Spheroids and organoids derived from colorectal cancer as tools for in vitro drug screening

Exploration of Targeted Anti-tumor Therapy, Journal Year: 2024, Volume and Issue: 5(2), P. 409 - 431

Published: April 25, 2024

Colorectal cancer (CRC) is a heterogeneous disease. Conventional two-dimensional (2D) culture employing cell lines was developed to study the molecular properties of CRC in vitro. Although these which are isolated from tumor niche develop, translation human model such as studying drug response often hindered by inability recapture original features and lack clinical tumors represented this 2D model, differed vivo condition. These limitations may be overcome utilizing three-dimensional (3D) consisting spheroids organoids. Over past decade, great advancements have been made optimizing method establish organoids solid including for multiple purposes screening establishing personalized medicine. structures proven versatile robust models progression deciphering its heterogeneity. This review will describe on advances 3D technology application well challenges CRC-derived mode screen anticancer drugs.

Language: Английский

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Predicting PROTAC-targeted Degradation and Designing Androgen Receptor Degraders with AiPROTAC

bioRxiv (Cold Spring Harbor Laboratory), Journal Year: 2025, Volume and Issue: unknown

Published: March 2, 2025

ABSTRACT Proteolysis-targeting chimeras (PROTACs), a pioneering class of heterobifunctional ligands, have emerged as transformative tools in combating cancer and immune-related diseases due to their ability target previously undruggable proteins overcome drug resistance. Accurate assessment the degradation potential PROTACs is essential for advancing therapeutic applications. However, development robust predictive models hindered by scarcity large-scale datasets domain-specific tools, well underutilization existing unlabeled data. To address these challenges, we developed an innovative method called AiPROTAC predict capacity PROTACs. In particular, integrates graph augmentation, message-passing enhanced encoders cross-attention mechanisms within contrastive learning framework. Moreover, leverages curated specialized dataset combined with PROTAC-DB enhance prediction accuracy. Experimental results across two six evaluation metrics demonstrate that consistently outperforms state-of-the-art models. Further case studies underline its superior sensitivity reliability. Notably, facilitated design novel androgen receptor (AR) degrader, PROTAC GT19, which achieved vitro compared Bavdegalutamide (ARV-110). This advancement highlights our AiPROTAC’s accelerate PROTAC-based optimization.

Language: Английский

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Probing the Multitargeted Potency of FDA-approved Amifostine against MRSA and Control Comparison with Sulfamethoxazole to Establish Alternative Medications

Microbial Pathogenesis, Journal Year: 2025, Volume and Issue: unknown, P. 107485 - 107485

Published: March 1, 2025

Language: Английский

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Use of Bayesian approaches in oncology clinical trials: A cross-sectional analysis

Frontiers in Pharmacology, Journal Year: 2025, Volume and Issue: 16

Published: March 25, 2025

Purpose Bayesian approaches may improve the efficiency of trials and accelerate decision-making, but reluctance to depart from traditional frequentist statistics limit their use. Because oncology generally involve severe conditions with no or limited therapeutic options, they are well-suited applying methodologies perceived as using these methods often in early phases. Objectives In this study, we aim describe use designs clinical last 20 years. Method A cross-sectional observational study was conducted identify registered clinicaltrials.gov between 2004 2024. Trials were searched , PubMed, through manual search cross-references. Results retrieved, main characteristics extracted R verified manually. Between 2024, 384,298 ; identified 84,850 (22%), which 640 (0.75%) used approaches. The adoption increased significantly after 2011, while half all studies started 5 years, paralleled overall increase research rather than an proportion trials. majority phase 1 2 studies, two-thirds efficacy objectives had single-arm designs, utilizing binary endpoints, such response, primary measure. Conclusion uptake has flattened is still scarce, mostly applied analysis treatment endpoints. There room for further potential advantages settings small populations unmet needs.

Language: Английский

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Synthesis and molecular docking of new bromhexine-conjugated thioureas as anticancer agents; in vitro MTT assay, structure-activity relationship (SAR), density functional theory (DFT), and inhibition potential of DNA topoisomerase II through docking studies

Journal of Molecular Structure, Journal Year: 2025, Volume and Issue: unknown, P. 142305 - 142305

Published: April 1, 2025

Language: Английский

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Pivotal Dose of Pembrolizumab: A Dose‐Finding Strategy for Immuno‐Oncology

Clinical Pharmacology & Therapeutics, Journal Year: 2021, Volume and Issue: 110(1), P. 200 - 209

Published: Jan. 19, 2021

Despite numerous publications emphasizing the value of dose finding, drug development in oncology is dominated by mindset that higher provides efficacy. Examples finding implemented biopharmaceutical firms can change this mindset. The purpose article to outline a pragmatic selection strategy for immuno-oncology (IO) and other targeted monoclonal antibodies (mAbs). approach was pembrolizumab. Selecting recommended phase II (RP2D) with novel mechanism action often challenging due uncertain relationships between pharmacodynamics measurements clinical end points. Additionally, I efficacy safety data are generally inadequate RP2D IO mAbs. Here, estimated based on (clinical study KN001 A A2) pharmacokinetics as required target saturation, which represents surrogate maximal pharmacological effect antagonist Due limitations associated collecting analyzing tumor biopsies, characterizing intratumoral engagement (TE) challenging. To overcome gap, physiologically-based pharmacokinetic model predict TE. As tumors spatially heterogeneous, TE predicted well-vascularized poorly vascularized regions. impact differences expression, example, interindividual variability cancer type, simulated. Simulations showed 200 mg every 3 weeks achieve ≥ 90% clinically relevant scenarios, resulting recommendation RP2D. Randomized comparison studies (KN001 B2 D) showing similar over fivefold dose/exposure range confirmed pivotal dose.

Language: Английский

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A brand new era of cancer immunotherapy: breakthroughs and challenges

Chinese Medical Journal, Journal Year: 2021, Volume and Issue: 134(11), P. 1267 - 1275

Published: May 19, 2021

Immunotherapy has opened a new era in cancer treatment. Drugs represented by immune checkpoint inhibitors have led to important breakthroughs the treatment of various solid tumors, greatly improving survival rate patients. Many types immunotherapeutic drugs become widely available; however, their efficacy is variable, and relatively few patients with advanced experience life-altering durable survival, reflecting complex highly regulated nature system. The research field immunotherapy (CIT) still faces many challenges pursuing broader social goal "curing cancer." Increasing attention been paid strengthening understanding molecular or cellular drivers resistance immunotherapy, actively exploring more effective therapeutic targets, developing combination therapy strategies. Here, we review key that emerged CIT possible solutions development directions overcome these difficulties, providing relevant references for basic modified clinical regimens.

Language: Английский

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How to choose a time zero for patients in external control arms

Pharmaceutical Statistics, Journal Year: 2021, Volume and Issue: 20(4), P. 783 - 792

Published: March 2, 2021

When a sponsor carries out single-arm trial of novel oncology compound, it may wish to assess the efficacy compound via comparison overall survival an external control arm, constructed using patients included in some retrospective registry. If is compared physician's choice chemotherapy, registry might qualify for inclusion arm at multiple different points time, when they receive chemotherapy treatments. For example, patient start their second, third and fourth lines therapy. From which line therapy should this patient's be participants trial? Some sponsors have elected include from last available database. Another possibility randomly select each among those available. In paper, we show, probabilistic arguments also simulation based on real data, that both these methods give rise bias favor trial. We further show can avoided by instead including times once time qualifying treatment.

Language: Английский

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Transcending toward Advanced 3D-Cell Culture Modalities: A Review about an Emerging Paradigm in Translational Oncology

Cells, Journal Year: 2021, Volume and Issue: 10(7), P. 1657 - 1657

Published: July 1, 2021

Cancer is a disorder characterized by an uncontrollable overgrowth and fast-moving spread of cells from localized tissue to multiple organs the body, reaching metastatic state. Throughout years, complexity cancer progression invasion, high prevalence incidence, as well rise in treatment failure cases leading poor patient prognosis accounted for continuous experimental investigations on animals cellular models, mainly with 2D- 3D-cell culture. Nowadays, these research models are considered main asset reflect physiological events many types terms characteristics features, replication mechanisms, metabolic pathways, biomarkers expression, chemotherapeutic agent resistance. In practice, based perspective hypothesis, scientists aim choose best model approach their understanding prove hypothesis. Recently, seen be highly incorporated crucial tool reflecting true cell microenvironment pharmacokinetic pharmacodynamics studies, addition intensity anticancer drug response pharmacogenomics trials. Hence, this review, we shed light unique 3D favoring its promising usage through comparative other specifically 2D-cell Plus, will discuss importance direct reflector intrinsic environment newest methods available 3D-cells implementation.

Language: Английский

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Targeting the Versatile Wnt/β-Catenin Pathway in Cancer Biology and Therapeutics: From Concept to Actionable Strategy

OMICS A Journal of Integrative Biology, Journal Year: 2019, Volume and Issue: 23(11), P. 517 - 538

Published: Oct. 15, 2019

This expert review offers a critical synthesis of the latest insights and approaches at targeting Wnt/β-catenin pathway in various cancers such as colorectal cancer, melanoma, leukemia, breast lung cancers. Notably, from organogenesis to signaling displays varied highly versatile biological functions animals, with virtually all tissues requiring one way or other. Aberrant expression members has been implicated many pathological conditions, particularly human Mutations genes have noted diverse Biochemical genetic data support idea that inhibition is beneficial cancer therapeutics. The interaction this important other systems also noteworthy, but remains an area for further research discovery. In addition, formation different complexes by components precise roles these cytoplasmic milieu are yet be fully elucidated. article highlights medical technologies imaging, single-cell omics, use artificial intelligence (e.g., machine learning techniques), genome sequencing, quantum computing, molecular docking, computational softwares modeling interactions between molecules predicting protein–protein compound–protein pertinent biology therapeutic value pathway. We discuss emerging relationship what currently needed move concept actionable strategies translating laboratory discoveries Wnt-targeted therapies diagnostics clinic.

Language: Английский

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