Search Results (354)

Background/Objectives: The tumor microenvironment (TME) of pancreatic ductal adenocarcinoma (PDAC) is characterized by an enriched stroma, hampering the effectiveness of therapy. This co-clinical study aimed to (1) provide insight into early post-treatment changes in the TME using multiparametric magnetic resonance imaging (mpMRI)-derived quantitative imaging biomarkers (QIBs) in a preclinical PDAC model treated with radiotherapy and correlate these QIBs with histology; (2) evaluate the feasibility of obtaining these QIBs in patients with PDAC using clinically approved mpMRI data acquisitions. Methods: Athymic mice (n = 12) at pre- and post-treatment as well as patients with PDAC (n = 11) at pre-treatment underwent mpMRI including diffusion-weighted (DW) and dynamic contrast-enhanced (DCE) data acquisition sequences. DW and DCE data were analyzed using monoexponential and extended Tofts models, respectively. DeepLIIF quantified the total percentage (%) of tumor cells in hematoxylin and eosin (H&E)-stained tissues from athymic mice. Spearman correlation and Wilcoxon signed rank tests were performed for statistical analysis. Results: In the preclinical PDAC model, mean pre- and post-treatment ADC and K^trans values differed significantly (p < 0.01), changing by 20.50% and 20.41%, respectively, and the median total tumor cells quantified by DeepLIIF was 24% (range: 15–53%). Post-treatment ADC values and relative change in v_e (rΔv_e) showed a significant negative correlation with total tumor cells (ρ = −0.77, p < 0.014 for ADC and ρ = −0.77, p = 0.009 for rΔv_e). In patients with PDAC, pre-treatment mean ADC and K^trans values were 1.76 × 10⁻³ (mm²/s) and 0.24 (min⁻¹), respectively. Conclusions: QIBs in both preclinical and clinical settings underscore their potential for future co-clinical research to evaluate emerging drug combinations targeting both tumor and stroma. Full article

Background: Gastric signet-ring cell carcinoma (GSRCC) is a distinct subtype of gastric cancer characterized by unique biological features, leading to low rates of early diagnosis, poor prognosis, and limited response to chemotherapy and immunotherapy. Effective targeted therapies for GSRCC remain scarce. Given these treatment challenges and the potential efficacy of antibody-drug conjugates (ADCs) in clinical settings, this study focuses on identifying novel ADCs with significant potential to improve the treatment outcomes of GSRCC. Methods: We conducted a comprehensive bioinformatics analysis of GSRCC using multi-omics data (including transcriptomics and proteomics) and identified the poliovirus receptor (PVR) as a potential therapeutic target for GSRCC. We selected deruxtecan (DXd) as an effective carrier for developing an ADC targeting GSRCC. The synthesized PVR monoclonal antibody-DXd complex (PVR-DXd) has a drug-to-antibody ratio (DAR) of 4. Results: PVR-DXd demonstrated potent antitumor activity in a human GSRCC xenograft model, effectively eliminating tumors while sparing normal tissue, highlighting its potential as a novel and impactful targeted therapy for this aggressive subtype of gastric signet ring cell carcinoma. Conclusions: This preliminary study supports the further development of PVR-DXd as a candidate therapy for advanced GSRCC. Full article

Cervical cancer remains a significant global health burden, disproportionately affecting women in low- and middle-income countries despite being preventable. Since 2018, rapid advances in molecular profiling, immunotherapy, refinement of minimally invasive surgery, and targeted therapeutics have transformed diagnostic and therapeutic paradigms. This narrative review synthesizes clinical and translational progress across the continuum of care from 2018 to 2025. We summarize the evolving landscape of precision screening—including HPV genotyping, DNA methylation assays, liquid biopsy, and AI-assisted cytology—and discuss their implications for global elimination goals. Surgical management has shifted toward evidence-based de-escalation with data from SHAPE, ConCerv, and ongoing RACC informing fertility preservation and minimally invasive approaches. For locally advanced disease, KEYNOTE-A18 establishes pembrolizumab plus chemoradiation as a new curative standard, while INTERLACE underscores the benefit of induction chemotherapy. In the metastatic setting, survival outcomes have improved with the integration of checkpoint inhibitors (KEYNOTE-826, BEATcc, EMPOWER-Cervical 1), vascular-targeted therapies, and antibody–drug conjugates, including tisotumab vedotin and emerging HER2 and TROP-2–directed agents. We further highlight emerging biomarkers—PD-L1, TMB, MSI status, HPV integration patterns, APOBEC signatures, methylation classifiers, ctHPV-DNA—and their evolving role in treatment selection and surveillance. Future directions include neoadjuvant checkpoint inhibition, PARP-IO combinations, HER3-directed ADCs, DDR-targeted radiosensitizers, HPV-specific cellular therapies, and AI-integrated precision medicine. Collectively, these advances are reshaping cervical cancer care toward biologically individualized, globally implementable strategies capable of accelerating WHO elimination targets. Full article

Background/Objectives: Small-cell lung cancer (SCLC) is an aggressive neuroendocrine malignancy characterized by rapid proliferation, early metastasis, and near-universal relapse after initial therapy. While chemo-immunotherapy modestly improves first-line outcomes, survival after progression remains poor and highlights the urgent need for biomarker-directed strategies. Methods: A comprehensive literature search was conducted using major medical databases looking at key relevant studies on SCLC antibody studies. All authors reviewed the literature, assessed study quality, and interpreted the results from each study. Results: Recent advances in antibody–drug conjugates (ADCs) and T-cell engagers (TCEs) have transformed therapeutic development by targeting antigens selectively expressed on SCLC cells, enabling more precise and potentially durable tumor control. DLL3 has emerged as the most clinically relevant target to date, with the bispecific TCE tarlatamab demonstrating meaningful and durable response, manageable cytokine-release toxicity, and ultimately achieving accelerated FDA approval for previously treated extensive-stage SCLC. Concurrently, DLL3-directed ADCs have shown variable efficacy, underscoring the importance of payload selection, linker chemistry, and antigen density. Beyond DLL3, next-generation ADCs targeting TROP2, B7-H3, and SEZ6 have reported encouraging early-phase activity, including response rates exceeding those of existing second-line cytotoxic options, though myelosuppression, interstitial lung disease, and hepatic toxicity remain key considerations. Conclusions: Collectively, these emerging immunotherapies illustrate a shift toward antigen-specific targeting in a disease historically defined by limited therapeutic innovation. Continued optimization of antigen selection, payload and linker engineering, and biomarker-driven trial design will be critical for translating early promise into durable clinical benefit and reshaping the treatment landscape for SCLC. Full article

Triple-Negative Breast Cancer (TNBC) remains the most aggressive breast cancer subtype, characterized by profound heterogeneity and a lack of effective targeted therapies. Although cytotoxic chemotherapy is the standard of care, the rapid emergence of resistance driven by cancer stem cells (CSCs), metabolic plasticity, and the tumor microenvironment limits long-term survival. This review highlights the paradigm shift in TNBC treatment from 2021 to 2025, moving beyond broad cytotoxicity to precision medicine. We first examine the limitations of earlier targeted therapies, such as PI3K/AKT/mTOR inhibitors, which failed due to compensatory feedback loops and toxicity. We then discuss emerging synthetic lethality strategies targeting the G2/M checkpoint (WEE1, ATR) and mitotic kinases (PLK1, TTK) to exploit genomic instability in TP53-mutant tumors. Furthermore, we explore how novel modalities like PROTACs and Antibody–Drug Conjugates (ADCs) are unlocking the “undrugged kinome,” including targets like TNIK, PTK7, and PAK4, which were previously inaccessible. Finally, we propose that future success lies in combinatorial strategies integrating these next-generation kinase inhibitors with ADCs and immunotherapies to dismantle therapeutic resistance. Full article

Background/Objectives: Approved for treatment of acute leukemia, gemtuzumab ozogamicin (GO) and inotuzumab ozogamicin (InO) are antibody–drug conjugates (ADCs) that deliver a toxic calicheamicin (CLM) derivative. The resistance mechanisms to GO/InO remain incompletely understood. Methods: We performed a genome-wide clustered regularly interspaced short palindromic repeat (CRISPR)/Cas9 screen for CLM sensitivity genes, and then performed confirmatory cytotoxicity assays. Results: Several DNA damage pathway regulation genes were identified, most notably TP53. Across 13 acute leukemia cell lines, the six TP53-mutant cell lines (TP53^MUT) were indeed 10- to 1000-fold less sensitive to CLM than the seven TP53^WT cell lines. In five TP53^WT/KO syngeneic cell line pairs we generated, TP53^KO cells were significantly less sensitive to CLM than their TP53^WT counterparts. In TP53^WT but not TP53^MUT cells, the MDM2 inhibitor and p53 activator, idasanutlin, enhanced CLM cytotoxicity, demonstrating that decoupling of cells from MDM2-p53 regulation sensitizes leukemia cells to CLM. The ATM inhibitors AZD1390 and lartesertib also significantly enhanced CLM efficacy but did so independent of the TP53 status. In contrast, neither an ATR inhibitor, Chk1/Chk2 inhibitor, Chk2 inhibitor, or a PARP inhibitor significantly impacted CLM-induced cytotoxicity across the thirteen cell lines. Together, our studies identify ATM, MDM2, and TP53—which are in the same cellular response to DNA damage pathway—as key modulators of CLM-induced cytotoxicity in acute leukemia cells. Conclusions: These results support further evaluation of combination therapies with corresponding small-molecule inhibitors (currently pursued for therapy of other cancers) toward clinical testing as novel strategies to increase the efficacy of CLM-based ADCs such as GO and InO. Full article

Breast cancer remains the most common malignancy and one of the leading causes of cancer-related death among women worldwide. Advances in antibody-based therapies have improved outcomes across all biological subtypes: HER2-positive, triple-negative, and luminal breast cancer. Monoclonal antibodies such as trastuzumab and pertuzumab have established HER2-targeted therapy as a standard of care, while immune checkpoint inhibitors have introduced immunotherapy into the treatment of triple-negative breast cancer. The emergence of antibody–drug conjugates (ADCs), including trastuzumab deruxtecan, sacituzumab govitecan, and datopotamab deruxtecan, has further expanded the available therapeutic options. Bispecific antibodies represent a new generation of agents with the potential to overcome resistance and enhance immune activation. Despite impressive progress, important challenges remain, including resistance mechanisms and the management of treatment-related toxicities. This review summarizes the biological rationale, clinical evidence, resistance mechanisms, and safety profiles of therapies based on monoclonal antibodies, bispecific antibodies, and antibody–drug conjugates in breast cancer. The development of these treatment modalities fosters the implementation of personalized, immunologically informed treatment strategies that are redefining precision oncology in breast cancer. Full article

Background: Cancer epidemiology data for people living with human immunodeficiency virus (PLWH) in Thailand, particularly in the era of combination antiretroviral therapy (ART), remain limited. In this study, we describe the prevalence, temporal trends, clinical characteristics, and survival outcomes of patients with AIDS-defining cancers (ADCs) and non-AIDS-defining cancers (NADCs). Methods: We retrospectively reviewed adult PLWH diagnosed with malignancy at Songklanagarind Hospital in Thailand during 2003–2023. Demographic, human immunodeficiency virus (HIV)-related, and clinical data were analyzed using chi-square and Wilcoxon rank-sum tests and the Kaplan–Meier method. Results: Among 444 patients, 231 had NADCs and 213 had ADCs. The NADC proportion increased markedly over time. Common ADCs included non-Hodgkin lymphoma and cervical cancer; common NADCs included lung cancer, non-nasopharyngeal head and neck cancer, and hepatocellular carcinoma. Compared with patients with ADCs, those with NADCs were older, more often male, and had higher proportions of undetectable HIV viral load, CD4 counts ≥200 cells/µL, and ART use. Approximately one-third of patients presented with advanced-stage disease, and the median overall survival was 15.9 months. Conclusions: Over two decades, NADCs have become the predominant malignancy in Thai PLWH, associated with older age, male sex, and improved immune function. This reflects the evolving cancer risk in the era of combination ART. We suggest employing multidisciplinary approaches involving HIV and cancer care to improve survival outcomes and integrating age-appropriate screening for common NADCs into HIV care. Full article

Objective: To evaluate the real-world efficacy and safety of disitamab vedotin (RC48-ADC) in patients with human epidermal growth factor receptor 2 (HER2) overexpression (immunohistochemistry [IHC] 2+ or 3+), advanced gastric/gastroesophageal junction cancer (GC/GEJC) with metastases who had received at least one line of prior systemic therapy. Patients and methods: Patients with HER2-overexpressing advanced or metastatic GC/GEJC who had previously received the anti-HER2 antibody-drug conjugate disitamab vedotin between December 2022 and April 2024 were enrolled in this study. The patients’ baseline characteristics, treatment procedures, and laboratory or imaging examinations were retrospectively collected and analyzed. The observation items included the objective response rate (ORR), disease control rate (DCR), progression-free survival (PFS), overall survival (OS), and treatment-related adverse events (TRAEs). Results: Of the 38 enrolled patients in the study, 27 were found to be HER2-positive. Most patients (29/38) received disitamab vedotin therapy as a third-line or subsequent treatment. A total of 68.4% of patients had previously received anti-HER2 therapy, and 13 patients underwent immunotherapy concurrently. The overall ORR and DCR were 31.6% and 65.8%, respectively. A higher ORR was observed in patients with a single metastatic site compared to those with multiple sites (53.3% vs. 17.4%, p = 0.022). In the general population, the median PFS was 6.5 months (95% confidence interval [CI] 3.3–9.8 months), and OS was 13.5 months (95% CI 9.0–17.9 months). The most common adverse event was anemia (89.5%), and eight patients suffered severe toxicities of grade ≥3. Conclusions: Disitamab vedotin exhibited encouraging anti-tumor effectiveness with a tolerable safety profile for advanced GC/GEJC patients with HER2 overexpression who had failed at least one line of systemic therapy in a real-world setting. Full article

Background: Muscle-invasive bladder cancer (MIBC) represents a highly aggressive malignancy associated with significant morbidity and mortality. The current standard treatment, which includes radical cystectomy and platinum-based chemotherapy, is burdened by high toxicity and a substantial risk of relapse. For this reason, over the past decade, novel therapeutic strategies involving immune checkpoint inhibitors (ICIs), antibody–drug conjugates (ADCs), and targeted therapies have been investigated. This review aims to summarize current clinical evidence and ongoing trials evaluating these approaches in the perioperative setting. Methods: A systematic search was conducted using PubMed, EMBASE, and Cochrane databases, along with abstracts from major oncology conferences (ASCO, ESMO, SGO). Clinical trials assessing ICIs, ADCs, and targeted therapies, either alone or in combination with each other or with chemotherapy, in MIBC, were included. Results: Several early-phase and phase III trials have investigated the perioperative management of MIBC. Various studies evaluated the addition of ICIs to standard chemotherapy, demonstrating promising results in terms of pathological complete response. In parallel, the encouraging outcomes with ICIs and ADCs alone in the neoadjuvant or adjuvant setting paved the way for their combination in integrated strategies. Biomarker-driven approaches, based on circulating tumor DNA and specific genomic alterations, are being actively explored to improve patient selection and personalize treatment. Conclusions: ICIs, ADCs, and targeted therapies are reshaping the therapeutic landscape of MIBC. While early results are promising, further data and biomarker validation are essential to establish their definitive role and guide clinical decision-making in the perioperative setting. Full article

Background: Chemotherapy, targeted therapy and radiotherapy are the cornerstones of cancer treatment. However, therapeutic resistance—not only to these classic modalities but also to novel therapeutics like immune checkpoint inhibitors (ICIs) and antibody-drug conjugates—remains a major hurdle. Resistance significantly limits efficacy and increases recurrence rates. A deep understanding of the molecular mechanisms driving this resistance is critical for developing personalized therapeutic strategies and improving patient outcomes. Recent Advances: Patient-derived cancer organoids have emerged as a powerful preclinical platform that faithfully recapitulates the genetic, phenotypic, and histological characteristics of original tumors. Consequently, PDOs are being widely utilized to evaluate drug responses, investigate resistance mechanisms, and discover novel therapeutic targets for a range of therapies. Limitations: While organoid models have been instrumental in studying resistance, significant limitations persist. First, standard organoid-only models lack key tumor microenvironment components, such as immune cells, limiting immunotherapy research. Second, there is a significant lack of research on acquired resistance, particularly in lung cancer. This gap is largely driven by the clinical infeasibility of rebiopsy in patients with progressive diseases. Third, the absence of standardized protocols for generating and validating resistance models hinders reproducibility and complicates clinical translation. Conclusions: This review summarizes recent advances in using organoid models to study resistance to chemotherapy, radiotherapy, and novel therapeutics (ICIs and ADCs). We emphasize the critical need for standardization in resistance organoid research. We also propose future directions to overcome existing challenges, including the integration of co-culture systems (to include the TME) and advanced technologies (e.g., scRNA-seq, Spatial Transcriptomics). Our specific focus is on advancing lung cancer resistance modeling to enable functional precision medicine. Full article

The limited efficacy of cytotoxic chemotherapy in the context of gastric cancer treatment is largely driven by profound molecular and biological heterogeneity. In contrast, the development of antibody-mediated therapies has ushered in a new era of precision oncology by enabling selective molecular targeting and immune modulation. This review includes a comprehensive overview of the evolution of antibody-based therapeutics in gastric cancer, highlighting early breakthroughs, subsequent setbacks, and recent advances that have reshaped the treatment landscape. We summarize the current standard regimens targeting HER2, VEGFR2, PD-1/PD-L1, and CLDN18.2 and examine pivotal clinical trials evaluating monoclonal antibodies directed against these pathways. We also discuss emerging therapeutic modalities, including next-generation antibody–drug conjugates (ADCs), bispecific antibodies, and chimeric antigen receptor (CAR) T-cell therapies. Trastuzumab first established HER2-targeted therapy in gastric cancer, but the failure of trastuzumab emtansine (T-DM1) led to a decade-long stagnation until the advent of trastuzumab deruxtecan (T-DXd), which demonstrated robust clinical activity and defined a new standard of care. While bevacizumab failed to improve survival, the anti-VEGFR2 antibody ramucirumab emerged as an effective second-line therapy. Immune checkpoint inhibitors, including nivolumab and pembrolizumab, have been incorporated into first-line treatment for PD-L1-positive disease based on landmark trials such as CheckMate 649 and KEYNOTE-811. More recently, the CLDN18.2-targeted antibody zolbetuximab has expanded therapeutic options for biomarker-selected patients. Concurrently, a diverse pipeline of immune-based strategies—such as TROP2-directed ADCs, bispecific antibodies, and CAR-T cell therapies—is undergoing active clinical development. Together, advances in biomarker-driven antibody therapeutics are accelerating personalized cancer care and improving clinical outcomes in patients with gastric cancer. Full article

Breast cancer is the most common cancer and the most important cause of cancer-related death in females worldwide. Antibody–drug conjugates (ADCs) represent a novel class of targeted therapies that combine the precision of monoclonal antibodies with the potent cell-killing activity of cytotoxic drugs. This review highlights recent mechanistic, technological, and clinical developments of ADCs in breast cancer, including next-generation ADCs beyond those that target HER2 (human epidermal growth factor receptor 2). Authors performed a systematic literature study for ADCs and their structural features, including their components (antibody, linker, and payload) and their therapeutic efficacy. A frame of preclinical research findings and clinical evidence integration of HER2-targeted therapy outcomes in HER2-positive, HER2-low, and triple-negative breast cancer (TNBC) subtypes were presented. Clinical studies of antibody–drug conjugates such as trastuzumab emtansine (T-DM1), trastuzumab deruxtecan (T-DXd), and sacituzumab govitecan have demonstrated significant improvements in progression-free survival and overall survival across diverse breast cancer patient populations. ADCs offer unique advantages in breast cancer therapy by combining the precision of targeted antibodies with the potency of chemotherapy drugs. This allows them to selectively kill cancer cells, overcome resistance, reduce toxicity to healthy tissues, and expand treatment options for difficult subtypes like HER2-low and triple-negative breast cancer. Unlike previous reviews focusing on HER2-targeted ADCs, herein we review exciting ADCs targeting HER3 HER3 (human epidermal growth factor receptor 3) and Nectin-4, as well as the implications of bispecific and immune-stimulatory ADCs in the clinic. Additionally, it features mechanism-based innovations and novel trial data that revolutionize ADC applications in the HER2-low as well as the triple-negative breast cancer subtypes. The advent of ADC is changing precision oncology in breast cancer. With a new design and indications evolving, they are an attractive avenue for bypassing resistance and reducing toxicity and ultimately improving patient outcomes in the molecular subtypes. The present review summarizes recent advancements in antibody–drug conjugates (ADCs) and emerging targeted therapeutic strategies for breast cancer. It covers mechanistic insights, linker–payload innovations, receptor-based targeting approaches, clinical trial progress, and next-generation modalities that extend beyond HER2-directed ADCs. Current challenges, safety profiles, and future opportunities in engineering more selective and effective ADC platforms are also discussed. Full article

Antibody–drug conjugates (ADCs) are a potent class of targeted cancer therapies that combine the specificity of monoclonal antibodies with the cytotoxic potency of chemotherapeutic agents. By targeting tumor cells with minimal impact on healthy tissues, ADCs achieve a favorable balance between efficacy and systemic toxicity. This therapeutic modality has demonstrated significant clinical success, as evidenced by the FDA approval of 15 ADCs by 2025, with one later withdrawn due to safety concerns, and indications continuing to expand across various cancer types. Beyond monotherapy, there is growing interest in ADC-based combination strategies aimed at enhancing therapeutic outcomes and managing resistance. Several combinations, especially with chemotherapy, immune checkpoint inhibitors, or molecularly targeted agents, have gained regulatory approval or advanced to late-stage clinical trials. While dual-agent regimens have historically dominated the research landscape, multiplet combinations are also gaining traction and represent a promising frontier in oncology. This evolving paradigm highlights the need for a comprehensive understanding of current ADC combination approaches. In this review, we examine recent clinical advances in ADC-based combinations, with a particular focus on regimens that incorporate FDA-approved ADCs. We also discuss the progression from dual-agent approaches to more complex multiplet strategies across a range of tumor types. Full article

Background/Objectives: The treatment of ovarian cancer (OC), which is predominantly diagnosed in advanced stages, poses a significant challenge to modern gynecologic oncology practice. A significant proportion of patients exhibit chemoresistance, underscoring the need for novel therapeutic interventions. This challenge is further compounded by the immunogenic nature of this neoplasm, prompting the exploration of alternative therapies. A notable example is the use of trastuzumab-deruxtecan (T-DXd), an antibody-drug conjugate (ADC), that has demonstrated encouraging outcomes in preliminary studies and has the potential to become a new treatment option. This systematic review aims to prove that. Methods: The Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) structure was employed to systematically search the PubMed and Scopus databases from December 2024. Furthermore, authors employed materials from the FDA’s official website and registry of clinical trials that are currently recruiting participants for T-DXd’s studies. Eligible studies included randomized controlled trials and observational studies assessing T-DXd in patients with OC. Outcomes of interest were objective response rate (ORR), median overall survival, adverse effects, and progression-free survival. Data was synthesized narratively. Results: Following a thorough review of available literature, 30 scientific papers were selected for inclusion. A total of 598 patients participated in clinical trials. The most common adverse effects were blurred vision and nausea, generally manageable. The risk of bias was low in most studies. Conclusions: T-DXd shows promising efficacy. A comparison of T-DXd with the ADC currently approved for OC therapy reveals that both demonstrate similar median overall survival and ORRs. However, the drug has exhibited significant adverse effects in breast cancer trials and has been studied on a relatively small number of patients. Therefore, further clinical trials focusing on OC patients are necessary to better assess the safety and efficacy of T-DXd in this population. Full article