搜索结果：Journal of experimental & clinical cancer research : CR

Cancer-associated fibroblasts (CAFs) are important contributors to malignant progression in bladder cancer (BLCA), yet the mechanisms by which they promote tumor progression remain incompletely understood. In this study, we integrated patient-derived CAFs with bulk and single-cell transcriptomics, spatial transcriptomics, and multi-cohort clinical datasets to systematically define the molecular mechanisms underlying CAF-driven BLCA progression. Integrated analyses of bulk RNA sequencing, single-cell transcriptomics, spatial transcriptomics, immunohistochemistry, and multiplex immunofluorescence of paraffin-embedded tissues, together with PCR, immunoblotting, and immunofluorescence in patient-derived normal fibroblasts and CAFs, consistently demonstrated marked enrichment of NOTCH3 in CAFs in bladder cancer. Silencing of NOTCH3 attenuated extracellular matrix deposition, contractile capacity, intracellular ROS accumulation, and the ability of CAFs to support tumor growth. Mechanistically, TGF-β induced NOTCH3 transcription through SMAD2 binding to the NOTCH3 promoter. In turn, NOTCH3 recruited HSPA8 to promote K48-linked ubiquitination and proteasomal degradation of P62, thereby suppressing the P62-NRF2 antioxidant pathway and sustaining intracellular ROS accumulation. Restoration of P62 expression or pharmacological scavenging of ROS effectively reversed NOTCH3-driven myofibroblastic differentiation and stromal support of tumor growth. In vivo, CAF-specific deletion of NOTCH3 significantly inhibited tumor growth, reduced collagen deposition, and attenuated stromal remodeling in both subcutaneous and orthotopic bladder cancer models. Collectively, these findings identify CAF-intrinsic NOTCH3 as important regulator of myofibroblastic differentiation through integration of upstream TGF-β signaling with redox and proteostatic control, highlighting stromal NOTCH3 as a potential therapeutic target to limit malignant progression in BLCA.

Management of locally advanced rectal cancer (LARC) increasingly highlights necessity of organ functionality preservation, with the achievement of a complete clinical or pathological response (CR) regarded as a fundamental treatment target. While established concurrent chemoradiation (CRT) is effective, it often results in only modest complete response rates, thus prompting exploration into the possible benefits of raising radiation dosages to boost clinical results. This meta-analysis of randomized controlled trials sought to elucidate whether dose-escalated neoadjuvant CRT augments tumor response and to evaluate its accompanying toxicity profile. By extracting data from 12 trials encompassing 1,803 patients, we discerned that the overall effect on a composite CR endpoint-incorporating both pathological and clinical complete responses-did not achieve statistical significance (RR 1.26, 95% CI: 0.95-1.68). Notably, the subgroup evaluation showed that in clinical trials with a uniform chemotherapy strategy for both control and experimental populations, raising the dosage led to an elevation in CR rates which was not statistically significant (RR 1.46, 95% CI: 1.00-2.12). Conversely, studies that altered concurrent chemotherapy did not show these benefits. Also, the assessment showed that raised radiation doses did not independently result in a marked rise in severe acute toxicity (RR 0.92, 95% CI: 0.53 - 1.59); instead, the gravity of toxicity appeared to be more directly associated with the chemotherapy methods used. These findings suggest that increasing radiation dose may modestly enhance tumor response in LARC. This technique corresponds with the progressing framework towards preserving organ function in rectal cancer.

Effective time-limited therapies remain an unmet need in chronic lymphocytic leukaemia (CLL). We evaluated a novel regimen combining ibrutinib with intermittent fludarabine, cyclophosphamide, and rituximab (FCR) in patients with CLL. This single-arm, multicentre, phase 2 trial was conducted at three centres in China. Eligible participants were adults (aged 18-65 years) with previously untreated CLL requiring therapy according to the International Workshop on Chronic Lymphocytic Leukaemia criteria. The regimen consisted of ibrutinib (420 mg daily) combined with three cycles of FCR administered on days 1-3 of cycles 1, 5, and 9. After the completion of induction therapy, among patients who had achieved complete remission (CR) with undetectable minimal residual disease (uMRD): those without TP53 deletion or mutation could discontinue treatment; those with TP53 deletion or mutation continued maintenance therapy for 6 months before discontinuing treatment; all other patients continued ibrutinib until they achieved CR-uMRD, followed by an additional 6 months of treatment. The primary endpoint was CR rate at best response. This trial is registered with ClinicalTrials.gov, NCT03980002. Between June 1, 2019, and July 30, 2023, 50 patients were enrolled with a median follow-up of 55 months (IQR 40-65). The median age of participants was 57 years (IQR 48-62), and 36 (72%) were male. Among 47 patients with available IGHV data, 18 (38%) had unmutated IGHV. TP53 deletion/mutation were present in four (8%) patients. The CR rate, the primary outcome, was 70% (35/50) at best response. 18 patients (36%) achieved CR with undetectable MRD in both bone marrow and peripheral blood, discontinuing treatment post-induction. Four deaths occurred; one due to Richter's transformation, two from COVID-19, and one from cerebral infarction. Grade 3/4 neutropenia occurred in 13 (26%) patients, leucopenia in 11 (22%) patients, and lymphocytopenia in 12 (24%) patients. No therapy-related cases of myelodysplastic syndrome or acute myeloid leukaemia were observed. This regimen achieved deep remissions with manageable toxicity. Whilst acknowledging study limitations and that pathway inhibitors are the current standard of care, these findings provide proof-of-principle that this regimen could be a feasible, time-limited treatment option for CLL. Particularly in resource-limited healthcare systems where continuous novel agents are less accessible. Future studies should explore long-term durability beyond 5 years and validate MRD thresholds for treatment cessation. National Nature Science Foundation of China, the Chinese Academy of Medical Sciences Innovation Fund for Medical Sciences, and Beijing Xisike Clinical Oncology Research Foundation.

BACKGROUND: Bladder cancer (BC) remains a major clinical challenge owing to its high recurrence, limited treatment options, and molecular heterogeneity. Despite recent therapeutic advances, prognosis remains poor and resistance to treatment is common, underscoring the need for improved experimental models to study tumorigenesis and therapeutic response. A critical obstacle in advanced BC research is the scarcity of in vivo models that accurately replicate invasive and metastatic behavior and serve as robust preclinical tools for evaluating new therapies, especially in immunocompetent settings. METHODS: To assess how the cell of origin and specific driver genes influence bladder tumorigenesis and subtype specification, we engineered four genetically modified mouse models of advanced BC. Two combinations of tumor suppressor genes—either Pten and Trp53, or Pten, Trp53, Rb1, and Rbl1— were targeted either basal or suprabasal urothelial cells via intravesical Cre-adenovirus delivery. From tumors arising in these models, we derived multiple cell lines and established syngeneic graft models. Both genetically engineered mouse models and derived mouse cell lines were extensively characterized and transcriptionally compared with advanced human BC and human BC cell lines, and were further utilized as preclinical platforms to evaluate therapeutic responses. RESULTS: Loss of the retinoblastoma gene family reduced cancer-specific survival and was associated with more differentiated carcinomas. In both genetic backgrounds, luminal-derived tumors appeared earlier but displayed fewer metastatic events. Histopathological and transcriptomic analyses revealed that these tumors resemble human basal-squamous and stroma-rich subtypes, sharing regulatory networks and activated signaling pathways with human invasive BC. Tumors lacking retinoblastoma family genes exhibited enhanced immune infiltration, reinforcing their value for diverse preclinical applications. To overcome detection and latency limitations, we established syngeneic graft models from tumor-derived cell lines. These models were validated as preclinical platforms, exhibiting therapeutic responses to CDK4/6 inhibition and anti-PD-L1 immunotherapy. CONCLUSIONS: These novel mouse models faithfully recapitulate key molecular, histological, and immune features of human invasive BC. They represent versatile and clinically relevant preclinical models for dissecting disease progression mechanisms and evaluating emerging therapeutic strategies within an intact immune environment.

Pancreatic ductal adenocarcinoma (PDAC) is often driven by KRAS mutations, but inhibitors targeting the most frequent KRAS substitutions in PDAC are not yet approved in the clinic. We previously discovered that KRAS-mutant PDAC is sensitive to the combination of SHP2 and ERK inhibitors, recently investigated in the Phase I/Ib clinical trial NCT04916236. Lately, RAS(ON) multi-selective inhibitors have entered clinical development, representing a promise for mono or combination therapies in PDAC. However, resistance may arise even for combination therapies. Here, we aimed at anticipating mechanisms of resistance to SHP2 plus ERK or RAS(ON) multi-selective inhibitors. We performed a genome-wide CRISPR-KO screening, followed by four follow-up focused screenings, leading to the identification of resistance mediators, which were further validated through functional genetic and pharmacological experiments, both in vitro and in vivo. Through unbiased CRISPR-based screenings, we identified mTOR and JUN hyperactivation as interconnected mechanisms that overcome MAPK suppression. Further investigation pointed at JUN as the most downstream resistance mediator, and indirect therapeutic target, using MAP2K4 inhibitors. Alterations in the PI3K/AKT/mTOR and JUN pathways can induce resistance to multiple combinations of MAPK pathway inhibitors, and may serve as biomarkers for sensitivity/resistance in clinical trials exploring such combinations in KRAS-mutant PDAC.

Metastatic colorectal cancer (CRC) harboring KRAS mutations presents a major therapeutic challenge due to its aggressive nature, poor prognosis, and resistance to EGFR-targeted therapies. This study aimed to identify novel drivers of metastasis specifically in KRAS-mutant CRC and to elucidate the underlying molecular mechanisms to undercover new therapeutic vulnerabilities. We integrated data from clinical databases (TCGA, CPTAC) with experimental validation using human CRC cell lines, a tissue microarray, and two distinct in vivo metastasis models (liver and lung colonization). ZBTB20 expression and function were analyzed by IHC, Western blotting, Transwell assays, and RNA-seq integrated with ChIP-seq data. The mechanism of ZBTB20 regulation was investigated via co-immunoprecipitation, mass spectrometry, truncation analysis, site-directed mutagenesis, and luciferase reporter assays. Statistical significance was determined using Student's t-tests, ANOVA, and survival analysis. ZBTB20 expression was significantly upregulated with metastatic progression specifically in KRAS-mutant CRC patients and correlated with reduced overall survival. Functionally, ZBTB20 promoted CRC cell migration, invasion, EMT in vitro, and drove metastatic colonization in vivo. Mechanistically, KRAS/ERK signaling directly phosphorylated ZBTB20 at Threonine 138, 142, and 232, a step essential for its nuclear localization and pro-metastatic activity. Integrating transcriptomic and cistromic data, we identified TGFBR2 as a direct transcriptional target of activated ZBTB20. Notably, pharmacological degradation of TGFBR2 with the inhibitor ITD-1 potently abrogated metastatic outgrowth in both liver and lung colonization models. Our findings delineate a novel KRAS-ERK-ZBTB20-TGFBR2 signaling axis that is a critical driver of metastasis colonization in KRAS-mutant CRC. The robust efficacy of a TGFBR2 degrader in multiple in vivo models validates this axis as a viable therapeutic target, offering a promising strategy to inhibit metastatic progression in patients with this aggressive disease.

Colorectal cancer (CRC) remains a major cause of cancer-related morbidity and mortality worldwide, highlighting the need for safer and more effective therapeutic agents. This study investigated the potential anticancer compounds and mechanisms of Paris polyphylla against CRC using an integrated approach combining network pharmacology, molecular docking, and in vitro validation. Bioactive compounds were screened from multiple databases, and their putative targets were intersected with CRC-related genes. Protein-protein interaction and enrichment analyses were performed to identify key targets and pathways, followed by the docking of selected compounds with major hub proteins. The cytotoxic and molecular effects of P. polyphylla rhizome extract (PPRE) were then evaluated in SW480 and HCT116 cells. A total of 74 compounds were identified, of which 12 were retained for target prediction, yielding 180 overlapping genes between P. polyphylla targets and CRC-associated genes. Network analysis highlighted STAT3, EGFR, SRC, IL-6, and AKT1 as key hub targets, with enrichment in cancer-related, EGFR resistance, and PI3K-Akt pathways. Docking showed favorable binding affinities, particularly between prosapogenin A and AKT1. Experimentally, PPRE reduced CRC cell viability and downregulated STAT3, EGFR, SRC, IL-6, and AKT1 expression. These findings suggest that P. polyphylla exerts anticancer effects through the coordinated modulation of multiple oncogenic pathways in CRC.

INTRODUCTION: Mycobacterium tuberculosis infection might result in fatal outcome in patients with haematologic malignancies or those with primary or iatrogenic immunodefects. However, in countries with low tuberculosis (TB) incidence the awareness for TB is still challenging, with an increasing need due to migrating populations from regions with high TB to low TB incidence countries. CASE REPORT AND EPIDEMIOLOGICAL ANALYSIS: A 52-year-old caucasian female, refugee from Afghanistan, presented at University Hospital Charité (Berlin, Germany) with progressive left-sided hearing loss due to ear canal obstruction as well as right axillary exophytic and ulcerating skin lesions, finally diagnosed as BRAF-V600E-mutated Langerhans cell histiocytosis (LCH). Following systemic chemotherapy, LCH showed complete remission (CR) with however unexpectedly progressive left-axillary lymphadenopathy. Biopsy of these lymph nodes revealed granulomatous inflammation with central caseous necroses. Mycobacterium tuberculosis DNA was undetectable in a biopsy from the lesion, but culture of fresh re-biopsy material showed growth of M. tuberculosis. Given the patient´s migration history from a high-prevalence (Afghanistan) to a low-prevalence (Germany) TB country, we also present the long-time trend of the total number of TB patients notified in Germany in 2002–2023, i.e. a total of 21 years, aggregated by country of birth. Whereas the number of TB patients born in Germany is decreasing since 2002, the number of patients born abroad exceeded the number of those born in Germany in 2012, and remained higher ever since. CONCLUSION: Our report highlights the challenge to treat patients at the crossroads of malignancy and TB, and the need for appropriate attention and awareness of physicians of the increased TB risk in people migrating from a high- to a low-burden TB country. Also, the case demonstrates once more the high value of culture for diagnosis of mycobacteria infection. CLINICAL TRIAL: Not applicable.

Next-generation sequencing (NGS) is central to precision oncology. However, its implementation in public healthcare systems is limited by economic and logistical barriers. In 2022, the Catalan Institute of Oncology (ICO) launched the PREICO project to expand access to comprehensive genomic profiling (CGP) beyond publicly funded indications across a cancer center network. We analyzed patients with advanced solid tumors, enrolled between February 2022 and March 2024. Molecular results were reviewed by a Molecular Tumor Board (MTB), which issued structured reports to support clinical decision-making. CGP was performed in 249 patients. At least one pathogenic or likely pathogenic alteration was identified in 96.3% of 242 evaluable samples. High tumor mutational burden (TMB ≥10 mut/Mb, TMB-H) was detected in 15.3% and microsatellite instability (MSI) in 1.7%. Overall, 47 tumor-agnostic ESCAT I actionable biomarkers were detected, including MSI, TMB-H, BRAF V600E mutation, and NTRK and FGFR fusions. 25 patients received NGS-matched therapies (10.3% of the cohort; 19% of treated patients), 56% within early-phase clinical trials, and 44% through compassionate use. Objective response rate was 20%, and clinical benefit rate (CR, PR, or SD≥4 months) was 40%. Median progression-free survival and overall survival were 3.3 and 11.4 months, respectively. The PREICO project suggests the feasibility of implementing a centralized CGP prescreening program in a public healthcare setting for tumor types without public NGS access. CGP identified potentially actionable alterations in a substantial proportion of patients across tumor types, informed treatment decisions and facilitated access to clinical trials in selected cases.

This study investigated the effect of Virtual Patient (VP) education on improving Clinical Reasoning (CR) skills among nursing students, addressing a major challenge in nursing education, particularly within the context of an oncology course. This quasi-experimental, two-group, pretest-posttest study was conducted in 2021 at the School of Nursing of Isfahan University of Medical Sciences, Iran. A total of 148 fourth- and fifth-semester nursing students were selected through a census sampling method. After obtaining informed consent, the subjects were randomly assigned to either the intervention or control group. After the pretest, five VPs (cancer module), designed and validated by eight nursing experts, were provided to the intervention group for 6 weeks, followed by a posttest. Data collection tools included two series of 23-item tests (KF) designed to assess CR skills, with a CVI = 0.94 and CVR = 0.84. The collected data were analyzed in SPSS software using correlation tests and t-tests. The mean (SD) of pretest scores was 25.01 (2.51) in the intervention group and 25.03 (2.71) in the control group, with no significant difference (p > 0.05). After training, posttest scores increased significantly in the intervention group, 32.22 (3.47), compared to the control group, 25.18 (2.47) (p ≤ 0.05). The intervention group showed significant improvement from pretest to posttest (p ≤ 0.05). The use of VPs in nursing education can effectively improve students CR skills and provide a foundation for enhancing nursing education.

CDK4 alterations are common in lung adenocarcinoma, but recent clinical trials only demonstrated modest therapeutic responses to CDK4/6 inhibitors. The mechanism of CDK4/6 inhibitor resistance has not been fully characterized. Patient-derived organoids and cell lines were tested for their sensitivity to CDK4/6 inhibitors. The drug resistance mechanism relating to stemness pathway was tested by in-vitro and in-vivo assays. Screening of small molecule library was performed to explore potential therapeutic agents that could potentiate the efficacy of CDK4/6 inhibitors. CDK4/6 inhibitors could inhibit the growth of lung adenocarcinoma patient-derived organoids and cell lines, and its drug resistance was associated with HES1 overexpression. We identified the vital role of HES1 in promoting cancer cell stemness through SOX9 upregulation via the phosphorylation of transcription factor STAT3. Inhibition of HES1 impaired lung cancer spheroid formation, reduced stemness marker expression, and enhanced the sensitivity of the spheroids towards the CDK4/6 inhibitor palbociclib. Knockdown of SOX9 recapitulated the functional effect of HES1 inhibition, confirming its role as a downstream effector mediating the stemness properties of lung cancer cells. Screening of small molecules revealed VR23 as a potent HES1 inhibitor, and it could suppress lung cancer growth and patient-derived organoids in a synergistic manner with palbociclib in-vitro and in-vivo. Moreover, the pSTAT3 inhibitor napabucasin could also afford synergy with palbociclib as well, further confirming the therapeutic vulnerability conferred by the HES1-pSTAT3-SOX9 pathway in potentiating CDK4/6 inhibitors. Our findings revealed a signalling pathway in which lung adenocarcinoma regulates stemness and tumourigenesis through HES1, and the targeting of this pathway by VR23 or napabucasin supports further preclinical development for CDK4/6 inhibitor combination therapy.

Both the nervous system and cancer-intrinsic neural features can govern cancer initiation, growth, progression, metastasis, and treatment resistance, while cancer can likewise influence the nervous system, promoting neural reprogramming and neuropsychiatric symptoms that worsen patient outcomes. The field of cancer neuroscience seeks to unravel this complex neuro-cancer crosstalk and holds the promise to develop neuroscience-instructed cancer therapies that improve disease control and quality of life. Here, we summarize the key discoveries of neuro-cancer crosstalk to date, including neuron-to-cancer synapses and paracrine and neuro-immuno-oncological interactions, and then explore emerging topics such as downstream effects on cancer cell pathophysiology, circadian influences, brain-body-cancer communication, and neural regulation of the metastatic cascade and the tumor microenvironment. Finally, we distill overarching principles, highlight relevant ongoing research, and outline conclusions to guide the development of cancer neuroscience, proposing hypotheses for future experimental validation.

BackgroundDespite intensive therapies, outcomes for high-risk pediatric brain tumors (PBTs) remain dismal, prompting the search for novel treatments. DNA methyltransferase inhibitors (DNMTi) have been shown to prime tumors to improve response to checkpoint inhibition. The aim of this study was to investigate the potential of decitabine (DAC), in combination with a PD-1 inhibitor, to improve survival in pediatric high-risk brain tumor models. Analysis of human PBT datasets was performed to determine gene expression levels of immune cell markers. Tumor response to DAC, with or without a PD-1 inhibitor, was tested in murine models representing H3-wildtype diffuse intrinsic pontine glioma (DIPG), H3K27-mutant diffuse midline glioma (DMG), atypical teratoid rhabdoid tumor (ATRT), and medulloblastoma (MB). CyTOF analysis of allograft tumors was performed to characterize changes within the tumor microenvironment. Analysis of PBT subtypes revealed heterogeneous expression of immune cell markers, checkpoint receptors, and MHC molecules. DAC treatment decreased DNA methylation and increased neoantigen expression in human and mouse tumor cells. DAC treatment resulted in prolonged survival in syngeneic mouse models of DIPG and ATRT but not DMG and MB models. However, no added survival benefit was observed when combined with a PD-1 inhibitor. CyTOF analysis of mouse tumors revealed changes in local immune cell infiltration. DAC alone or in combination with a checkpoint inhibitor can alter the immune microenvironment in mouse tumor models. Changes were observed in H3-wildtype DIPG and ATRT models, suggesting that certain tumor subtypes may respond to immune priming with DNMTi.

The high clinical recurrence rate of colorectal cancer (CRC) is driven by the survival of residual tumor cells that evade therapy-induced death by entering a dormant state. While dormancy is a recognized mechanism of treatment resistance, the molecular drivers governing this "quiescent reservoir" and its associated vulnerabilities remain poorly characterized, limiting the development of strategies to eradicate these dormant seeds. We developed a COAD-specific Dormancy Score (CADS) derived from NMF analysis of ~ 69,000 single cells to quantify and identify a dormant subpopulation at single-cell resolution. Mechanistically, the IFN-β/cDC1 axis and its downstream MEK/ERK dependency were validated using a GFP-p27K- dormancy reporter system, spatial transcriptomics, and CRISPR/Cas9-mediated Ifnar1 knockdown. Finally, the synergistic efficacy of anti-PD-1 combined with MEK inhibition (Trametinib) was evaluated in orthotopic CRC mouse models. The CADS effectively identified a distinct dormant subpopulation in CRC characterized by profound G0/G1 arrest, enhanced stemness, and multi-drug resistance. We uncovered a novel evasion mechanism mediated by the hijacking of IFN-β signaling. Conventionally recognized for its anti-proliferative roles, IFN-β signaling is exploited by surviving tumor cells to enter a deep quiescent state. This phenotype acts as a biological reservoir that fuels intratumoral heterogeneity and underpins the relapse of colorectal tumors by conferring resistance to conventional cytotoxic regimens. Effective anti-PD-1 therapy paradoxically enriches this dormant population via an enhanced IFN-β-conventional type 1 dendritic cell (cDC1) axis. Mechanistically, IFN-β-induced dormancy depends on MEK/ERK pathway activity, which sustains survival while suppressing apoptosis. This creates a synthetic lethal vulnerability: MEK inhibition (e.g., Trametinib) synergizes with IFN-β to re-sensitize dormant cells to apoptosis. Consequently, combining Trametinib with anti-PD-1 therapy overcomes this evasion mechanism, eliminates the dormant subpopulation, remodels the immune microenvironment, and shows strong synergistic efficacy in preclinical models. Our work redefines an immune-cell death paradox, revealing how tumors exploit IFN-β to evade therapy. We propose CADS as a translational biomarker for identifying tumors reliant on this pathway and validate a mechanism-based combination therapy that selectively targets dormancy-associated death resistance, offering a promising strategy to improve CRC outcomes.

Papillary thyroid carcinoma (PTC) undergoes dedifferentiation into aggressive poorly differentiated (PDTC) or anaplastic (ATC) carcinomas in 10–15% of cases, a process potentially driven by cancer-associated fibroblasts (CAFs) within the tumor microenvironment (TME), though their spatiotemporal dynamics remain poorly understood. Resveratrol (Res), a natural compound, has shown anticancer potential by promoting redifferentiation and apoptosis while inhibiting oncogenic signaling, suggesting utility in countering PTC dedifferentiation. Using spatial transcriptomics (10× Visium) on three surgical specimens, we obtained 14,191 high-quality spots annotated via UMAP and Leiden clustering into seven cell types, including CAFs, T cells, B cells, and others. Comparative gene expression and functional enrichment analyses revealed CAFs in poorly differentiated regions exhibited heightened glycolytic activity, correlated with ZFP57 upregulation and PKM2 induction. Glycolysis was validated through immunofluorescence, Seahorse assays, glucose/lactate measurements, and ZFP57-PKM2 reporter assays. CAF-conditioned media promoted PTC proliferation, invasion, and dedifferentiation while reducing radioiodine uptake in co-culture models. In xenografts, ZFP57 overexpression increased tumor growth and impaired radioiodine retention, whereas Res suppressed ZFP57, restored differentiation, enhanced radioiodine avidity, and inhibited glycolysis. Mechanistically, CAF-secretated lactate activated TGF-β/Smad2/3 signaling, fostering dedifferentiation and malignancy. Resveratrol reversed these effects by targeting ZFP57, normalizing CAF metabolism, and restoring PTC differentiation, indicating a promising therapeutic strategy against PTC progression.

This Phase I/II clinical trial (NCT04471064) evaluated the preliminary efficacy, safety, and pharmacokinetics of XY0206, a novel oral FMS-like tyrosine kinase 3 (FLT3) inhibitor, in patients with relapsed or refractory acute myeloid leukemia (R/R AML). From September 2020 to December 2022, this open-label, multicenter study enrolled patients aged ≥ 18 years with R/R AML. The trial included dose-escalation and dose-expansion phases, with six cohorts receiving XY0206 at doses ranging from 12.5 to 62.5 mg once daily or 25 mg twice daily. Of the 61 enrolled participants, 37 had FLT3 mutation-positive (FLT3mut+) AML. The overall response rate (ORR) was 34.4% in the entire cohort and 48.6% in FLT3mut+ patients. Among FLT3mut+ patients, the composite complete remission rate (CRc) was 45.9%, including a complete remission (CR) rate of 5.4% and a CR with partial hematologic recovery (CRh) rate of 13.5% and a CR with incomplete hematologic recovery (CRi) rate of 27.0%. In patients with FLT3 internal tandem duplication (FLT3-ITD) mutations, the ORR was 56.7%, with a CRc of 53.3% (CR: 6.7%; CRh: 16.7% ; CRi: 30.0%). The 37.5 mg dose cohort, identified as the target dose, was expanded exclusively for FLT3mut+ patients. XY0206 exhibited a favorable safety profile and demonstrated potent antileukemic activity, particularly in FLT3mut+ R/R AML patients, supporting its further clinical development. Trial Registration: CTR20201214 (CDE); ClinicalTrials.gov ID: NCT04471064.

Bulevirtide 2 mg/day is approved in Europe, Australia, Russia, and Canada for treatment of compensated chronic hepatitis D (CHD). However, long-term outcomes after treatment discontinuation are unknown. Patients with CHD (n=150) were randomized to immediate treatment with bulevirtide 2 mg/day (n=49) or 10 mg/day (n=50) for 144 weeks (W), or 48W of delayed treatment (DT; n=51) followed by bulevirtide 10 mg/day for 96W (DT/10 mg; n=50), and 96W of posttreatment follow-up (FU96) in the MYR301 study. Efficacy endpoints included virologic response (VR; undetectable hepatitis D virus [HDV] RNA or ≥2 log10 IU/mL decline from baseline), combined response (CR; VR and alanine aminotransferase [ALT] normalization), ALT normalization, and undetectable HDV RNA. At the end of treatment (EOT), response rates in the 2, 10, and DT/10 mg groups were: VR, 73%, 76%, and 92%; ALT normalization, 59%, 60%, and 58%; CR, 57%, 54%, and 56%; HDV RNA undetectability, 29%, 50%, and 52%. At FU96, VR rates declined to 33%, 30%, and 32%, respectively; CR rates were 24% across all groups. HDV RNA undetectability rates were 20%, 22%, and 20% at FU96. Sustained undetectability through follow-up was observed in 23/64 (36%) patients with undetectable HDV RNA at EOT, with weeks continuously undetectable at EOT being the most important predictor of sustained undetectability. Posttreatment hepatic serious adverse events occurred in 20/142 (14%) patients and resolved in 17/20 (85%). Bulevirtide treatment for CHD for up to 144W was safe and effective. Response rates decreased after treatment discontinuation; however, some patients had sustained undetectable HDV RNA throughout 2 years of follow-up. (Funded by Gilead Sciences; MYR301 ClinicalTrials.gov number, NCT03852719). Although bulevirtide is approved for treatment of chronic hepatitis D (CHD) in the European Economic Area, the United Kingdom, Switzerland, the Russian Federation, Australia, and Canada, treatment outcomes beyond 2 years and after bulevirtide discontinuation remain unknown. In this analysis, we demonstrate that efficacy was maintained with bulevirtide monotherapy for up to 144 weeks compared with that at 96 weeks, while rates of HDV RNA undetectability continued to improve with extended treatment duration. Virologic and biochemical responses decreased after treatment discontinuation, but some patients who were undetectable at EOT maintained HDV RNA undetectability posttreatment, with duration of continuous HDV RNA undetectability at EOT being the strongest predictor of non-relapse. While most patients benefit from continued bulevirtide therapy, a subset of those who achieve undetectable HDV RNA may be able to discontinue treatment without loss of response even in the absence of HBsAg loss. NCT03852719.

Prostate cancer, particularly metastatic castration-resistant prostate cancer (mCRPC), presents therapeutic challenges rooted in adaptive lineage plasticity and neuroendocrine transdifferentiation. Conventional genome-based models fail to account for the divergent clinical trajectories observed among tumors that share identical driver mutations. This limitation requires reconceptualizing cancer as a dynamic system in which tumor cells can execute context-dependent molecular programs governed by epigenetic and transcriptional network remodeling. This review critically evaluates three convergent technological pillars reshaping prostate cancer research and clinical care. First, conditional reprogramming (CR) enables the rapid generation of patient-derived models that preserve genomic fidelity, intratumoral heterogeneity, and reversible phenotypic plasticity without genetic manipulation. Second, single-cell and spatial multi-omics approaches have clarified the cellular trajectories underlying luminal-to-neuroendocrine transdifferentiation, identifying a therapeutically actionable intermediate state. They have revealed the hierarchical transcription factor network (FOXA2-NKX2-1-p300/CBP) which orchestrates chromatin remodeling during this lethal transition. Third, physics-informed machine learning and digital twin architectures aim to move beyond correlative risk prediction toward mechanistically sound forecasting of tumor evolution, treatment response, and resistance emergence. We address unresolved challenges in prospective clinical validation, spatial heterogeneity capture, regulatory pathways for functional diagnostics, and the imperative for causal, as opposed to associative, inference from perturbational datasets. The integration of these three domains through closed-loop experimental-computational feedback cycles represents a paradigm shift from reactive to anticipatory precision oncology.

BACKGROUND: Checkpoint inhibitors targeting PD-1 and PD-L1 have revolutionized cancer immunotherapy; however, their efficacy remains limited in immune-excluded tumors characterized by scarce T-cell infiltration and a profoundly immunosuppressive tumor microenvironment (TME). Activation of the stimulator of interferon genes (STING) pathway represents a promising strategy to overcome immune exclusion by promoting TME remodeling and immune cell recruitment. This study investigated the therapeutic potential of combining 8803, a potent STING agonist with broad cross-species activity, and 27907, a novel Fc-engineered dual-specific antibody targeting PD-L1 and PD-L2, designed to enhance antibody-dependent cytotoxicity and phagocytosis. METHODS: The activity of 8803 was assessed in human and murine STING reporter cell lines and in co-culture systems with tumor, endothelial, and immune cells. The Fc-mediated effector functions of 27907 were characterized through ADCC and ADCP reporter bioassays. Antitumor efficacy was evaluated in B16-PD-L2 melanoma (C57BL/6) and TS/A mammary carcinoma (BALB/c) mouse models treated with intratumoral 8803 and/or systemic 27907. Tumor growth and survival were monitored, and immune and vascular remodeling were analyzed by flow cytometry, immunohistochemistry, and immunofluorescence. Statistical analyses were performed using two-way ANOVA with Bonferroni post-test for tumor growth, Mantel–Cox log-rank test for survival, and unpaired Student’s t-test or one-way ANOVA for in vitro and ex vivo data. RESULTS: The combination of 8803 and 27907 resulted in significant tumor growth inhibition and prolonged survival compared with single-agent treatments. STING activation by 8803 remodeled the TME by reducing intratumoral M2-like macrophages and mature regulatory dendritic cells (mregDCs) while enhancing T-cell and myeloid cell infiltration. It also induced PD-L1 and PD-L2 upregulation on tumor and endothelial cells. The dual-specific antibody 27907 efficiently mediated antibody-dependent cellular cytotoxicity and phagocytosis, leading to selective endothelial cell killing, vascular disruption, extensive necrosis, and enhanced immune infiltration in the combination treatment group. CONCLUSIONS: Dual PD-L1/PD-L2 blockade synergizes with STING pathway activation to promote immune and vascular remodeling, resulting in superior antitumor efficacy in preclinical tumor models. These findings provide a strong rationale for the clinical development of combination strategies that integrate STING agonists with cytotoxic checkpoint antibodies to overcome immune exclusion and enhance cancer immunotherapy outcomes.