Patient-derived xenograft models in cancer therapy: technologies and applications

Signal Transduction and Targeted Therapy, Год журнала: 2023, Номер 8(1)

Опубликована: Апрель 12, 2023

Abstract Patient-derived xenograft (PDX) models, in which tumor tissues from patients are implanted into immunocompromised or humanized mice, have shown superiority recapitulating the characteristics of cancer, such as spatial structure cancer and intratumor heterogeneity cancer. Moreover, PDX models retain genomic features across different stages, subtypes, diversified treatment backgrounds. Optimized engraftment procedures modern technologies multi-omics deep learning enabled a more comprehensive depiction molecular landscape boosted utilization models. These irreplaceable advantages make an ideal choice studies, preclinical trials novel drugs, validating drug combinations, screening drug-sensitive patients, exploring resistance mechanisms. In this review, we gave overview history process model establishment. Subsequently, review presents strengths weaknesses highlights integration research. Finally, delineated broad application chemotherapy, targeted therapy, immunotherapy, other therapies.

Язык: Английский

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Precision Medicine: Disease Subtyping and Tailored Treatment

Cancers, Год журнала: 2023, Номер 15(15), С. 3837 - 3837

Опубликована: Июль 28, 2023

The genomics-based concept of precision medicine began to emerge following the completion Human Genome Project. In contrast evidence-based medicine, will allow doctors and scientists tailor treatment different subpopulations patients who differ in their susceptibility specific diseases or responsiveness therapies. current model was proposed precisely classify into subgroups sharing a common biological basis for more effective tailored achieve improved outcomes. Precision has become term that symbolizes new age medicine. this review, we examine history, development, future perspective We also discuss concepts, principles, tools, applications related fields. our view, work, two essential objectives need be achieved. First, classified various subtypes. Second, targeted therapies must available each disease subtype. Therefore, focused review on progress meeting these objectives.

Язык: Английский

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Pharmacotypes across the genomic landscape of pediatric acute lymphoblastic leukemia and impact on treatment response

Nature Medicine, Год журнала: 2023, Номер 29(1), С. 170 - 179

Опубликована: Янв. 1, 2023

Abstract Contemporary chemotherapy for childhood acute lymphoblastic leukemia (ALL) is risk-adapted based on clinical features, genomics and minimal residual disease (MRD); however, the pharmacological basis of these prognostic variables remains unclear. Analyzing samples from 805 children with newly diagnosed ALL three consecutive trials, we determined ex vivo sensitivity primary cells to 18 therapeutic agents across 23 molecular subtypes defined by genomics. There was wide variability in drug response, favorable exhibiting greatest L-asparaginase glucocorticoids. Leukemia two highly associated MRD although distinct patterns only B cell ALL. We identified six patient clusters pharmacotypes, which were event-free survival, even after adjusting MRD. Pharmacotyping a T subset poor prognosis that sensitive targeted agents, pointing alternative strategies. Our study comprehensively described heterogeneity ALL, highlighting opportunities further individualizing therapy this most common cancer.

Язык: Английский

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Patient-derived tumor organoids: a new avenue for preclinical research and precision medicine in oncology

Experimental & Molecular Medicine, Год журнала: 2024, Номер 56(7), С. 1531 - 1551

Опубликована: Июль 1, 2024

Over the past decade, emergence of patient-derived tumor organoids (PDTOs) has broadened repertoire preclinical models and progressively revolutionized three-dimensional cell culture in oncology. PDTO can be grown from patient samples with high efficiency faithfully recapitulates histological molecular characteristics original tumor. Therefore, PDTOs serve as invaluable tools oncology research, their translation to clinical practice is exciting for future precision medicine In this review, we provide an overview methods establishing various applications cancer starting basic research ending identification new targets validation anticancer compounds medicine. Finally, highlight challenges associated implementation PDTO, such its representativeness, success rate, assay speed, lack a microenvironment. Technological developments autologous cocultures stromal cells are currently ongoing meet these optimally exploit full potential models. The use standard could lead era coming decade.

Язык: Английский

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Organoids for Functional Precision Medicine in Advanced Pancreatic Cancer

Gastroenterology, Год журнала: 2024, Номер 167(5), С. 961 - 976.e13

Опубликована: Июнь 10, 2024

Patient-derived organoids (PDOs) are promising tumor avatars that could enable ex vivo drug tests to personalize patients' treatments in the frame of functional precision oncology. However, clinical evidence remains scarce. This study aims evaluate whether PDOs can be implemented practice benefit patients with advanced refractory pancreatic ductal adenocarcinoma (PDAC).

Язык: Английский

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Droplet Microarrays for Miniaturized and High‐Throughput Experiments: Progress and Prospectives

Advanced Materials Interfaces, Год журнала: 2025, Номер unknown

Опубликована: Янв. 9, 2025

Abstract Miniaturization in life sciences and chemical offers substantial advantages to experimental workflows, such as increased throughput, reduced costs, lower environmental impact. While microtiter plates are effective, further miniaturization is necessary enhance efficiency throughput. However, cannot be easily miniaturized volumes below 5 µL, primarily because adhesive capillary forces become stronger than the gravitational needed confine liquid within wells. To overcome this, droplet microarray (DMA) developed, utilizing patterned regions on a liquid‐repellent background immobilize sub‐microliter droplets without physical barriers. This unique format enables novel applications merging parallel ultra‐high‐throughput manipulations. review provides an overview of DMA's diverse highlights new opportunities it offers, establishing versatile tool for highly miniaturized, high‐throughput biological experiments. The evolving requirements future DMA approach also discussed.

Язык: Английский

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The drug-induced phenotypic landscape of colorectal cancer organoids

Nature Communications, Год журнала: 2022, Номер 13(1)

Опубликована: Июнь 6, 2022

Abstract Patient-derived organoids resemble the biology of tissues and tumors, enabling ex vivo modeling human diseases. They have heterogeneous morphologies with unclear biological causes relationship to treatment response. Here, we use high-throughput, image-based profiling quantify phenotypes over 5 million individual colorectal cancer after >500 small molecules. Integration data using multi-omics identifies axes morphological variation across organoids: Organoid size is linked IGF1 receptor signaling, cystic vs. solid organoid architecture associated LGR5 + stemness. Treatment-induced morphology reflects viability, drug mechanism action, biologically interpretable. Inhibition MEK leads reorganization increases expression , while inhibition mTOR induces signaling. In conclusion, identify shared for morphology, their underlying mechanisms, pharmacological interventions ability move along them.

Язык: Английский

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The Warburg Effect Explained: Integration of Enhanced Glycolysis with Heterogeneous Mitochondria to Promote Cancer Cell Proliferation

International Journal of Molecular Sciences, Год журнала: 2023, Номер 24(21), С. 15787 - 15787

Опубликована: Окт. 31, 2023

The Warburg effect is the long-standing riddle of cancer biology. How does aerobic glycolysis, inefficient in producing ATP, confer a growth advantage to cells? A new evaluation large set literature findings covering and its yeast counterpart, Crabtree effect, led an innovative working hypothesis presented here. It holds that enhanced glycolysis partially inactivates oxidative phosphorylation induce functional rewiring TCA cycle enzymes generate non-canonical metabolic pathways sustain faster rates. has been structured by constructing two maps, one for metabolism other effect. New lines investigation, suggested these are discussed as instrumental leading toward better understanding biology order allow development more efficient metabolism-targeted anticancer drugs.

Язык: Английский

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Trellis tree-based analysis reveals stromal regulation of patient-derived organoid drug responses

Cell, Год журнала: 2023, Номер 186(25), С. 5606 - 5619.e24

Опубликована: Дек. 1, 2023

Patient-derived organoids (PDOs) can model personalized therapy responses; however, current screening technologies cannot reveal drug response mechanisms or how tumor microenvironment cells alter therapeutic performance. To address this, we developed a highly multiplexed mass cytometry platform to measure post-translational modification (PTM) signaling, DNA damage, cell-cycle activity, and apoptosis in >2,500 colorectal cancer (CRC) PDOs cancer-associated fibroblasts (CAFs) clinical therapies at single-cell resolution. compare patient- microenvironment-specific responses thousands of datasets, "Trellis"-a scalable, tree-based treatment effect analysis method. Trellis revealed that on-target blockage DNA-damage effects are common, even chemorefractory PDOs. However, drug-induced is rarer, patient-specific, aligns with cell PTM signaling. We find CAFs regulate PDO plasticity-shifting proliferative colonic stem (proCSCs) slow-cycling revival (revCSCs) protect from chemotherapy.

Язык: Английский

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Precision medicine applied to metastatic colorectal cancer using tumor-derived organoids and in-vitro sensitivity testing: a phase 2, single-center, open-label, and non-comparative study

Journal of Experimental & Clinical Cancer Research, Год журнала: 2023, Номер 42(1)

Опубликована: Май 5, 2023

Abstract Background Patients with colorectal metastatic disease have a poor prognosis, limited therapeutic options, and frequent development of resistance. Strategies based on tumor-derived organoids are powerful tool to assess drug sensitivity at an individual level suggest new treatment options or re-challenge. Here, we evaluated the method’s feasibility clinical outcome as applied patients no satisfactory options. Methods In this phase 2, single-center, open-label, non-comparative study (ClinicalTrials.gov, register NCT03251612), enrolled 90 cancer following progression after standard therapy. Participants were 18 years older Eastern Cooperative Oncology Group performance status 0–2, adequate organ function, metastasis available for biopsy. Biopsies from site cultured using model. Sensitivity testing was performed panel drugs proven activity in II III trials. At discretion investigator considering toxicity, highest relative offered. The primary endpoint proportion alive without two months per local assessment. Results 82 processed cell culture, which 44 successfully generated least one suggested. precision cohort 34 started endpoint, progression-free survival (PFS) met 17 (50%, 95% CI 32–68), exceeding pre-defined (14 45; 31%). median PFS 67 days (95% 51–108), overall 189 103–277). Conclusions Patient-derived in-vitro feasible cancer. met, half months. Cancer may benefit functional organoids. Trial registration ClinicalTrials.gov, NCT03251612.

Язык: Английский

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