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1.
F1000Res ; 12: 954, 2023.
Artigo em Inglês | MEDLINE | ID: mdl-37799492

RESUMO

With diminishing returns and high clinical failure rates from traditional preclinical and animal-based drug discovery strategies, more emphasis is being placed on alternative drug discovery platforms. Ex vivo approaches represent a departure from both more traditional preclinical animal-based models and clinical-based strategies and aim to address intra-tumoural and inter-patient variability at an earlier stage of drug discovery. Additionally, these approaches could also offer precise treatment stratification for patients within a week of tumour resection in order to direct tailored therapy. One tumour group that could significantly benefit from such ex vivo approaches are high-grade gliomas, which exhibit extensive heterogeneity, cellular plasticity and therapy-resistant glioma stem cell (GSC) niches. Historic use of murine-based preclinical models for these tumours has largely failed to generate new therapies, resulting in relatively stagnant and unacceptable survival rates of around 12-15 months post-diagnosis over the last 50 years. The near universal use of DNA damaging chemoradiotherapy after surgical resection within standard-of-care (SoC) therapy regimens provides an opportunity to improve current treatments if we can identify efficient drug combinations in preclinical models that better reflect the complex inter-/intra-tumour heterogeneity, GSC plasticity and inherent DNA damage resistance mechanisms. We have therefore developed and optimised a high-throughput ex vivo drug screening platform; GliExP, which maintains GSC populations using immediately dissociated fresh surgical tissue. As a proof-of-concept for GliExP, we have optimised SoC therapy responses and screened 30+ small molecule therapeutics and preclinical compounds against tumours from 18 different patients, including multi-region spatial heterogeneity sampling from several individual tumours. Our data therefore provides a strong basis to build upon GliExP to incorporate combination-based oncology therapeutics in tandem with SoC therapies as an important preclinical alternative to murine models (reduction and replacement) to triage experimental therapeutics for clinical translation and deliver rapid identification of effective treatment strategies for individual gliomas.


Assuntos
Neoplasias Encefálicas , Glioblastoma , Glioma , Humanos , Animais , Camundongos , Glioblastoma/tratamento farmacológico , Avaliação Pré-Clínica de Medicamentos , Avatar , Neoplasias Encefálicas/tratamento farmacológico , Detecção Precoce de Câncer , Células-Tronco Neoplásicas
2.
Orphanet J Rare Dis ; 15(1): 170, 2020 06 30.
Artigo em Inglês | MEDLINE | ID: mdl-32605631

RESUMO

BACKGROUND: Fanconi anemia is a rare disease clinically characterized by malformations, bone marrow failure and an increased risk of solid tumors and hematologic malignancies. The only therapies available are hematopoietic stem cell transplantation for bone marrow failure or leukemia, and surgical resection for solid tumors. Therefore, there is still an urgent need for new therapeutic options. With this aim, we developed a novel high-content cell-based screening assay to identify drugs with therapeutic potential in FA. RESULTS: A TALEN-mediated FANCA-deficient U2OS cell line was stably transfected with YFP-FANCD2 fusion protein. These cells were unable to form fluorescent foci or to monoubiquitinate endogenous or exogenous FANCD2 upon DNA damage and were more sensitive to mitomycin C when compared to the parental wild type counterpart. FANCA correction by retroviral infection restored the cell line's ability to form FANCD2 foci and ubiquitinate FANCD2. The feasibility of this cell-based system was interrogated in a high content screening of 3802 compounds, including a Prestwick library of 1200 FDA-approved drugs. The potential hits identified were then individually tested for their ability to rescue FANCD2 foci and monoubiquitination, and chromosomal stability in the absence of FANCA. CONCLUSIONS: While, unfortunately, none of the compounds tested were able to restore cellular FANCA-deficiency, our study shows the potential capacity to screen large compound libraries in the context of Fanconi anemia therapeutics in an optimized and cost-effective platform.


Assuntos
Anemia de Fanconi , Dano ao DNA , Avaliação Pré-Clínica de Medicamentos , Anemia de Fanconi/tratamento farmacológico , Anemia de Fanconi/genética , Proteína do Grupo de Complementação A da Anemia de Fanconi/genética , Proteína do Grupo de Complementação D2 da Anemia de Fanconi/genética , Humanos
3.
Br J Pharmacol ; 176(3): 436-450, 2019 02.
Artigo em Inglês | MEDLINE | ID: mdl-30427531

RESUMO

BACKGROUND AND PURPOSE: Small cell lung cancer (SCLC) is an aggressive disease with median survival of <2 years. Tumour biopsies for research are scarce, especially from extensive-stage patients, with repeat sampling at disease progression rarely performed. We overcame this limitation for relevant preclinical models by developing SCLC circulating tumour cell derived explants (CDX), which mimic the donor tumour pathology and chemotherapy response. To facilitate compound screening and identification of clinically relevant biomarkers, we developed short-term ex vivo cultures of CDX tumour cells. EXPERIMENTAL APPROACH: CDX tumours were disaggregated, and the human tumour cells derived were cultured for a maximum of 5 weeks. Phenotypic, transcriptomic and pharmacological characterization of these cells was performed. KEY RESULTS: CDX cultures maintained a neuroendocrine phenotype, and most changes in the expression of protein-coding genes observed in cultures, for up to 4 weeks, were reversible when the cells were re-implanted in vivo. Moreover, the CDX cultures exhibited a similar sensitivity to chemotherapy compared to the corresponding CDX tumour in vivo and were able to predict in vivo responses to therapeutic candidates. CONCLUSIONS AND IMPLICATIONS: Short-term cultures of CDX provide a tractable platform to screen new treatments, identify predictive and pharmacodynamic biomarkers and investigate mechanisms of resistance to better understand the progression of this recalcitrant tumour.


Assuntos
Antineoplásicos/farmacologia , Indazóis/farmacologia , Neoplasias Pulmonares/tratamento farmacológico , Células Neoplásicas Circulantes/efeitos dos fármacos , Carcinoma de Pequenas Células do Pulmão/tratamento farmacológico , Sulfonamidas/farmacologia , Animais , Antineoplásicos/química , Proliferação de Células/efeitos dos fármacos , Relação Dose-Resposta a Droga , Avaliação Pré-Clínica de Medicamentos , Ensaios de Seleção de Medicamentos Antitumorais , Humanos , Indazóis/química , Neoplasias Pulmonares/patologia , Camundongos , Camundongos Endogâmicos , Camundongos SCID , Neoplasias Experimentais/tratamento farmacológico , Neoplasias Experimentais/patologia , Células Neoplásicas Circulantes/patologia , Carcinoma de Pequenas Células do Pulmão/patologia , Relação Estrutura-Atividade , Sulfonamidas/química , Células Tumorais Cultivadas
4.
Cell Death Dis ; 9(8): 810, 2018 07 24.
Artigo em Inglês | MEDLINE | ID: mdl-30042422

RESUMO

Karonudib (TH1579) is a novel compound that exerts anti-tumor activities and has recently entered phase I clinical testing. The aim of this study was to conduct a pre-clinical trial in patient-derived xenografts to identify the possible biomarkers of response or resistance that could guide inclusion of patients suffering from metastatic melanoma in phase II clinical trials. Patient-derived xenografts from 31 melanoma patients with metastatic disease were treated with karonudib or a vehicle for 18 days. Treatment responses were followed by measuring tumor sizes, and the models were categorized in the response groups. Tumors were harvested and processed for RNA sequencing and protein analysis. To investigate the effect of karonudib on T-cell-mediated anti-tumor activities, tumor-infiltrating T cells were injected in mice carrying autologous tumors and the mice treated with karonudib. We show that karonudib has heterogeneous anti-tumor effect on metastatic melanoma. Thus, based on the treatment responses, we could divide the 31 patient-derived xenografts in three treatment groups: progression group (32%), suppression group (42%), and regression group (26%). Furthermore, we show that karonudib has anti-tumor effect, irrespective of major melanoma driver mutations. Also, we identify high expression of ABCB1, which codes for p-gp pumps as a resistance biomarker. Finally, we show that karonudib treatment does not hamper T-cell-mediated anti-tumor responses. These findings can be used to guide future use of karonudib in clinical use with a potential approach as precision medicine.


Assuntos
Resistencia a Medicamentos Antineoplásicos , Inibidores Enzimáticos/uso terapêutico , Melanoma/tratamento farmacológico , Pirimidinas/uso terapêutico , Membro 1 da Subfamília B de Cassetes de Ligação de ATP/metabolismo , Animais , Biomarcadores Tumorais/metabolismo , Avaliação Pré-Clínica de Medicamentos , Inibidores Enzimáticos/farmacologia , Humanos , Melanoma/patologia , Camundongos , Pirimidinas/farmacologia , Transplante Heterólogo , Células Tumorais Cultivadas , Regulação para Cima
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