Search Results (1,228)

Background: Antibody-drug conjugates (ADCs) are gaining rapidly expanding clinical utility, with a growing number of approved indications across compounds that differ in target antigen, payload mechanism, and linker design. However, treatment response remains heterogeneous, and predictive biomarkers to identify patients most likely to benefit are limited. Given that ADC efficacy depends on sufficient target antigen expression and distribution across tumor lesions, positron emission tomography (PET) imaging offers a unique opportunity to non-invasively assess whole-body target availability. We therefore conducted a systematic literature review to evaluate the relationship between PET-measured tumor antigen expression and the therapeutic response to ADCs targeting the same antigen. Method: A systematic comprehensive search of PubMed, EMBASE and Web of Science databases was conducted in accordance with Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines, using terms related to targeted PET, ADC treatment and response assessment. Article screening, eligibility assessment, and data extraction were performed independently using predefined criteria by two reviewers. Disagreements were resolved by consensus. Results: A total of 5628 records were identified. After removing duplicates, 4323 records were screened by title and abstract. Fifty-eight underwent full-text review and seven were included in the final review. Four trials investigated human epidermal growth factor receptor 2 (HER2)-targeted therapy, one Nectin-4, one mesothelin and one STEAP1. In all HER2- and Nectin-4-related trials, patients with a higher uptake on targeted PET had a higher probability of responding to targeted treatment. Included trials were generally small and had a moderate risk of bias. Conclusion: Targeted PET imaging showed potential to predict treatment response in trials evaluating clinically active agents. Additional clinical trials across a broader range of targets, along with standardized acquisition protocols and harmonized study designs, are needed to enable the integration of this technique into clinical practice and ultimately translate its benefits to patients. Full article

Monoclonal antibodies are emerging as advanced therapies in companion-animal medicine, with approved or clinically evaluated applications in canine and feline osteoarthritis pain, canine atopic dermatitis, and selected infectious-disease and oncological settings. This critical narrative review integrates peer-reviewed studies, regulatory records, product information, and publicly available therapeutic-antibody sequence resources to examine target biology, species adaptation, Fc function, developability, and clinical implementation. Anti-NGF and anti-IL-31 products demonstrate the clinical value of long dosing intervals, whereas oncology and infectious-disease programmes remain subject to indication-specific efficacy and safety requirements. Canine and feline IgG subclasses, Fc-receptor and FcRn biology, incomplete feline framework resources, manufacturing economics, and owner-funded care all influence candidate design and deployment. Emerging bispecific antibodies, antibody–drug conjugates, VHHs, mRNA-based approaches, and AI-assisted strategies are most relevant when they address a defined veterinary use case. We propose a translational framework linking target validation, species-adapted engineering, species-matched assays, manufacturability, regulatory evidence, and real-world deployment. Full article

Antibody–drug conjugates (ADCs) have emerged as a powerful class of targeted therapeutics in many clinical areas, such as in oncology. Despite their efficacy, the onset of adverse events has been a major drawback in their clinical use. Among other explanations, the clinical performance of the ADCs has been associated with the chemistry of the linker connecting the antibody and payload. Linkers determine plasma stability, intracellular activation, and payload diffusibility, thereby influencing the therapeutic index, off-tumour toxicity, and by-stander activity. Mechanistic insights increasingly show that linker–payload properties govern catabolite permeability and intratumoral distribution, particularly in antigen-heterogeneous settings. Current developments include enzyme-cleavable and tumour-selective linkers, polarity-modulating masking strategies, alternative self-immolative spacers, and dual-trigger systems designed to enhance selectivity and decouple efficacy from toxicity. In parallel, linker behaviour intersects with broader mechanisms of tumour resistance. This review focuses on understanding these processes, which are essential for designing the next generation of linkers capable of improving stability, safety, and long-term therapeutic effectiveness across diverse tumour contexts. Full article

Background/Objectives: Cutaneous adverse events (cAEs) are among the most common toxicities associated with modern anticancer therapies and can significantly affect quality of life, treatment adherence, and therapeutic outcomes. This narrative review aims to provide an updated overview of the mechanisms, clinical manifestations, prognostic implications, and management strategies of cancer therapy-related cutaneous toxicities, with a particular focus on precision oncodermatology. Methods: A narrative review of the recent literature was performed, integrating evidence from clinical studies, meta-analyses, pharmacovigilance investigations, consensus guidelines, and translational research. The review examines cutaneous toxicities associated with immune checkpoint inhibitors, targeted therapies, antibody–drug conjugates, and other emerging anticancer treatments. Results: Four major axes were identified: immune disinhibition, epithelial signaling inhibition, cytotoxic epithelial injury, and cytokine-driven immune activation. Cutaneous immune-related adverse events (cirAEs) emerged as potential biomarkers of treatment efficacy, particularly vitiligo, lichenoid, and psoriasiform eruptions. Increasing evidence supports the use of steroid-sparing biologic therapies, including dupilumab, omalizumab, anti-IL-17 agents, and Janus kinase inhibitors, although prospective validation remains limited. Recent advances in immunologic endotyping have identified distinct inflammatory pathways that may enable personalized therapeutic approaches. Antibody–drug conjugates represent an expanding source of unique dermatologic toxicities requiring dedicated management strategies. Emerging biomarkers, including cytokine signatures and microRNAs, may further refine risk stratification and treatment selection. Conclusions: The management of cancer therapy-related cutaneous toxicities is evolving toward a precision medicine model integrating clinical phenotype, immunologic endotype, and biomarker profiling. Early multidisciplinary intervention and mechanism-based therapeutic strategies may improve patient outcomes while preserving anticancer efficacy. Prospective studies are needed to validate biomarker-guided and steroid-sparing approaches in oncodermatology. Full article

Background/Objectives: Small-cell lung cancer (SCLC) remains one of the most therapeutically challenging malignancies despite recent advances in chemoimmunotherapy. Although platinum–etoposide combined with programmed death ligand 1 (PD-L1) blockade has modestly improved survival in extensive-stage disease, most patients ultimately develop treatment resistance. This review examines the evolving biological basis of therapeutic resistance and discusses how emerging treatment strategies may be integrated into biologically informed clinical development. Methods: We conducted a narrative review of recent translational studies, clinical trials, regulatory updates, and major oncology meeting presentations addressing emerging therapeutic strategies, biomarkers, and adaptive resistance mechanisms in SCLC. Results: Advances in molecular profiling have established that SCLC comprises dynamically evolving transcriptional states characterized by lineage plasticity, replication-stress dependency, immune suppression, and antigen remodeling. These biological insights have accelerated the development of delta-like ligand 3 (DLL3)-directed immune-redirection strategies, next-generation antibody–drug conjugates, DNA damage response-targeting therapies, and epigenetic approaches. Across these platforms, however, clinical translation remains constrained by antigen heterogeneity, biomarker instability, lineage plasticity, immune dysfunction, and cumulative toxicity. We organize the available evidence across three clinically relevant treatment windows—induction, post-induction residual disease, and relapse—to clarify how therapeutic timing may influence the role and expected clinical performance of each strategy. Conclusions: Future clinical development should prioritize the prospective validation of dynamic biomarkers and treatment strategies tailored to specific disease stages. Such an approach may improve patient selection, guide therapeutic sequencing, and increase the durability of treatment benefit in extensive-stage SCLC. Full article

The epidermal growth factor receptor (EGFR) was the first receptor tyrosine kinase identified soon after v-Src was recognized as a tyrosine kinase. EGFR signaling begins when EGF binds to EGFR at the cell surface, inducing receptor dimerization, activation, and autophosphorylation. The resulting phosphotyrosine sites recruit downstream effectors that activate signaling cascades such as the RAS-RAF-MEK-ERK and PI3K-Akt pathways, thereby regulating cell growth, proliferation, and survival. EGF binding also promotes EGFR endocytosis, which can direct the receptor to lysosomal degradation. Aberrant EGFR activity is associated with many cancers, and the receptor has been therapeutically targeted using small-molecule tyrosine kinase inhibitors (TKIs) and monoclonal antibodies (mAbs). Furthermore, EGFR endocytosis has been exploited for the targeted delivery of anticancer agents into EGFR-expressing cancer cells through antibody–drug conjugates (ADCs) and antibody–nanoparticle conjugates (ANCs). Although ADCs and ANCs both utilize mAbs as homing mechanisms to recognize cancer-associated antigens, they further harness EGFR endocytosis to deliver therapeutic payloads directly into target cells. In this review, we briefly discuss EGFR structure, activation, signaling, and endocytosis, as well as the mechanisms underlying EGFR function in cancer development. We then focus on current advances and future perspectives in using EGFR endocytosis pathways to improve targeted cancer drug delivery and therapy, particularly in the context of ANCs. Full article

Background: Next-generation sequencing (NGS)-detected ERBB2 amplification occurs in a subset of urothelial carcinomas, but its role as a treatment-selection marker for trastuzumab deruxtecan (T-DXd) remains uncertain. Methods: We retrospectively reviewed four patients with metastatic urothelial carcinoma treated with T-DXd in routine practice from 2024. Treatment selection was based on NGS-detected ERBB2 amplification because HER2 immunohistochemistry and in situ hybridization were unavailable. Results: Four men aged 65–76 years received T-DXd: one in the second line and three in the fourth or fifth line. The best radiological responses, abstracted from contemporaneous radiology reports and oncology medical records, were complete response in one patient, partial response in one, and stable disease in two. Three patients had previously received enfortumab vedotin. Documented adverse events included fatigue, anemia, diarrhea, rash, and leukopenia. No interstitial lung disease or pneumonitis was documented in the available records. Conclusions: These observations are descriptive and hypothesis-generating. They do not establish the efficacy or safety of T-DXd or validate ERBB2 amplification as a predictive biomarker, but they support prospective evaluation of genomic ERBB2 amplification when standard HER2 testing is unavailable. Full article

Human epidermal growth factor receptor 2 (HER2) and trophoblast cell surface antigen 2 (Trop-2) are tumor-associated antigens widely overexpressed in multiple malignant tumors, which drive malignant proliferation, invasion, metastasis, and therapeutic resistance by activating key downstream signaling pathways. Antibody–drug conjugates (ADCs) targeting HER2 and Trop-2 leverage their antigen-specific binding capacity to achieve precise targeted delivery of cytotoxic drugs, representing a significant breakthrough in solid tumor therapy. This review systematically outlines the biological functions and carcinogenic mechanisms of HER2 and Trop-2, focusing on the latest research and development progress of related ADCs. We also summarize and analyze key clinical data and application prospects in breast cancer (BC), gastric cancer (GC), non-small cell lung cancer (NSCLC), and urothelial carcinoma (UC), while also delving into the challenges and future directions within this field. Full article

Pharmacogenetics has transformed oncology by enabling personalized, effective and safer use of anticancer therapies. Among clinically relevant pharmacogenetic biomarkers, polymorphisms in the UGT1A1 gene influence the metabolism of irinotecan and other SN-38-based agents, increasing the risk of treatment-related toxicities. Beyond SN-38-based therapies, UGT1A1 contributes to the metabolism of endogenous compounds and several drugs, and its activity may be affected by concomitant inhibitors or inducers, highlighting its broader clinical relevance. Although substantial evidence supports the association between UGT1A1 genotype and drug safety, implementation of genotype-guided treatment remains inconsistent. This narrative review summarizes the biological basis and clinical relevance of UGT1A1 polymorphisms in patients receiving SN-38-based therapies. Original studies, systematic reviews, meta-analyses, and international and regional pharmacogenetic guidelines were evaluated regarding genotype-guided dosing, clinical outcomes, implementation strategies, and barriers to routine testing. Reduced-function UGT1A1 variants are associated with increased risk of irinotecan-induced neutropenia and diarrhea, particularly at higher doses. However, recommendations from scientific societies differ regarding testing indications, dose adjustment strategies, and patient selection. Uncertainties remain concerning the clinical implications of UGT1A1 variability for newer antibody–drug conjugates carrying an SN-38 payload. Practical barriers, including inconsistent guideline recommendations, limited access to testing, reimbursement issues, and heterogeneous clinical workflows, continue to restrict implementation. UGT1A1 genotyping represents a valuable tool for improving the safety of selected anticancer therapies, yet its incorporation into clinical practice remains incomplete. As precision oncology evolves, pharmacogenetic testing may optimize treatment selection, reduce toxicity, and improve outcomes. Further harmonization of international recommendations, high-quality prospective studies, and wider access to pharmacogenetic testing are needed to support routine implementation. Full article

Epidermal growth factor receptor (EGFR)-targeted therapy represents one of the earliest and most established examples of precision oncology in non-small-cell lung cancer (NSCLC), with more than 10 approved agents, including tyrosine kinase inhibitors, bispecific antibodies and antibody–drug conjugates. Over the past two decades, the diagnostic and therapeutic landscape of EGFR-mutant NSCLC has evolved from empiric treatment to mutation subtype-guided strategies, from advanced disease to earlier-stage interventions, and from monotherapy to rational combination regimens. Somatic EGFR mutations remain key predictive biomarkers guiding treatment selection, therapeutic intensification, resistance mechanism-directed treatment, and disease monitoring through plasma circulating tumor DNA burden. In parallel, germline EGFR alterations are increasingly recognized as contributors to inherited lung cancer susceptibility, particularly among never-smokers and familial clusters. Germline EGFR T790M is the best-characterized pathogenic variant, creating a permissive background for multifocal lung nodules and lung adenocarcinoma development, often following acquisition of a second somatic EGFR driver mutation. Recent familial, regional, and paired tumor–normal sequencing studies have expanded the evidence beyond isolated case reports and support an emerging hereditary lung cancer predisposition phenotype. Clinically, germline EGFR should be suspected when EGFR T790M is detected prior to TKI exposure, particularly at variant allele fractions near 50%, or in patients with multifocal ground-glass nodules, multiple primary lung adenocarcinomas, early-onset disease, never/light smoking history, or family history of lung cancer. Confirmation requires germline testing and genetic counseling. This review highlights the current knowledge, recent advances, and future directions in somatic and germline EGFR-mutant NSCLC, emphasizing translational relevance for clinicians and researchers. Full article

Background/Objectives: Sacituzumab govitecan (SG, IMMU-132) is a TROP2-directed antibody–drug conjugate carrying SN-38. Patients with colorectal liver metastasis (CRLM) still have limited treatment options after first-line systemic therapy, and the preclinical pharmacological value of TROP2-directed SN-38 delivery in CRLM remains insufficiently defined. Methods: Public single-cell RNA-sequencing data were reanalyzed to explore the distribution of TACSTD2/TROP2-positive epithelial-associated cells in adjacent normal tissues, primary colorectal cancer, and CRLM. The prognostic relevance of TACSTD2 was evaluated using the Kaplan–Meier Plotter database. TROP2-knockdown and TROP2-overexpressing colorectal cancer models were used to assess IMMU-132 response in vitro and in vivo. Pharmacological antitumor activity was further evaluated using subcutaneous xenografts, syngeneic intrasplenic liver metastasis models, and CRLM patient-derived organoids (PDOs). Transcriptomic profiling and γ-H2AX immunofluorescence were used to explore treatment-associated molecular changes. Results: At the patient/sample level, TACSTD2/TROP2-positive epithelial-associated cells showed numerically higher proportions in primary colorectal tumors and liver metastases than in adjacent normal tissues, and high TACSTD2 expression was associated with inferior overall survival in a public survival database. TROP2 knockdown attenuated IMMU-132-induced growth inhibition, apoptosis, and suppression of colony formation. In vivo, IMMU-132 suppressed colorectal tumor growth and reduced liver metastatic burden, with more evident activity in human TROP2-overexpressing models. In a limited exploratory CRLM PDO cohort established after first-line therapy, liver metastasis-derived PDOs showed lower normalized AUC values than primary tumor-derived PDOs. Transcriptomic analysis and representative γ-H2AX immunofluorescence suggested that IMMU-132 treatment was associated with changes in adhesion/cytoskeletal-related pathways, Wnt/cancer-associated transcriptional programs, and DNA damage-associated signals. Conclusions: These in vitro, in vivo, and PDO-based findings support further preclinical pharmacological evaluation of TROP2-directed SN-38 delivery by IMMU-132 in biomarker-annotated CRLM models, particularly in the post-first-line systemic therapy setting. Full article

Thymic epithelial tumors (TETs), comprising thymomas and thymic carcinomas, are rare, biologically heterogeneous thoracic malignancies with limited therapeutic advances since platinum-based regimens were adopted decades ago. Recent genomic and immunophenotypic profiling has uncovered recurrent genomic alterations and high programmed death-ligand 1 (PD-L1) expression, particularly in thymic carcinoma, yet few targeted or immunotherapies have achieved regulatory approval. This mini-review synthesizes current knowledge on TET heterogeneity and the genomic landscape, evaluates the clinical evidence supporting targeted agents and immune checkpoint inhibitors, and examines emerging biomarkers, including circulating tumor DNA. We also address practical barriers to precision oncology in TETs: challenges of next-generation sequencing implementation and cost in resource-limited settings; scarcity of large, biomarker-driven trials; and safety concerns unique to TETs (immune-related toxicity). Finally, we discuss the translational hurdles for antibody–drug conjugates and cellular therapies, limited validated cell surface targets, antigen heterogeneity, and preclinical model gaps and outline strategic paths forward to enable rational, safe, and equitable precision therapeutics for TET patients. Full article

The emergence of antibody-drug conjugates (ADCs) targeting trophoblast cell-surface antigen 2 (TROP2) represents a potential paradigm shift in the treatment of EGFR-mutated non-small cell lung cancer (NSCLC), a setting historically characterized by limited therapeutic options following progression on EGFR tyrosine kinase inhibitors (TKIs). This review examines the biological rationale and clinical challenges underpinning the development of anti-TROP2 ADCs in EGFR-mutated NSCLC. From a mechanistic standpoint, TROP2 occupies a unique and dynamic role in EGFR-mutated NSCLC, providing strong biological rationale for clinical development of anti-TROP2 ADCs in this population. Three TROP2-directed ADCs are currently in clinical development in this setting. Available clinical data in previously treated EGFR-mutated patients are critically reviewed here, focusing on efficacy, toxicity profiles, clinical challenges and potential future perspectives. Full article

Cyclin-dependent kinase 4/6 inhibitors have fundamentally changed the management of hormone receptor-positive, human epidermal growth factor receptor 2-negative breast cancer. However, these drugs are not interchangeable and the field is moving away from the notion of a uniform “class effect.” In early breast cancer, adjuvant abemaciclib and ribociclib improve invasive disease-free survival in patients at a high risk of recurrence, whereas palbociclib does not. This difference likely stems from agent-specific pharmacological profiles, differences in trial design, and patient selection, rather than simply dosing nuances. In metastatic breast cancer, all three agents prolong progression-free survival when combined with endocrine therapy, but only ribociclib and potentially abemaciclib have shown an overall survival advantage. In addition, resistance remains a major obstacle in clinical practice. We propose that resistance mechanisms can be meaningfully grouped into two categories: target-driven (e.g., RB1 loss, CDK6 amplification) and bypass-driven (e.g., ESR1 mutations, PI3K/AKT pathway activation, APOBEC3-mediated mutagenesis). Distinguishing between these classes helps in the design of rational sequencing algorithms and combinatorial regimens. Emerging strategies, such as next-generation protein degraders, oral selective estrogen receptor degraders, antibody–drug conjugates, and inhibition of autophagy, are promising methods for overcoming resistance. Moving forward, the greatest need in breast cancer treatment will be not simply developing additional agents but using current therapies more intelligently by refining biomarker-guided patient selection, tailoring treatment duration, and ensuring broad global access. Full article

Breast cancer remains one of the most prevalent malignancies affecting women worldwide and continues to be a leading cause of cancer-related morbidity and mortality. Patients may present with either localized or advanced disease, with clinical outcomes increasingly influenced by molecular subtype and genetic profile. This review highlights the key genetic factors involved in breast cancer, current diagnostic and therapeutic strategies, and promising emerging approaches that may shape future clinical management. Breast cancer diagnosis typically involves clinical breast examination, imaging techniques such as mammography and ultrasound, and confirmatory biopsies. Genetic mutations in specific genes are strongly linked to the development, progression, and metastasis of the disease. Treatment options for localized breast cancer continue to include surgery (lumpectomy or mastectomy) and radiotherapy, combined with systemic therapies tailored to tumor biology, such as endocrine therapy, human epidermal growth factor receptor 2 (HER2)-targeted therapy, and cyclin-dependent kinase (CDK)4/6 inhibitors. For advanced or metastatic breast cancer, recent therapeutic advances include the use of immunotherapy (e.g., immune checkpoint inhibitors), Poly (ADP-ribose) polymerase (PARP) inhibitors for Breast Cancer gene (BRCA)-mutated cancers, antibody–drug conjugates, and novel targeted agents, which have significantly improved patient outcomes in selected populations. Recent findings in breast cancer genetics have highlighted the critical role of germline and somatic mutations, particularly in genes such as BRCA1, BRCA2, phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit alpha (PIK3CA), and TP53, in driving tumor initiation, progression, and therapeutic response. Molecular profiling and next-generation sequencing technologies have enabled more precise tumor classification and facilitated the development of personalized treatment strategies. Despite these advances, treatment resistance and disease recurrence remain major challenges, particularly in aggressive subtypes such as triple-negative breast cancer. Consequently, ongoing research is exploring alternative and complementary approaches, including nanotechnology-based drug delivery systems, gene editing techniques such as clustered regularly interspaced short palindromic repeats-Cas9 (CRISPR-associated protein 9) (CRISPR-Cas9), cancer vaccines, and the integration of traditional and plant-derived compounds. These strategies aim to enhance therapeutic efficacy, reduce systemic toxicity, and overcome resistance mechanisms. Full article