This study introduces a novel drug-disease modeling framework designed to assess the benefit-risk balance of antibody-drug conjugates (ADC) in oncology. The framework integrates dose levels, pharmacokinetics, tumor growth dynamics, progression-free survival (PFS), and dose-adjusted adverse events. We demonstrated this through its application to tusamitamab ravtansine (Tusa), an ADC targeting Carcinoembryonic Antigen-Related Cell Adhesion Molecule 5 in non-squamous non-small cell lung cancer (nsq NSCLC). We developed our model using phase I trial safety data from 254 patients (doses: 5-190 mg/m2) and efficacy data from 88 nsq NSCLC patients (dose 100 mg/m2). This model accurately predicted phase III outcomes for the Tusa arm via an iterative simulation. Using phase III baseline characteristics, simulations of Tusa doses comparing three dose levels (80, 100, and 120 mg/m2 every 2 weeks) revealed a critical trade-off: while higher doses increased response rates, they also substantially increased corneal toxicity without improving survival. These findings demonstrate how early-phase data can inform optimal dose selection by quantifying benefit-risk. This robust framework and methodology is generalizable beyond Tusa, offering value to support dose selection and trial decision-making in oncology drug development.

Drug repurposing through pathway perturbation dynamics: A systems biology approach for precision oncology.

Fragmentation of Health Benefits Plans in Chile: Findings from a comparative policy analysis and implications for advancing Universal Health Coverage.

Canada’s Drug Agency (CDA-AMC) recommends that Imfinzi be reimbursed by public drug plans for the treatment of patients with muscle invasive bladder cancer (MIBC) in combination with gemcitabine-cisplatin as neoadjuvant treatment, followed by Imfinzi as adjuvant monotherapy after radical cystectomy if certain conditions are met. The pan-Canadian Oncology Drug Review Expert Review Committee (pERC) determined that Imfinzi in combination with gemcitabine-cisplatin as neoadjuvant treatment, followed by Imfinzi as adjuvant monotherapy after radical cystectomy demonstrates acceptable clinical value versus neoadjuvant gemcitabine-cisplatin in patients with MIBC. Given that Imfinzi is expected to be an additive treatment to gemcitabine-cisplatin, acceptable clinical value refers to added value versus gemcitabine-cisplatin alone. Evidence from 1 clinical trial (NIAGARA) demonstrated that in patients with MIBC, treatment with Imfinzi in combination with gemcitabine-cisplatin as neoadjuvant treatment, followed by Imfinzi as adjuvant monotherapy after radical cystectomy resulted in a statistically significant improvement in pathologic complete response (pCR), event-free survival (EFS) at 24 months, and overall survival (OS) at 36 months compared to neoadjuvant gemcitabine-cisplatin and no adjuvant therapy after radical cystectomy. Imfinzi should only be covered for adults with stage T2N0-1M0 to T4aN0-1M0 bladder cancer who are eligible for surgery and have not received prior systemic chemotherapy or immunotherapy for the treatment of MIBC. Patients should also have a good performance status.

Although conventional modalities such as chemotherapy and radiotherapy have markedly reduced cancer incidence, they are frequently accompanied by profound adverse effects, including systemic toxicity and the emergence of multidrug resistance. While advances in immunotherapy and targeted therapy have addressed certain limitations, such as the need for precision drug delivery, cancer treatment continues to face major challenges, particularly in overcoming tumor biological barriers to enhance therapeutic efficacy and prevent acquired resistance. With the rapid advent of novel biomaterials, polymer-based nanoparticles are reshaping traditional drug delivery paradigms and accelerating the evolution of precision oncology and intelligent drug delivery platforms. Nevertheless, comprehensive and systematic investigations remain limited regarding how polymer nanoparticles can overcome the inherent drawbacks of conventional delivery strategies in oncology. This review aims to systematically synthesize recent advances in the application of polymer nanoparticles for cancer therapy. We highlight how the intrinsic properties of polymeric nanomaterials - such as chemical tunability, stimuli-responsive mechanisms, surface engineering, and multifunctional integration - enable breakthroughs in drug synergy, tumor barrier penetration, and spatiotemporally controlled delivery. Furthermore, we delineate the major challenges and future directions in this rapidly evolving field, with the aim of providing a conceptual framework and potential roadmap for the next generation of cancer therapeutics.

The burden of care for cancer patients in East Africa has, over the years, been exacerbated by limitations like the absence of comprehensive cancer care pathways, the lack of a specialised oncology workforce, and under provision of the necessary cancer medicines from national governments. The primary objective of this scoping review is to analyse previously documented research, synthesise the available evidence, and characterise these limitations based on individual demographic factors. Data from the appraised evidence alluded to the absence of a specialised oncology workforce, who were found to be centralised within urban centres, resulting in inequitable access to specialised cancer care among patients residing in underserved regions. The review also noted a significant trend of task shifting to the mid-level healthcare workforce, who lack formal standardised training. Similarly, most cancer care facilities were reported to have limited cancer care drugs and diagnostic commodities, with the available drugs being overpriced to match the huge demand. All these factors have a role to play in causing cancer diagnostic delays, and clinical expertise is moot, resulting in most patients being diagnosed with advanced-stage cancer with limited pharmacotherapeutic agents to see them through their disease cycle trajectory. Although most facilities are embracing task shifting and decentralised service delivery approaches, they often face financial constraints and supply chain breakdowns that incapacitate the sustainability of these novel approaches

Canada’s Drug Agency (CDA-AMC) recommends that Enhertu be reimbursed by public drug plans for the treatment of adult patients with unresectable or metastatic hormone receptor (HR)-positive, HER2-low (immunohistochemistry [IHC] 1+ or IHC 2+ or in situ hybridization [ISH]-negative) or HER2-ultralow (IHC 0 with membrane staining) breast cancer who have received at least 1 endocrine therapy in the metastatic setting and who are not considered suitable for further endocrine therapy as the next line of therapy if certain conditions are met. The pan-Canadian Oncology Drug Review Expert Review Committee (pERC) determined that Enhertu demonstrates acceptable clinical value compared with chemotherapy in adult patients with unresectable or metastatic HR-positive, HER2-low or HER2-ultralow breast cancer who have received at least 1 endocrine therapy in the metastatic setting and who are not considered suitable for endocrine therapy as the next line of therapy. This determination was sufficient for pERC to recommend that Enhertu be reimbursed. Given that Enhertu is expected to be an alternative to chemotherapy, acceptable clinical value refers to added value versus chemotherapy. Evidence from a clinical trial demonstrated that, compared with chemotherapy, Enhertu likely results in added clinical benefit in progression-free survival (PFS) in adults with HR-positive metastatic breast cancer (MBC) with low or ultralow HER2 expression who have received 1 or more lines of endocrine-based therapy and no previous chemotherapy for MBC. Overall survival (OS) was consistent with the results observed in the PFS analysis, suggesting a trend toward superiority for Enhertu. Compared to chemotherapy, Enhertu met some of the identified patient needs as it likely delays disease progression and may prolong survival. Enhertu should only be covered for patients with HR-positive disease who have received at least 1 endocrine therapy in the metastatic setting and are not considered suitable for endocrine therapy as the next line of therapy. Patients should have a good performance status and must not have symptomatic spinal compression, clinically active central nervous system metastases, current interstitial lung disease (ILD) or pneumonitis, or received prior chemotherapy for advanced or MBC.

Covering up to 2025Natural products (NPs) from the terrestrial biodiversity play a key role in oncology drug discovery. While historically identified through bioactivity-guided fractionation, recent advances in high-content screening (HCS) assays, metabolomics, and in silico modeling have significantly enhanced the potential and attractiveness of flora-derived NPs for the development of anticancer therapeutics. This includes immunomodulatory molecules that are able to target the tumor microenvironment to promote immune-mediated clearance of the tumor, thereby improving patient response. This review highlights the untapped potential of molecules extracted from the South Pacific's terrestrial flora in the search for novel antitumor and immunomodulatory compounds. The unique biodiversity of Oceania, including Australia, New Zealand, and Pacific Island Countries and Territories (PICTs) across Micronesia, Melanesia and Polynesia, offers a promising yet largely unexplored reservoir for discovering plant-derived molecules with antitumor and immunomodulatory activities. Herein, we examine the recent pharmacological advances in this field and highlight the need for sustainable and collaborative research. Leveraging cutting-edge technologies could help overcome the challenge of NP-based drug discovery on these geographically isolated islands, unlocking the region's vast potential for plant-derived cancer therapeutics.

Computational investigation of natural phenolic-3,4,5-trimethoxybenzoates as potential anticancer agent targeting estrogen receptor alpha.

Background:Pancreatic cancers (PCs)—especially pancreatic ductal adenocarcinoma (PDAC)—are among the deadliest digestive system cancers, with a 5 year survival of approximately 13%. Beta blockers (BBs), which inhibit beta-adrenergic receptor-mediated angiogenesis and immunosuppression, are potential candidates for oncological drug repurposing. However, the clinical evidence is inconsistent, and robust subgroup analyses are lacking. This study systematically evaluated the association between BB use and survival in PC patients. Furthermore, subgroup analyses were conducted to clarify differential clinical effects.Methods:This study was conducted in accordance with PRISMA guidelines and registered with PROSPERO (CRD420251106076). The PubMed, Embase, Cochrane Library, and Web of Science databases were searched to identify observational studies on all-cause mortality (ACM) and cancer-specific mortality (CSM). Hazard ratios (HRs) and 95% confidence intervals (CIs) were calculated using RevMan 5.3 and R, and the results were presented in forest plots.Results:This analysis included nine retrospective cohort studies involving over 30 000 patients. There were no significant associations between BB use and ACM (HR = 1.07; 95% CI [0.95-1.20]) or CSM (HR = 0.89; 95% CI [0.70-1.14]). However, subgroup analysis revealed that BB use was significantly associated with increased ACM risk in surgical patients (HR = 1.18; 95% CI [1.05-1.31]). Moreover, non-selective BB (NSBB) use significantly reduced CSM risk (HR = 0.81; 95% CI [0.68-0.97]). Both sensitivity and trim-and-fill analyses confirmed the robustness and consistency of these results.Conclusions:This meta-analysis presents the first systematic evidence regarding the potential role of NSBBs in mitigating CSM, thus providing support for their potential repurposing. In addition, these findings indicate that perioperative BB use may be associated with increased ACM risk, highlighting the need for careful perioperative risk assessment. To further substantiate these findings, future prospective studies should explore combined approaches, particularly those integrating immune or anti-angiogenic therapies.

Establishing FDA-approved oncology drugs as GPR176 inhibitor through homology modelling, molecular docking, MMGBSA, DFT, and molecular dynamics simulation.

The landscape of innovative oncology drug targets.

Discovery of anti-tumor targets based on photo-affinity labeling.

Classic and hybrid pharmacometric-machine learning models (hPMxML) are gaining momentum for applications in clinical drug development and precision medicine, especially within the oncology therapeutic area. However, standardized workflows are needed to ensure transparency, rigor, and effective communication for broader adoption. In this tutorial, we review pharmacometric (PMx) and machine learning (ML) reporting standards and evaluate them against hPMxML works in oncology contexts as a motivational example to identify current deficiencies and propose mitigation strategies for future efforts. The revealed gaps include insufficient benchmarking, absence of error propagation, feature stability assessments, and ablation studies, limited focus on external validation and final parametrization, and discrepancies between the performance metrics chosen and the original clinical questions. To address these, we propose a checklist for hPMxML model development and reporting, consisting of steps for estimand definition, data curation, covariate selection, hyperparameter tuning, convergence assessment, model explainability, diagnostics, uncertainty quantification, validation and verification with sensitivity analyses. This standardized approach is expected to enhance the reliability and reproducibility of hPMxML outputs, enabling their confident application in oncology clinical drug development, while fostering trust among all stakeholders.

The discovery of selective and potent KRASG12D inhibitors remains a critical priority in oncology drug development. Here, we performed comparative all-atom molecular dynamics (MD) simulations on four KRASG12D-inhibitor complexes (PDB IDs: 7RPZ, 7RT2, 7EWB, 7EW9) spanning a wide affinity range (IC50 = 2 nM-14 µM). By integrating high-resolution crystallographic data with ex-tensive all-atom MD simulations, we aimed to elucidate the structural and dynamic determinants that differentiate high- and low-affinity inhibitor binding. Alchemical free-energy calculations yielded ΔG values of -11.3 to -6.2 kcal mol-1, which showed a strong correlation with experimental pIC50 (R2 = 0.92). Per-residue energy decomposition revealed five dominant polar interaction hotspots (D12 ≈ -34, G60 ≈ -13, E62 ≈ -20, D69 ≈ -17, and D92 ≈ -6 kcal mol-1) driving stable bind- ing, whereas weak inhibitors exhibited markedly reduced contributions at these residues. Structural dynamics analysis further showed that strong binders maintained compact binding pockets (RMSD: 1.8-2.2 Å) and reduced ligand flexibility, whereas weak binders sampled expanded and less stable conformations (RMSD: 2.7-3.4 Å). These findings delineate the structural and energetic determinants underlying KRASG12D inhibitor potency and provide quantitative guidelines for the rational design of next-generation KRASG12D inhibitors.

This descriptive analysis evaluates design strategies, regulatory outcomes, and temporal trends in oncology accelerated approvals (AAs) over three decades, comparing solid tumors with hematologic malignancies. We retrospectively reviewed publicly available U.S. Food and Drug Administration (FDA)data on oncology drugs granted AA between December 1992 and January 2025, focusing on those with completed post-approval assessments. Key measures included trial design, endpoints, conversion and withdrawal rates, and time to regulatory resolution. Of 204 AAs representing 204 drug-indication pairs (across 133 drugs), 138 had completed post-approval assessments; 77.5% converted to regular approval, 22.5% were withdrawn. Solid tumors accounted for 63% (87/138) of AAs, and had higher conversion rates to regular approvals compared to hematologic malignancies (82% vs. 71%, respectively). Withdrawals were more frequent in hematologic malignancies compared to solid tumors (29% vs. 18%, respectively). Orphan drug designation and post-approval label modifications were more common in hematologic malignancies than solid tumors (76% vs. 45%, and 18% vs. 11%, respectively). Randomized controlled trials (RCTs) drove most successful conversions (63%). Among 105 AA trials for solid tumors, overall response rate (ORR) was the primary endpoint in 74%, with progression-free survival (PFS) and overall survival (OS) in 13% and 9% AAs, respectively. Hematologic trials favored ORR (33%) and disease-specific endpoints. The most common AA → confirmatory pathway was ORR → PFS (46%). OS as a confirmatory endpoint after surrogate-based AA was linked to higher withdrawal rates, whereas consistent endpoints (e.g., OS → OS) had none. RCTs and aligned endpoints drive successful oncology AA conversions, while surrogate-confirmed OS often precedes withdrawal.

Oncology Drug Revenue and Price Negotiation

Design, synthesis and biological activity evaluation of a novel selective inhibitor in PLK1 with acyl or sulfonyl substituted dihydroindole structure.

Small molecules developed to target proteins or DNA may also bind RNA, but the extent and biological significance of such interactions among oncology drugs remain poorly defined. Here, we systematically profiled RNA interactions of a cohort of clinically approved anticancer agents and uncovered widespread RNA off-targeting. Cisplatin, a frontline chemotherapeutic agent for solid tumors, has emerged as a prominent RNA-binding drug. While the primary mechanism of action of cisplatin has been attributed to DNA damage-induced apoptosis, it has also been shown to bind RNA molecules. However, the extent of RNA binding in cancer cells and its functional relevance in platinum-based chemotherapy remained unknown. To map specific RNA targets of cisplatin in vivo, we developed PlatRNA-seq, a click-chemistry-enabled transcriptome-wide assay. Using this approach and integrated genomic, biophysical, and computational analysis, we show that cisplatin binding is enriched at guanine-rich regions of transcripts, with a pronounced affinity for RNA G-quadruplexes (rG4s) secondary structures. Cisplatin accumulates preferentially near the 5′ ends of transcripts associated with R-loop formation and RNA pol II stalling. Mechanistically, cisplatin binding to rG4s modulates their formation and stability. Importantly, we provide evidence that cisplatin-induced cytotoxicity is mediated in part through its binding to RNA, revealing a noncanonical RNA-based mechanism of action. Analysis of single-cell RNA-seq data from tumor biopsies of treatment-naïve ovarian cancer patients further shows that the expression of rG4-enriched cisplatin-RNA targets predicts platinum sensitivity, underscoring the prognostic and clinical relevance of drug-RNA interactions. Together, these results demonstrate that RNA off-targeting by small molecules is not passive but can modulate therapeutic outcomes and may be leveraged to overcome current limitations of chemotherapeutic agents. Our findings highlight the importance of systematically investigating RNA interactions of clinically used small molecules to better inform therapeutic and prognostic strategies.

Aim: Osimertinib’s clinical application is limited by poor aqueous solubility and systemic toxicity. Nano-niosomal formulations can address these challenges by providing controlled release and enhancing delivery. To develop and systematically evaluate nano-niosomal formulations of osimertinib using different surfactants, focusing on physicochemical characteristics, release kinetics, and cytotoxic activity. Methods: Four niosomal formulations were prepared using Span 60, Tween 60, Pluronic F-127, and Brij 52 (each at a 1:1 cholesterol-to-surfactant ratio). Particle size, zeta potential, and entrapment efficiency were measured. In vitro drug release was analyzed using Franz diffusion cells and fitted to standard kinetic models. Cytotoxicity was assessed by MTT assay in KAIMRC-2, MDA-MB231, and HCT-116 cell lines. Vesicle morphology was visualized by transmission electron microscopy. Results: All nano-niosomal formulations showed nanoscale particle sizes (47–292 nm), negative zeta potentials (−18.7 to −26.5 mV), and high entrapment efficiencies (69.8%–76.2%). Release studies indicated Span 60, Tween 60, and Pluronic F-127 followed diffusion-controlled kinetics (Higuchi/Korsmeyer–Peppas model, R2 up to 0.97), while Brij 52 provided a sustained zero-order release (R2 = 0.98). Compared to free osimertinib, all niosomal systems significantly prolonged release. Cytotoxicity studies demonstrated that all formulations enhanced anti-cancer effects, with Span 60-based niosomes exhibiting the greatest potency across cell lines. Conclusions: Optimized nano-niosomal encapsulation of osimertinib enables sustained and controlled drug release, improved cellular uptake, and enhanced cytotoxicity in vitro. Differences in surfactant composition critically influence formulation performance, supporting the further development of niosomal osimertinib as a promising strategy for oncological drug delivery applications.