc/noac079.096.
Abstract (sommario):
Abstract Malignant brain tumors are the leading cause of childhood death in Germany, with Diffuse Midline Glioma (DMG) being the most lethal of all paediatric brain tumors. Current treatment strategies are limited to irradiation which prolongs survival only by a few months. Preclinical studies have identified effective drug candidates, but translation into the clinic remains a major obstacle. It is known that interactions between tumor cells and components of the TME (tumor microenvironment), such as cell to cell contacts between malignant and non-malignant cells or secreted factors, can increase therapy resistance and progression of brain tumors. However, these important factors are not present in most conventional cell culture models for drug testing. Consequently, there is a need for more realistic DMG models to improve the relevance and translational potential of current drug screening. Therefore, the goal of this study was to develop a new DMG model for drug testing, consisting of induced pluripotent stem cell (iPSC) derived human brain cells and patient derived DMG cells to better mimic the complex tumor microenvironment. We co-cultured three-dimensional cerebral organoids with DMG tumor spheres resulting in the formation of DMG-Brain-Organoids (DBO). Preliminary results show that co-culture induces distinct tumor cell subpopulations corresponding to those detected in DMG tumors by single cell RNA sequencing (Filbin et al., 2018). These subpopulations mainly differ in their proliferative capacity and their differential response to clinical interventions may be critical for therapeutic success. DBOs subjected to drug treatments (single or combination) were sectioned and individual therapy effects on tumor cell subpopulations and proliferative capacity were monitored using multiplexed immunofluorescence imaging. By observing drug effects in a realistic setup, we hope to improve the predictive power of our preclinical drug screens and to find new combination therapies for DMG.
3
Costa, Alice, Livia Gozzellino, Margherita Nannini, Annalisa Astolfi, Maria Abbondanza Pantaleo e Gianandrea Pasquinelli. "Preclinical Models of Visceral Sarcomas". Biomolecules 13, n. 11 (6 novembre 2023): 1624. http://dx.doi.org/10.3390/biom13111624.
Abstract (sommario):
Visceral sarcomas are a rare malignant subgroup of soft tissue sarcomas (STSs). STSs, accounting for 1% of all adult tumors, are derived from mesenchymal tissues and exhibit a wide heterogeneity. Their rarity and the high number of histotypes hinder the understanding of tumor development mechanisms and negatively influence clinical outcomes and treatment approaches. Although some STSs (~20%) have identifiable genetic markers, as specific mutations or translocations, most are characterized by complex genomic profiles. Thus, identification of new therapeutic targets and development of personalized therapies are urgent clinical needs. Although cell lines are useful for preclinical investigations, more reliable preclinical models are required to develop and test new potential therapies. Here, we provide an overview of the available in vitro and in vivo models of visceral sarcomas, whose gene signatures are still not well characterized, to highlight current challenges and provide insights for future studies.
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Llaguno-Munive, Monserrat, Wilberto Villalba-Abascal, Alejandro Avilés-Salas e Patricia Garcia-Lopez. "Near-Infrared Fluorescence Imaging in Preclinical Models of Glioblastoma". Journal of Imaging 9, n. 10 (6 ottobre 2023): 212. http://dx.doi.org/10.3390/jimaging9100212.
Abstract (sommario):
Cancer is a public health problem requiring ongoing research to improve current treatments and discover novel therapies. More accurate imaging would facilitate such research. Near-infrared fluorescence has been developed as a non-invasive imaging technique capable of visualizing and measuring biological processes at the molecular level in living subjects. In this work, we evaluate the tumor activity in two preclinical glioblastoma models by using fluorochrome (IRDye 800CW) coupled to different molecules: tripeptide Arg-Gly-Asp (RGD), 2-amino-2-deoxy-D-glucose (2-DG), and polyethylene glycol (PEG). These molecules interact with pathological conditions of tumors, including their overexpression of αvβ3 integrins (RGD), elevated glucose uptake (2-DG), and enhanced permeability and retention effect (PEG). IRDye 800CW RGD gave the best in vivo fluorescence signal from the tumor area, which contrasted well with the low fluorescence intensity of healthy tissue. In the ex vivo imaging (dissected tumor), the accumulation of IRDye 800CW RGD could be appreciated at the tumor site. Glioblastoma tumors were presently detected with specificity and sensitivity by utilizing IRDye 800CW RGD, a near-infrared fluorophore combined with a marker of αvβ3 integrin expression. Further research is needed on its capacity to monitor tumor growth in glioblastoma after chemotherapy.
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Sewduth, Raj N., e Konstantina Georgelou. "Relevance of Carcinogen-Induced Preclinical Cancer Models". Journal of Xenobiotics 14, n. 1 (5 gennaio 2024): 96–109. http://dx.doi.org/10.3390/jox14010006.
Abstract (sommario):
Chemical agents can cause cancer in animals by damaging their DNA, mutating their genes, and modifying their epigenetic signatures. Carcinogen-induced preclinical cancer models are useful for understanding carcinogen-induced human cancers, as they can reproduce the diversity and complexity of tumor types, as well as the interactions with the host environment. However, these models also have some drawbacks that limit their applicability and validity. For instance, some chemicals may be more effective or toxic in animals than in humans, and the tumors may differ in their genetics and phenotypes. Some chemicals may also affect normal cells and tissues, such as by causing oxidative stress, inflammation, and cell death, which may alter the tumor behavior and response to therapy. Furthermore, some chemicals may have variable effects depending on the exposure conditions, such as dose, route, and duration, as well as the animal characteristics, such as genetics and hormones. Therefore, these models should be carefully chosen, validated, and standardized, and the results should be cautiously interpreted and compared with other models. This review covers the main features of chemically induced cancer models, such as genetic and epigenetic changes, tumor environment, angiogenesis, invasion and metastasis, and immune response. We also address the pros and cons of these models and the current and future challenges for their improvement. This review offers a comprehensive overview of the state of the art of carcinogen-induced cancer models and provides new perspectives for cancer research.
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Roosen, Mieke, Chris Meulenbroeks, Phylicia Stathi, Joris Maas, Julie Morscio, Jens Bunt e Marcel Kool. "BIOL-11. PRECLINICAL MODELLING OF PEDIATRIC BRAIN TUMORS USING ORGANOID TECHNOLOGY". Neuro-Oncology 25, Supplement_1 (1 giugno 2023): i8. http://dx.doi.org/10.1093/neuonc/noad073.030.
Abstract (sommario):
Abstract Molecular characterization has resulted in improved classification of pediatric brain tumors, leading to many novel (sub)types with distinct oncodriving events. To study tumor biology and to perform translational research on each of these tumors, preclinical models are essential. However, we are currently lacking sufficient models, especially in vitro, to represent each (sub)type and their heterogeneity. To generate large series of preclinical in vitro models for pediatric brain tumors, we are using organoid technology. Cells from patient samples and patient-derived xenograft samples have been taken into culture to establish 3D organoids using tumor type specific culture conditions. These organoid lines retain the molecular characteristics of the original tumor tissue. They can be used to perform high-throughput drug screens, genetic manipulations, and co-cultures with, for instance, immune cells. Viable tissue is not always available for all tumor (sub)types and specific oncodrivers. To circumvent this lack of tissue, we can also induce tumors in vitro. Therefore, we generate cerebral and cerebellar brain organoids from human pluripotent stem cells. These organoids mimic human developing brain cells and can be genetically manipulated to model different brain tumor types. These genetically engineered brain tumor models allow us to study the cellular origins of pediatric brain tumors and the different tumor driving mechanisms. Tumors induced in the brain organoids histologically and molecularly resemble human patient samples based on (single cell) transcriptomic analyses. Moreover, the tumor cells are able to establish xenografts in mouse brains. In summary, organoid technology provides a novel avenue to establish in vitro models for pediatric brain tumors. At the meeting we will present data for various new ependymoma, medulloblastoma and embryonal brain tumor organoid models.
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Stripay, Jennifer L., Thomas E. Merchant, Martine F. Roussel e Christopher L. Tinkle. "Preclinical Models of Craniospinal Irradiation for Medulloblastoma". Cancers 12, n. 1 (5 gennaio 2020): 133. http://dx.doi.org/10.3390/cancers12010133.
Abstract (sommario):
Medulloblastoma is an embryonal tumor that shows a predilection for distant metastatic spread and leptomeningeal seeding. For most patients, optimal management of medulloblastoma includes maximum safe resection followed by adjuvant craniospinal irradiation (CSI) and chemotherapy. Although CSI is crucial in treating medulloblastoma, the realization that medulloblastoma is a heterogeneous disease comprising four distinct molecular subgroups (wingless [WNT], sonic hedgehog [SHH], Group 3 [G3], and Group 4 [G4]) with distinct clinical characteristics and prognoses has refocused efforts to better define the optimal role of CSI within and across disease subgroups. The ability to deliver clinically relevant CSI to preclinical models of medulloblastoma offers the potential to study radiation dose and volume effects on tumor control and toxicity in these subgroups and to identify subgroup-specific combination adjuvant therapies. Recent efforts have employed commercial image-guided small animal irradiation systems as well as custom approaches to deliver accurate and reproducible fractionated CSI in various preclinical models of medulloblastoma. Here, we provide an overview of the current clinical indications for, and technical aspects of, irradiation of pediatric medulloblastoma. We then review the current literature on preclinical modeling of and treatment interventions for medulloblastoma and conclude with a summary of challenges in the field of preclinical modeling of CSI for the treatment of leptomeningeal seeding tumors.
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Sitta, Juliana, Pier Paolo Claudio e Candace M. Howard. "Virus-Based Immuno-Oncology Models". Biomedicines 10, n. 6 (18 giugno 2022): 1441. http://dx.doi.org/10.3390/biomedicines10061441.
Abstract (sommario):
Immunotherapy has been extensively explored in recent years with encouraging results in selected types of cancer. Such success aroused interest in the expansion of such indications, requiring a deep understanding of the complex role of the immune system in carcinogenesis. The definition of hot vs. cold tumors and the role of the tumor microenvironment enlightened the once obscure understanding of low response rates of solid tumors to immune check point inhibitors. Although the major scope found in the literature focuses on the T cell modulation, the innate immune system is also a promising oncolytic tool. The unveiling of the tumor immunosuppressive pathways, lead to the development of combined targeted therapies in an attempt to increase immune infiltration capability. Oncolytic viruses have been explored in different scenarios, in combination with various chemotherapeutic drugs and, more recently, with immune check point inhibitors. Moreover, oncolytic viruses may be engineered to express tumor specific pro-inflammatory cytokines, antibodies, and antigens to enhance immunologic response or block immunosuppressive mechanisms. Development of preclinical models capable to replicate the human immunologic response is one of the major challenges faced by these studies. A thorough understanding of immunotherapy and oncolytic viruses’ mechanics is paramount to develop reliable preclinical models with higher chances of successful clinical therapy application. Thus, in this article, we review current concepts in cancer immunotherapy including the inherent and synthetic mechanisms of immunologic enhancement utilizing oncolytic viruses, immune targeting, and available preclinical animal models, their advantages, and limitations.
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Ortiz, Michael Vincent, Armaan Siddiquee, Daoqi You, Prabhjot Singh Mundi, Lianna Marks, Kristina Guillan, Daniel Diolaiti et al. "Preclinical evaluation of XPO1 inhibition in Wilms tumors." Journal of Clinical Oncology 38, n. 15_suppl (20 maggio 2020): 3580. http://dx.doi.org/10.1200/jco.2020.38.15_suppl.3580.
Abstract (sommario):
3580 Background: XPO1 is a nuclear export protein that selectively transports tumor and growth regulatory proteins out of the nucleus, thereby effectively inhibiting their function. We previously utilized the Virtual Inference of Protein-activity by Enriched Regulon analysis (VIPER) algorithm to discover that malignant rhabdoid tumors were dependent upon XPO1 inhibition and then evaluated a preclinical cohort using selinexor (KPT-330), the first-in-class selective inhibitor of nuclear export, to demonstrate that XPO1 inhibition was sufficient to cause cell cycle arrest, apoptosis, and disease control in multiple cell line and patient derived xenograft (PDXs) models. Our subsequent analysis revealed that the most common childhood kidney tumor, Wilms tumor, has even high higher inferred activity of XPO1 than rhabdoid tumors leading to our hypothesis that XPO1 inhibition is an effective therapeutic strategy to treat Wilms tumors. Methods: A panel of 9 Wilms tumor cell lines and 3 Wilms tumor PDXs were genomically characterized and tested to evaluate the pre-clinical efficacy of XPO1 inhibition in Wilms tumors. Results: Proliferation rate, increased XPO1 protein expression, and loss of function mutations in TP53 correlated with in vitro Wilms tumor cell line sensitivity to selinexor. Evaluation of co-segregation of all single nucleotide variant changes using with inferred activity of XPO1 on VIPER in all TGCA tumors demonstrates a strong association with TP53 alterations. XPO1 inhibition was effective in all Wilms tumor models tested, most significantly in MSKREN-57196, a favorable histology Wilms tumor PDX with somatic 1q gain as well as WTX and MYCN mutations, as well as in MSKREN-31827, a diffusely anaplastic TP53 mutant Wilms tumor PDX. Eltanexor (KPT-8602) is an XPO1 inhibitor with decreased CNS penetration and an improved toxicity profile; this drug was tested in these in vivo models and found to be at least as effective as selinexor. Conclusions: Somatic 1q gain in favorable histology Wilms tumors and TP53 mutations in diffusely anaplastic Wilms tumors have a particularly poor prognosis in the relapsed setting. Our study demonstrates that XPO1 inhibition may provide a rational therapeutic option to treat such high-risk Wilms tumors. Future clinical trials evaluating XPO1 inhibitors should evaluate its efficacy in children with relapsed Wilms tumors.
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Bella, Ángela, Claudia Augusta Di Trani, Myriam Fernández-Sendin, Leire Arrizabalaga, Assunta Cirella, Álvaro Teijeira, José Medina-Echeverz, Ignacio Melero, Pedro Berraondo e Fernando Aranda. "Mouse Models of Peritoneal Carcinomatosis to Develop Clinical Applications". Cancers 13, n. 5 (25 febbraio 2021): 963. http://dx.doi.org/10.3390/cancers13050963.
Abstract (sommario):
Peritoneal carcinomatosis of primary tumors originating in gastrointestinal (e.g., colorectal cancer, gastric cancer) or gynecologic (e.g., ovarian cancer) malignancies is a widespread type of tumor dissemination in the peritoneal cavity for which few therapeutic options are available. Therefore, reliable preclinical models are crucial for research and development of efficacious treatments for this condition. To date, a number of animal models have attempted to reproduce as accurately as possible the complexity of the tumor microenvironment of human peritoneal carcinomatosis. These include: Syngeneic tumor cell lines, human xenografts, patient-derived xenografts, genetically induced tumors, and 3D scaffold biomimetics. Each experimental model has its own strengths and limitations, all of which can influence the subsequent translational results concerning anticancer and immunomodulatory drugs under exploration. This review highlights the current status of peritoneal carcinomatosis mouse models for preclinical development of anticancer drugs or immunotherapeutic agents.
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Mahmoudian, Reihaneh Alsadat, Moein Farshchian, Fatemeh Fardi Golyan, Parvaneh Mahmoudian, Ali Alasti, Vahid Moghimi, Mina Maftooh et al. "Preclinical tumor mouse models for studying esophageal cancer". Critical Reviews in Oncology/Hematology 189 (settembre 2023): 104068. http://dx.doi.org/10.1016/j.critrevonc.2023.104068.
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Tada, Takuya, Thomas D. Norton, Rebecca Leibowitz e Nathaniel R. Landau. "Checkpoint inhibitor-expressing lentiviral vaccine suppresses tumor growth in preclinical cancer models". Journal for ImmunoTherapy of Cancer 12, n. 4 (aprile 2024): e008761. http://dx.doi.org/10.1136/jitc-2023-008761.
Abstract (sommario):
BackgroundWhile immunotherapy has been highly successful for the treatment of some cancers, for others, the immune response to tumor antigens is weak leading to treatment failure. The resistance of tumors to checkpoint inhibitor therapy may be caused by T cell exhaustion resulting from checkpoint activation.MethodsIn this study, lentiviral vectors that expressed T cell epitopes of an experimentally introduced tumor antigen, ovalbumin, or the endogenous tumor antigen, Trp1 were developed. The vectors coexpressed CD40 ligand (CD40L), which served to mature the dendritic cells (DCs), and a soluble programmed cell death protein 1 (PD-1) microbody to prevent checkpoint activation. Vaccination of mice bearing B16.OVA melanomas with vector-transduced DCs induced the proliferation and activation of functional, antigen-specific, cytolytic CD8 T cells.ResultsVaccination induced the expansion of CD8 T cells that infiltrated the tumors to suppress tumor growth. Vector-encoded CD40L and PD-1 microbody increased the extent of tumor growth suppression. Adoptive transfer demonstrated that the effect was mediated by CD8 T cells. Direct injection of the vector, without the need for ex vivo transduction of DCs, was also effective.ConclusionsThis study suggests that therapeutic vaccination that induces tumor antigen-specific CD8 T cells coupled with a vector-expressed checkpoint inhibitor can be an effective means to suppress the growth of tumors that are resistant to conventional immunotherapy.
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Baniahmad, Aria. "Tumor spheroids and organoids as preclinical model systems". Medizinische Genetik 33, n. 3 (1 settembre 2021): 229–34. http://dx.doi.org/10.1515/medgen-2021-2093.
Abstract (sommario):
Abstract The generation of three-dimensional (3D) cancer models is a novel and fascinating development in the study of personalized medicine and tumor-specific drug delivery. In addition to the classical two-dimensional (2D) adherent cell culture models, 3D spheroid and organoid cancer models that mimic the microenvironment of cancer tissue are emerging as an important preclinical model system. 3D cancer models form, similar to cancer, multiple cell–cell and cell–extracellular matrix interactions and activate different cellular cascades/pathways, like proliferation, quiescence, senescence, and necrotic or apoptotic cell death. Further, it is possible to analyze genetic variations and mutations, the microenvironment of cell–cell interactions, and the uptake of therapeutics and nanoparticles in nanomedicine. Important is also the analysis of cancer stem cells (CSCs), which could play key roles in resistance to therapy and cancer recurrence. Tumor spheroids can be generated from one tumor-derived cell line or from co-culture of two or more cell lines. Tumor organoids can be derived from tumors or may be generated from CSCs that differentiate into multiple facets of cancerous tissue. Similarly, tumorspheres can be generated from a single CSC. By transplanting spheroids and organoids into immune-deficient mice, patient-derived xenografts can serve as a preclinical model to test therapeutics in vivo. Although the handling and analysis of 3D tumor spheroids and organoids is more complex, it will provide insights into various cancer processes that cannot be provided by 2D culture. Here a short overview of 3D tumor systems as preclinical models is provided.
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Tellez-Gabriel, Marta, Denis Cochonneau, Marie Cadé, Camille Jubelin, Marie-Françoise Heymann e Dominique Heymann. "Circulating Tumor Cell-Derived Pre-Clinical Models for Personalized Medicine". Cancers 11, n. 1 (24 dicembre 2018): 19. http://dx.doi.org/10.3390/cancers11010019.
Abstract (sommario):
The main cause of death from cancer is associated with the development of metastases, resulting from the inability of current therapies to cure patients at metastatic stages. Generating preclinical models to better characterize the evolution of the disease is thus of utmost importance, in order to implement effective new cancer biomarkers and therapies. Circulating Tumor Cells (CTCs) are good candidates for generating preclinical models, making it possible to follow up the spatial and temporal heterogeneity of tumor tissues. This method is a non-invasive liquid biopsy that can be obtained at any stage of the disease. It partially summarizes the molecular heterogeneity of the corresponding tumors at a given time. Here, we discuss the CTC-derived models that have been generated so far, from simplified 2D cultures to the most complex CTC-derived explants (CDX models). We highlight the challenges and strengths of these preclinical tools, as well as some of the recent studies published using these models.
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Ehrenberg, Karl Roland, Jianpeng Gao, Felix Oppel, Stephanie Frank, Na Kang, Sebastian M. Dieter, Friederike Herbst et al. "Systematic Generation of Patient-Derived Tumor Models in Pancreatic Cancer". Cells 8, n. 2 (10 febbraio 2019): 142. http://dx.doi.org/10.3390/cells8020142.
Abstract (sommario):
In highly aggressive malignancies like pancreatic cancer (PC), patient-derived tumor models can serve as disease-relevant models to understand disease-related biology as well as to guide clinical decision-making. In this study, we describe a two-step protocol allowing systematic establishment of patient-derived primary cultures from PC patient tumors. Initial xenotransplantation of surgically resected patient tumors (n = 134) into immunodeficient mice allows for efficient in vivo expansion of vital tumor cells and successful tumor expansion in 38% of patient tumors (51/134). Expansion xenografts closely recapitulate the histoarchitecture of their matching patients’ primary tumors. Digestion of xenograft tumors and subsequent in vitro cultivation resulted in the successful generation of semi-adherent PC cultures of pure epithelial cell origin in 43.1% of the cases. The established primary cultures include diverse pathological types of PC: Pancreatic ductal adenocarcinoma (86.3%, 19/22), adenosquamous carcinoma (9.1%, 2/22) and ductal adenocarcinoma with oncocytic IPMN (4.5%, 1/22). We here provide a protocol to establish quality-controlled PC patient-derived primary cell cultures from heterogeneous PC patient tumors. In vitro preclinical models provide the basis for the identification and preclinical assessment of novel therapeutic opportunities targeting pancreatic cancer.
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Pinto, Bárbara, Ana C. Henriques, Patrícia M. A. Silva e Hassan Bousbaa. "Three-Dimensional Spheroids as In Vitro Preclinical Models for Cancer Research". Pharmaceutics 12, n. 12 (6 dicembre 2020): 1186. http://dx.doi.org/10.3390/pharmaceutics12121186.
Abstract (sommario):
Most cancer biologists still rely on conventional two-dimensional (2D) monolayer culture techniques to test in vitro anti-tumor drugs prior to in vivo testing. However, the vast majority of promising preclinical drugs have no or weak efficacy in real patients with tumors, thereby delaying the discovery of successful therapeutics. This is because 2D culture lacks cell–cell contacts and natural tumor microenvironment, important in tumor signaling and drug response, thereby resulting in a reduced malignant phenotype compared to the real tumor. In this sense, three-dimensional (3D) cultures of cancer cells that better recapitulate in vivo cell environments emerged as scientifically accurate and low cost cancer models for preclinical screening and testing of new drug candidates before moving to expensive and time-consuming animal models. Here, we provide a comprehensive overview of 3D tumor systems and highlight the strategies for spheroid construction and evaluation tools of targeted therapies, focusing on their applicability in cancer research. Examples of the applicability of 3D culture for the evaluation of the therapeutic efficacy of nanomedicines are discussed.
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Davy, Mélodie, Laurie Genest, Christophe Legrand, Océane Pelouin, Guillaume Froget, Vincent Castagné e Tristan Rupp. "Evaluation of Temozolomide and Fingolimod Treatments in Glioblastoma Preclinical Models". Cancers 15, n. 18 (8 settembre 2023): 4478. http://dx.doi.org/10.3390/cancers15184478.
Abstract (sommario):
Glioblastomas are malignant brain tumors which remain lethal due to their aggressive and invasive nature. The standard treatment combines surgical resection, radiotherapy, and chemotherapy using Temozolomide, albeit with a minor impact on patient prognosis (15 months median survival). New therapies evaluated in preclinical translational models are therefore still required to improve patient survival and quality of life. In this preclinical study, we evaluated the effect of Temozolomide in different models of glioblastoma. We also aimed to investigate the efficacy of Fingolimod, an immunomodulatory drug for multiple sclerosis also described as an inhibitor of the sphingosine-1-phosphate (S1P)/S1P receptor axis. The effects of Fingolimod and Temozolomide were analyzed with in vitro 2D and 3D cellular assay and in vivo models using mouse and human glioblastoma cells implanted in immunocompetent or immunodeficient mice, respectively. We demonstrated both in in vitro and in vivo models that Temozolomide has a varied effect depending on the tumor type (i.e., U87MG, U118MG, U138MG, and GL261), demonstrating sensitivity, acquired resistance, and purely resistant tumor phenotypes, as observed in patients. Conversely, Fingolimod only reduced in vitro 2D tumor cell growth and increased cytotoxicity. Indeed, Fingolimod had little or no effect on 3D spheroid cytotoxicity and was devoid of effect on in vivo tumor progression in Temozolomide-sensitive models. These results suggest that the efficacy of Fingolimod is dependent on the glioblastoma tumor microenvironment. Globally, our data suggest that the response to Temozolomide varies depending on the cancer model, consistent with its clinical activity, whereas the potential activity of Fingolimod may merit further evaluation.
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Koptyra, Mateusz, Valerie Baubet, David Beale, Luke Patterson, Ian Biluck, Madison Hollawell, Christopher M. Beck et al. "MODL-30. Children’s Brain Tumor Network preclinical tumor models development and sharing platform: collaborative model empowering pediatric brain tumor discovery and global research." Neuro-Oncology 24, Supplement_1 (1 giugno 2022): i175—i176. http://dx.doi.org/10.1093/neuonc/noac079.653.
Abstract (sommario):
Abstract Pediatric brain tumor preclinical field suffered for years from the lack of in vitro and in vivo models. With the explosion of novel therapy approaches for solid and brain tumors, including the immunotherapies it is essential to maximize the access to preclinical models for preclinical specificity, efficacy as well and safety. One of the many ways the Children’s Brain Tumor Network (CBTN) accelerates the pediatric brain tumor research and discovery is through support of the tumor model development program. This program focuses on the generation, characterization, and distribution of diverse models to investigators worldwide provided free of charge. Here we present the resource platform with over 150 cell lines, organoids and patient derived xenografts (PDX) developed and/or propagated at D3b at CHOP on behalf of CBTN. This platform maximizes the tumor tissue use to generate a combination of cell line, organoids and/or xenograft models grown in animals. In recent years, consortium supported over 40 requests for cells lines used in basic biology and translational studies internationally. Current efforts focusing also on supporting large-scale data generation and testing through its collaborative model (Childhood Cancer Model Atlas, Procan, National Center for Advancing Translational Sciences) to maximize the molecular information available for each tumor model essential in preclinical screenings. The generated and returned to consortia data are bound with the deidentified patient clinical information and genomic data and freely available through Kid’s First Data, Cavatica and PedcBio portals. These efforts have already attracted interest from pharma stakeholders previously not observed in pediatric brain environment. This open-source repository model is an example of a unique research partnership supported by patients and their families and built with one mission to bring fast change to kids suffering from brain tumors.
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Mohr, Hermine, e Natalia S. Pellegata. "Animal models of MEN1". Endocrine-Related Cancer 24, n. 10 (ottobre 2017): T161—T177. http://dx.doi.org/10.1530/erc-17-0249.
Abstract (sommario):
Animal models of cancer have been instrumental in advancing our understanding of the biology of tumor initiation and progression, in studying gene function and in performing preclinical studies aimed at testing novel therapies. Several animal models of the MEN1 syndrome have been generated in different organisms by introducing loss-of-function mutations in the orthologues of the humanMEN1gene. In this review, we will discuss MEN1 and MEN1-like models in Drosophila, mice and rats. These model systems with their specific advantages and limitations have contributed to elucidate the function of Menin in tumorigenesis, which turned out to be remarkably conserved from flies to mammals, as well as the biology of the disease. Mouse models of MEN1 closely resemble the human disease in terms of tumor spectrum and associated hormonal changes, although individual tumor frequencies are variable. Rats affected by the MENX (MEN1-like) syndrome share some features with MEN1 patients albeit they bear a germline mutation inCdkn1b(p27) and not inMen1. BothMen1-knockout mice and MENX rats have been exploited for therapy-response studies testing novel drugs for efficacy against neuroendocrine tumors (NETs) and have provided promising leads for novel therapies. In addition to presenting well-established models of MEN1, we also discuss potential models which, if implemented, might broaden even further our knowledge of neuroendocrine tumorigenesis. In the future, patient-derived xenografts in zebrafish or mice might allow us to expand the tool-box currently available for preclinical studies of MEN1-associated tumors.
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Minami, Jenna, Nicholas Bayley, Christopher Tse, Henan Zhu, Danielle Morrow, William Yong, Linda Liau, Timothy Cloughesy, Thomas Graeber e David Nathanson. "TAMI-06. PRECLINICAL MODELS REVEAL BRAIN-MICROENVIRONMENT SPECIFIC METABOLIC DEPENDENCIES IN GLIOBLASTOMA". Neuro-Oncology 22, Supplement_2 (novembre 2020): ii214. http://dx.doi.org/10.1093/neuonc/noaa215.895.
Abstract (sommario):
Abstract Metabolic reprogramming is a hallmark of cancer, and malignant cells must acquire metabolic adaptations to fuel neoplastic progression. Mutations or changes in metabolic gene expression can impose nutrient dependencies in tumors, and even in the absence of metabolic defects, cancer cells can become auxotrophic for particular nutrients or metabolic byproducts generated by other cells in the tumor microenvironment (TME). Conventional cell lines do not recapitulate the metabolic heterogeneity of glioblastoma (GBM), while primary cultured cells do not account for the influences of the microenvironment and the blood brain barrier on tumor biology. Additionally, these systems are under strong selective pressure divergent from that in vivo, leading to reduced heterogeneity between cultured tumor cells. Here, we describe a biobank of direct-from-patient derived orthotopic xenografts (GliomaPDOX) and gliomaspheres that reveal a subset of gliomas that, while able to form in vivo, cannot survive in vitro. RNA sequencing of tumors that can form both in vivo and in vitro (termed “TME-Indifferent”) compared to that of tumors that can only form in vivo (termed “TME-Dependent”) revealed transcriptional changes associated with altered nutrient availability, emphasizing the unique metabolic programs impacted by the tumor microenvironment. Furthermore, TME-dependent tumors lack metabolic signatures associated with nutrient biosynthesis, thus indicating a potential dependency of these tumors on scavenging specific nutrients from the extracellular milieu. Collectively, these data emphasize the metabolic heterogeneity within GBM, and reveal a subset of gliomas that lack metabolic plasticity, indicating a potential brain-microenvironment specific metabolic dependency that can be targeted for therapy.
21
Hollawell, Madison, Valerie Baubet, David Beale, Luke Patterson, Ian Biluck, Ciana Anthony, Peeyush Goel et al. "BIOL-22. CHILDREN’S BRAIN TUMOR NETWORK PRECLINICAL TUMOR MODELS DEVELOPMENT AND SHARING PLATFORM: COLLABORATIVE MODEL EMPOWERING PEDIATRIC BRAIN TUMOR DISCOVERY AND GLOBAL RESEARCH". Neuro-Oncology 25, Supplement_1 (1 giugno 2023): i10—i11. http://dx.doi.org/10.1093/neuonc/noad073.041.
Abstract (sommario):
Abstract Pediatric brain tumor preclinical development has suffered from the lack of robust in vitro and in vivo models that span the large number of brain tumor histologies. Opportunities for precision medicine approaches for solid and brain tumors are expanding, including immunotherapies, so it is essential to maximize access to preclinical models for studies of specificity, efficacy, and safety of treatments in ways that align patient models to patient samples and their clinical course. The Children’s Brain Tumor Network (CBTN) seeks to accelerate pediatric brain tumor research and discovery through support of the tumor model development program paired with molecularly characterized patient samples and longitudinal clinical data. This program focuses on the generation, characterization, and distribution of diverse models to investigators worldwide. Here we present currently available preclinical model resources comprising over 150 cell lines, organoids, and patient derived xenografts (PDX) developed and/or propagated at D3b at CHOP on behalf of CBTN. This platform maximizes the use of tumor tissue to generate a combination of cell lines, organoids and/or xenograft models grown in animals. To date, consortium-supported lines have been provided internationally to over 50 projects, encompassing basic biology and translational studies. Molecular data (whole genome sequencing and RNAseq) is currently available for over 80 models and a substantial portion of that cohort undergoes additional large-scale data generation and drug testing through collaborative work with Childhood Cancer Model Atlas, ProCan, and National Center for Advancing Translational Sciences. All models’ data are accompanied with patient molecular and clinical longitudinal information accessible through Kids First Data Resource, CAVATICA and PedcBio portals. This open-source repository model is an example of a unique research partnership supported by patients and their families and built with one mission – to accelerate therapeutic discovery for children suffering from brain tumors.
22
Hansson, Karin, Katarzyna Radke, Kristina Aaltonen, Jani Saarela, Adriana Mañas, Jonas Sjölund, Emma M. Smith et al. "Therapeutic targeting of KSP in preclinical models of high-risk neuroblastoma". Science Translational Medicine 12, n. 562 (23 settembre 2020): eaba4434. http://dx.doi.org/10.1126/scitranslmed.aba4434.
Abstract (sommario):
Neuroblastoma is a childhood malignancy with often dismal prognosis; relapse is common despite intense treatment. Here, we used human tumor organoids representing multiple MYCN-amplified high-risk neuroblastomas to perform a high-throughput drug screen with approved or emerging oncology drugs. Tumor-selective effects were calculated using drug sensitivity scores. Several drugs with previously unreported anti-neuroblastoma effects were identified by stringent selection criteria. ARRY-520, an inhibitor of kinesin spindle protein (KSP), was among those causing reduced viability. High expression of the KSP-encoding gene KIF11 was associated with poor outcome in neuroblastoma. Genome-scale loss-of-function screens in hundreds of human cancer cell lines across 22 tumor types revealed that KIF11 is particularly important for neuroblastoma cell viability. KSP inhibition in neuroblastoma patient-derived xenograft (PDX) cells resulted in the formation of abnormal monoastral spindles, mitotic arrest, up-regulation of mitosis-associated genes, and apoptosis. In vivo, KSP inhibition caused regression of MYCN-amplified neuroblastoma PDX tumors. Furthermore, treatment of mice harboring orthotopic neuroblastoma PDX tumors resulted in increased survival. Our results suggested that KSP inhibition could be a promising treatment strategy in children with high-risk neuroblastoma.
23
Minami, Jenna, Nicholas Bayley, Christopher Tse, Henan Zhu, Danielle Morrow, William Yong, Linda Liau, Timothy F. Cloughesy, Thomas Graeber e David A. Nathanson. "ETMM-02. PRECLINICAL MODELS REVEAL BRAIN-MICROENVIRONMENT SPECIFIC METABOLIC DEPENDENCIES IN GLIOBLASTOMA". Neuro-Oncology Advances 3, Supplement_1 (1 marzo 2021): i14. http://dx.doi.org/10.1093/noajnl/vdab024.058.
Abstract (sommario):
Abstract Metabolic reprogramming is a hallmark of cancer, and malignant cells must acquire metabolic adaptations in response to a multitude of intrinsic and extrinsic factors to fuel neoplastic progression. Mutations or changes in metabolic gene expression can impose nutrient dependencies in tumors, and even in the absence of metabolic defects, cancer cells can become auxotrophic for particular nutrients or metabolic byproducts generated by other cells in the tumor microenvironment (TME). Conventional cell lines do not recapitulate the metabolic heterogeneity of glioblastoma (GBM), while primary cultured cells do not account for the influences of the microenvironment and the blood brain barrier on tumor biology. Additionally, these systems are under strong selective pressure divergent from that in vivo, leading to reduced heterogeneity between cultured tumor cells. Here, we describe a biobank of direct-from-patient derived orthotopic xenografts (GliomaPDOX) and gliomaspheres that reveal a subset of gliomas that, while able to form in vivo, cannot survive in vitro. RNA sequencing of tumors that can form both in vivo and in vitro (termed “TME-Indifferent”) compared to that of tumors that can only form in vivo (termed “TME-Dependent”) revealed transcriptional changes associated with altered nutrient availability, emphasizing the unique metabolic programs impacted by the tumor microenvironment. Furthermore, TME-dependent tumors lack metabolic signatures associated with nutrient biosynthesis, thus indicating a potential dependency of these tumors on scavenging specific nutrients from the extracellular milieu. Collectively, these data emphasize the metabolic heterogeneity within GBM and reveal a subset of gliomas that lack metabolic plasticity, indicating a potential brain-microenvironment specific metabolic dependency that can be targeted for therapy.
24
Sgouros, George, Robert F. Hobbs e Diane S. Abou. "The Role of Preclinical Models in Radiopharmaceutical Therapy". American Society of Clinical Oncology Educational Book, n. 34 (maggio 2014): e121-e125. http://dx.doi.org/10.14694/edbook_am.2014.34.e121.
Abstract (sommario):
Radiopharmaceutical therapy (RPT) is a treatment modality that involves the use of radioactively labeled targeting agents to deliver a cytotoxic dose of radiation to tumor while sparing normal tissue. The biologic function of the target and the biologic action of the targeting agent is largely irrelevant as long as the targeting agent delivers cytotoxic radiation to the tumor. Preclinical RPT studies use imaging and ex vivo evaluation of radioactivity concentration in target and normal tissues to obtain biodistribution and pharmacokinetic data that can be used to evaluate radiation absorbed doses. Since the efficacy and toxicity of RPT depend on radiation absorbed dose, this quantity can be used to translate results from preclinical studies to human studies. The absorbed dose can also be used to customize therapy to account for pharmacokinetic and other differences among patients so as to deliver a prespecified absorbed dose to the tumor or to dose-limiting tissue. The combination of RPT with other agents can be investigated and optimized by identifying the effect of other agents on tumor or normal tissue radiosensitivity and also on how other agents change the absorbed dose to these tissues. RPT is a distinct therapeutic modality whose mechanism of action is well understood. Measurements can be made in preclinical models to help guide clinical implementation of RPT and optimize combination therapy using RPT.
25
Dobson, Tara, e Vidya Gopalakrishnan. "Preclinical Models of Pediatric Brain Tumors—Forging Ahead". Bioengineering 5, n. 4 (2 ottobre 2018): 81. http://dx.doi.org/10.3390/bioengineering5040081.
Abstract (sommario):
Approximately five out of 100,000 children from 0 to 19 years old are diagnosed with a brain tumor. These children are treated with medication designed for adults that are highly toxic to a developing brain. Those that survive are at high risk for a lifetime of limited physical, psychological, and cognitive abilities. Despite much effort, not one drug exists that was designed specifically for pediatric patients. Stagnant government funding and the lack of economic incentives for the pharmaceutical industry greatly limits preclinical research and the development of clinically applicable pediatric brain tumor models. As more data are collected, the recognition of disease sub-groups based on molecular heterogeneity increases the need for designing specific models suitable for predictive drug screening. To overcome these challenges, preclinical approaches will need continual enhancement. In this review, we examine the advantages and shortcomings of in vitro and in vivo preclinical pediatric brain tumor models and explore potential solutions based on past, present, and future strategies for improving their clinical relevancy.
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Forde, Patrick F., Mira Sadadcharam, Michael G. Bourke, Thomas A. Conway, Shane R. Guerin, Marcel de Kruijf, Gerald C. O’Sullivan, Joseph Impellizeri, Anthony J. P. Clover e Declan M. Soden. "Preclinical evaluation of an endoscopic electroporation system". Endoscopy 48, n. 05 (4 aprile 2016): 477–83. http://dx.doi.org/10.1055/s-0042-101343.
Abstract (sommario):
Background and study aims: Targeted delivery of specific chemotherapeutic drugs into tumors can be achieved by delivering electrical pulses directly to the tumor tissue. This causes a transient formation of pores in the cell membrane that enables passive diffusion of normally impermeant drugs. A novel device has been developed to enable the endoscopic delivery of this tumor permeabilizing treatment. The aim of the preclinical studies described here was to investigate the efficacy and safety of this nonthermal ablation system in the treatment of gastrointestinal cancer models. Methods: Murine, porcine, and canine gastrointestinal tumors and tissues were used to assess the efficacy and safety of electroporation delivered through the special device in combination with bleomycin. Tumor cell death, volume, and overall survival were recorded. Results: Murine tumors treated with electrochemotherapy showed excellent responses, with cell death being induced rapidly, mainly via an apoptotic-type mechanism. Use of the system in canine gastrointestinal cancers demonstrated successful local endoluminal tumor resolution, with no safety or adverse effects noted. Conclusions: Electroporation via the new device in combination with bleomycin offers a nonthermal tumor ablative approach, and presents clinicians with a new option for the management of gastrointestinal cancers.
27
Chen, Stephen R., Frederick F. Lang e Peter Kan. "Preclinical animal brain tumor models for interventional neuro-oncology". Journal of NeuroInterventional Surgery 14, n. 5 (12 aprile 2022): neurintsurg—2022–018968. http://dx.doi.org/10.1136/neurintsurg-2022-018968.
28
Wu, Jianrong, e Peter J. Houghton. "Assessing Cytotoxic Treatment Effects in Preclinical Tumor Xenograft Models". Journal of Biopharmaceutical Statistics 19, n. 5 (7 agosto 2009): 755–62. http://dx.doi.org/10.1080/10543400903105158.
29
Banerjee, Sulagna, Venugopal Thayanithy, Veena Sangwan, Tiffany N. Mackenzie, Ashok K. Saluja e Subbaya Subramanian. "Minnelide reduces tumor burden in preclinical models of osteosarcoma". Cancer Letters 335, n. 2 (luglio 2013): 412–20. http://dx.doi.org/10.1016/j.canlet.2013.02.050.
30
Vitale, Giovanni, Silvia Carra, Ylenia Alessi, Federica Campolo, Carla Pandozzi, Isabella Zanata, Annamaria Colao e Antongiulio Faggiano. "Carcinoid Syndrome: Preclinical Models and Future Therapeutic Strategies". International Journal of Molecular Sciences 24, n. 4 (10 febbraio 2023): 3610. http://dx.doi.org/10.3390/ijms24043610.
Abstract (sommario):
Carcinoid syndrome represents a debilitating paraneoplastic disease, caused by the secretion of several substances, occurring in about 10–40% of patients with well-differentiated neuroendocrine tumors (NETs). The main signs and symptoms associated with carcinoid syndrome are flushing, diarrhea, hypotension, tachycardia, bronchoconstriction, venous telangiectasia, dyspnea and fibrotic complications (mesenteric and retroperitoneal fibrosis, and carcinoid heart disease). Although there are several drugs available for the treatment of carcinoid syndrome, the lack of therapeutic response, poor tolerance or resistance to drugs are often reported. Preclinical models are indispensable tools for investigating the pathogenesis, mechanisms for tumor progression and new therapeutic approaches for cancer. This paper provides a state-of-the-art overview of in vitro and in vivo models in NETs with carcinoid syndrome, highlighting the future developments and therapeutic approaches in this field.
31
McCloskey, Curtis, Galaxia Rodriguez, Kristianne Galpin e Barbara Vanderhyden. "Ovarian Cancer Immunotherapy: Preclinical Models and Emerging Therapeutics". Cancers 10, n. 8 (26 luglio 2018): 244. http://dx.doi.org/10.3390/cancers10080244.
Abstract (sommario):
Immunotherapy has emerged as one of the most promising approaches for ovarian cancer treatment. The tumor microenvironment (TME) is a key factor to consider when stimulating antitumoral responses as it consists largely of tumor promoting immunosuppressive cell types that attenuate antitumor immunity. As our understanding of the determinants of the TME composition grows, we have begun to appreciate the need to address both inter- and intra-tumor heterogeneity, mutation/neoantigen burden, immune landscape, and stromal cell contributions. The majority of immunotherapy studies in ovarian cancer have been performed using the well-characterized murine ID8 ovarian carcinoma model. Numerous other animal models of ovarian cancer exist, but have been underutilized because of their narrow initial characterizations in this context. Here, we describe animal models that may be untapped resources for the immunotherapy field because of their shared genomic alterations and histopathology with human ovarian cancer. We also shed light on the strengths and limitations of these models, and the knowledge gaps that need to be addressed to enhance the utility of preclinical models for testing novel immunotherapeutic approaches.
32
Dondossola, Eleonora, Andrey S. Dobroff, Serena Marchiò, Marina Cardó-Vila, Hitomi Hosoya, Steven K. Libutti, Angelo Corti, Richard L. Sidman, Wadih Arap e Renata Pasqualini. "Self-targeting of TNF-releasing cancer cells in preclinical models of primary and metastatic tumors". Proceedings of the National Academy of Sciences 113, n. 8 (8 febbraio 2016): 2223–28. http://dx.doi.org/10.1073/pnas.1525697113.
Abstract (sommario):
Circulating cancer cells can putatively colonize distant organs to form metastases or to reinfiltrate primary tumors themselves through a process termed “tumor self-seeding.” Here we exploit this biological attribute to deliver tumor necrosis factor alpha (TNF), a potent antitumor cytokine, directly to primary and metastatic tumors in a mechanism that we have defined as “tumor self-targeting.” For this purpose, we genetically engineered mouse mammary adenocarcinoma (TSA), melanoma (B16-F10), and Lewis lung carcinoma cells to produce and release murine TNF. In a series of intervention trials, systemic administration of TNF-expressing tumor cells was associated with reduced growth of both primary tumors and metastatic colonies in immunocompetent mice. We show that these malignant cells home to tumors, locally release TNF, damage neovascular endothelium, and induce massive cancer cell apoptosis. We also demonstrate that such tumor-cell–mediated delivery avoids or minimizes common side effects often associated with TNF-based therapy, such as acute inflammation and weight loss. Our study provides proof of concept that genetically modified circulating tumor cells may serve as targeted vectors to deliver anticancer agents. In a clinical context, this unique paradigm represents a personalized approach to be translated into applications potentially using patient-derived circulating tumor cells as self-targeted vectors for drug delivery.
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Hicks, William H., Cylaina E. Bird, Jeffrey I. Traylor, Diana D. Shi, Tarek Y. El Ahmadieh, Timothy E. Richardson, Samuel K. McBrayer e Kalil G. Abdullah. "Contemporary Mouse Models in Glioma Research". Cells 10, n. 3 (23 marzo 2021): 712. http://dx.doi.org/10.3390/cells10030712.
Abstract (sommario):
Despite advances in understanding of the molecular pathogenesis of glioma, outcomes remain dismal. Developing successful treatments for glioma requires faithful in vivo disease modeling and rigorous preclinical testing. Murine models, including xenograft, syngeneic, and genetically engineered models, are used to study glioma-genesis, identify methods of tumor progression, and test novel treatment strategies. Since the discovery of highly recurrent isocitrate dehydrogenase (IDH) mutations in lower-grade gliomas, there is increasing emphasis on effective modeling of IDH mutant brain tumors. Improvements in preclinical models that capture the phenotypic and molecular heterogeneity of gliomas are critical for the development of effective new therapies. Herein, we explore the current status, advancements, and challenges with contemporary murine glioma models.
34
Ernst, Kati, Konstantin Okonechnikov, Laura von Soosten, Nina Hofmann, Norman Mack, Benjamin Schwalm, Robert J. Wechsler-Reya et al. "BIOL-07. DISTINCTIVE FEATURES OF HIGH-GRADE GLIOMA MOUSE MODELS REVEALED BY SINGLE-NUCLEUS RNA-SEQUENCING GUIDE PRE-CLINICAL MODEL SELECTION". Neuro-Oncology 25, Supplement_1 (1 giugno 2023): i7. http://dx.doi.org/10.1093/neuonc/noad073.026.
Abstract (sommario):
Abstract Glioma is the most common pediatric central nervous system tumor, with high-grade gliomas (HGG) having one of the worst prognoses of all human cancers. In order to develop better diagnostics and therapies, it is essential to use faithful disease models. Currently, highly passaged patient-derived xenograft (PDX) models are most widely used in preclinical studies, although alternative immunocompetent models are becoming increasingly available. Here, we compare several in vivo glioma models on a single-cell level and investigate their similarity to primary human tumors. Single-nucleus sequencing was used to analyze >125,000 nuclei of primary patient samples, xenografts, autochthonous mouse tumors and related allografts including early and late in vivo passages – with a focus on MET-fusion-driven as well as H3 K27M-mutant HGG. Transcriptomic profiles of single tumor cells and associated stromal/immune components reveal insights into model-specific intratumoral heterogeneity, tumor evolution, and similarities between mouse models and patient samples. In addition, matched tumors engrafted into immunocompromised and immunocompetent animals are used to examine tumor-immune crosstalk and the modifying role of the tumor microenvironment. This improved understanding of how the analyzed model systems evolve over time and how they reflect patient’s tumor compositions will allow to prioritize and refine modern preclinical trials.
35
Chauhan, Aman, Piotr Rychahou, Tadahide Izumi, Susanne M. Arnold, Lowell Brian Anthony, Mark Evers e Charles Kunos. "Antitumor efficacy of M3814 as a radiation sensitizer in neuroendocrine tumor (NET) preclinical models." Journal of Clinical Oncology 37, n. 15_suppl (20 maggio 2019): e15699-e15699. http://dx.doi.org/10.1200/jco.2019.37.15_suppl.e15699.
Abstract (sommario):
e15699 Background: Recent FDA approval of peptide receptor radiotherapy paved the way for radiation-based treatment for gastroenteropancreatic neuroendocrine tumors (GEPNETs). M-3814, a DNA-dependent Protein Kinase Inhibitor (DNA-PKi), is known to potentiate the effects of radiation therapy in various solid tumor in vivo models. Currently there is no data evaluating anti-tumor efficacy of DNA-PK inhibitors in preclinical NET models. M-3814 inhibits DNA damage repair mechanism; antitumor efficacy of M-3814 in NETs is unknown. Methods: The efficacy of M-3814 in combination with radiation therapy (XRT) was evaluated in QGP-1 (pancreatic NET cell line) mouse model. Mice were injected with QGP-1 cells (5 mice) in 100 µL of PBS into the flank of mice with a 27-gauge needle. When tumor volumes reached average ~200 mm3, tumors were excised, separated into equal size tumor pieces and implanted subcutaneously into athymic nude mice. Next, mice were randomized into 4 groups for treatment with either placebo (n = 5), M-3814 (n = 5) alone (100 mg/Kg body weight (BW), XRT (n = 5) alone or in combination with M-3814 (n = 5). Treatment started when palpable tumors were established (200 mm3). Mice received M-3814 by gavage 30 minute prior to radiation therapy and irradiated with 4 daily doses of XRT at 2Gy per dose. Results: XRT and XRT+M-3814 treatment significantly decreased tumor size compared to control group. Combination treatment resulted in marked anti-tumor activity compared to both control group and XRT group. Tumors treated with XRT+M-3814 were also visibly less vascular. (Images will be provided in the poster). M-3814 alone had no effect on tumor growth as expected. Similar mouse weight changes were observed in both XRT and XRT+M-3814 treatment groups. Conclusions: M-3814 is a potent radiation sensitizer in preclinical neuroendocrine models. Strong antitumor activity was observed in QGP-1 xenograft model with marked reduction of tumor growth. Our enthusiasm for current project is driven not only by its inherent scientific importance, but also by its translational potential and the possibility to provide a more effective and less toxic radiation based treatment regimen for neuroendocrine tumors. [Table: see text]
36
Haskell-Mendoza, Aden, Lucas Wachsmuth e Peter Fecci. "LMAP-09 RECAPITULATING LASER INTERSTITIAL THERMAL THERAPY IN PRECLINICAL BRAIN TUMOR MODELS". Neuro-Oncology Advances 5, Supplement_3 (1 agosto 2023): iii11. http://dx.doi.org/10.1093/noajnl/vdad070.040.
Abstract (sommario):
Abstract Laser interstitial thermal therapy (LITT) is a minimally-invasive option for cytoreduction of recurrent or otherwise difficult-to-access intracranial tumors. Relative to resection, ablated tumor tissue remains in situ, facilitating recognition of tumor antigens and a targetable immune response. To investigate the immune consequences of LITT, we developed a model of stereotactic laser ablation for use with existing syngeneic glioma and intracranial metastasis cell lines. A 1064 nm diode-based Nd:YAG laser (Monteris Medical) was used to thermally ablate normal brain tissue or CT-2A tumors in C57BL6/J mice. Ablations were performed at 10 days post-implantation at + 2 ML, + 1 AP, -3 DV using a stereotactic frame. Simultaneous temperature measurements were taken using a thermocouple probe implanted to the same depth 2 mm posterior. We first used serial T2-weighted MRI imaging to accurately track the tumor growth characteristics and identify a safe lesion size for ablation, selecting 10 days post-implantation for subsequent experiments and 2 mm posterior as the ideal position to monitor temperature at the lesion edge. To assess the thermal characteristics of our laser, we ablated mouse brains at 1 W and 2 W for 30, 60, or 90 seconds each, finding that 1 W for 90 seconds produced an ablation that did not char or coagulate tissue outside the ablation zone and recapitulated human ablation findings on H&E staining 24h post-LITT. We next implanted CT-2A tumors for ablation with the selected dose, following mice for survival between the LITT and sham-ablated groups. A subset of mice were imaged using T2-MRI at 1, 3, 7, and 14 days post-surgery. Our model recapitulates the essential clinicopathological findings of LITT and is well suited apply to a variety of intracranial tumor models and LITT-adjunctive therapies.
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Lee, Jung Woo, Jia Kim, Youngjae Shin, Byung Hoon Chi, Jung Hoon Kim e Se Young Choi. "Patient-Specific Tumor Microenvironment Models". Korean Journal of Urological Oncology 19, n. 4 (30 novembre 2021): 197–222. http://dx.doi.org/10.22465/kjuo.2021.19.4.197.
Abstract (sommario):
The heterogeneity of cancer makes it difficult to predict the prognosis of treatment. There is still a lack of preclinical model systems that reflect the clinical characteristics of patients who have heterogenetic tumors. Advances in 3-dimentional (3D) cell culture are leading to discoveries that occur in the development and progression of cancer that has not been known. There are many models including patient-derived xenograft, patient-derived organoid and spheroid, patient-derived explant, scaffold-based model, and system-based model. Each 3D model has its strengths and limitations. One model cannot answer every question, so it seems most reasonable to approach multiple models when studying cancer heterogeneity. Hopefully, 3D tumor modeling will make tremendous progress on this path by fusion of innovative biomaterials and advanced modeling techniques that can partially mimic the heterogeneous environment of real tumors.
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Kalra, Jessica, Jennifer Baker, Justin Song, Alastair Kyle, Andrew Minchinton e Marcel Bally. "Inter-Metastatic Heterogeneity of Tumor Marker Expression and Microenvironment Architecture in a Preclinical Cancer Model". International Journal of Molecular Sciences 22, n. 12 (13 giugno 2021): 6336. http://dx.doi.org/10.3390/ijms22126336.
Abstract (sommario):
Background: Preclinical drug development studies rarely consider the impact of a candidate drug on established metastatic disease. This may explain why agents that are successful in subcutaneous and even orthotopic preclinical models often fail to demonstrate efficacy in clinical trials. It is reasonable to anticipate that sites of metastasis will be phenotypically unique, as each tumor will have evolved heterogeneously with respect to gene expression as well as the associated phenotypic outcome of that expression. The objective for the studies described here was to gain an understanding of the tumor heterogeneity that exists in established metastatic disease and use this information to define a preclinical model that is more predictive of treatment outcome when testing novel drug candidates clinically. Methods: Female NCr nude mice were inoculated with fluorescent (mKate), Her2/neu-positive human breast cancer cells (JIMT-mKate), either in the mammary fat pad (orthotopic; OT) to replicate a primary tumor, or directly into the left ventricle (intracardiac; IC), where cells eventually localize in multiple sites to create a model of established metastasis. Tumor development was monitored by in vivo fluorescence imaging (IVFI). Subsequently, animals were sacrificed, and tumor tissues were isolated and imaged ex vivo. Tumors within organ tissues were further analyzed via multiplex immunohistochemistry (mIHC) for Her2/neu expression, blood vessels (CD31), as well as a nuclear marker (Hoechst) and fluorescence (mKate) expressed by the tumor cells. Results: Following IC injection, JIMT-1mKate cells consistently formed tumors in the lung, liver, brain, kidney, ovaries, and adrenal glands. Disseminated tumors were highly variable when assessing vessel density (CD31) and tumor marker expression (mkate, Her2/neu). Interestingly, tumors which developed within an organ did not adopt a vessel microarchitecture that mimicked the organ where growth occurred, nor did the vessel microarchitecture appear comparable to the primary tumor. Rather, metastatic lesions showed considerable variability, suggesting that each secondary tumor is a distinct disease entity from a microenvironmental perspective. Conclusions: The data indicate that more phenotypic heterogeneity in the tumor microenvironment exists in models of metastatic disease than has been previously appreciated, and this heterogeneity may better reflect the metastatic cancer in patients typically enrolled in early-stage Phase I/II clinical trials. Similar to the suggestion of others in the past, the use of models of established metastasis preclinically should be required as part of the anticancer drug candidate development process, and this may be particularly important for targeted therapeutics and/or nanotherapeutics.
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Spoormans, Kaat, Melissa Crabbé, Lara Struelens, Marijke De Saint-Hubert e Michel Koole. "A Review on Tumor Control Probability (TCP) and Preclinical Dosimetry in Targeted Radionuclide Therapy (TRT)". Pharmaceutics 14, n. 10 (22 settembre 2022): 2007. http://dx.doi.org/10.3390/pharmaceutics14102007.
Abstract (sommario):
Targeted radionuclide therapy (TRT) uses radiopharmaceuticals to specifically irradiate tumor cells while sparing healthy tissue. Response to this treatment highly depends on the absorbed dose. Tumor control probability (TCP) models aim to predict the tumor response based on the absorbed dose by taking into account the different characteristics of TRT. For instance, TRT employs radiation with a high linear energy transfer (LET), which results in an increased effectiveness. Furthermore, a heterogeneous radiopharmaceutical distribution could result in a heterogeneous dose distribution at a tissue, cellular as well as subcellular level, which will generally reduce the tumor response. Finally, the dose rate in TRT is protracted, relatively low, and variable over time. This allows cells to repair more DNA damage, which may reduce the effectiveness of TRT. Within this review, an overview is given on how these characteristics can be included in TCP models, while some experimental findings are also discussed. Many parameters in TCP models are preclinically determined and TCP models also play a role in the preclinical stage of radiopharmaceutical development; however, this all depends critically on the calculated absorbed dose. Accordingly, an overview of the existing preclinical dosimetry methods is given, together with their limitation and applications. It can be concluded that although the theoretical extension of TCP models from external beam radiotherapy towards TRT has been established quite well, the experimental confirmation is lacking. Thus, requiring additional comprehensive studies at the sub-cellular, cellular, and organ level, which should be provided with accurate preclinical dosimetry.
40
Barachini, Serena, Mariangela Morelli, Orazio Santo Santonocito e Chiara Maria Mazzanti. "Preclinical glioma models in neuro-oncology: enhancing translational research". Current Opinion in Oncology 35, n. 6 (1 settembre 2023): 536–42. http://dx.doi.org/10.1097/cco.0000000000000997.
Abstract (sommario):
Purpose of review Gliomas represent approximately 25% of all primary brain and other central nervous system (CNS) tumors and 81% of malignant tumors. Unfortunately, standard treatment approaches for most CNS cancers have shown limited improvement in patient survival rates. Recent findings The current drug development process has been plagued by high failure rates, leading to a shift towards human disease models in biomedical research. Unfortunately, suitable preclinical models for brain tumors have been lacking, hampering our understanding of tumor initiation processes and the discovery of effective treatments. In this review, we will explore the diverse preclinical models employed in neuro-oncology research and their contributions to translational science. Summary By utilizing a combination of these preclinical models and fostering interdisciplinary collaborations, researchers can deepen their understanding of glioma brain tumors and develop novel therapeutic strategies to combat these devastating diseases. These models offer promising prospects for personalized and efficacious treatments for these challenging malignancies. Although it is unrealistic to fully replicate the complexity of the human body in vitro, the ultimate goal should be to achieve the closest possible resemblance to the clinical context.
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Kemper, Kristel, Ellis Gielen, Peter Boross, Mischa Houtkamp, Theo S. Plantinga, Stefanie AH de Poot, Saskia M. Burm et al. "Mechanistic and pharmacodynamic studies of DuoBody-CD3x5T4 in preclinical tumor models". Life Science Alliance 5, n. 11 (8 settembre 2022): e202201481. http://dx.doi.org/10.26508/lsa.202201481.
Abstract (sommario):
CD3 bispecific antibodies (bsAbs) show great promise as anticancer therapeutics. Here, we show in-depth mechanistic studies of a CD3 bsAb in solid cancer, using DuoBody-CD3x5T4. Cross-linking T cells with tumor cells expressing the oncofetal antigen 5T4 was required to induce cytotoxicity. Naive and memory CD4+ and CD8+ T cells were equally effective at mediating cytotoxicity, and DuoBody-CD3x5T4 induced partial differentiation of naive T-cell subsets into memory-like cells. Tumor cell kill was associated with T-cell activation, proliferation, and production of cytokines, granzyme B, and perforin. Genetic knockout of FAS or IFNGR1 in 5T4+ tumor cells abrogated tumor cell kill. In the presence of 5T4+ tumor cells, bystander kill of 5T4− but not of 5T4−IFNGR1− tumor cells was observed. In humanized xenograft models, DuoBody-CD3x5T4 antitumor activity was associated with intratumoral and peripheral blood T-cell activation. Lastly, in dissociated patient-derived tumor samples, DuoBody-CD3x5T4 activated tumor-infiltrating lymphocytes and induced tumor-cell cytotoxicity, even when most tumor-infiltrating lymphocytes expressed PD-1. These data provide an in-depth view on the mechanism of action of a CD3 bsAb in preclinical models of solid cancer.
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Golebiewska, Anna, Ann-Christin Hau, Anais Oudin, Daniel Stieber, Yahaya A. Yabo, Yong-Jun Kwon, Barbara Klink et al. "TMOD-08. PRIMARY AND RECURRENT GLIOMA PATIENT-DERIVED ORTHOTOPIC XENOGRAFTS (PDOX) REPRESENT RELEVANT PATIENT AVATARS FOR PRECISION MEDICINE". Neuro-Oncology 22, Supplement_2 (novembre 2020): ii229. http://dx.doi.org/10.1093/neuonc/noaa215.959.
Abstract (sommario):
Abstract Patient-derived cancer models are essential tools for studying tumor biology and for preclinical interventions. Although numerous clinical cancer trials are being conducted, many fail due to inappropriate selection of compounds at the preclinical stage. Therefore, better preclinical models are crucial for predicting successful clinical impact. Orthotropic patient-derived xenograft (PDOX) models are of particular importance for brain cancers, as they allow to better recapitulate the brain tumor environment and the blood brain barrier. We created a large collection of PDOXs from primary and recurrent gliomas with and without mutations in IDH1. PDOX models were based on 3D organoids, derived from mechanically minced patient material. Organoids were implanted in the brain of immunodeficient mice and further propagated by serial intracranial transplantations. High grade glioma PDOX models, starting with viable patient-derived organoids, have generally a high tumor take rate, a reproducible phenotype and tumor development time. PDOXs retain histopathological, genetic, epigenetic and transcriptomic features of patient tumors with no mouse-specific clonal evolution. Longitudinal PDOX models confirmed limited evolution of gliomas upon treatment observed in patient tumors. PDOX-derived standardized tumor organoid cultures enabled assessment of drug responses, which were validated in mice. PDOXs showed clinically relevant responses to Temozolomide and to targeted treatments such as EGFR and CDK4/6 inhibitors in (epi)genetically defined groups, according to MGMT promoter and EGFR/CDK status respectively. These data indicate that glioma PDOXs represent clinically relevant avatars for personalized treatment. The use of these models should lead to a more realistic evaluation of the efficacy of novel drugs, thereby increasing the success of clinical studies.
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Yu, Rong, Ewetse Paul Maswikiti, Yang Yu, Lei Gao, Chenhui Ma, Huanhuan Ma, Xiaobo Deng, Na Wang, Bofang Wang e Hao Chen. "Advances in the Application of Preclinical Models in Photodynamic Therapy for Tumor: A Narrative Review". Pharmaceutics 15, n. 1 (5 gennaio 2023): 197. http://dx.doi.org/10.3390/pharmaceutics15010197.
Abstract (sommario):
Photodynamic therapy (PDT) is a non-invasive laser light local treatment that has been utilized in the management of a wide variety of solid tumors. Moreover, the evaluation of efficacy, adverse reactions, the development of new photosensitizers and the latest therapeutic regimens are inseparable from the preliminary exploration in preclinical studies. Therefore, our aim was to better comprehend the characteristics and limitations of these models and to provide a reference for related research. Methods: We searched the databases, including PubMed, Web of Science and Scopus for the past 25 years of original research articles on the feasibility of PDT in tumor treatment based on preclinical experiments and animal models. We provided insights into inclusion and exclusion criteria and ultimately selected 40 articles for data synthesis. Results: After summarizing and comparing the methods and results of these studies, the experimental model selection map was drawn. There are 7 main preclinical models, which are used for different research objectives according to their characteristics. Conclusions: Based on this narrative review, preclinical experimental models are crucial to the development and promotion of PDT for tumors. The traditional animal models have some limitations, and the emergence of organoids may be a promising new insight.
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Saito, Yasuyuki, Afroj Tania, Satomi Komori, Tomoko Takai, Okechi S. Oduori, Takenori Kotani, Yohei Funakoshi et al. "Preclinical Evaluation of the Efficacy of Human Sirpα Antibodies for B-Cell Lymphoma Immunotherapy in Humanized Mouse Models". Blood 142, Supplement 1 (28 novembre 2023): 1646. http://dx.doi.org/10.1182/blood-2023-181926.
Abstract (sommario):
Tumor-associated macrophages (TAMs) are abundant in the tumor microenvironment and are considered potential targets to enhance cancer immunotherapy against B-cell lymphomas. However, faithful and predictive preclinical tumor models of human B-cell lymphomas for the evaluation of therapeutics targeting human TAMs have not been established yet. To examine the antitumor effects of agents targeting human TAMs in vivo, we here established preclinical tumor xenograft models based on Rag2-/-Il2rg-/- immunodeficient mice that express multiple human cytokines, such as M-CSF, IL-3, GM-CSF, and THPO (MITRG mice), and have been reconstituted with a human immune system (HIS) by transplantation of human CD34+ hematopoietic stem and progenitor cells (HIS-MITRG mice). HIS-MITRG mice supported the growth of both the human cell line (Raji)-derived and diffuse large B cell lymphoma (DLBCL) patient-derived xenograft tumors as well as the infiltration of human macrophages into these tumors. We examined the potential antitumor effect of an antibody to human SIRPα (SE12C3) that inhibits the interaction of CD47 on tumor cells with SIRPα on human macrophages and thereby promotes Fcγ receptor-mediated phagocytosis of tumor cells by human macrophages. Combined treatment with rituximab and SE12C3 inhibited Raji tumor growth in HIS-MITRG mice to a markedly greater extent than did rituximab monotherapy in a therapeutic model started after the engraftment of the tumor. This enhanced antitumor effect was dependent on human macrophages and attributable to enhanced rituximab-dependent phagocytosis of lymphoma cells by human macrophages. Treatment with rituximab and SE12C3 also induced reprogramming of human TAMs towards a proinflammatory phenotype. Furthermore, the combination treatment essentially prevented the growth of DLBCL patient-derived xenograft tumors in HIS-MITRG mice. Our findings thus support the utility of HIS-MITRG mice as a model for the preclinical in vivo evaluation of potential therapeutics, such as antibodies to human SIRPα, that target human TAMs.
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Zhu, Menghan, Nan Jia, Yanyan Nie, Jun Chen, Yahui Jiang, Tianjiao Lv, Yuanyuan Li, Liangqing Yao e Weiwei Feng. "Establishment of Patient-Derived Tumor Xenograft Models of High-Risk Endometrial Cancer". International Journal of Gynecologic Cancer 28, n. 9 (novembre 2018): 1812–20. http://dx.doi.org/10.1097/igc.0000000000001365.
Abstract (sommario):
ObjectiveHigh-risk endometrial cancers (ECs), including high-grade EC, serous carcinoma (SC), clear cell carcinoma, and carcinosarcoma, account for 50% of deaths due to ECs. Therapies for these cancers are limited, and patient-derived tumor xenograft (PDTX) models are useful tools for preclinical drug evaluation, biomarker identification, and personalized medicine strategies. Here, we used and compared 2 methods to establish PDTX models.MethodsFresh tumor tissues collected from 18 primary high-risk EC patients (10 high-grade ECs, 6 SCs, 1 clear cell carcinoma, and 1 carcinosarcoma) were engrafted subcutaneously and in the subrenal capsule in NOD/SCID for establishment and Balb/c-nu/nu mice for expansion. Histology and cytokeratin, estrogen receptor, progesterone receptor, and P53 expression were evaluated to assess the similarity of primary tumors and different generations of PDTX tumors. Whole-exome sequencing (WES) and RNA sequencing were used in 2 high-grade EC models to verify whether the genetic mutation profiles and gene expression were similar between primary and PDTX tumors.ResultsThe total tumor engraftment rate was 77.8% (14/18) regardless of the engraft method. The tumor engraftment rate was increased in subrenal capsule models compared with subcutaneous models (62.5% vs 50%, P = 0.464). The time to tumor formation varied significantly from 2 to 11 weeks. After subrenal capsular grafting, grafted tumors could be successfully transplanted to subcutaneous sites. We observed good similarity between primary tumors and corresponding different passages of xenografts.ConclusionsThe combination of 2 engrafting methods increases the tumor engraftment rate. The high tumor engraftment rate ensures the establishment of a high-risk EC biobank, which is a powerful resource for performing preclinical drug-sensitivity tests and identifying biomarkers for response or resistance.
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Matei, Daniela. "Abstract IA018: Epigenome targeting in ovarian cancer: preclinical models to clinic". Cancer Research 84, n. 5_Supplement_2 (4 marzo 2024): IA018. http://dx.doi.org/10.1158/1538-7445.ovarian23-ia018.
Abstract (sommario):
Abstract DNA methylation causes silencing of tumor suppressor (TSGs) and differentiation-associated genes, being linked to chemoresistance. Ovarian cancer (OC) is uniquely suited for epigenome targeting as a disease driven by loss of TSGs, rather than oncogenes. Hypomethylating agents (HMA) have been shown to re-sensitize OC to chemotherapy and immunotherapy. A novel HMA (4-thio-decitabine) effectively depleted DNMTs, induced global hypomethylation and transcriptional reprogramming leading to inhibition of OC cell proliferation and tumor growth. Mechanistically, among other gene sets, NTX-301 significantly altered the fatty acid metabolism pathway. A key enzyme in this pathway, the stearoyl co-A desaturase which regulates the last step in lipogenesis, converting saturated fatty acids into unsaturated fatty acids (UFAs) was potently inhibited by NTX-301. This led to depletion of UFAs in cells and tumors treated with the HMA and cell death through ferroptosis. In a clinical trial for women with recurrent, platinum resistant OC, epigenetic priming was used to enhance response to immune checkpoint inhibitors. Among 35 evaluable patients, the clinical benefit rate was 31.4% (95% CI: 16.9 – 49.3%). Methylomic and transcriptomic analyses revealed activation of pathways related to anti-tumor immunity in post-treatment biopsies. High dimensional immune profiling of PBMCs showed higher frequency of peripheral naive and/or central memory CD4+ T cells subsets and of classical monocytes in patients deriving clinical benefit. Multiplex immunohistochemistry indicated that baseline higher density of CD8+ T cells and CD20+ B cells in tumor tissue and presence of putative tertiary lymphoid structures were associated with clinical benefit. These results propose novel mechanisms by which HMAs exert anti-tumor activity in preclinical and clinical models. Citation Format: Daniela Matei. Epigenome targeting in ovarian cancer: preclinical models to clinic [abstract]. In: Proceedings of the AACR Special Conference on Ovarian Cancer; 2023 Oct 5-7; Boston, Massachusetts. Philadelphia (PA): AACR; Cancer Res 2024;84(5 Suppl_2):Abstract nr IA018.
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Iaia, Ilenia, Loretta Gammaitoni, Giulia Cattaneo, Lidia Giraudo, Chiara Donini, Erika Fiorino, Luca Primo et al. "Recruitment, Infiltration, and Cytotoxicity of HLA-Independent Killer Lymphocytes in Three-Dimensional Melanoma Models". Cancers 13, n. 10 (11 maggio 2021): 2302. http://dx.doi.org/10.3390/cancers13102302.
Abstract (sommario):
Cancer adoptive cell therapy (ACT) with HLA-independent tumor killer lymphocytes is a promising approach, with intrinsic features potentially addressing crucial tumor-escape mechanisms of checkpoint inhibitors. Cytokine-induced Killer (CIK) and Natural Killer (NK) lymphocytes share similar tumor-killing mechanisms, with preclinical evidence of intense activity against multiple solid tumors and currently testing in clinical studies. To improve the effective clinical translation of such ACT approaches, several fundamental questions still need to be addressed within appropriate preclinical contexts, capable of overcoming limitations imposed by most traditional two-dimensional assays. Here, we developed a novel experimental approach to explore, dissect, and visualize the interactions of CIK and NK lymphocytes with melanoma tumors in vitro in 3D. Primary melanoma cells were assembled into small tumors that were dispersed in a 3D matrix and challenged with patient-derived CIK or the NK-92 cell line. By means of imaging-based methods, we reported, visualized, and quantitatively measured the recruitment of CIK and NK on the 3D targets, their infiltration, and cytotoxic activity. Our results support the effective tumor recruitment and tumor infiltration by CIK and NK. Such features appeared dependent on the specific geometric aspects of the environment but can be explained in terms of directional migration toward the tumor, without invoking major feedback components. Overall, our 3D platform allows us to monitor the processes of tumor recruitment, infiltration, and killing by means of live measurements, revealing important kinetic aspects of ACT with CIK and NK against melanoma.
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Grausam, Katie, David Rincon Fernandez Pacheco, Emily Hatanaka, Stephen Shiao e Joshua Breunig. "MODL-34. A SERIES OF EGFR-MUTANT MODELS OF GLIOBLASTOMA THAT RECAPITULATES PATIENT TUMOR HETEROGENEITY AND RESPONSE TO TREATMENT". Neuro-Oncology 25, Supplement_5 (1 novembre 2023): v306. http://dx.doi.org/10.1093/neuonc/noad179.1185.
Abstract (sommario):
Abstract Glioblastoma (GBM) is the most common and aggressive brain cancer, with a treatment regimen that has remained disappointingly unaltered for the last few decades. Preclinical testing of immunotherapy has generated promising results, sometimes leading to elimination of the tumor over time in mouse models; however, when tested clinically, patients show limited responses with no impact on patient survival. Current mouse models (e.g., GL261) for preclinical testing involve orthotopic transplantation of a cell line with tumor mutations not commonly found in patient tumors. Most of these models elicit a strong anti-tumor immune response which is typically not found clinically. Single cell sequencing has revealed that different mutations in GBM are associated with differences in the aggressiveness and composition of the tumor immune microenvironment. We therefore developed an immunocompetent, autochthonous platform for generating mouse models of GBM using combinations of clinically-relevant mutations, including mutant EGFR driving tumor growth and various single guide RNAs with CRISPR-Cas9 to elicit loss of function of tumor suppressor genes. Histopathology from tumors in mice mirrors the typical features of GBM, while single-cell RNA sequencing identified expression patterns similar to patients with different driver combinations altering expression patterns in ways that mimic their human counterparts, including the heterogeneity that is the hallmark of GBM. The immune cell population of these tumors was composed of predominantly microglia, with a small population of peripherally derived immune cells. Finally, treatment studies of radiation and anti-PD-1 using this new mouse model do not result in long-term survival, similar to human trials of these agents, paving the way for more accurate preclinical testing. In conclusion, using this unique modeling system that more closely resembles human tumors genetically and immunologically, we can better explore the mechanisms of therapeutic resistance and identify more relevant targets to improve outcomes in this challenging disease.
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Odunsi, Adekunle, A. J. Robert McGray, Anthony Miliotto, Yali Zhang, Jianming Wang, Adebukola Abiola, Cheryl Eppolito e Ruea-Yea Huang. "Fidelity of human ovarian cancer patient-derived xenografts in a partially humanized mouse model for preclinical testing of immunotherapies". Journal for ImmunoTherapy of Cancer 8, n. 2 (novembre 2020): e001237. http://dx.doi.org/10.1136/jitc-2020-001237.
Abstract (sommario):
BackgroundImmune checkpoint blockers (ICBs) have been approved by the Food and Drug Administration to be used alone in front-line therapies or in combination with other regimens for certain advanced cancers. Since ICB only works in a subset of patients and has limited efficacy in treating ovarian cancer (OVC), developing preclinical models that help to understand which patients may derive benefit from ICB would be of tremendous benefit in OVC.MethodsHere, we generated preclinical human OVC models from freshly resected tumors, which include six patient-derived xenografts (PDXs) from six different patient tumors, three transplantable OVC PD spheroid lines (PD-sphs), and 3 cell lines (PD-CLs). We tested the therapeutic combination of anti-PD1/CTLA4 antibodies with (1) autologous tumor-associated leukocytes (TALs) on the growth of PD-sphs in a coculture system in vitro, (2) with adoptively transferred autologous peripheral blood mononuclear cells or TALs in patient-derived OVC models using partially humanized mice, NSG-HHDxSGM3 (N-HSGM3).ResultsWe show that PD-1 and CTLA-4 dual blockade when combined with autologous TALs effectively reduced PD-sph number in a co-culture system and led to regression of established PD-CLs and PDXs in the N-HSGM3 mice. Combinatorial PD-1 and CTLA-4 blockade increased the frequency and function of tumor-specific CD8 T cells. These CD8 T cells persisted in the tumor microenvironment, exhibited memory phenotype and protected animals from tumor growth on tumor rechallenge. Gene expression analysis of tumors resistant to dual PD1/CTLA4 blockade treatment identified upregulation of antigen processing and presentation pathways and downregulation of extracellular matrix organization genes.ConclusionsThese findings describe a novel platform for developing patient-derived preclinical tumor models suitable for rationally testing combinatorial ICB in the context of autologous tumor-reactive T cells. This platform can be further developed for testing additional targeted therapies relevant to OVC.
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Franklin, M., M. Thayer, D. Draper, D. Saims e S. Wise. "Preclinical assessment of anti-tumor activity and immune response in syngeneic tumor models". European Journal of Cancer 69 (dicembre 2016): S97. http://dx.doi.org/10.1016/s0959-8049(16)32887-8.