Cancer Science最新文献

Immune checkpoint inhibitors (ICIs) have revolutionized the treatment of advanced renal cell carcinoma (RCC). However, ICIs often induce immune-related adverse events (irAEs), which vary greatly among individuals and may influence treatment outcomes. This study aimed to identify genetic markers associated with the risk of severe treatment-related adverse events (trAEs) and assess their impact on patient prognosis. From August 19, 2019, to September 30, 2020, patient recruitment for nivolumab treatment in advanced clear cell RCC (ccRCC) was conducted across 23 institutions in Japan, with follow-up concluding on March 31, 2021 (protocol ID: UMIN000037739). A genome-wide association study (GWAS) was conducted in a development cohort to identify single nucleotide polymorphisms (SNPs) associated with severe trAEs following nivolumab. Sixteen SNPs were identified, and thirteen were genotyped in a validation cohort. Eight SNPs showed consistent trends with the development cohort, but they have not reached statistical significance in the validation cohort. Among them, rs2545737, corresponding to CHD1, was significantly linked to prolonged progression-free survival (PFS), highlighting its potential as a biomarker for both safety and efficacy. Further analysis indicated that high CHD1 expression in tumors correlated with improved overall survival in nivolumab-treated patients but not in those receiving everolimus. Given the failure to replicate the development set findings in our validation cohort, further re-validation within the RCC population is warranted. However, these results enhance our understanding of the genetic predisposition to trAEs and provide a significant step toward safer and more effective cancer treatment strategies. This study was registered on the University Hospital Medical Information Network (UMIN) in Japan on August 20, 2019 (protocol ID: UMIN000037739).

Radionuclides such as Rhenium-188 (Re188) hold promise for treating metastatic cancers due to their cytotoxic effects and potential to stimulate systemic anti-tumor immunity. However, mononuclear phagocyte system-mediated clearance of liposome encapsulated Re188 (Lipo-Re188) limits its tumor delivery. This study aimed to enhance the therapeutic effect of Lipo-Re188 against lung metastases through macrophage depletion and immune checkpoint blockade. A lung metastatic colon cancer model was established via intravenous injection of CT26-luciferase cells and then treated with Lipo-Re188 (11.1 MBq, 30% of MTD), liposomal clodronate (Lipo-clod) for macrophage depletion, and/or anti-PD-L1 antibody. Tumor progression was monitored by bioluminescence imaging, and radionuclide biodistribution was assessed at 1, 24, and 48 h post-injection. Flow cytometry was used to assess immune cell populations in the spleen and tumor microenvironment (TME). Cytokine levels were measured using a bead-based multiplex assay and analyzed by flow cytometry. Macrophage depletion significantly enhanced tumor accumulation of Lipo-Re188 while reducing hepatic uptake and prolonging survival. The combination of Lipo-clod and Lipo-Re188 promoted B cells, restored functional T cells, and suppressed MDSC in both spleen and TME. Notably, IL-1α and GM-CSF levels were significantly elevated in the combination group. Triple therapy with Lipo-clod, Lipo-Re188, and anti-PD-L1 provided the greatest survival benefit, highest intratumoral B cell accumulation, and lowest interstitial macrophage levels, with no significant biological toxicity. Our study reveals that triple therapy overcomes immunosuppressive feedback and promotes a tumor-suppressive microenvironment. These findings support a rational combination strategy integrating radiopharmaceutical therapy with immune modulation for metastatic cancer treatment.

T-cell receptor (TCR) bispecific proteins represent a pioneering therapeutic modality that harnesses the diverse target recognition capabilities inherent to TCRs while preserving the beneficial characteristics associated with protein therapeutics. However, investigations into TCR bispecific proteins, particularly within the context of lung diseases, remain limited. This study aims to elucidate their potential for the treatment of lung cancer. We employed a humanized murine model to evaluate the efficacy of TCR bispecific proteins in eradicating lung tumors in vivo. Cytotoxic activity was assessed against various lung cancer cell lines, and statistical tests were used to analyze the data. To address concerns regarding toxic side effects from systemic administration, mesenchymal stem cells (MSCs) were explored as vehicles for the targeted delivery of TCR bispecific proteins. Our findings demonstrate that TCR bispecific proteins exhibit substantial cytotoxic activity against a variety of lung cancer cell lines. MSCs, with optimal pulmonary targeting properties, were shown to persist within the lungs for over 7 days. By employing MSCs to locally secrete TCR bispecific proteins, we achieved therapeutic effects comparable to systemic administration without manifestations of immune overactivation in murine subjects. Additionally, we evaluated various cytokine combinations and discovered that the combination of IL-7, IL-21, and TCR bispecific proteins significantly augmented their capacity to eliminate antigen-negative cells in a heterogeneous tumor model. Collectively, our findings suggest that the combinatorial therapy of TCR bispecific proteins and MSCs holds considerable promise for clinical application in the treatment of lung cancer, potentially enhancing therapeutic efficacy while minimizing adverse effects.

At the first interim analysis of the global, randomized, phase 3, double-blind ADRIATIC trial in patients with limited-stage small-cell lung cancer (LS-SCLC) not progressing after concurrent chemoradiotherapy (cCRT), consolidation durvalumab significantly improved overall survival (OS; hazard ratio [HR] 0.73) and progression-free survival (PFS) by blinded independent central review (BICR; HR 0.76) versus placebo (dual primary endpoints). We report an exploratory analysis in patients enrolled in Japan. Patients received durvalumab 1500 mg (N = 264), durvalumab+tremelimumab 75 mg (4 doses, N = 200; arm remained blinded), or placebo (N = 266) every 4 weeks for ≤ 24 months. Prior cCRT ± prophylactic cranial irradiation (PCI) was per local standards of care. In the Japan subgroup, 19 and 31 patients received durvalumab and placebo, respectively; prior cCRT comprised cisplatin-etoposide/carboplatin-etoposide in 94.7/5.3% and 87.1/12.9% and once-daily/twice-daily radiotherapy in 10.5/89.5% and 0/100%; 52.6% and 58.1% received PCI. Median OS was not reached versus 44.9 months (3-year OS 67.4% versus 58.1%; HR 0.67, 95% CI 0.24–1.62). Median PFS by BICR was 44.2 versus 29.4 months (24-month PFS 59.6% vs. 58.6%; HR 1.05, 95% CI 0.44–2.36); median PFS by investigator assessment (sensitivity analysis) was 44.2 versus 19.7 months (24-month PFS 65.6% vs. 47.0%; HR 0.68, 95% CI 0.28–1.51). With durvalumab and placebo, 21.1% and 19.4% had maximum grade 3–4 adverse events (AEs), 21.1% and 9.7% had AEs leading to treatment discontinuation, and 52.6% and 45.2% had pneumonitis/radiation pneumonitis (grade 3–4: 0% and 6.5%). In conclusion, consolidation durvalumab demonstrated a favorable risk/benefit profile in Japanese patients with LS-SCLC post cCRT.

Trial Registration: ClinicalTrials.gov identifier: NCT03703297.

Choriocarcinoma is a rare gynecologic malignancy. MicroRNAs, which are noncoding RNAs approximately 22 nucleotides in length, are known to regulate gene expression and play important roles in various cancers; however, their functions in choriocarcinoma remain largely unknown. This study aimed to identify disease-specific microRNAs involved in choriocarcinoma development. Eleven cases of choriocarcinoma and five cases of complete hydatidiform mole treated at our institution were analyzed. Total RNA was extracted from trophoblast cells in formalin-fixed, paraffin-embedded specimens using laser capture microdissection, and microRNA sequencing was performed. The analysis revealed that 87 microRNAs were significantly upregulated, whereas 28 were downregulated in choriocarcinoma compared to complete hydatidiform mole. Notably, 13 of the 28 downregulated microRNAs belonged to the chromosome 19 microRNA cluster. In vitro experiments demonstrated that overexpression of miR-517a-3p, a representative member of this cluster, significantly suppressed cell proliferation, migration, and invasion in JEG-3 and BeWo cell lines. Further transcriptome sequencing and computational analysis identified SRSF1 as a target gene of miR-517a-3p, which was validated by dual-luciferase reporter assays. Knockdown of SRSF1 also led to significant reductions in proliferation, migration, and invasion, supporting its functional relevance. Immunohistochemical analysis confirmed that SRSF1 protein was highly expressed in choriocarcinoma tissues compared to complete hydatidiform mole. These findings indicate that downregulation of the chromosome 19 microRNA cluster is a characteristic feature of choriocarcinoma and that miR-517a-3p functions as a tumor suppressor by directly regulating SRSF1 expression.

The development of cervical cancer is strongly associated with persistent high-risk HPV infection. Microbiota and metabolomics offer new perspectives. This article focuses on the role of microbial dysbiosis and metabolic reprogramming in the development of cervical cancer, revealing its synergistic regulation of the tumor immune microenvironment and treatment resistance. Machine learning and multi-omics have identified new biomarkers, while treatment strategies include microbiota modulation, metabolic targeting, and combination therapies. Despite limitations such as small sample size and unclear mechanisms, this review proposes a multi-target precision medicine framework. In the future, we should focus on multi-center and multi-omics research and optimized clinical trials.

Antibacterial quinolones are widely used to treat bacterial infections in humans. They inhibit bacterial DNA gyrase and topoisomerase IV, whose analogous enzymes are present in mammalian mitochondria. Quinolones inhibit mitochondrial topoisomerases, thereby leading to mitochondrial DNA (mtDNA) replication suppression and cancer cell death. Meanwhile, high concentrations of quinolones are required to induce cancer cell death, possibly owing to poor delivery to the mitochondria. In this study, we synthesized nalidixic acid (NA) and ciprofloxacin (CFX) conjugated with the mitochondria-targeting moiety triphenylphosphonium (TPP), NX–TPP and CFX–TPP, to enhance mitochondrial delivery and examined their anticancer efficacy. NX–TPP and CFX–TPP markedly reduced the antibacterial activity, although CFX–TPP was more active than NX–TPP. However, both NX–TPP and CFX–TPP significantly induced cell death in colon HT-29, pancreatic MIAPaCa-2, and other cancer cells but not in non-cancerous cells including normal dermal fibroblasts and human vascular endothelial cells at a comparative level. NX–TPP induced necrosis-like cell death characterized by cell membrane ballooning and rupture. Mechanistically, NX–TPP was efficiently incorporated into the mitochondria, leading to increased mitochondrial reaction oxygen species (mtROS) generation and mitophagy, and decreased mtDNA copy number and mitochondrial respiration. NX–TPP inhibited tumor growth in HT-29 and MIAPaCa-2 xenograft mouse models without any apparent adverse effects. These results suggest that mtDNA replication-targeting quinolone derivatives, termed MitoQNs, that exhibit reduced antibacterial activity, thereby decreasing antibiotic resistance induction, and enhanced anticancer efficacy, are candidate drugs for cancer therapy.

Despite advances in androgen receptor signaling inhibitors (ARSIs) and poly (ADP-ribose) polymerase inhibitors (PARPIs), metastatic castration-resistant prostate cancer (mCRPC) remains lethal. PARPIs clinical efficacy is limited in patients with homologous recombination repair deficiencies, such as BRCA1/2 mutations, due to resistance. Thus, identifying novel synthetic lethal interactions with PARP may expand treatment options and improve therapeutic efficacy. Here, to identify genes that influence sensitivity to the PARPI olaparib, we conducted a genome-wide CRISPR-Cas9 knockout screening of 18,010 genes in DU145, 22Rv1, and LNCaP prostate cancer cell lines. Our screening identified PARP and LIG1 as synthetic lethality-inducing factors, whereas TP53 conferred resistance to PARPIs. Simultaneous inhibition of LIG1 and PARP increased DNA damage and apoptosis. Additionally, the combination of the LIG1 inhibitor L82-G17 with olaparib exhibited synergistic effects. To the best of our knowledge, we validated this combination therapy in vivo for the first time, suppressing tumor growth in a DU145 xenograft model while minimizing toxicity in normal tissues. Immunohistochemical analysis revealed that LIG1 was overexpressed in CRPC tissues, suggesting its potential as a therapeutic target. This study established LIG1 as a novel synthetic lethality-inducing factor in prostate cancer, showing that L82-G17 enhances the efficacy of olaparib, regardless of the BRCA mutation status. These findings suggest that the combination of PARP and LIG1 inhibitors could be a novel therapeutic strategy for mCRPC.

Tumor metastasis remains a poor prognosis because it occurs in all tissues and is difficult to diagnose or prevent before metastatic tumor nodules form. Metastasis is a multi-step process involving tumor cells, bone marrow-derived cells, and tissue resident cells, making it a biological three-body problem. It has been shown that a pre-metastatic soil/niche (PMN) is formed in metastatic tissue before tumor cells physically appear at the metastatic site, and suppressing this PMN is key to preventing metastasis. Recent studies highlighted the importance of protein citrullination, an irreversible post-translational modification of proteins, in tumor metastasis. Peptidyl arginine deiminase (PADI) catalyzes the modification of arginine to citrulline. In this enzymatic reaction, the amino acid residue's net charge changes, inducing a structural change in the protein. This review discusses the role of protein citrullination in cancer metastasis. Intracellular citrullination regulates gene expression and genome structure by citrullinating RNA polymerase and histones, while extracellular citrullination provides a pro-metastatic environment. These factors play an important role in PMN formation. Additionally, we discuss PADI inhibitors and anti-metastatic immune cells from the viewpoint of metastasis prevention.

Cancer treatment is shifting from an organ-based approach to one driven by biological phenotypes, emphasizing the need to understand molecular mechanisms. DNA methylation plays a pivotal role in tumor biology, not only through gene silencing but also by inducing distinct behaviors beyond genetic mutations. In gynecologic cancers, molecular diagnostics, such as homologous recombination deficiency status guiding poly(ADP-ribose) polymerase (PARP) inhibitor therapy in ovarian cancer and deficient mismatch repair/microsatellite instability-high status informing immune checkpoint inhibitor (ICI) therapy in endometrial cancer have already been used in clinical practice. However, tumors with epigenetically driven functional deficiencies, such as BRCA1 promoter methylation in homologous recombination-deficient ovarian cancers or MLH1 promoter methylation in deficient mismatch repair/microsatellite instability-high endometrial cancers, often exhibit poorer prognoses and reduced therapeutic responses compared to their genetically mutated counterparts. Given the unique impact of DNA methylation, precise detection is crucial. Integrating methylation analysis into molecular classification could refine diagnostics—both by identifying mechanistic contributors to treatment response and by serving as predictive biomarkers for therapy selection—thereby optimizing patient management. This review explores the role of DNA methylation in modulating responses to PARP inhibitors and ICIs, highlights its promise as a biomarker in precision oncology, and outlines current developments and clinical challenges in BRCA1 and MLH1 methylation assays.