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

Exploration of Targeted Anti-tumor Therapy, Год журнала: 2024, Номер 5(2), С. 409 - 431

Опубликована: Апрель 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.

Язык: Английский

---

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

Clinical Pharmacology & Therapeutics, Год журнала: 2021, Номер 110(1), С. 200 - 209

Опубликована: Янв. 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.

Язык: Английский

---

A brand new era of cancer immunotherapy: breakthroughs and challenges

Chinese Medical Journal, Год журнала: 2021, Номер 134(11), С. 1267 - 1275

Опубликована: Май 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.

Язык: Английский

---

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

Cells, Год журнала: 2021, Номер 10(7), С. 1657 - 1657

Опубликована: Июль 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.

Язык: Английский

---

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

Pharmaceutical Statistics, Год журнала: 2021, Номер 20(4), С. 783 - 792

Опубликована: Март 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.

Язык: Английский

---

Anticancer activity and QSAR study of sulfur-containing thiourea and sulfonamide derivatives

Heliyon, Год журнала: 2022, Номер 8(8), С. e10067 - e10067

Опубликована: Авг. 1, 2022

Sulfur-containing compounds are considered as attractive pharmacophores for discovery of new drugs regarding their versatile properties to interact with various biological targets. Quantitative structure-activity relationship (QSAR) modeling is one well-recognized in silico tools successful drug discovery. In this work, a set 38 sulfur-containing derivatives (Types I-VI) were evaluated vitro anticancer activities against 6 cancer cell lines. findings indicated that compound 13 was the most potent cytotoxic agent toward HuCCA-1 line (IC50 = 14.47 μM). Compound 14 exhibited 3 investigated lines (i.e., HepG2, A549, and MDA-MB-231: IC50 range 1.50-16.67 10 showed best activity MOLT-3 1.20 μM) whereas 22 noted T47D 7.10 Subsequently, six QSAR models built using multiple linear regression (MLR) algorithm. All constructed provided reliable predictive performance (training sets: Rtr 0.8301-0.9636 RMSEtr 0.0666-0.2680; leave-one-out cross validation RCV 0.7628-0.9290 RMSECV 0.0926-0.3188). From modeling, chemical such mass, polarizability, electronegativity, van der Waals volume, octanol-water partition coefficient, well frequency/presence C-N, F-F, N-N bonds molecule essential key predictors compounds. summary, series promising fluoro-thiourea (10, 13, 14, 22) suggested potential molecules future development agents. Key knowledge obtained from be advantageous suggesting effective rational design related improved bioactivities properties.

Язык: Английский

---

Augmenting randomized clinical trial data with historical control data: Precision medicine applications

JNCI Journal of the National Cancer Institute, Год журнала: 2022, Номер 115(1), С. 14 - 20

Опубликована: Сен. 26, 2022

Abstract As precision medicine becomes more precise, the sizes of molecularly targeted subpopulations become increasingly smaller. This can make it challenging to conduct randomized clinical trials therapies in a timely manner. To help with this problem small patient subpopulation, study design that is frequently proposed trial (RCT) intent augmenting RCT control arm data historical from set patients who have received treatment outside (historical data). In particular, strategies been developed compare outcomes across cohorts treated standard (control) guide use analysis; lessen potential well-known biases using controls without any randomization. Using some simple examples and completed studies, we demonstrate commentary these are unlikely be useful applications.

Язык: Английский

---

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

bioRxiv (Cold Spring Harbor Laboratory), Год журнала: 2025, Номер unknown

Опубликована: Март 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.

Язык: Английский

---

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

Microbial Pathogenesis, Год журнала: 2025, Номер unknown, С. 107485 - 107485

Опубликована: Март 1, 2025

Язык: Английский

---

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

Frontiers in Pharmacology, Год журнала: 2025, Номер 16

Опубликована: Март 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.

Язык: Английский

---