Cancer Science最新文献

We conducted a phase 1b study evaluating safety and tolerability of tafasitamab, a CD19-targeting immunotherapy, in Japanese patients with B-cell non-Hodgkin lymphoma (NHL). Eligible patients were ≥ 18 years old with relapsed/refractory (R/R) B-cell NHL (Group 1), R/R diffuse large B-cell lymphoma (DLBCL; Groups 3 and 4), or untreated DLBCL (Group 5). Patients received tafasitamab starting at 12 mg/kg qw (Group 1, n = 6), tafasitamab + lenalidomide starting at 25 mg qd for ≤ 12 cycles (Group 3, n = 6), tafasitamab + parsaclisib starting at 20 mg qd (Days 1-56) then 2.5 mg qd (Group 4, n = 6), or tafasitamab + lenalidomide combined with R-CHOP for ≤ 6 cycles (Group 5, n = 6). Primary objective was safety and tolerability of tafasitamab alone and in combination; exploratory objectives included efficacy. At data cutoff (August 31, 2023), 24 patients were treated. All patients experienced treatment-emergent adverse events (TEAEs). Two patients experienced a dose-limiting toxicity; liver disorder (grade 4) considered related to lenalidomide (Group 3, n = 1), and febrile neutropenia (grade 3) considered related to lenalidomide and R-CHOP (Group 5, n = 1). Most common TEAEs across groups were hematological and included neutropenia, leukopenia, thrombocytopenia, and anemia; most common non-hematological TEAEs included increased alanine aminotransferase, increased aspartate aminotransferase, diarrhea, nausea, constipation, and infusion-related reactions. No serious tafasitamab treatment-related or fatal TEAEs were observed. Results suggest tafasitamab alone or in combination demonstrates a manageable safety profile in Japanese patients with B-cell NHL. Preliminary efficacy results from the study are reported. However, results should be interpreted with caution due to the small sample size, with further studies warranted to confirm these findings. Trial Registration: NCT04661007; jRCT2031200357.

All-trans retinoic acid (ATRA) combined with arsenic trioxide (ATO) has become the international standard of care for newly diagnosed acute promyelocytic leukemia (APL), demonstrating superior efficacy and safety over ATRA-chemotherapy regimens. However, in Japan, ATO has been approved only for relapsed/refractory APL, and prospective data on its frontline use are lacking. We conducted FBMTG-APL2017, a prospective multicenter phase II trial in Japan, to evaluate ATRA-ATO in newly diagnosed APL patients, including both low-intermediate-risk and high-risk groups. Eighty-one patients were enrolled between 2017 and 2021 and treated with ATRA plus delayed ATO during induction, followed by four cycles of ATRA-ATO consolidation. Complete remission was achieved in 95.1% of patients. With a median follow-up of 55 months, 3-year disease-free survival (DFS) and overall survival (OS) were 93.6% and 95.0%, respectively, consistent with international ATRA-ATO trials. DFS was 96.9% in low-intermediate-risk and 80.0% in high-risk patients, with no significant difference. Molecular remission was achieved in 99% after consolidation, and only two molecular relapses occurred. Differentiation syndrome developed in 56.8% but was generally manageable, with only one fatal case; early death occurred in 4.9%, comparable to international data. These results provide the first prospective evidence in Japan that frontline chemo-free ATRA-ATO is highly effective and safe across all risk groups. They support its adoption as a new standard therapy and bridge the gap with established global practice. Trial Registration: Japan Registry of Clinical Trials: jRCTs071180040.

Head and neck squamous cell carcinoma (HNSCC) is a highly aggressive malignancy with a poor prognosis, often necessitating multimodal treatment approaches. While cisplatin (CDDP) remains the first-line chemotherapeutic agent, treatment failure frequently occurs due to drug resistance. To address this challenge, the FTO inhibitor FB23-2 has emerged as a promising candidate to enhance therapeutic efficacy. Consequently, this study aims to evaluate the combined efficacy of CDDP and FB23-2 in HNSCC and investigate their synergistic mechanisms. Using CCK-8 assays, colony formation assays, and flow cytometry for proliferation and cell cycle analysis, we observed that the CDDP-FB23-2 combination synergistically suppressed HNSCC proliferation. This treatment induced S/G2 phase cell cycle arrest and subsequent mitotic catastrophe. We further validated these findings in vivo using 4NQO-induced HNSCC mouse models. Additionally, drug safety was assessed via H&E staining of visceral organs, which revealed that a semi-combined regimen reduced treatment-related side effects. Mechanistic investigations involving immunofluorescence (IF), quantitative real-time PCR (qRT-PCR), co-immunoprecipitation (Co-IP), and western blot analyses demonstrated that FB23-2 potentiated CDDP-induced DNA damage while inhibiting DNA repair mechanisms, thereby promoting apoptotic cell death. Specifically, FB23-2 blocked the assembly and nuclear translocation of XPF/ERCC1 complexes in CDDP-treated cells, directly increasing cellular sensitivity to CDDP. Collectively, our findings demonstrate that FB23-2 enhances CDDP sensitivity in HNSCC by targeting the XPF/ERCC1 complex, providing a theoretical basis and experimental support for their clinical application in HNSCC treatment.

Pleural mesothelioma (PM) is a malignancy with a poor prognosis owing to its resistance to chemotherapy. To develop a novel treatment for PM, podoplanin (PDPN), a transmembrane glycoprotein, has attracted significant attention because it is highly expressed in PM and is used for its diagnosis. We previously reported that NZ-12, a human chimeric antihuman PDPN antibody, exhibits antitumor effects against human PM cells through antibody-dependent cellular cytotoxicity (ADCC) and complement-dependent cytotoxicity (CDC). Additionally, we developed a cancer-specific monoclonal antibody (CasMab) production technology and produced a mouse-human chimeric cancer-specific antihuman PDPN antibody, chLpMab-2, along with an afucosylated version, chLpMab-2f, to enhance ADCC activity. This study aimed to evaluate whether chLpMab-2f exhibits specific antitumor effects against PM in a preclinical model. We demonstrated that chLpMab-2f recognized the surface PDPN of human PM cell lines and human PM patient tissue but did not react with human normal tissues such as lung and kidney tissues. Furthermore, these antibodies exhibited ADCC and CDC activity against PDPN-positive PM cells while showing reduced toxicity toward non-malignant kidney-derived PDPN-positive cells, such as HEK-293FT. Additionally, chLpMab-2f demonstrated stronger ADCC activity through more efficient NK cell activation in comparison to chLpMab-2. Moreover, chLpMab-2f suppressed tumor progression in subcutaneously and intrathoracically transplanted human PM cells in mice. These findings suggest that PDPN-targeting immunotherapy with chLpMab-2f generated by CasMab technology could provide an effective treatment for PM with decreased toxicity toward normal tissues.

Retraction: Q. Yao, C. Tu, D. Lu, Y. Zou, H. Liu, and S. Zhang, "Clinicopathological Significance of the MicroRNA-146a/WASP-Family Verprolin-Homologous Protein-2 Axis in Gastric Cancer," Cancer Science 108, no. 7 (2017): 1285-1292, https://doi.org/10.1111/cas.13254. The above article, published online on 07 April 2017 in Wiley Online Library (wileyonlinelibrary.com), has been retracted by agreement between the journal Editor-in-Chief, Masanori Hatakeyama; the Japanese Cancer Association; and John Wiley & Sons Australia, Ltd. The retraction has been agreed upon following concerns about the reliability of data and images raised by a third party. An investigation also identified duplication of images between Figures 2b and 2c. The authors did not respond to invitations to comment on these concerns nor provide supporting data to support the findings. The editors therefore consider the results and conclusions of this article unreliable. The authors did not respond to our notice of retraction.

Interferon regulatory factor 4 (IRF4), a critical member of the IRF transcription factor family, harbors an elusive biological role in cervical cancer. Through immunohistochemical staining and immunoblotting, CCK-8 viability assays, EdU incorporation tests, clonogenic survival experiments, flow cytometric detection, transmission electron microscopy, immunofluorescence staining and heterotopic transplantation model, we discover that IRF4 expression was markedly decreased in cervical cancer tissues and cell lines compared to normal controls. Overexpression of IRF4 suppressed proliferation, migration, and invasion in both Siha and HeLa cells, while concurrently enhancing radiosensitivity. Mechanistically, IRF4 upregulated autophagy-related proteins (LC3, Beclin-1) and promoted autophagosome formation, while downregulating P62 by inhibiting the PI3K/Akt/mTOR pathway. In vivo studies demonstrated that IRF4 augmented the tumor response to radiation and further potentiated the effects when combined with rapamycin treatment, confirming its pivotal role in promoting radiosensitivity through PI3K/Akt/mTOR-mediated autophagy. IRF4 emerges as a critical regulator of cervical cancer progression via modulation of autophagy and influences the tumor's response to radiotherapy. It holds promise as a potential therapeutic target to enhance cervical cancer radiosensitivity.

Radiation therapy effectively treats prostate cancer, but tumor recurrence remains a clinical challenge, highlighting the need for strategies to enhance radiosensitivity. In this study, we developed a simple, high-throughput drug repurposing screening platform to find radiosensitizers from compounds approved by the U.S. Food and Drug Administration. A library of 1134 compounds was systematically screened at two concentrations (0.2 and 2 μM) using LNCaP cells stably expressing Metridia luciferase, allowing highly sensitive and quantitative assessment of cell viability through luciferase activity in culture supernatants. In the primary screening, 8 and 12 candidate radiosensitizers were identified at 0.2 μM and 2 μM, respectively. In the secondary screening, 19 compounds were evaluated at two radiation doses (4 Gy and 6 Gy) and six drug concentrations, identifying 5 radiation-sensitizing candidate compounds. Through this stepwise screening approach, cladribine was identified as the most potent radiosensitizer. Cladribine increased radiation-induced cytotoxicity in multiple prostate cancer cell lines (22Rv1, DU145, and PC3), with dose-modifying factors of 1.46, 1.55, and 1.43, respectively, based on the radiation dose needed to achieve 90% cell death. Mechanistically, cladribine prevented the repair of radiation-induced DNA double-strand breaks, shown by increased γH2AX levels. Importantly, its radiosensitizing effect was further confirmed in vivo using 22Rv1 and DU145 xenograft models. This study demonstrates that a luciferase-based high-throughput drug repurposing platform is useful for identifying clinically relevant radiosensitizers, revealing that cladribine is a promising candidate for further translational research in prostate cancer radiotherapy.

Esophageal squamous cell carcinoma (ESCC) remains a leading cause of cancer-related mortality, with early detection being challenging. Although endoscopic screening can aid in diagnosis, its invasiveness and cost limit widespread compliance. To address this, we developed and validated a non-invasive diagnostic panel based on urinary exosomal microRNAs (miRNAs) for early ESCC detection. Urine samples were prospectively collected from ESCC patients and healthy controls across five institutions, and exosomal miRNA profiles were obtained using small RNA sequencing. A diagnostic panel was constructed using machine learning with recursive feature elimination in a proof-of-concept (POC) cohort comprising 99 ESCC and 93 control samples, and its performance was evaluated by five-fold cross-validation. This panel was subsequently tested in a blinded validation cohort of 50 ESCC and 61 control samples. In the POC cohort, the multi-miRNA panel achieved an area under the curve (AUC) of 0.90. In the validation cohort, the AUC was 0.85 (95% CI: 0.77-0.92), with 84% sensitivity and 66% specificity. The panel showed high sensitivity across disease stages-100% for Stage 0, 91% for Stage I, and 73% for Stages II-IV-and its performance was not significantly affected by sex, body mass index, alcohol use, or smoking. Furthermore, in early-stage cases, the diagnostic score significantly declined after treatment (p = 0.026). These findings suggest that the urinary exosomal miRNA panel may offer a practical screening approach for the early detection of ESCC.

Advanced-stage and metastatic endometrial cancer (EC) are characterized by markedly poor survival outcomes, necessitating a deeper understanding of the mechanisms driving disease advancement. Tumor-associated macrophages (TAMs), particularly the M2 subtype, are instrumental in remodeling the tumor microenvironment and promoting EC proliferation, migration, and metastasis. However, the specific mediators responsible for TAM-driven EC progression remain inadequately elucidated. In this study, we investigated the role of the C-X-C motif chemokine ligand 1 (CXCL1) and its receptor, chemokine receptor 2 (CXCR2), in TAM-induced EC progression. CXCR2, as the primary receptor for CXCL1, activates the NF-κB signaling pathway upon binding, thereby mediating the epithelial-mesenchymal transition process in EC cells and enhancing metastatic potential. This mechanism can be effectively inhibited by silencing CXCR2 or by employing the NF-κB inhibitor BAY 11-7082. Neutralizing CXCL1 markedly diminished the proliferative and migratory burdens imposed by TAMs on EC in subcutaneous xenograft EC models. Additionally, in EC tissue samples, CXCL1 and CXCR2 expression, as well as the extent of macrophage infiltration, exhibited a significant positive relationship with disease progression, suggesting an unfavorable prognosis. In conclusion, targeting the CXCL1/CXCR2 axis is a potential therapeutic approach for EC treatment.

Antibody-drug conjugates (ADCs) are emerging as a promising class of targeted cancer therapy. Trastuzumab deruxtecan (T-DXd), a human epidermal growth factor receptor 2 (HER2)-directed ADC, has demonstrated clinical efficacy in HER2-positive gastric and breast cancers, as well as in HER2-mutant non-small cell lung cancer. However, the development of acquired resistance limits their long-term efficacy. To elucidate the resistance mechanism, we established T-DXd-resistant cell lines derived from HER2-amplified gastric xenografts (N87 acquired resistance [AR]) and leptomeningeal carcinomatosis (Calu-3 AR) lung cancer cells. N87 AR cells exhibited cross-resistance to T-DXd, payload DXd, and topoisomerase I inhibitor SN-38 despite preserved HER2 expression and intact drug internalization. As payload resistance-related molecules, ATP-binding cassette (ABC) transporter ABCG2 and ABCB1 were markedly upregulated in N87 AR and Calu-3 cells, respectively. Inhibition of ABCG2 and ABCB1 in N87 AR and Calu-3 cells, respectively, through siRNA-mediated knockdown restored T-DXd sensitivity in both models. As a strategy to overcome resistance, pharmacological inhibitors of ABCG2 and ABCB1 restored the T-DXd sensitivity of N87 AR and Calu-3 cells, respectively. Moreover, BB-1701, a novel HER2-ADC containing eribulin as a payload, to which N87 AR cells are sensitive, exhibited antitumor effects in N87 AR cells in vitro and in vivo. These findings indicate that ABC transporter-mediated drug efflux is an important mechanism underlying T-DXd resistance in HER2-positive gastric and lung cancer models. Furthermore, our study suggests that both targeting drug efflux pathways and utilizing alternative payloads may be effective strategies for overcoming T-DXd resistance in HER2-positive gastric and lung cancers.