To see the other types of publications on this topic, follow the link: Colorectal Cancer/Preclinical Model/Drug screening.
Journal articles on the topic 'Colorectal Cancer/Preclinical Model/Drug screening'
Create a spot-on reference in APA, MLA, Chicago, Harvard, and other styles
Consult the top 50 journal articles for your research on the topic 'Colorectal Cancer/Preclinical Model/Drug screening.'
Next to every source in the list of references, there is an 'Add to bibliography' button. Press on it, and we will generate automatically the bibliographic reference to the chosen work in the citation style you need: APA, MLA, Harvard, Chicago, Vancouver, etc.
You can also download the full text of the academic publication as pdf and read online its abstract whenever available in the metadata.
Browse journal articles on a wide variety of disciplines and organise your bibliography correctly.
1
Pinho, Diana, Denis Santos, Ana Vila, and Sandra Carvalho. "Establishment of Colorectal Cancer Organoids in Microfluidic-Based System." Micromachines 12, no. 5 (April 28, 2021): 497. http://dx.doi.org/10.3390/mi12050497.
Full textAbstract:
Colorectal cancer is the second leading cause of cancer death worldwide. Significant advances in the molecular mechanisms underlying colorectal cancer have been made; however, the clinical approval of new drugs faces many challenges. Drug discovery is a lengthy process causing a rapid increase in global health care costs. Patient-derived tumour organoids are considered preclinical models with the potential for preclinical drug screening, prediction of patient outcomes, and guiding optimized therapy strategies at an individual level. Combining microfluidic technology with 3D tumour organoid models to recapitulate tumour organization and in vivo functions led to the development of an appropriate preclinical tumour model, organoid-on-a-chip, paving the way for personalized cancer medicine. Herein, a low-cost microfluidic device suitable for culturing and expanding organoids, OrganoidChip, was developed. Patient-derived colorectal cancer organoids were cultured within OrganoidChip, and their viability and proliferative activity increased significantly. No significant differences were verified in the organoids’ response to 5-fluorouracil (5-FU) treatment on-chip and on-plate. However, the culture within the OrganoidChip led to a significant increase in colorectal cancer organoid-forming efficiency and overall size compared with conventional culture on a 24-well plate. Interestingly, early-stage and late-stage organoids were predominantly observed on-plate and within the OrganoidChip, respectively. The OrganoidChip thus has the potential to generate in vivo-like organotypic structures for disease modelling and drug screening applications.
2
Sensi, Francesca, Edoardo D’Angelo, Martina Piccoli, Piero Pavan, Francesca Mastrotto, Paolo Caliceti, Andrea Biccari, et al. "Recellularized Colorectal Cancer Patient-Derived Scaffolds as In Vitro Pre-Clinical 3D Model for Drug Screening." Cancers 12, no. 3 (March 13, 2020): 681. http://dx.doi.org/10.3390/cancers12030681.
Full textAbstract:
Colorectal cancer (CRC) shows highly ineffective therapeutic management. An urgent unmet need is the random assignment to adjuvant chemotherapy of high-risk stage II and stage III CRC patients without any predictive factor of efficacy. In the field of drug discovery, a critical step is the preclinical evaluation of drug cytotoxicity, efficacy, and efficiency. We proposed a patient-derived 3D preclinical model for drug evaluation that could mimic in vitro the patient’s disease. Surgically resected CRC tissue and adjacent healthy colon mucosa were decellularized by a detergent-enzymatic treatment. Scaffolds were recellularized with HT29 and HCT116 cells. Qualitative and quantitative characterization of matched recellularized samples were evaluated through histology, immunofluorescences, scanning electron microscopy, and DNA amount quantification. A chemosensitivity test was performed using an increasing concentration of 5-fluorouracil (5FU). In vivo studies were carried out using zebrafish (Danio rerio) animal model. Permeability test and drug absorption were also determined. The decellularization protocol allowed the preservation of the original structure and ultrastructure. Five days after recellularization with HT29 and HCT116 cell lines, the 3D CRC model exhibited reduced sensitivity to 5FU treatments compared with conventional 2D cultures. Calculated the half maximal inhibitory concentration (IC50) for HT29 treated with 5FU resulted in 11.5 µM in 3D and 1.3 µM in 2D, and for HCT116, 9.87 µM in 3D and 1.7 µM in 2D. In xenograft experiments, HT29 extravasation was detected after 4 days post-injection, and we obtained a 5FU IC50 fully comparable to that observed in the 3D CRC model. Using confocal microscopy, we demonstrated that the drug diffused through the repopulated 3D CRC scaffolds and co-localized with the cell nuclei. The bioengineered CRC 3D model could be a reliable preclinical patient-specific platform to bridge the gap between in vitro and in vivo drug testing assays and provide effective cancer treatment.
3
Ramzy, George M., Thibaud Koessler, Eloise Ducrey, Thomas McKee, Frédéric Ris, Nicolas Buchs, Laura Rubbia-Brandt, Pierre-Yves Dietrich, and Patrycja Nowak-Sliwinska. "Patient-Derived In Vitro Models for Drug Discovery in Colorectal Carcinoma." Cancers 12, no. 6 (May 31, 2020): 1423. http://dx.doi.org/10.3390/cancers12061423.
Full textAbstract:
Lack of relevant preclinical models that reliably recapitulate the complexity and heterogeneity of human cancer has slowed down the development and approval of new anti-cancer therapies. Even though two-dimensional in vitro culture models remain widely used, they allow only partial cell-to-cell and cell-to-matrix interactions and therefore do not represent the complex nature of the tumor microenvironment. Therefore, better models reflecting intra-tumor heterogeneity need to be incorporated in the drug screening process to more reliably predict the efficacy of drug candidates. Classic methods of modelling colorectal carcinoma (CRC), while useful for many applications, carry numerous limitations. In this review, we address the recent advances in in vitro CRC model systems, ranging from conventional CRC patient-derived models, such as conditional reprogramming-based cell cultures, to more experimental and state-of-the-art models, such as cancer-on-chip platforms or liquid biopsy.
4
Voutsadakis, Ioannis A. "Cell Models for Chromosome 20q11.21 Amplification and Drug Sensitivities in Colorectal Cancer." Medicina 57, no. 9 (August 24, 2021): 860. http://dx.doi.org/10.3390/medicina57090860.
Full textAbstract:
Background and objectives: The chromosome locus 20q11.21 is a commonly amplified locus in colorectal cancer, with a prevalence of 8% to 9%. Several candidate cancer-associated genes are transcribed from the locus. The therapeutic implications of the amplification in colorectal cancer remain unclear. Materials and Methods: Preclinical cell line models of colorectal cancer included in the Cancer Cell Line Encyclopedia (CCLE) collection were examined for the presence of amplifications in 20q11.21 genes. Correlations of the presence of 20q11.21 amplifications with gene essentialities and drug sensitivities were surveyed on salient databases for determination of therapeutic leads. Results: A significant subset of colorectal cancer cell lines in the CCLE (12 of 63 cell lines, 19%) bear amplifications of genes located at 20q11.21. Cancer-associated genes of the locus include ASXL1, DNMT3B, BCL2L1, TPX2, KIF3B and POFUT1. These genes are all amplified in the 12 cell lines, but they are variably over-expressed at the mRNA level, compared to non-amplified lines. 20q11.21 amplified cell lines are sensitive to various tyrosine kinase inhibitors and are resistant to chemotherapy drugs targeting the mitotic apparatus and microtubules. CRISPR and RNAi dependencies screening revealed, besides the β-catenin and KRAS genes, a few recurrent gene dependencies in more than one cell line, including YAP1 and JUP. Conclusions: Cell line models of colorectal cancer with 20q11.21 gene amplifications display dependencies on the presence of specific genes and resistance or sensitivity to specific drugs and drug categories. Observations from in vitro models may form the basis for clinical drug development in this subtype of colorectal cancer. Genetic lesions conferring synthetic lethality to certain drugs or categories of drugs could be discovered with this approach.
5
Rupp, Tristan, Christophe Legrand, Marion Hunault, Laurie Genest, David Babin, Guillaume Froget, and Vincent Castagné. "A Face-To-Face Comparison of Tumor Chicken Chorioallantoic Membrane (TCAM) In Ovo with Murine Models for Early Evaluation of Cancer Therapy and Early Drug Toxicity." Cancers 14, no. 14 (July 21, 2022): 3548. http://dx.doi.org/10.3390/cancers14143548.
Full textAbstract:
Ethical considerations, cost, and time constraints have highlighted the need to develop alternatives to rodent in vivo models for evaluating drug candidates for cancer. The tumor chicken chorioallantoic membrane (TCAM) model provides an affordable and fast assay that permits direct visualization of tumor progression. Tumors from multiple species including rodents and human cell lines can be engrafted. In this study, we engrafted several tumor models onto the CAM and demonstrated that the TCAM model is an alternative to mouse models for preliminary cancer drug efficacy testing and toxicity analysis. Tumor cells were deposited onto CAM, and then grown for up to an additional 10 days before chronic treatments were administered. The drug response of anticancer therapies was screened in 12 tumor cell lines including glioblastoma, melanoma, breast, prostate, colorectal, liver, and lung cancer. Tumor-bearing eggs and tumor-bearing mice had a similar chemotherapy response (cisplatin and temozolomide) in four human and mouse tumor models. We also demonstrated that lethality observed in chicken embryos following chemotherapies such as cisplatin and cyclophosphamide were associated with corresponding side-effects in mice with body weight loss. According to our work, TCAM represents a relevant alternative model to mice in early preclinical oncology screening, providing insights for both the efficacy and the toxicity of anticancer drugs.
6
Invrea, Federica, Simona Punzi, Consalvo Petti, Rosalba Minelli, Michael D. Peoples, Christopher A. Bristow, Valentina Vurchio, et al. "Synthetic Lethality Screening Highlights Colorectal Cancer Vulnerability to Concomitant Blockade of NEDD8 and EGFR Pathways." Cancers 13, no. 15 (July 28, 2021): 3805. http://dx.doi.org/10.3390/cancers13153805.
Full textAbstract:
Colorectal cancer (CRC) is a heterogeneous disease showing significant variability in clinical aggressiveness. Primary and acquired resistance limits the efficacy of available treatments, and identification of effective drug combinations is needed to further improve patients’ outcomes. We previously found that the NEDD8-activating enzyme inhibitor pevonedistat induced tumor stabilization in preclinical models of poorly differentiated, clinically aggressive CRC resistant to available therapies. To identify drugs that can be effectively combined with pevonedistat, we performed a “drop-out” loss-of-function synthetic lethality screening with an shRNA library covering 200 drug-target genes in four different CRC cell lines. Multiple screening hits were found to be involved in the EGFR signaling pathway, suggesting that, rather than inhibition of a specific gene, interference with the EGFR pathway at any level could be effectively leveraged for combination therapies based on pevonedistat. Exploiting both BRAF-mutant and RAS/RAF wild-type CRC models, we validated the therapeutic relevance of our findings by showing that combined blockade of NEDD8 and EGFR pathways led to increased growth arrest and apoptosis both in vitro and in vivo. Pathway modulation analysis showed that compensatory feedback loops induced by single treatments were blunted by the combinations. These results unveil possible therapeutic opportunities in specific CRC clinical settings.
7
Cornet, Carles, Sylvia Dyballa, Javier Terriente, and Valeria Di Giacomo. "ZeOncoTest: Refining and Automating the Zebrafish Xenograft Model for Drug Discovery in Cancer." Pharmaceuticals 13, no. 1 (December 24, 2019): 1. http://dx.doi.org/10.3390/ph13010001.
Full textAbstract:
The xenograft of human cancer cells in model animals is a powerful tool for understanding tumor progression and metastatic potential. Mice represent a validated host, but their use is limited by the elevated experimental costs and low throughput. To overcome these restrictions, zebrafish larvae might represent a valuable alternative. Their small size and transparency allow the tracking of transplanted cells. Therefore, tumor growth and early steps of metastasis, which are difficult to evaluate in mice, can be addressed. In spite of its advantages, the use of this model has been hindered by lack of experimental homogeneity and validation. Considering these facts, the aim of our work was to standardize, automate, and validate a zebrafish larvae xenograft assay with increased translatability and higher drug screening throughput. The ZeOncoTest reliability is based on the optimization of different experimental parameters, such as cell labeling, injection site, automated individual sample image acquisition, and analysis. This workflow implementation finally allows a higher precision and experimental throughput increase, when compared to previous reports. The approach was validated with the breast cancer cell line MDA-MB-231, the colorectal cancer cells HCT116, and the prostate cancer cells PC3; and known drugs, respectively RKI-1447, Docetaxel, and Mitoxantrone. The results recapitulate growth and invasion for all tested tumor cells, along with expected efficacy of the compounds. Finally, the methodology has proven useful for understanding specific drugs mode of action. The insights gained bring a step further for zebrafish larvae xenografts to enter the regulated preclinical drug discovery path.
8
Kwon, Junhye, Sungryong Oh, Misun Park, Joon Seog Kong, Sunyi Lee, Hyunsook Lee, Younjoo Kim, Kyu-Tae Kang, Ui Sup Shin, and Joohee Jung. "Advanced Xenograft Model with Cotransplantation of Patient-Derived Organoids and Endothelial Colony-Forming Cells for Precision Medicine." Journal of Oncology 2021 (July 13, 2021): 1–9. http://dx.doi.org/10.1155/2021/9994535.
Full textAbstract:
Preclinical evaluation models have been developed for precision medicine, with patient-derived xenograft models (PDXs) and patient-derived organoids (PDOs) attracting increasing attention. However, each of these models has application limitations. In this study, an advanced xenograft model was established and used for drug screening. PDO and endothelial colony-forming cells (ECFCs) were cotransplanted in NRGA mice (PDOXwE) to prepare the model, which could also be subcultured in Balb/c nude mice. Our DNA sequencing analysis and immunohistochemistry results indicated that PDOXwE maintained patient genetic information and tumor heterogeneity. Moreover, the model enhanced tumor growth more than the PDO-bearing xenograft model (PDOX). The PDO, PDOXwE, and clinical data were also compared in the liver metastasis of a colorectal cancer patient, demonstrating that the chemosensitivity of PDO and PDOXwE coincided with the clinical data. These results suggest that PDOXwE is an improvement of PDOX and is suitable as an evaluation model for precision medicine.
9
Flechner, Marie, Juergen Loskutov, Ulrike Pfohl, Katja Osman, Christian R. Regenbrecht, Katja Uhlig, and Lena Wedeken. "Abstract 6209: TumOC: A tumor organoid-on-chip platform for real-time cell vitality measurements." Cancer Research 82, no. 12_Supplement (June 15, 2022): 6209. http://dx.doi.org/10.1158/1538-7445.am2022-6209.
Full textAbstract:
Abstract Colorectal carcinomas (CRC) are one of the most common malignant tumors. Due to its heterogeneity and high probability to metastasize, the disease is often incurable and novel, improved therapies are needed. Enhanced, physiologically relevant in-vitro tumor models significantly increase the success rate in new drug development, reduce the number of animal experiments and result finally in better therapies for cancer patients. Furthermore, they have the potential to offer new approaches to personalized oncology. In recent years, 3D cell cultures were established as relevant preclinical cancer models, suitable for high-throughput-screening. However, their capacity to model and/or measure physiological processes can still be enhanced. In this project, we developed a tumor organoid-on-chip platform (TumOC) by combining most recent technological advances: We integrated patient-derived 3D cell cultures (organoids) from colorectal carcinomas and microsensor particles measuring oxygen concentration and therefore allowing assessment of cell vitality in real time in a microfluidic system. The resulting TumOC platform allows for defined exposition of cytostatic drugs including dynamic treatments. Measurements of cell vitality in real time enables analysis of not only the final effect of a drug treatment, but also the kinetics of drug response. At the same time, utilizing organoids allows for recapitulating tumor architecture and heterogeneity. Here we report the first proof of principle results generated with this system. We measured the cell vitality in real time over 72 hours during treatment with classic chemotherapeutics or targeted cancer drugs and compared the results to end-point measurements on the same organoids in a static system. In conclusion, our TumOC platform with its ability to recapitulate tumor heterogeneity in combination with dynamic treatments and real-time cell vitality assessment is an in-vitro tumor model closely recapitulating the physiological situation in a patient. TumOC provides an impressive opportunity to test and, consequently, predict the effectiveness of anti-cancer therapies. Therefore, this system is of interest not only for pre-clinical drug development but also for personal oncology. Citation Format: Marie Flechner, Juergen Loskutov, Ulrike Pfohl, Katja Osman, Christian R. Regenbrecht, Katja Uhlig, Lena Wedeken. TumOC: A tumor organoid-on-chip platform for real-time cell vitality measurements [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 6209.
10
Mastropaolo, Maria, Helen Kuo, John Nguyen, Florencia Madorsky Rowdo, Jared Capuano, Jenna Moyer, M. Laura Martin, Julianne Hall, and Olivier Elemento. "Abstract B55: Patient-Derived Organoids model time-dependent sensitivities to PARP inhibitors in patients with metastatic colorectal cancer." Cancer Immunology Research 10, no. 12_Supplement (December 1, 2022): B55. http://dx.doi.org/10.1158/2326-6074.tumimm22-b55.
Full textAbstract:
Abstract Background: Poly (ADP-ribose) polymerase inhibitors (PARPi) have been approved as monotherapy and combination therapy for BRCA-mutated breast, ovarian, and prostate cancer and it is proposed that they may be effective for other BRCA-mutated cancer as well. However, recent clinical trials show inconsistent efficacy of PARPi on BRCA-mutated cancers, partially due to imperfect biomarker definition and unknown resistance mechanism. BRCA status alone may not be a good indicator for PARPi responsiveness as many proteins are involved in the homologous recombination (HR) pathway, which is why this experiment raises the question of whether time plays a role in tumor drug sensitivity. Patient-derived tumor organoids (PDTOs) can be used to study the pharmacogenomics between PARPis and HR deficient cancer. PDTOs are emerging ex vivo cancer models used for precision medicine because they harbor the mutational landscape of primary tumors. The common pipeline for organoid preclinical research includes confirming mutation profile, performing drug screening, and proposing clinically relevant candidates. The goal of this experiment was to model if the responses of patient-derived colorectal cancer organoids with BRCA gene deletion and TP53, SMAD4, and KRAS gene mutations to the PARPi talazoparib and olaparib differ depending on time.Methods: Patient sample: Colorectal: rectal cancer with BRCA1 gene deletion. Mutations in ⦁ KRAS p.Gly12Val ⦁ TP53 p.Arg175His ⦁ SMAD4 p.Arg361Cys + control: Puromycin 2 ug/mL - control: DMSO PARPi: talazoparib and olaparib In a 96 well plate, 1500 cells per well were plated in 10uL of a media/matrigel mixture and 100 uL of additional media were added to each well. The plate was put in the incubator at 37 C for 48 hours. The PARPi talazoparib and olaparib were then added after a serial dilution at max 50 uM concentration. The plates with the drugs (additional 100uL media with 2X drugs) were put in the incubator at 37 C for 120 hours. The plate for timepoint 1 was then read using the viability assay called Cell Titer Glo 3D. The next timepoint was taken after 168 hours using the same method. In addition, cell viability was measured by high content imaging which is being developed at EIPM.Results: Patient-Derived organoids were sensitive to talazoparib at hour 120 and hour 168 (IC50 1.6 and 1.9 respectively). Patient-derived organoids were not sensitive to olaparib at any time point tested and did not yield a meaningful IC50.Conclusion: The sensitivity of patient-derived colorectal cancer organoids with BRCA gene deletion and TP53, SMAD4, and KRAS gene mutations to the PARPi talazoparib and olaparib did not significantly differ depending on time. However, organoids were more sensitive to talazoparib than to olaparib. These results can guide which PARPi should be used in similar ex vivo experiments to yield meaningful results to eventually lead to successful clinical treatments for patients. Citation Format: Maria Mastropaolo, Helen Kuo, John Nguyen, Florencia Madorsky Rowdo, Jared Capuano, Jenna Moyer, M. Laura Martin, Julianne Hall, Olivier Elemento. Patient-Derived Organoids model time-dependent sensitivities to PARP inhibitors in patients with metastatic colorectal cancer [abstract]. In: Proceedings of the AACR Special Conference: Tumor Immunology and Immunotherapy; 2022 Oct 21-24; Boston, MA. Philadelphia (PA): AACR; Cancer Immunol Res 2022;10(12 Suppl):Abstract nr B55.
11
Xu, Xiaoxi, Marco Tognetti, Yuehan Feng, Limei Shang, Leilei Chen, Jessie Wang, Roland Bruderer, Ludovic Bourré, and Henry Li. "Abstract 3110: Identification of the phosphorylation network in PDX and corresponding organoid (PDXO) models upon targeted therapy treatment using deep phosphoproteomic analysis[MB1]." Cancer Research 82, no. 12_Supplement (June 15, 2022): 3110. http://dx.doi.org/10.1158/1538-7445.am2022-3110.
Full textAbstract:
Abstract In precision medicine, genomic, transcriptomic, and proteomic data has contributed to the identification of novel driver genes and the molecular-level characterization of cancers. This data has led to a better understanding of drug modulation and resistance mechanisms. Patient-derived tumor models, including patient-derived xenograft (PDX) and organoid counterparts (PDXO), have been increasingly viewed as predictive preclinical cancer models. These models closely recapitulate tumor complexity, enabling the study of tumor identity for personalized medicine. Leveraging our large PDX collection models which are genomically and phenotypically annotated and validated, we have established and characterized a series of PDXO models to be used as scalable and high throughput compatible drug screening platforms. Here we conducted methodical analysis of drug response in paired PDX and PDXO models. In addition, trough deep whole- and phospho-proteomic analysis, we have analyzed and compared the effect of targeted therapies on protein expression and phosphorylation in both PDX and PDXO tumor models. Indeed, one of the most common post-translational modifications that is involved in cell regulation and intracellular signal transduction is reversible protein phosphorylation catalyzed by protein kinases. For this purpose, we have tested a KRAS inhibitor (AMG510), BCR-ABL TKI (Ponatinib) and EGFR TKI (Afatinib) respectively in lung NSCLC model carrying KRAS G12C mutation, colorectal model with RET fusion and Lung NSCLC model with EGFR exon 19 deletion. According to our historical data, a specific relationship between area under the curve value of organoid drug dose response and in vivo tumor growth has been observed, irrespective of the drug treatment. Furthermore, comparison between PDX and PDXO models deploying quantitative proteomic data enabled deep characterization of both global expression and signaling cascades modulated through small molecule inhibitors. Thus, we demonstrate the predictivity of organoid cultures to not only model in vivo drug responses but also to serve as a powerful platform to investigate target identification, mechanism of action and resistance mechanism via deep proteomics analysis. Citation Format: Xiaoxi Xu, Marco Tognetti, Yuehan Feng, Limei Shang, Leilei Chen, Jessie Wang, Roland Bruderer, Ludovic Bourré, Henry Li. Identification of the phosphorylation network in PDX and corresponding organoid (PDXO) models upon targeted therapy treatment using deep phosphoproteomic analysis[MB1] [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 3110.
12
Invrea, Federica, Alessandro Carugo, Consalvo Petti, Giulio Draetta, and Enzo Medico. "Abstract B022: The NEDD8 pathway as a therapeutic target in HER2-amplified colorectal cancer." Cancer Research 82, no. 23_Supplement_1 (December 1, 2022): B022. http://dx.doi.org/10.1158/1538-7445.crc22-b022.
Full textAbstract:
Abstract Colorectal cancer (CRC) is a heterogeneous disease with a wide spectrum of clinical outcomes, from indolent resectable disease to aggressive-metastatic cases. Primary and acquired resistance limits the efficacy of available treatments, and the identification of effective drug combinations is needed to further improve patients' outcomes. We previously found that the NEDD8-activating enzyme inhibitor pevonedistat induces tumor stabilization in preclinical models of poorly differentiated, clinically aggressive CRC resistant to available therapies. To identify drugs that can be effectively combined with pevonedistat, we performed a drop-out loss-of-function synthetic lethality screening with a shRNA library covering 200 drug-target genes in four different CRC cell lines. Multiple screening hits were found to be involved in the EGFR signaling pathway, suggesting that, rather than inhibition of a specific gene, interference with the EGFR pathway at various levels could be effectively leveraged for combination therapies based on pevonedistat. Exploiting both BRAF-mutant and RAS/RAF wild-type CRC models, we validated the therapeutic relevance of our findings by showing that combined blockade of NEDD8 and EGFR pathways led to increased growth arrest and apoptosis both in vitro and in vivo. Pathway modulation analysis showed that compensatory feedback loops induced by single treatments were blunted by the combinations. Our results suggested possible therapeutic opportunities in specific CRC clinical settings. We further focused on HER2-amplified CRC and found marked sensitivity to pevonedistat in a CRC cell line carrying HER2 amplification. In these cells, long-term in vitro treatment with a combination of lapatinib and trastuzumab induces the emergence of colonies of long-term persisters (i.e., cells surviving to several weeks of HER2/EGFR blockade). These persisters display extremely slow growth and senescence features, however they fully recover upon removal of the blockade, mimicking disease relapse in patients after treatment suspension. Interestingly, persister colonies maintained sensitivity to pevonedistat, displaying a marked decrease when pevonedistat was added after six weeks of HER2/EGFR blockade, independently of the continuation of the blockade. These results unveil the possibility of employing pevonedistat in HER2-amplified CRC patients subsequently to tumor stabilization or regression by HER-2/EGFR blockade. Citation Format: Federica Invrea, Alessandro Carugo, Consalvo Petti, Giulio Draetta, Enzo Medico. The NEDD8 pathway as a therapeutic target in HER2-amplified colorectal cancer [abstract]. In: Proceedings of the AACR Special Conference on Colorectal Cancer; 2022 Oct 1-4; Portland, OR. Philadelphia (PA): AACR; Cancer Res 2022;82(23 Suppl_1):Abstract nr B022.
13
Invrea, Federica, Alessandro Carugo, Sabrina Arena, Alberto Bardelli, Giulio F. Draetta, and Enzo Medico. "Abstract 2611: The NEDD8 pathway as a therapeutic target in HER2-amplified colorectal cancer." Cancer Research 82, no. 12_Supplement (June 15, 2022): 2611. http://dx.doi.org/10.1158/1538-7445.am2022-2611.
Full textAbstract:
Abstract Colorectal cancer (CRC) is a heterogeneous disease with a wide spectrum of clinical outcomes, from indolent resectable disease to aggressive-metastatic cases. Primary and acquired resistance limits the efficacy of available treatments, and the identification of effective drug combinations is needed to further improve patients' outcomes. We previously found that the NEDD8-activating enzyme inhibitor pevonedistat induced tumor stabilization in preclinical models of poorly differentiated, clinically aggressive CRC resistant to available therapies. To identify drugs that can be effectively combined with pevonedistat, we performed a "drop-out" loss-of-function synthetic lethality screening with an shRNA library covering 200 drug-target genes in four different CRC cell lines. Multiple screening hits were found to be involved in the EGFR signaling pathway, suggesting that, rather than inhibition of a specific gene, interference with the EGFR pathway at any level could be effectively leveraged for combination therapies based on pevonedistat. Exploiting both BRAF-mutant and RAS/RAF wild-type CRC models, we validated the therapeutic relevance of our findings by showing that combined blockade of NEDD8 and EGFR pathways led to increased growth arrest and apoptosis both in vitro and in vivo. Pathway modulation analysis showed that compensatory feedback loops induced by single treatments were blunted by the combinations. Our results suggested possible therapeutic opportunities in specific CRC clinical settings. We further focused on HER2 amplified CRC cells and we observed cooperation between pevonedistat and HER2/EGFR blockade by the trastuzumab + lapatinib combination -the current standard treatment for HER2-amplified CRC. In addition, to confirm cooperation in reducing colony formation in vitro, we explored the effect of pevonedistat on long-term persisters, i.e., cell surviving to several weeks of HER2/EGFR blockade. Interestingly, we observed a marked decrease of cell colonies when pevonedistat was added to persisters survived to three weeks of trastuzumab + lapatinib treatment. These results unveil the possibility of testing in vivo the addition of pevonedistat subsequently to tumor stabilization or reduction by HER2/EGFR blockade, to promote further tumor regression. Citation Format: Federica Invrea, Alessandro Carugo, Sabrina Arena, Alberto Bardelli, Giulio F. Draetta, Enzo Medico. The NEDD8 pathway as a therapeutic target in HER2-amplified colorectal cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 2611.
14
Grinkevitch, Vera, Mark Wappett, Nyree Crawford, Stacey Price, Andrea Lees, Christopher McCann, Katherine McAllister, et al. "Functional Genomic Identification of Predictors of Sensitivity and Mechanisms of Resistance to Multivalent Second-Generation TRAIL-R2 Agonists." Molecular Cancer Therapeutics 21, no. 4 (January 27, 2022): 594–606. http://dx.doi.org/10.1158/1535-7163.mct-21-0532.
Full textAbstract:
Abstract Multivalent second-generation TRAIL-R2 agonists are currently in late preclinical development and early clinical trials. Herein, we use a representative second-generation agent, MEDI3039, to address two major clinical challenges facing these agents: lack of predictive biomarkers to enable patient selection and emergence of resistance. Genome-wide CRISPR knockout screens were notable for the lack of resistance mechanisms beyond the canonical TRAIL-R2 pathway (caspase-8, FADD, BID) as well as p53 and BAX in TP53 wild-type models, whereas a CRISPR activatory screen identified cell death inhibitors MCL-1 and BCL-XL as mechanisms to suppress MEDI3039-induced cell death. High-throughput drug screening failed to identify genomic alterations associated with response to MEDI3039; however, transcriptomics analysis revealed striking association between MEDI3039 sensitivity and expression of core components of the extrinsic apoptotic pathway, most notably its main apoptotic effector caspase-8 in solid tumor cell lines. Further analyses of colorectal cell lines and patient-derived xenografts identified caspase-8 expression ratio to its endogenous regulator FLIP(L) as predictive of sensitivity to MEDI3039 in several major solid tumor types and a further subset indicated by caspase-8:MCL-1 ratio. Subsequent MEDI3039 combination screening of TRAIL-R2, caspase-8, FADD, and BID knockout models with 60 compounds with varying mechanisms of action identified two inhibitor of apoptosis proteins (IAP) that exhibited strong synergy with MEDI3039 that could reverse resistance only in BID-deleted models. In summary, we identify the ratios of caspase-8:FLIP(L) and caspase-8:MCL-1 as potential predictive biomarkers for second-generation TRAIL-R2 agonists and loss of key effectors such as FADD and caspase-8 as likely drivers of clinical resistance in solid tumors.
15
Hribar, Kolin C., Bin Xue, Christopher Harrod, Timothy Jensen, and Julia Schüler. "Abstract 1880: High throughput screening of 30 PDX cell lines in a 3D ECM hydrogel platform, incorporating tumor, stroma and immune components to demonstrate simultaneous investigation of multiple anti-tumor modalities." Cancer Research 82, no. 12_Supplement (June 15, 2022): 1880. http://dx.doi.org/10.1158/1538-7445.am2022-1880.
Full textAbstract:
Abstract High throughput screening offers tangible benefits towards rapidly testing various permutations of novel or existing therapeutic agents. In particular, tumor panels that cover a range of histotypes and molecular subtypes have been previously developed, such as the NCI-60, however they utilize cell lines and, in some cases, a 2D cell culture format, which limit their translatability to preclinical and clinical trials. Moreover, the biological complexity of the tumor microenvironment (TME) has revealed a need for more translatable 3D in vitro tumor models that reflect the in vivo physiological outcome to therapies, particularly with the explosion of immunotherapy programs in drug discovery which target the immune compartment of the TME. Here, we describe for the first time a 3D in vitro PDX panel comprising 30 distinct PDX models in coculture with fibroblasts and PBMCs in engineered extracellular matrix hydrogels that display distinct similarities to the three compartments of the TME - tumor, stroma, and immune cells. Histotypes in the panel include, amongst others, Non-small cell lung, colorectal, breast, pancreatic, gastric, melanoma, and renal cancers. The panel is constructed in a high throughput 96-well format and rapidly assays tumor growth delay and other endpoints such as apoptosis in a dose-dependent manner across various drug modalities such as small molecules, biologics and cell therapy. The panel has been tested against targeted therapy (Docetaxel, Cisplatin) and immunomodulatory agents (Pembrolizumab, Atezolizumab) and the results correlate to the corresponding PDX in vivo data. Interestingly, cisplatin treatment displayed an average size reduction of >30% for melanoma but a varied response in NSCLC tumors. And, several NSCLC responded more favorably to checkpoint inhibitors, however, the lung epidermoid PDX demonstrated no significant response. Moreover, subsequent cytokine analysis and immunofluorescence staining of several models revealed protein signatures of cancer-associated fibroblasts and CD3+ sequestration in the tumor stroma in some 3D models, suggesting the fibroblasts’ critical role in regulating the immune response. In short, the 30-PDX Panel described here represents a large step forward towards achieving translatable efficacy data at the earliest stages of drug discovery where little is known about the mechanism of action for a particular therapeutic agent or combination of agents. Citation Format: Kolin C. Hribar, Bin Xue, Christopher Harrod, Timothy Jensen, Julia Schüler. High throughput screening of 30 PDX cell lines in a 3D ECM hydrogel platform, incorporating tumor, stroma and immune components to demonstrate simultaneous investigation of multiple anti-tumor modalities [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 1880.
16
De Censi, Andrea, Juergen Burhenne, Walter E. Haefeli, Johanna Weiß, Wilfried Roth, Andrea Parodi, Michael Gnant, et al. "High accumulation of metformin in colonic tissue of subjects with diabetes or metabolic syndrome." Journal of Clinical Oncology 35, no. 15_suppl (May 20, 2017): 1557. http://dx.doi.org/10.1200/jco.2017.35.15_suppl.1557.
Full textAbstract:
1557 Background: Epidemiological studies consistently observed an association between metformin use in diabetic patients and decreased colon cancer incidence and mortality at clinical doses (1500-2250 mg day), corresponding to plasma levels of 0.003-0.045 mM. Preclinical models report much higher doses of metformin, ranging between 1 and 40 mM for in vitro and 0.006-0.145 mM for in vivo studies. A recent trial using a low dose of metformin (250 mg/day, Higurashi T et al. Lancet 2016;17:475) showed a 40% reduction of colorectal adenoma recurrence. We performed a pilot study to measure metformin in plasma and colonic tissue of subjects with diabetes or metabolic syndrome and to explore their correlation with different tissue biomarkers, including Ki-67, pS6k, a mTOR effector protein, and EGFR expression. Methods: We used LC-MS/MS to quantify metformin in plasma and colonic tissues from 13 volunteers with diabetes or metabolic syndrome undergoing screening colonoscopy. All patients had received metformin at 1000-1850 mg/day for a median of 6.5 yrs (range 2-15), except for one who served as untreated control. Tissue quantifications were performed on specimens derived from right and left colon biopsies with or without washing to exclude a potential contamination due to lumen accumulation by the drug. Biomarker assessment was performed by standard IHC assay. Results: The mean plasma metformin was 0.025 mM/L (range 5x10-5-0.017), whereas the colonic tissue was ~100 fold higher in right [0.39 mM/Kg (range 0.034-1.75)] and left colon [0.46 mM/Kg (range 5x10-3-1.86)]. There was no significant difference between washed and unwashed biopsies. No significant correlations were detected between metformin levels in plasma/tissue and tissue biomarkers. Conclusions: Metformin can attain ~100 fold higher colonic tissue levels than in plasma. These levels are in the range of a direct antitumor effect observed in in vivo preclinical models. A two-by-two clinical trial of metformin and aspirin in colon cancer patients is underway by our group to further elucidate independent and synergistic antitumor effects.
17
Xue, Bin, Julia Schuler, Christopher Harrod, and Kolin Hribar. "943 3D in vitro tumor model platform rapidly assays immunotherapy efficacy with high content imaging and downstream phenotypic changes with flow cytometry and cytokine analysis." Journal for ImmunoTherapy of Cancer 9, Suppl 2 (November 2021): A990. http://dx.doi.org/10.1136/jitc-2021-sitc2021.943.
Full textAbstract:
BackgroundCancer immunotherapy represents a burgeoning new direction for oncology therapeutic innovation, with the principal thesis of activating one’s own immune system to irradicate cancer as opposed to the injection of foreign cytotoxic agents like chemotherapy. The first generation of checkpoint inhibitors unleash cytotoxic T cells to locate and kill their tumor target, however, only a small subset of patients (e.g. ~30% of NSCLC patients1) respond favorably. In order to advance the next generation of immunotherapy to the clinic, we critically need models which more accurately represent the immunosuppressive tumor microenvironment (TME).MethodsHere, we describe a novel 3D in vitro tumor model platform which engineers the tumor, stromal, and immune cell compartments of the TME in an extracellular matrix hydrogel (VersaGel2) and a high throughput 96-well format. The system has been extensively tested across multiple solid tumor indications, such as colorectal, lung, pancreatic, breast, and others. Specifically for this study, we utilized NSCLC PDX cells from the Charles River compendium and cocultured with human dermal fibroblasts (HDF) and PBMCs to study the effects of checkpoint inhibitor monoclonal antibodies, Pembrolizumab (anti-PD1) and Atezolizumab (anti-PDL1), on T cell infiltration and T cell-mediated killing using high content imaging. Supernatants were analyzed for cytokines and the 3D models were subsequently digested for flow cytometry.ResultsThe 3D models demonstrated varying degrees of T cell infiltration and killing capacity across PDX in a dose-dependent manner to checkpoint inhibitors, and the inclusion of fibroblasts played a critical role in further modulating response. Moreover, the data revealed clinically-relevant levels of CD3+, CD4+, and CD8+ T cell subpopulations and cytokine secretions such as IFN-gamma.ConclusionsThese data suggest a novel 3D model platform for assaying immunotherapeutic efficacy as well as its mechanism of action in the context of the TME. Future studies will include applying this novel platform to additional tumor models and screening multiple forms of immunotherapy – such as small molecules, biologics, and cell and gene therapy – in drug discovery, preclinical testing, and precision medicine.ReferencesHaslam A, Prasad V. Estimation of the percentage of US patients with cancer who are eligible for and respond to checkpoint inhibitor immunotherapy drugs. JAMA Netw 2019;2(5):e192535.Hribar KC, Wheeler CJ, Bazarov A, Varshneya K, Yamada R, Buckley P, Patil CG. A simple three-dimensional hydrogel platform enables ex vivo cell culture of patient and PDX tumors for assaying their response to clinically relevant therapies. Mol Canc Ther 2019;18(3):718–725.
18
Curigliano, G., G. Spitaleri, T. De Pas, C. Noberasco, L. Giovannoni, H. Menssen, L. Zardi, A. Milani, D. Neri, and F. de Braud. "A dose finding pharmacokinetic study of the tumor-targeting human L19-IL2 monoclonal antibody-cytokine fusion protein in patients with advanced solid tumors." Journal of Clinical Oncology 25, no. 18_suppl (June 20, 2007): 3057. http://dx.doi.org/10.1200/jco.2007.25.18_suppl.3057.
Full textAbstract:
3057 Background: L19-IL2 is a tumor targeting immunocytokine constituted by a single chain Fragment variable format directed against ED-B domain of fibronectin and the human cytokine interleukin-2 (IL-2). It has striking anticancer activity in preclinical models. We evaluated safety, pharmacokinetic profile (PK) and activity of L19-IL2 in advanced cancer patients. Patients and Methods: Five cohorts of patients with recurrent/refractory solid tumors received a dose escalation intravenous infusion of L19-IL2 (5, 10, 15, 22.5 e 30 Mio IU IL2 equivalent dose) on days 1, 3 and 5 every 21 days. Serum samples for PK assessment, immunophenotyping and assays for detection of human antifusion protein antibodies to L19 (HAFA) were collected at screening and on day 1, 3, 5 and 10 of each cycle. Results: Eighteen solid cancer patients were enrolled from 11/05 to 9/06 (6 colorectal and 3 renal cell cancer (RCC) patients, 3 with melanoma, and 1 neuroendocrine tumor, thymic carcinoma, biliary tract carcinoma, breast cancer, peritoneal mesothelioma and parotid gland carcinoma). Median age was 49 years (range 35–69), 14 patients were male and 4 female. All patients were evaluable for safety and activity. The maximum tolerated dose was determined to be 22.5 Mio IU IL-2 equivalent. Drug-related dose-limiting toxicities at 30 Mio IU L19-IL2 were hypotension requiring vaso-pressor support and acute renal failure. Treatment-related deaths did not occur, and all toxicities were reversible. Five patients achieved stable disease (RCC, n=3; biliary tract carcinoma, n=1; peritoneal mesothelioma, n=1). All other patients progressed. Immunophenotyping disclosed IL2-typical transient activation of T-cell subsets. Very preliminary data showed a weak induction of HAFA at day 10 in 5 patients. These data could not be confirmed by competition ELISA experiments. Conclusions: Up to 22.5 Mio IU IL2 equivalent of L19-IL2 can be safely administered to advanced solid cancer patients in an outpatient setting. Some evidence of clinical activity in patients susceptible to immunomodulatory therapy (RCC) was found. All observed toxicity was mild and reversible. An expanded study at recommended dose in RCC patients is currently ongoing. [Table: see text]
19
Sung, Na Young, Jae Kwan Jun, Youn Nam Kim, Inkyung Jung, Sohee Park, Gyu Ri Kim, and Chung Mo Nam. "Estimating age group-dependent sensitivity and mean sojourn time in colorectal cancer screening." Journal of Medical Screening 26, no. 1 (September 27, 2018): 19–25. http://dx.doi.org/10.1177/0969141318790775.
Full textAbstract:
Objective In evaluating the efficacy of cancer screening programmes, sojourn time (duration of the preclinical detectable phase) and sensitivity of the screening test are the two key parameters. Studies suggest that in breast cancer screening, both parameters may vary depending on age at the time of screening, but few studies have examined other cancers. We expanded an existing probability model for periodic screening by performing simultaneous estimation of age group-dependent and sensitivity at preclinical onset time, and tested the expanded model using data from the Korean National Colorectal Cancer Screening Programme. Methods Simulation studies were conducted to assess the performance of the proposed probability model. The method was then applied to the analysis of 376,542 participants aged 50 or over who underwent fecal occult blood testing (FOBT) as part of the National Colorectal Cancer Screening Programme between 2004 and 2007. Age group-dependent mean sojourn time and screening sensitivity of FOBT for colorectal cancer were derived using maximum likelihood estimation. Results The method performed well in terms of bias, standard deviation, and coverage probability. National Colorectal Cancer Screening Programme data results indicated that the sensitivity of FOBT to detect colorectal cancer increases with age, while mean sojourn time decreases with age (approximately 4.3 years for participants aged 50–54, 3.9 years at age 55–59, 3.4 years at age 60–64, and 3.6 years at age 65–69, with corresponding sensitivity estimates around 41%, 47%, 45%, and 51%, respectively). Conclusion Simulation studies showed that the proposed stochastic model considering both mean sojourn time and sensitivity yields highly accurate results.
20
Buczacki, Simon J. A., Semiramis Popova, Emma Biggs, Chrysa Koukorava, Jon Buzzelli, Louis Vermeulen, Lee Hazelwood, Hayley Francies, Mathew J. Garnett, and Douglas J. Winton. "Itraconazole targets cell cycle heterogeneity in colorectal cancer." Journal of Experimental Medicine 215, no. 7 (May 31, 2018): 1891–912. http://dx.doi.org/10.1084/jem.20171385.
Full textAbstract:
Cellular dormancy and heterogeneity in cell cycle length provide important explanations for treatment failure after adjuvant therapy with S-phase cytotoxics in colorectal cancer (CRC), yet the molecular control of the dormant versus cycling state remains unknown. We sought to understand the molecular features of dormant CRC cells to facilitate rationale identification of compounds to target both dormant and cycling tumor cells. Unexpectedly, we demonstrate that dormant CRC cells are differentiated, yet retain clonogenic capacity. Mouse organoid drug screening identifies that itraconazole generates spheroid collapse and loss of dormancy. Human CRC cell dormancy and tumor growth can also be perturbed by itraconazole, which is found to inhibit Wnt signaling through noncanonical hedgehog signaling. Preclinical validation shows itraconazole to be effective in multiple assays through Wnt inhibition, causing both cycling and dormant cells to switch to global senescence. These data provide preclinical evidence to support an early phase trial of itraconazole in CRC.
21
Lin, T. Y. "Quantitative Models for Modeling Overdetection in Population-Based Screening for Colorectal Cancer." Journal of Global Oncology 4, Supplement 2 (October 1, 2018): 209s. http://dx.doi.org/10.1200/jgo.18.84400.
Full textAbstract:
Background: Overdetection resulting from population-based cancer screening has been debatable over the past decade. However, a systematic approach for quantitative estimation of overdetection has been barely addressed. Contextually, mass screening for breast cancer and prostate cancer has been well documented, but colorectal cancer (CRC) has been scarcely highlighted. Aim: The aim of this study is to develop a systematic approach for quantitative estimation of overdetection and elucidating the mechanism of overdetection in population-based colorectal cancer screening. Methods: The graphic method was first proposed by comparing cumulative incidence curves of advanced and nonadvanced cancers. Then, the modeling approaches used for quantitative methods were developed. We proposed the standardized overdetection ratio (SOR), the index including expected and observed which are simulated by a 3-state Markov model (normal, preclinical detectable phase, clinical phase) based on screened group and control group, respectively. Moreover, we developed the 5-state Markov model in conjunction with SOR to quantify the extent of overdetection. Two randomized controlled trials on guaiac–fecal occult blood test (gFOBT) in U.K. and Denmark and population-based service screening using fecal immunochemical test (FIT) in Taiwan were applied to assess the proposed methods to quantify overdetection in population-based cancer screening. Results: Using the graphic method, the average of overdetection was 31.1% and 24.9% for the UK trial and the Denmark trial, respectively. However, the estimated proportion of overdetection may be biased because the graphic method did not take the natural history of adenoma and high awareness in the routine clinical practice into account. According to the proposed 3-state Markov model, the overdetection of CRC was 9% with gFOBT based on the 2 randomized controlled trials in Europe and 7% with FIT based on a nationwide screening program in Taiwan. The estimated overdetection by the 5-state Markov model were 6.1% and 9.2% for the U.K. and Denmark trial, respectively. Moreover, the main pathway for overdetection in population-based CRC screening is from nonadvanced in the preclinical phase to advanced in the preclinical phase which is supported by the evidence that SOR decreases from 1.29 to 1.16 and 1.16 to 0.97 for the U.K. and Denmark trial, respectively. Conclusion: This study developed the graphic method and the disease natural progression model for quantitative assessment of overdetection in colorectal cancer. The index, SOR, was proposed not only to assess the extent of overdetection but also to elucidate the mechanism to know how overdetection affects the progression of colorectal cancer from the preclinical phase to the clinical phase with information of cancer stage.
22
Huang, Jiao-Ren, Mei-Hsien Lee, Wen-Shan Li, and Han-Chun Wu. "Liposomal Irinotecan for Treatment of Colorectal Cancer in a Preclinical Model." Cancers 11, no. 3 (February 27, 2019): 281. http://dx.doi.org/10.3390/cancers11030281.
Full textAbstract:
Colorectal cancer (CRC) is the most frequently diagnosed cancer and leading cause of cancer-related deaths worldwide. Because of the use of first-line CRC treatments, such as irinotecan (IRI), is hindered by dose-limiting side effects, improved drug delivery systems may have major clinical benefits for CRC treatment. In this study, we generate and characterize liposomal irinotecan (Lipo-IRI), a lipid-based nanoparticle, which shows excellent bioavailability and pharmacokinetics. Additionally, this formulation allows IRI to be maintained in active form and prolongs its half-life in circulation compared to IRI in solution. Compared with IRI statistically, the level of prostaglandin E2 (PGE2) in colonic tissue decreases, and Bifidobacterium spp. (beneficial intestinal microbiota) content increases in the Lipo-IRI-treated group. Moreover, no damage is observed by the hematoxylin and eosin staining of the normal tissue samples from the Lipo-IRI-treated group. In a xenograft mouse model, CRC tumors shrink markedly following Lipo-IRI treatment, and mice receiving a targeted combination of Lipo-IRI and liposomal doxorubicin (Lipo-Dox) extend their survival rate significantly. Overall, our results demonstrate that this formulation of Lipo-IRI shows a great potential for the treatment of colorectal cancer.
23
Ahmed, Shamima Nasreen, Biswajit Das, and Jashabir Chakraborty. "PROSPECTIVE AND RETROSPECTIVE ANIMAL MODEL USED IN THE PHARMACOLOGICAL SCREENING OF ANTI-CANCER DRUG." International Journal of Current Pharmaceutical Research 10, no. 4 (July 16, 2018): 13. http://dx.doi.org/10.22159/ijcpr.2018v10i4.28472.
Full textAbstract:
Cancer is a disease characterized by uncontrolled proliferation of cells that have transformed from the normal cells of the body. The widely used cancer drugs suffers from the drawback of high toxicity not within the reach of a common man. This urgently necessitating the screening of these compounds. This review focuses on the major contributions of preclinical screening models to anticancer drug development over the years till recent times, from the empirical drug screening of cytotoxic agents against uncharacterized tumor models to the target-orientated drug screening of agents with defined mechanisms of action,, a general transition has been observed. The newer approaches to anticancer drug development involve the molecular characterization of models along with an appreciation of the pharmacodynamics and pharmacokinetic properties of compounds [e. g., the US National Cancer Institute (NCI) in vitro 60-cell line panel, hollow fibre assay, and s. c. xenograft]. In vivo tumor models including orthotopic, metastatic, and genetically engineered mouse models are also reviewed. The preclinical screening efforts of the European are also included. In 2015 with the rapid development of cancer modeling in zebrafish, great opportunities exist for chemical screens to find anticancer drug since 1970 the European Organisation for Research and Treatment of Cancer and Cancer Research UK, have been collaborating with the NCI in the acquisition and screening of compounds.
24
Sensi, Francesca, Edoardo D’Angelo, Sara D’Aronco, Roberto Molinaro, and Marco Agostini. "Preclinical three-dimensional colorectal cancer model: The next generation of in vitro drug efficacy evaluation." Journal of Cellular Physiology 234, no. 1 (September 13, 2018): 181–91. http://dx.doi.org/10.1002/jcp.26812.
Full text
25
Meyer, Th, J. Goehl, G. Bernhardt, Th SpruB, C. Christl, and W. Hohenberger. "A preclinical experimental model for cytostatic drug screening in the treatment of malignant melanoma." Melanoma Research 4, no. 2 (September 1994): 32. http://dx.doi.org/10.1097/00008390-199409001-00060.
Full text
26
Dang, Rajan Paul, Celina Ang, Randall F. Holcombe, Max W. Sung, Ross L. Cagan, Eric Schadt, Marshall R. Posner, et al. "Genomic analysis and personalized cancer therapy for metastatic colorectal cancer." Journal of Clinical Oncology 33, no. 3_suppl (January 20, 2015): 568. http://dx.doi.org/10.1200/jco.2015.33.3_suppl.568.
Full textAbstract:
568 Background: Standard approaches in cancer research identify new therapies based on observed benefit to average populations but without emphasis on individual patients whose responses can vary considerably. Also, targeted therapies rarely account for the genomic complexity of patient tumors; the result is poor efficacy and rapid resistance. We would identify drugs or drug cocktails that (1) target the details of an individual’s tumor and (2) account for its complexity. Models using the fruit fly Drosophila represent a potential new paradigm in cancer therapy. We have developed fly models that can include up to 10 of a patient’s tumor’s driver mutations; the result is an inexpensive drug-screening platform to identify drug cocktails through empirical screening. Methods: Patients with metastatic CRC who have progressed or become intolerant to fluoropyrimidines, oxaliplatin, irinotecan, avastin, and (if KRAS wild-type) EGFR inhibitor therapy. Mutations identified by deep DNA and RNA sequencing of individual tumors are screened for tumor drivers, which are then incorporated into the “personal” Drosophila model and tested against a library of FDA approved drugs. Fly mortality is used as a surrogate for toxicity; improvements in tumor mutation-linked eye and/or wing abnormalities serve to quantify efficacy. This allows rapid and parallel screening of up to 800 drugs and subsequent drug combinations. The most efficacious and least toxic combinations are presented to a multidisciplinary tumor board of experts, who will then select the best therapeutic option for the patient. Results: To demonstrate that the personalized Drosophila model approach is superior to the current standard, regorafenib, which performed best in CRC with a 10% response rate (RR) against placebo in a phase III trial. Using the 10% RR as a benchmark, we will apply a sequential Bayesian method for 50 MTC patients enrolled to receive personalized treatment to demonstrate that this approach has greater efficacy, or at minimum, substantially similar efficacy with reduced toxicity. Conclusions: To demonstrate that personalized cancer therapy is superior to the current standard and is an effective therapy worth exploring for other cancers too.
27
Lee, Myoung Woo, Hye Jin Kim, Dae Seong Kim, Meong Hi Son, Soo Hyun Lee, Hye Lim Jung, Keon Hee Yoo, Ki Woong Sung, and Hong Hoe Koo. "Establishment of Bioluminescence Imaging Based Leukemia In Vivo Model for Preclinical Testing." Blood 118, no. 21 (November 18, 2011): 4879. http://dx.doi.org/10.1182/blood.v118.21.4879.4879.
Full textAbstract:
Abstract Abstract 4879 Background. A hematological malignant animal model is an essential tool for evaluating efficacy of anti-cancer drugs and elucidating underlying mechanism of leukemogenesis. Intraperitoneal (IP) and intravenous (IV) xenograft of acute lymphoblastic leukemia (ALL) cells have limited capacity as in vivo anti-cancer drug screening system. Purpose. In this study, we aimed to establish an ALL animal model using NOD/SCID mouse and evaluate efficiency and sensitivity of the model as a preclinical drug screening system. Materials and Methods. Firefly luciferase (fLuc)-gene introduced ALL (ALL/fLuc) cell line and patient-originated ALL cells were transplanted into a tibia of NOD/SCID mouse. We conducted a comparative analysis of intra-bone marrow (IBMT) transplanted leukemia model with IP and IV transplantation of leukemic cells. Results. IBMT of ALL/fLuc cells effectively established a bioluminescent leukemia NOD/SCID mouse model. Upon comparison of IBMT model with IP and IV transplantation models, infusing identical number of ALL/fLuc cells into NOD/SCID mice resulted in IBMT model with evaluable bioluminescent signal, but not in IP and IV models. In IBMT model, bioluminescent signals of ALL/fLuc cells emitted from peripheral blood, tibia and infiltrated organs indicated that leukemia model was established. The changes in these signals' strength reflected dose-dependent cytotoxic effects of vincristine, which allowed leukemia model with evaluable bioluminescent signal to be utilized as a preclinical drug screening system. IBMT leukemia model was also established using primary ALL cells that can provide additional insights for the development of leukemia therapeutics. Conclusion. IBMT of ALL/fLuc cells enables development of leukemia mouse model with the greater bioluminescent sensitivity than IP and IV in NOD/SCID to evaluate candidate for development of anti-cancer drug. Disclosures: No relevant conflicts of interest to declare.
28
Kuntz, Karen M., Iris Lansdorp-Vogelaar, Carolyn M. Rutter, Amy B. Knudsen, Marjolein van Ballegooijen, James E. Savarino, Eric J. Feuer, and Ann G. Zauber. "A Systematic Comparison of Microsimulation Models of Colorectal Cancer." Medical Decision Making 31, no. 4 (June 14, 2011): 530–39. http://dx.doi.org/10.1177/0272989x11408730.
Full textAbstract:
Background. As the complexity of microsimulation models increases, concerns about model transparency are heightened. Methods. The authors conducted model “experiments” to explore the impact of variations in “deep” model parameters using 3 colorectal cancer (CRC) models. All natural history models were calibrated to match observed data on adenoma prevalence and cancer incidence but varied in their underlying specification of the adenocarcinoma process. The authors projected CRC incidence among individuals with an underlying adenoma or preclinical cancer v. those without any underlying condition and examined the impact of removing adenomas. They calculated the percentage of simulated CRC cases arising from adenomas that developed within 10 or 20 years prior to cancer diagnosis and estimated dwell time—defined as the time from the development of an adenoma to symptom-detected cancer in the absence of screening among individuals with a CRC diagnosis. Results. The 20-year CRC incidence among 55-year-old individuals with an adenoma or preclinical cancer was 7 to 75 times greater than in the condition-free group. The removal of all adenomas among the subgroup with an underlying adenoma or cancer resulted in a reduction of 30% to 89% in cumulative incidence. Among CRCs diagnosed at age 65 years, the proportion arising from adenomas formed within 10 years ranged between 4% and 67%. The mean dwell time varied from 10.6 to 25.8 years. Conclusions. Models that all match observed data on adenoma prevalence and cancer incidence can produce quite different dwell times and very different answers with respect to the effectiveness of interventions. When conducting applied analyses to inform policy, using multiple models provides a sensitivity analysis on key (unobserved) “deep” model parameters and can provide guidance about specific areas in need of additional research and validation.
29
Rosendahl, Jennifer, Andreas Svanström, Mattias Berglin, Sarunas Petronis, Yalda Bogestål, Patrik Stenlund, Simon Standoft, et al. "3D Printed Nanocellulose Scaffolds as a Cancer Cell Culture Model System." Bioengineering 8, no. 7 (July 10, 2021): 97. http://dx.doi.org/10.3390/bioengineering8070097.
Full textAbstract:
Current conventional cancer drug screening models based on two-dimensional (2D) cell culture have several flaws and there is a large need of more in vivo mimicking preclinical drug screening platforms. The microenvironment is crucial for the cells to adapt relevant in vivo characteristics and here we introduce a new cell culture system based on three-dimensional (3D) printed scaffolds using cellulose nanofibrils (CNF) pre-treated with 2,2,6,6-tetramethylpyperidine-1-oxyl (TEMPO) as the structural material component. Breast cancer cell lines, MCF7 and MDA-MB-231, were cultured in 3D TEMPO-CNF scaffolds and were shown by scanning electron microscopy (SEM) and histochemistry to grow in multiple layers as a heterogenous cell population with different morphologies, contrasting 2D cultured mono-layered cells with a morphologically homogenous cell population. Gene expression analysis demonstrated that 3D TEMPO-CNF scaffolds induced elevation of the stemness marker CD44 and the migration markers VIM and SNAI1 in MCF7 cells relative to 2D control. T47D cells confirmed the increased level of the stemness marker CD44 and migration marker VIM which was further supported by increased capacity of holoclone formation for 3D cultured cells. Therefore, TEMPO-CNF was shown to represent a promising material for 3D cell culture model systems for cancer cell applications such as drug screening.
30
Seyfried, Nick, Can Yurttas, Markus Burkard, Benedikt Oswald, Alexander Tolios, Franziska Herster, Joseph Kauer, et al. "Prolonged Exposure to Oxaliplatin during HIPEC Improves Effectiveness in a Preclinical Micrometastasis Model." Cancers 14, no. 5 (February 24, 2022): 1158. http://dx.doi.org/10.3390/cancers14051158.
Full textAbstract:
Cytoreductive surgery combined with hyperthermic intraperitoneal chemotherapy (HIPEC) was considered a promising treatment for patients with peritoneal metastasis from colorectal cancer. However, the recently published randomized controlled PRODIGE 7 trial failed to demonstrate survival benefits through the addition of short-term oxaliplatin-based HIPEC. Constituting a complex multifactorial treatment, we investigated HIPEC in a preclinical model concerning the elimination of minimal tumor residues, thereby aiming to better understand the size of effects and respective clinical trial results. Patient samples of peritoneal perfusates obtained during HIPEC treatments and oxaliplatin-containing solutions at clinically relevant dosages, conforming with established HIPEC protocols, were assessed regarding their ability to eliminate modelled ~100 µm thickness cancer cell layers. Impedance-based real-time cell analysis and classical end-point assays were used. Flow cytometry was employed to determine the effect of different HIPEC drug solvents on tumor cell properties. Effectiveness of peritoneal perfusate patient samples and defined oxaliplatin-containing solutions proved limited but reproducible. HIPEC simulations for 30 min reduced the normalized cell index below 50% with peritoneal perfusates from merely 3 out of 9 patients within 72 h, indicating full-thickness cytotoxic effects. Instead, prolonging HIPEC to 1 h enhanced these effects and comprised 7 patients’ samples, while continuous drug exposure invariably resulted in complete cell death. Further, frequently used drug diluents caused approximately 25% cell size reduction within 30 min. Prolonging oxaliplatin exposure improved effectiveness of HIPEC to eliminate micrometastases in our preclinical model. Accordingly, insufficient penetration depth, short exposure time, and the physicochemical impact of drug solvents may constitute critical factors.
31
Bae, JuneSung, Yun Sik Choi, Gunsik Cho, and Se Jin Jang. "The Patient-Derived Cancer Organoids: Promises and Challenges as Platforms for Cancer Discovery." Cancers 14, no. 9 (April 25, 2022): 2144. http://dx.doi.org/10.3390/cancers14092144.
Full textAbstract:
The cancer burden is rapidly increasing in most countries, and thus, new anticancer drugs for effective cancer therapy must be developed. Cancer model systems that recapitulate the biological processes of human cancers are one of the cores of the drug development process. PDCO has emerged as a unique model that preserves the genetic, physiological, and histologic characteristics of original cancer, including inter- and intratumoral heterogeneities. Due to these advantages, the PCDO model is increasingly investigated for anticancer drug screening and efficacy testing, preclinical patient stratification, and precision medicine for selecting the most effective anticancer therapy for patients. Here, we review the prospects and limitations of PDCO compared to the conventional cancer models. With advances in culture success rates, co-culture systems with the tumor microenvironment, organoid-on-a-chip technology, and automation technology, PDCO will become the most promising model to develop anticancer drugs and precision medicine.
32
Bae, JuneSung, Yun Sik Choi, Gunsik Cho, and Se Jin Jang. "The Patient-Derived Cancer Organoids: Promises and Challenges as Platforms for Cancer Discovery." Cancers 14, no. 9 (April 25, 2022): 2144. http://dx.doi.org/10.3390/cancers14092144.
Full textAbstract:
The cancer burden is rapidly increasing in most countries, and thus, new anticancer drugs for effective cancer therapy must be developed. Cancer model systems that recapitulate the biological processes of human cancers are one of the cores of the drug development process. PDCO has emerged as a unique model that preserves the genetic, physiological, and histologic characteristics of original cancer, including inter- and intratumoral heterogeneities. Due to these advantages, the PCDO model is increasingly investigated for anticancer drug screening and efficacy testing, preclinical patient stratification, and precision medicine for selecting the most effective anticancer therapy for patients. Here, we review the prospects and limitations of PDCO compared to the conventional cancer models. With advances in culture success rates, co-culture systems with the tumor microenvironment, organoid-on-a-chip technology, and automation technology, PDCO will become the most promising model to develop anticancer drugs and precision medicine.
33
Betzler, Alexander M., Lahiri K. Nanduri, Barbara Hissa, Linda Blickensdörfer, Michael H. Muders, Janine Roy, Moritz Jesinghaus, et al. "Differential Effects of Trp53 Alterations in Murine Colorectal Cancer." Cancers 13, no. 4 (February 15, 2021): 808. http://dx.doi.org/10.3390/cancers13040808.
Full textAbstract:
Background: Colorectal cancer (CRC) development is a multi-step process resulting in the accumulation of genetic alterations. Despite its high incidence, there are currently no mouse models that accurately recapitulate this process and mimic sporadic CRC. We aimed to develop and characterize a genetically engineered mouse model (GEMM) of Apc/Kras/Trp53 mutant CRC, the most frequent genetic subtype of CRC. Methods: Tumors were induced in mice with conditional mutations or knockouts in Apc, Kras, and Trp53 by a segmental adeno-cre viral infection, monitored via colonoscopy and characterized on multiple levels via immunohistochemistry and next-generation sequencing. Results: The model accurately recapitulates human colorectal carcinogenesis clinically, histologically and genetically. The Trp53 R172H hotspot mutation leads to significantly increased metastatic capacity. The effects of Trp53 alterations, as well as the response to treatment of this model, are similar to human CRC. Exome sequencing revealed spontaneous protein-modifying alterations in multiple CRC-related genes and oncogenic pathways, resulting in a genetic landscape resembling human CRC. Conclusions: This model realistically mimics human CRC in many aspects, allows new insights into the role of TP53 in CRC, enables highly predictive preclinical studies and demonstrates the value of GEMMs in current translational cancer research and drug development.
34
Wang, Jianzheng, Jinxi Huang, Hui Wang, Wei Yang, Qiwen Bai, Zhentao Yao, Qingli Li, et al. "Personalized Treatment of Advanced Gastric Cancer Guided by the MiniPDX Model." Journal of Oncology 2022 (January 27, 2022): 1–11. http://dx.doi.org/10.1155/2022/1987705.
Full textAbstract:
Background. The morbidity and mortality of gastric cancer are high in China. There are challenges to develop precise and individualized drug regimens for patients with gastric cancer after a standard treatment. Choosing the most appropriate anticancer drug after a patient developing drug resistance is very important to improve the patient’s prognosis. MiniPDX has been widely used as a new and reliable preclinical research model to predict the sensitivity of anticancer drugs. Methods. The OncoVee® MiniPDX system developed by Shanghai LIDE Biotech Co., Ltd. was used to establish the MiniPDX models using specimens of patients with gastric cancer. The cancer tissues were biopsied under endoscopy, and then, the tumor cell suspension was prepared for a drug sensitivity test by subcutaneously implanting into Balb/c-nude mice. The selected optimal regimen obtained from the MiniPDX assay was used to treat patients with drug-resistant gastric cancer. Results. We successfully established an individualized and sensitive drug screening system for four patients from January 2021 to July 2021. MiniPDX models identified potentially effective drugs for these four patients, with partial remission in two of the patients after treatment and disease progression in the remaining of two patients. Severe side effects from chemotherapy or targeted therapy were not observed in all patients. Conclusion. Establishing a personalized drug screening system for patients with drug-resistant gastric cancer can guide the selection of clinical drugs, improve the clinical benefit of patients, and avoid ineffective treatments. It can be an effective supplement for treatment options.
35
Valli, Debora, Alicja M. Gruszka, and Myriam Alcalay. "Has Drug Repurposing Fulfilled Its Promise in Acute Myeloid Leukaemia?" Journal of Clinical Medicine 9, no. 6 (June 17, 2020): 1892. http://dx.doi.org/10.3390/jcm9061892.
Full textAbstract:
Drug repurposing is a method of drug discovery that consists of finding a new therapeutic context for an old drug. Compound identification arises from screening of large libraries of active compounds, through interrogating databases of cell line gene expression response upon treatment or by merging several types of information concerning disease–drug relationships. Although, there is a general consensus on the potential and advantages of this drug discovery modality, at the practical level to-date no non-anti-cancer repurposed compounds have been introduced into standard acute myeloid leukaemia (AML) management, albeit that preclinical validation yielded several candidates. The review presents the state-of-the-art drug repurposing approach in AML and poses the question of what has to be done in order to take a full advantage of it, both at the stage of screening design and later when progressing from the preclinical to the clinical phases of drug development. We argue that improvements are needed to model and read-out systems as well as to screening technologies, but also to more funding and trust in drug repurposing strategies.
36
Bleijs, Margit, Corine Pleijte, Sem Engels, Femke Ringnalda, Friederike Meyer-Wentrup, Marc van de Wetering, and Hans Clevers. "EWSR1-WT1 Target Genes and Therapeutic Options Identified in a Novel DSRCT In Vitro Model." Cancers 13, no. 23 (December 2, 2021): 6072. http://dx.doi.org/10.3390/cancers13236072.
Full textAbstract:
Desmoplastic small round cell tumor (DSRCT) is a rare and aggressive soft tissue sarcoma with a lack of effective treatment options and a poor prognosis. DSRCT is characterized by a chromosomal translocation, resulting in the EWSR1-WT1 gene fusion. The molecular mechanisms driving DSRCT are poorly understood, and a paucity of preclinical models hampers DSRCT research. Here, we establish a novel primary patient-derived DSRCT in vitro model, recapitulating the original tumor. We find that EWSR1-WT1 expression affects cell shape and cell survival, and we identify downstream target genes of the EWSR1-WT1 fusion. Additionally, this preclinical in vitro model allows for medium-throughput drug screening. We discover sensitivity to several drugs, including compounds targeting RTKs. MERTK, which has been described as a therapeutic target for several malignancies, correlates with EWSR1-WT1 expression. Inhibition of MERTK with the small-molecule inhibitor UNC2025 results in reduced proliferation of DSRCT cells in vitro, suggesting MERTK as a therapeutic target in DSRCT. This study underscores the usefulness of preclinical in vitro models for studying molecular mechanisms and potential therapeutic options.
37
Calar, Kristin, Simona Plesselova, Somshuvra Bhattacharya, Megan Jorgensen, and Pilar de la Puente. "Human Plasma-Derived 3D Cultures Model Breast Cancer Treatment Responses and Predict Clinically Effective Drug Treatment Concentrations." Cancers 12, no. 7 (June 29, 2020): 1722. http://dx.doi.org/10.3390/cancers12071722.
Full textAbstract:
Lack of efficacy and a low overall success rate of phase I-II clinical trials are the most common failures when it comes to advancing cancer treatment. Current drug sensitivity screenings present several challenges including differences in cell growth rates, the inconsistent use of drug metrics, and the lack of translatability. Here, we present a patient-derived 3D culture model to overcome these limitations in breast cancer (BCa). The human plasma-derived 3D culture model (HuP3D) utilizes patient plasma as the matrix, where BCa cell lines and primary BCa biopsies were grown and screened for drug treatments. Several drug metrics were evaluated from relative cell count and growth rate curves. Correlations between HuP3D metrics, established preclinical models, and clinical effective concentrations in patients were determined. HuP3D efficiently supported the growth and expansion of BCa cell lines and primary breast cancer tumors as both organoids and single cells. Significant and strong correlations between clinical effective concentrations in patients were found for eight out of ten metrics for HuP3D, while a very poor positive correlation and a moderate correlation was found for 2D models and other 3D models, respectively. HuP3D is a feasible and efficacious platform for supporting the growth and expansion of BCa, allowing high-throughput drug screening and predicting clinically effective therapies better than current preclinical models.
38
Chen, Lei, Shuncong Wang, Yuanbo Feng, Jinyong Zhang, Yuqing Du, Jiang Zhang, Chantal Van Ongeval, Yicheng Ni, and Yue Li. "Utilisation of Chick Embryo Chorioallantoic Membrane as a Model Platform for Imaging-Navigated Biomedical Research." Cells 10, no. 2 (February 22, 2021): 463. http://dx.doi.org/10.3390/cells10020463.
Full textAbstract:
The fertilised chick egg and particularly its chorioallantoic membrane (CAM) have drawn continuing interest in biomedicine and bioengineering fields, especially for research on vascular study, cancer, drug screening and development, cell factors, stem cells, etc. This literature review systemically introduces the CAM’s structural evolution, functions, vascular features and the circulation system, and cell regulatory factors. It also presents the major and updated applications of the CAM in assays for pharmacokinetics and biodistribution, drug efficacy and toxicology testing/screening in preclinical pharmacological research. The time course of CAM applications for different assays and their advantages and limitations are summarised. Among these applications, two aspects are emphasised: (1) potential utility of the CAM for preclinical studies on vascular-disrupting agents (VDAs), promising for anti-cancer vascular-targeted therapy, and (2) modern imaging technologies, including modalities and their applications for real-time visualisation, monitoring and evaluation of the changes in CAM vasculature as well as the interactions occurring after introducing the tested medical, pharmaceutical and biological agents into the system. The aim of this article is to help those working in the biomedical field to familiarise themselves with the chick embryo CAM as an alternative platform and to utilise it to design and optimise experimental settings for their specific research topics.
39
Wang, Zhaohui, Emilio Cortes-Sanchez, Chieh-Hsiang Yang, Daniel Nelson, Daniel Delubac, Shiaowen David Hsu, Alana Welm, and Xiling Shen. "Micro-organospheres: An automated patient-derived model platform for rapid drug screening of breast cancer." Journal of Clinical Oncology 39, no. 15_suppl (May 20, 2021): e12628-e12628. http://dx.doi.org/10.1200/jco.2021.39.15_suppl.e12628.
Full textAbstract:
e12628 Background: Patient-derived breast cancer (BC) organoids are valuable preclinical models to study patient drug responses, demonstrating good correlations with patients’ clinical outcomes. However, establishment and expansion of such organoids from patient tumors for drug screening is currently a time-consuming and labor-intensive process. A more rapid and high-throughput method will enable broader utility in diagnostics and drug development. Methods: An automated, rapid and scalable microfluidic platform was used to process and develop BC micro-organospheres. Drug sensitivities studies on BC micro-organospheres were performed on day 3 and day 6 using 10-FDA approved drugs, including palbociclib, adriamycin, 5-FU, gemcitabine, methotrexate, everolimus, paclitaxel, docetaxel, ixabepilone, and vinblastine. The responses of micro-organospheres and organoids to the drugs were assessed by CellTiter 3D Glo assay on day 6 after the drug treatment. The growth and establishment of the micro-organospheres by imaging. The drug sensitivity and resistance of the micro-organospheres were analyzed by calculating the percentage cell viability and normalized growth rate inhibition (GRI) and compared to organoids. Results: We successfully established micro-organospheres from eight patient-derived BC organoids with a 100% success rate. The micro-organospheres preserved similar cell morphologies to the bulk organoids. 7/8 micro-organosphere models had similar drug response patterns to organoids between day 3 and day 6 as evident by the GRI heatmap. Specifically, we treated matching micro-organospheres and conventional organoids from two patients with 10 frontline BC chemotherapy drugs, and both showed similar response patterns with GRI heatmap. For the other 6 patient-derived models, the responses of micro-organospheres to docetaxel and everolimus also matched the historical drug responses of in bulk organoid culture with similar GRI heatmap. Conclusions: We have now shown the feasibility of establishing micro-organospheres as a rapid, scalable, and cost-effective platform to study patient-derived BC drug response. This technology has the potential to be used for both diagnostics to guide patient treatment and as a screening platform for new BC drug discovery.
40
Yin, Shenyi, Ruibin Xi, Aiwen Wu, Shu Wang, Yingjie Li, Chaobin Wang, Lei Tang, et al. "Patient-derived tumor-like cell clusters for drug testing in cancer therapy." Science Translational Medicine 12, no. 549 (June 24, 2020): eaaz1723. http://dx.doi.org/10.1126/scitranslmed.aaz1723.
Full textAbstract:
Several patient-derived tumor models emerged recently as robust preclinical drug-testing platforms. However, their potential to guide clinical therapy remained unclear. Here, we report a model called patient-derived tumor-like cell clusters (PTCs). PTCs result from the self-assembly and proliferation of primary epithelial, fibroblast, and immune cells, which structurally and functionally recapitulate original tumors. PTCs enabled us to accomplish personalized drug testing within 2 weeks after obtaining the tumor samples. The defined culture conditions and drug concentrations in the PTC model facilitate its clinical application in precision oncology. PTC tests of 59 patients with gastric, colorectal, or breast cancers revealed an overall accuracy of 93% in predicting their clinical outcomes. We implemented PTC to guide chemotherapy selection for a patient with mucinous rectal adenocarcinoma who experienced recurrence with metastases after conventional therapy. After three cycles of a nonconventional therapy identified by the PTC, the patient showed a positive response. These findings need to be validated in larger clinical trials, but they suggest that the PTC model could be prospectively implemented in clinical decision-making for therapy selection.
41
Brunet, E., A. Selva, F. Bas-Cutrina, A. Brujats, B. Caballol, B. Gomez, C. Gonzalez, et al. "OP23 Asymptomatic inflammatory bowel disease diagnosed during the colorectal cancer population screening in Catalonia." Journal of Crohn's and Colitis 17, Supplement_1 (January 30, 2023): i31—i32. http://dx.doi.org/10.1093/ecco-jcc/jjac190.0023.
Full textAbstract:
Abstract Background Background: It has been postulated that early treatment of inflammatory bowel disease (IBD) is associated with a better long-term response. In Catalonia, the early detection program for colorectal cancer (EDPCRC) has been active since 2010, and was extended to the entire Catalan territory in 2015. The aim of this study is to describe the natural history of IBD asymptomatic diagnosed through the EDPCRC in Catalonia. Methods Methods: Observational, longitudinal and retrospective study of patients with IBD detected in the EDPCRC with a positive faecal immunological test in 21 centers in Catalonia between 2010 and 2019. Data was collected from the clinical histories. Results Results: 237 patients were identified; 35 patients had symptoms before endoscopy and were excluded from the study, finally 200 patients were diagnosed with asymptomatic IBD during the EDPCRC; 109 ulcerative colitis (54.5%), 63 Crohn's disease (31.5%) and 28 unclassifiable colitis (14%). 35.5% were women (n=71) with an average age of 60 years (range 49-79). Of the asymptomatic, 40.5% developed symptoms (n=81), being diarrhea the most frequent (n=45; 55.6%). The median time to first symptom was 368 days. Treatment was prescribed in 74.5% (n=149) of the patients. Mesalazine was the most frequently prescribed drug (n=130). The main reason for prescribing it was endoscopic activity (n=107), followed by the appearance of symptoms (n=39) and the biochemical activity (n=9). Only 19 patients (9.5%) required biological treatment (5 infliximab, 10 adalimumab, 2 vedolizumab and 2 ustekinumab). 4 patients (2%) required surgery. Conclusion Conclusion: Less than half of patients diagnosed with IBD at a preclinical stage develop symptoms after the first year of follow-up. Only 9.5% require biological treatment and 2% surgery. Three-quarters of patients are prescribed treatment; the most used was mesalazine.
42
van Ballegooijen, Marjolein, Carolyn M. Rutter, Amy B. Knudsen, Ann G. Zauber, James E. Savarino, Iris Lansdorp-Vogelaar, Rob Boer, Eric J. Feuer, J. Dik F. Habbema, and Karen M. Kuntz. "Clarifying Differences in Natural History between Models of Screening." Medical Decision Making 31, no. 4 (June 14, 2011): 540–49. http://dx.doi.org/10.1177/0272989x11408915.
Full textAbstract:
Background. Microsimulation models are important decision support tools for screening. However, their complexity makes them difficult to understand and limits realization of their full potential. Therefore, it is important to develop documentation that clarifies their structure and assumptions. The authors demonstrate this problem and explore a solution for natural history using 3 independently developed colorectal cancer screening models. Methods. The authors first project effectiveness and cost-effectiveness of colonoscopy screening for the 3 models (CRC-SPIN, SimCRC, and MISCAN). Next, they provide a conventional presentation of each model, including information on structure and parameter values. Finally, they report the simulated reduction in clinical cancer incidence following a one-time complete removal of adenomas and preclinical cancers for each model. They call this new measure the maximum clinical incidence reduction (MCLIR). Results. Projected effectiveness varies widely across models. For example, estimated mortality reduction for colonoscopy screening every 10 years from age 50 to 80 years, with surveillance in adenoma patients, ranges from 65% to 92%. Given only conventional information, it is difficult to explain these differences, largely because differences in structure make parameter values incomparable. In contrast, the MCLIR clearly shows the impact of model differences on the key feature of natural history, the dwell time of preclinical disease. Dwell times vary from 8 to 25 years across models and help explain differences in projected screening effectiveness. Conclusions. The authors propose a new measure, the MCLIR, which summarizes the implications for predicted screening effectiveness of differences in natural history assumptions. Including the MCLIR in the standard description of a screening model would improve the transparency of these models.
43
Harris, Emily, Jonathan Strope, Shaunna Beedie, Phoebe Huang, Andrew Goey, Kristina Cook, Christopher Schofield, et al. "Preclinical Evaluation of Discorhabdins in Antiangiogenic and Antitumor Models." Marine Drugs 16, no. 7 (July 19, 2018): 241. http://dx.doi.org/10.3390/md16070241.
Full textAbstract:
Elements of the hypoxia inducible factor (HIF) transcriptional system, a key regulator of the cellular hypoxic response, are up-regulated in a range of cancer cells. HIF is fundamentally involved in tumor angiogenesis, invasion, and energy metabolism. Inhibition of the transcriptional activity of HIF may be of therapeutic benefit to cancer patients. We recently described the identification of two marine pyrroloiminoquinone alkaloids with potent activity in inhibiting the interaction between the oncogenic transcription factor HIF-1α and the coactivator protein p300. Herein, we present further characterization data for these two screening hits: discorhabdin H (1) and discorhabdin L (2), with a specific focus on their anti-angiogenic and anti-tumor effects. We demonstrated that only discorhabdin L (2) possesses excellent anti-angiogenic activity in inhibiting endothelial cell proliferation and tube formation, as well as decreasing microvessel outgrowth in the ex vivo rat aortic ring assay. We further showed that discorhabdin L (2) significantly inhibits in vivo prostate tumor growth in a LNCaP xenograft model. In conclusion, our findings suggest that discorhabdin L (2) represents a promising HIF-1α inhibitor worthy of further drug development.
44
Inoue, Deem, Kopetz, Heffernan, Draetta, and Carugo. "Current and Future Horizons of Patient-Derived Xenograft Models in Colorectal Cancer Translational Research." Cancers 11, no. 9 (September 6, 2019): 1321. http://dx.doi.org/10.3390/cancers11091321.
Full textAbstract:
Our poor understanding of the intricate biology of cancer and the limited availability of preclinical models that faithfully recapitulate the complexity of tumors are primary contributors to the high failure rate of novel therapeutics in oncology clinical studies. To address this need, patient-derived xenograft (PDX) platforms have been widely deployed and have reached a point of development where we can critically review their utility to model and interrogate relevant clinical scenarios, including tumor heterogeneity and clonal evolution, contributions of the tumor microenvironment, identification of novel drugs and biomarkers, and mechanisms of drug resistance. Colorectal cancer (CRC) constitutes a unique case to illustrate clinical perspectives revealed by PDX studies, as they overcome limitations intrinsic to conventional ex vivo models. Furthermore, the success of molecularly annotated "Avatar" models for co-clinical trials in other diseases suggests that this approach may provide an additional opportunity to improve clinical decisions, including opportunities for precision targeted therapeutics, for patients with CRC in real time. Although critical weaknesses have been identified with regard to the ability of PDX models to predict clinical outcomes, for now, they are certainly the model of choice for preclinical studies in CRC. Ongoing multi-institutional efforts to develop and share large-scale, well-annotated PDX resources aim to maximize their translational potential. This review comprehensively surveys the current status of PDX models in translational CRC research and discusses the opportunities and considerations for future PDX development.
45
Klenner, Marbod, Pia Freidel, Mariella G. Filbin, and Alexander Beck. "DIPG-39. New preclinical models for Diffuse Midline Glioma." Neuro-Oncology 24, Supplement_1 (June 1, 2022): i27. http://dx.doi.org/10.1093/neuonc/noac079.096.
Full textAbstract:
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.
46
Zhao, Wenting, Eleonora Spinazzi, Athanassios Dovas, Pavan Upadhyayula, Tamara Marie, Michael Sisti, Jeff Bruce, Peter D. Canoll, and Peter Sims. "COMP-12. SINGLE-CELL TRANSCRIPTOME PROFILING OF GBM TISSUE ACUTE SLICE CULTURES FOR PERSONALIZED DRUG SCREENING." Neuro-Oncology 21, Supplement_6 (November 2019): vi63. http://dx.doi.org/10.1093/neuonc/noz175.255.
Full textAbstract:
Abstract Glioblastoma (GBM) is the most common and malignant type of primary brain tumor, and more effective treatment options are needed. Both inter- and intratumoral heterogeneity present major challenges to the application of targeted therapies in GBM. Therefore, precision medicine approaches to GBM would benefit significantly from the ability to predict drugs or drug combinations that target specific subpopulations of tumor cells. Model systems, such as adherent cell lines, neurospheres, patient-derived xenografts (PDXs), and patient-derived organoids, have been reported as platforms for drug screening and accessing drug responses. However, these models do not recapitulate the full heterogeneity of GBM tissue, lack key components of the tumor microenvironment or take weeks to months to establish, which limits the predictive power of drug response assays or delays clinical decision-making. To address these limitations, we are combining ex vivo slices of intact, patient-derived GBM tissue with single-cell RNA-seq (scRNA-seq) for small-scale drug screening and assessment of patient- and cell type-specific drug responses. We generated slices from both preclinical mouse glioma models and surgical specimens from GBM patients and showed that acute slices preserved both the tumor heterogeneity and tumor microenvironment observed in scRNA-seq of cells directly isolated from tumor tissue. To test drug responses, we treated tissue slices from GBM mouse models and five different patients with six drugs for 18hr. By performing scRNA-Seq and analyzing transcriptional profiles of treated and untreated control slices, we identified drug-induced transcriptional responses in specific subpopulations of tumor cells, patient-specific drug sensitivities, and drug effects conserved in both mouse and human tumors. The GBM tissue slices were generated immediately following surgical resection, and experiments were completed within 24 hours. With these features, our method is attractive for rapidly accessing cell type- and patient-specific drug responses and has potential for preclinical drug screening and guiding personalized treatment for GBM.
47
Falvo, Elisabetta, Alessandro Arcovito, Giamaica Conti, Giuseppe Cipolla, Martina Pitea, Veronica Morea, Verena Damiani, Gianluca Sala, Giulio Fracasso, and Pierpaolo Ceci. "Engineered Human Nanoferritin Bearing the Drug Genz-644282 for Cancer Therapy." Pharmaceutics 12, no. 10 (October 20, 2020): 992. http://dx.doi.org/10.3390/pharmaceutics12100992.
Full textAbstract:
Gastrointestinal tumors, including pancreatic and colorectal cancers, represent one of the greatest public health issues worldwide, leading to a million global deaths. Recent research demonstrated that the human heavy chain ferritin (HFt) can encapsulate different types of drugs in its cavity and can bind to its receptor, CD71, in several solid and hematological tumors, thus highlighting the potential use of ferritin for tumor-targeting therapies. Here, we describe the development and characterization of a novel nanomedicine based on the HFt that is named The-0504. In particular, this novel system is a nano-assembly comprising an engineered version of HFt that entraps about 80 molecules of a potent, wide-spectrum, non-camptothecin topoisomerase I inhibitor (Genz-644282). The-0504 can be produced by a standardized pre-industrial process as a pure and homogeneously formulated product with favourable lyophilization properties. The preliminary anticancer activity was evaluated in cultured cancer cells and in a mouse model of pancreatic cancer. Overall results reported here make The-0504 a candidate for further preclinical development against CD-71 expressing deadly tumors.
48
Kang, Bo, Xiaobing Zhang, Weibing Wang, Shiqi She, Wenjie Chen, Cheng Chen, Yisha Wang, Xiaoyun Pan, Ouyuan Xu, and Yingjie Wang. "The Novel IGF-1R Inhibitor PB-020 Acts Synergistically with Anti-PD-1 and Mebendazole against Colorectal Cancer." Cancers 14, no. 23 (November 23, 2022): 5747. http://dx.doi.org/10.3390/cancers14235747.
Full textAbstract:
CRC is one of the leading causes of cancer mortality worldwide. Chemotherapy is widely used for the treatment of CRC, but its efficacy remains unsatisfactory, mainly due to drug resistance. Therefore, it is urgent to develop new strategies to overcome drug resistance. Combination therapy that aims to achieve additive or synergistic therapeutic effects is an effective approach to tackle the development of drug resistance. Given its established roles in tumor development, progression and metastasis, IGF-1R is a promising drug target for combination therapy against CRC. In this study, we revealed that the novel IGF-1R inhibitor PB-020 can act synergistically with mebendazole (MBZ) to reduce the viability of CRC cells and block xenograft CRC progression. Moreover, the PB-020/anti-PD-1 combination synergistically blocked CRC propagation in the MC38 murine colon carcinoma model. Both combination therapies potently suppressed the PI3K/AKT signaling pathway genes in CRC that may be associated with the development of drug resistance. Our findings establish a preclinical proof-of-concept for combating CRC using combined multi-target treatment with PB-020 and clinical anticancer drugs, which may provide useful clues for clinical trials to evaluate the efficacy and safety of these drug combinations in CRC patients.
49
Brulin, Bénédicte, John C. Nolan, Tecla Marangon, Milan Kovacevic, Mathias Chatelais, Pierre Meheust, Jérome Abadie, et al. "Evaluation of the Chemotherapy Drug Response Using Organotypic Cultures of Osteosarcoma Tumours from Mice Models and Canine Patients." Cancers 13, no. 19 (September 29, 2021): 4890. http://dx.doi.org/10.3390/cancers13194890.
Full textAbstract:
Improvements in the clinical outcome of osteosarcoma have plateaued in recent decades with poor translation between preclinical testing and clinical efficacy. Organotypic cultures retain key features of patient tumours, such as a myriad of cell types organized within an extracellular matrix, thereby presenting a more realistic and personalised screening of chemotherapeutic agents ex vivo. To test this concept for the first time in osteosarcoma, murine and canine osteosarcoma organotypic models were maintained for up to 21 days and in-depth analysis identified proportions of immune and stromal cells present at levels comparable to that reported in vivo in the literature. Cytotoxicity testing of a range of chemotherapeutic drugs (mafosfamide, cisplatin, methotrexate, etoposide, and doxorubicin) on murine organotypic culture ex vivo found limited response to treatment, with immune and stromal cells demonstrating enhanced survival over the global tumour cell population. Furthermore, significantly decreased sensitivity to a range of chemotherapeutics in 3D organotypic culture relative to 2D monolayer was observed, with subsequent investigation confirming reduced sensitivity in 3D than in 2D, even at equivalent levels of drug uptake. Finally, as proof of concept for the application of this model to personalised drug screening, chemotherapy testing with doxorubicin was performed on biopsies obtained from canine osteosarcoma patients. Together, this study highlights the importance of recapitulating the 3D tumour multicellular microenvironment to better predict drug response and provides evidence for the utility and possibilities of organotypic culture for enhanced preclinical selection and evaluation of chemotherapeutics targeting osteosarcoma.
50
Fritz, Justine, Olivier Lefebvre, Aurore Fernandez, Jordane Schmidt, and Dominique Bagnard. "Prediction of Drug Efficacy in Colon Cancer Preclinical Models Using a Novel Ranking Method of Gene Expression." Cancers 12, no. 1 (January 8, 2020): 149. http://dx.doi.org/10.3390/cancers12010149.
Full textAbstract:
The presence of stromal cells in tumors is altering the significance of molecular profiling when using standard methods of gene expression quantification. We developed a novel normalization method to rank target gene expression in tumor samples by comparisons with reference samples representing the different cell types found in a tumor. The score for each target gene obtained after normalization, is aimed to be predictive of targeted therapies efficiency. We performed this qPCR analysis on human colorectal cancers to demonstrate the importance of reference samples to obtain accurate data and on a collection of patient-derived xenografted (PDX) colon tumors treated with Cetuximab (anti-EGFR) to demonstrate that the calculated EGFR score is predictive of Cetuximab efficacy. Interestingly, the score allowed to select an efficient treatment in a PDX model refractory to standard of care. This method is opening a novel way to predict targeted therapy efficiency which could be extended to several tumor types, and to unlimited target genes.