Cancer Science最新文献

AXL-Mediated Drug Resistance in ALK-Rearranged NSCLC Enhanced by GAS6 From Macrophages and MMP11 Positive Fibroblasts. 巨噬细胞和 MMP11 阳性成纤维细胞的 GAS6 增强了 ALK 重组 NSCLC 中 AXL 介导的耐药性

IF 5.7 2区医学

Cancer Science Pub Date : 2025-02-04 DOI: 10.1111/cas.70006

Takahiro Utsumi, Hayato Mizuta, Yosuke Seto, Ken Uchibori, Makoto Nishio, Isamu Okamoto, Ryohei Katayama

{"title":"AXL-Mediated Drug Resistance in ALK-Rearranged NSCLC Enhanced by GAS6 From Macrophages and MMP11 Positive Fibroblasts.","authors":"Takahiro Utsumi, Hayato Mizuta, Yosuke Seto, Ken Uchibori, Makoto Nishio, Isamu Okamoto, Ryohei Katayama","doi":"10.1111/cas.70006","DOIUrl":"https://doi.org/10.1111/cas.70006","url":null,"abstract":"Anaplastic lymphoma kinase (ALK) rearranged non-small cell lung cancer (NSCLC) shows marked tumor shrinkage by ALK-tyrosine kinase inhibitors (TKIs). However, tumors almost inevitably relapse owing to the development of acquired resistance. Resistance mechanisms include secondary ALK mutations and the activation of bypass pathways, such as cMET, cKIT, or EGFR, though some remain unknown. In this study, we analyzed alectinib-resistant patient samples and identified a significant increase in AXL expression in the tumor, and a high level of GAS6, the ligand for AXL, in the pleural effusion. AXL-overexpressing H3122 ALK-rearranged NSCLC cells exhibited partial resistance to alectinib, which was enhanced by GAS6 supplementation but could be overcome by the ALK/AXL inhibitor gilteritinib. Moreover, GAS6-overexpressing NIH3T3 cells and AXL-expressing H3122 cells were subcutaneously injected into the left and right sides of nude mice simultaneously, followed by alectinib treatment. The supply of GAS6 from NIH3T3 may have accelerated tumor relapse under alectinib treatment. However, even without GAS6-overexpressing NIH3T3, AXL-overexpressing H3122 tumor relapsed within 1 month possibly due to increased host mouse Gas6 expression. Single-cell RNA sequencing revealed that specific cancer-associated fibroblasts (CAFs) and a subset of tumor-associated macrophages (TAMs) are the primary sources of Gas6 in the tumor microenvironment (TME). During alectinib treatment, TAMs increased their infiltration into the TME, whereas CAFs altered their expression patterns, substantially upregulating Mmp11. These findings suggest that AXL expression in resistant cancer cells, combined with increased Gas6 production in the TME, contributes to enhanced ALK-TKI resistance.","PeriodicalId":48943,"journal":{"name":"Cancer Science","volume":" ","pages":""},"PeriodicalIF":5.7,"publicationDate":"2025-02-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143191116","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

CML With Mutant ASXL1 Showed Decreased Sensitivity to TKI Treatment via Upregulation of the ALOX5-BLTR Signaling Pathway.

IF 5.7 2区医学

Cancer Science Pub Date : 2025-02-04 DOI: 10.1111/cas.70007

Naoki Miyashita, Masahiro Onozawa, Kohei Kasahara, Toshihiro Matsukawa, Yasuhito Onodera, Kohjin Suzuki, Tomoiku Takaku, Takanori Teshima, Takeshi Kondo

{"title":"CML With Mutant ASXL1 Showed Decreased Sensitivity to TKI Treatment via Upregulation of the ALOX5-BLTR Signaling Pathway.","authors":"Naoki Miyashita, Masahiro Onozawa, Kohei Kasahara, Toshihiro Matsukawa, Yasuhito Onodera, Kohjin Suzuki, Tomoiku Takaku, Takanori Teshima, Takeshi Kondo","doi":"10.1111/cas.70007","DOIUrl":"https://doi.org/10.1111/cas.70007","url":null,"abstract":"In this study, the mechanisms of tyrosine kinase inhibitor (TKI) resistance in chronic myeloid leukemia (CML) were investigated focusing additional sex combs-like 1 (ASXL1) gene mutations and their downstream effects. While TKIs have improved the prognosis of CML, some patients have shown resistant to therapy. Cases with mutations in epigenome-related genes such as ASXL1 are known to have a poor prognosis, but the underlying mechanisms of the poor prognosis are unclear. We showed that mutated ASXL1 reduces TKI sensitivity in CML cell lines, and RNA microarray analysis revealed that arachidonate 5-lipoxygenase (ALOX5) is a significantly upregulated gene under the conditional expression of mutated ASXL1. Enforced ALOX5 expression induced TKI resistance, while ALOX5 knockout increased TKI sensitivity. ALOX5 downstream signal inhibition by LY293111, a leukotriene B4 receptor (BLTR) antagonist, suppressed AKT phosphorylation and enhanced TKI sensitivity. This study revealed that TKI resistance in CML with ASXL1 mutation was induced via ALOX5 overexpression. ASXL1 mutations may confer a clonal advantage through activation of the AKT pathway following ALOX5 overexpression. While combined use of LY293111 with TKIs and asciminib showed synergistic effects against CML cells, the ALOX5-BLTR signaling pathway is novel therapeutic target for CML patients with mutated ASXL1.","PeriodicalId":48943,"journal":{"name":"Cancer Science","volume":" ","pages":""},"PeriodicalIF":5.7,"publicationDate":"2025-02-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143191118","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Susceptibility of Brca1^(L63X/+) rat to ovarian reserve dissipation by chemotherapeutic agents to breast cancer.

IF 5.7 2区医学

Cancer Science Pub Date : 2025-02-03 DOI: 10.1111/cas.16412

Satoshi Kaseki, Reina Sonehara, Yashiro Motooka, Hideaki Tanaka, Tomoko Nakamura, Satoko Osuka, Shinya Akatsuka, Hiroaki Kajiyama, Tomoji Mashimo, Tatsuhiko Imaoka, Shinya Toyokuni

{"title":"Susceptibility of Brca1(L63X/+) rat to ovarian reserve dissipation by chemotherapeutic agents to breast cancer.","authors":"Satoshi Kaseki, Reina Sonehara, Yashiro Motooka, Hideaki Tanaka, Tomoko Nakamura, Satoko Osuka, Shinya Akatsuka, Hiroaki Kajiyama, Tomoji Mashimo, Tatsuhiko Imaoka, Shinya Toyokuni","doi":"10.1111/cas.16412","DOIUrl":"https://doi.org/10.1111/cas.16412","url":null,"abstract":"BRCA1 is one of the causative genes for hereditary breast and ovarian cancer syndrome with a high risk of early-onset breast cancer. Whereas olaparib (OLA), an inhibitor of poly-ADP-ribose polymerase, has been applied as adjuvant therapy to those cancer patients, its effect on ovarian reproductive function remains unelucidated. Recently, a rat model (MUT; Brca1(L63X/+) mutation) mimicking a human BRCA1 pathogenic variant has been established. Using this model, we evaluated the effects of OLA on ovarian reproductive function in comparison with the wild-type (WT) rats. MUT showed a significantly reduced number of primordial follicles and subfertility in accordance with aging. Oxidative stress was significantly elevated in the young MUT granulosa cells (GCs) accompanied by increased mTOR but decreased PTEN signals. OLA administration in MUT further decreased primordial follicles, with gene set enrichment analysis, indicating upregulated DNA repair pathways. Furthermore, a combination of OLA and cyclophosphamide (CPA) induced empty primordial follicles, recognized as CPA-induced severe ovarian toxicity. Whereas OLA + CPA caused greater reduction in primordial follicles both in MUT and WT in comparison with CPA alone, MUT ovaries were more susceptible to oxidative stress, potentially depleting primordial follicles via activation of GCs and inducing oocyte death due to accumulated DNA damage by OLA treatment. Our findings in this preclinical model underscore the importance of evaluating ovarian reserve prior to chemotherapy by performing reproductive consultation with female patients with BRCA1 pathogenic variants.","PeriodicalId":48943,"journal":{"name":"Cancer Science","volume":" ","pages":""},"PeriodicalIF":5.7,"publicationDate":"2025-02-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143123563","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Supersulfide metabolome of exhaled breath condensate applied as diagnostic biomarkers for esophageal cancer.

IF 5.7 2区医学

Cancer Science Pub Date : 2025-02-02 DOI: 10.1111/cas.16430

Seji Asamitsu, Yohei Ozawa, Hiroshi Okamoto, Seiryo Ogata, Tetsuro Matsunaga, Jun Yoshitake, Kazuki Fusegawa, Yusuke Taniyama, Chiaki Sato, Hirotaka Ishida, Takaaki Abe, Hozumi Motohashi, Takaaki Akaike, Takashi Kamei

{"title":"Supersulfide metabolome of exhaled breath condensate applied as diagnostic biomarkers for esophageal cancer.","authors":"Seji Asamitsu, Yohei Ozawa, Hiroshi Okamoto, Seiryo Ogata, Tetsuro Matsunaga, Jun Yoshitake, Kazuki Fusegawa, Yusuke Taniyama, Chiaki Sato, Hirotaka Ishida, Takaaki Abe, Hozumi Motohashi, Takaaki Akaike, Takashi Kamei","doi":"10.1111/cas.16430","DOIUrl":"https://doi.org/10.1111/cas.16430","url":null,"abstract":"Early detection of esophageal cancer is essential for esophagogastroduodenoscopy and histopathological diagnosis. However, endoscopic examinations are sometimes invasive, which limits their clinical application and compliance, and traditional blood tumor markers are unsuitable for cancer screening. The current study aimed to evaluate the usefulness of sulfur metabolites as new biomarkers for esophageal cancer using blood samples and exhaled breath condensate (EBC), which can be readily obtained and is non-invasive. We collected EBC and plasma samples from 50 patients with esophageal cancer and 30 healthy controls. Sulfur metabolome analysis using tandem mass spectrometry was performed to compare the metabolic profile between the two groups. Supersulfide metabolic profiles were different between the two cohorts. Supersulfide metabolome analysis showed that cysteine hydropersulfide (CysSSH) and homocysteine hydropersulfide (HomoCysSSH) were increased in the plasma of patients with esophageal cancer. Elevated levels of HomoCysSSH could distinguish patients with esophageal cancer from healthy subjects (area under the curve [AUC]: 0.93, sensitivity: 89%, specificity: 96%). Interestingly, we also detected an elevation of supersulfides in the EBC analysis. CysSSH levels significantly increased in the EBC recovered from patients with esophageal cancer (AUC: 0.71, sensitivity: 60%, specificity: 96%). In addition, the observed level was correlated with that of HomoCysSSH in the plasma (r = 0.27). Supersulfides, such as CysSSH and HomoCysSSH, are potential biomarkers for detecting esophageal cancer. CysSSH from EBC may serve as a valuable non-invasive biomarker with similar detection ability but with superior precision and convenience compared with the currently available blood biomarkers.","PeriodicalId":48943,"journal":{"name":"Cancer Science","volume":" ","pages":""},"PeriodicalIF":5.7,"publicationDate":"2025-02-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143081723","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Genomic profiles of patients with skin melanoma in the era of immune checkpoint inhibitors. 免疫检查点抑制剂时代皮肤黑色素瘤患者的基因组概况。

IF 5.7 2区医学

Cancer Science Pub Date : 2025-01-29 DOI: 10.1111/cas.16338

Yao Liang, Osamu Maeda, Kazuki Nishida, Basile Chretien, Yuichi Ando

{"title":"Genomic profiles of patients with skin melanoma in the era of immune checkpoint inhibitors.","authors":"Yao Liang, Osamu Maeda, Kazuki Nishida, Basile Chretien, Yuichi Ando","doi":"10.1111/cas.16338","DOIUrl":"https://doi.org/10.1111/cas.16338","url":null,"abstract":"The use of immune checkpoint inhibitors (ICIs) for treating melanoma has dramatically improved patient prognosis. The genomic profiles of patients receiving ICI therapy would provide valuable information for disease management and treatment. We investigated the genomic profiles of patients with melanoma who had received ICI therapy and explored associations with clinical features and outcomes via a large-scale nationwide database in Japan (the C-CAT database). We identified 339 patients eligible for this study. The most frequent genetic mutations were found in the BRAF (27%), TERT (24%), and NRAS (19%) genes, and the most common copy number variations (CNVs) were in the CDKN2A (36%), CDKN2B (26%), and MTAP (19%) genes. Associations with high tumor mutational burden (TMB-high) status were significant for TERT (p < 0.001), NF1 (p < 0.001), ROS1 (p = 0.015), POLE (p = 0.045), and POLD1 (p = 0.008) mutations, along with older age (≥65 years, p = 0.036). Patients with multiple metastases (two or more) were more likely to have NOTCH3 mutations (p = 0.017) and be younger than 65 years (p = 0.024). In particular, as well as younger age, patients with brain metastases were more likely to harbor BRAF mutations (p < 0.001), while those with liver metastases were more likely to harbor NOTCH3 mutations (p < 0.001) but not CDKN2B CNVs (p = 0.041). Patients with NRAS mutations were less likely to respond to ICI therapy (p = 0.014) and exhibited shorter overall survival (p = 0.006). In this population, the frequency of BRAF mutations was lower than that in fair-skinned populations, but the associations between genomic profiles, clinical features, and outcomes were similar to those previously reported in fair-skinned populations.","PeriodicalId":48943,"journal":{"name":"Cancer Science","volume":" ","pages":""},"PeriodicalIF":5.7,"publicationDate":"2025-01-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143068756","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

EXPRESSION OF CONCERN: Subtype-Specific Alterations of the Wnt Signaling Pathway in Breast Cancer: Clinical and Prognostic Significance.

IF 5.7 2区医学

Cancer Science Pub Date : 2025-01-24 DOI: 10.1111/cas.16460

{"title":"EXPRESSION OF CONCERN: Subtype-Specific Alterations of the Wnt Signaling Pathway in Breast Cancer: Clinical and Prognostic Significance.","authors":"","doi":"10.1111/cas.16460","DOIUrl":"https://doi.org/10.1111/cas.16460","url":null,"abstract":"Expression of concern: N. Mukherjee, N. Bhattacharya, N. Alam, A. Roy, S. Roychoudhury, and C.K. Panda, \"Subtype-Specific Alterations of the Wnt Signaling Pathway in Breast Cancer: Clinical and Prognostic Significance,\" Cancer Science 103, no. 2 (2012): 210-220, https://doi.org/10.1111/j.1349-7006.2011.02131.x. This Expression of Concern is for the above article, published online on 25 October 2011, in Wiley Online Library (wileyonlinelibrary.com), and has been issued by agreement between the journal Editor-in-Chief, Masanori Hatakeyama; the Japanese Cancer Association; and John Wiley & Sons Australia Ltd. The Expression of Concern has been agreed due to concerns raised by a third party after publication regarding the similarity of certain bands in Figure 2b and the underlying data that they represent. The authors could not provide the original data given the time that had elapsed since publication. Because the publisher was not able to examine the original data, it was not possible to investigate fully the concerns raised. Therefore, the journal is issuing this Expression of Concern because the concerns regarding the integrity of the data and the results presented cannot be resolved. Chinmay K. Panda agrees with this decision on behalf of the authors.","PeriodicalId":48943,"journal":{"name":"Cancer Science","volume":" ","pages":""},"PeriodicalIF":5.7,"publicationDate":"2025-01-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143034685","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Transplantation of the MSLN-deficient Thymus Generates MSLN Epitope Reactive T Cells to Attenuate Tumor Progression.

IF 5.7 2区医学

Cancer Science Pub Date : 2025-01-23 DOI: 10.1111/cas.16458

Hanchao Gao, Haiyan Wu, Lvwen Ning, Liying Zhou, Mengtao Cao, Wenting Huang, Xihong Xie, Haidong Wu, Xiehui Chen, Feiqiang Chen, Jinqi Song, Kai Deng, Pengfei Chen

{"title":"Transplantation of the MSLN-deficient Thymus Generates MSLN Epitope Reactive T Cells to Attenuate Tumor Progression.","authors":"Hanchao Gao, Haiyan Wu, Lvwen Ning, Liying Zhou, Mengtao Cao, Wenting Huang, Xihong Xie, Haidong Wu, Xiehui Chen, Feiqiang Chen, Jinqi Song, Kai Deng, Pengfei Chen","doi":"10.1111/cas.16458","DOIUrl":"https://doi.org/10.1111/cas.16458","url":null,"abstract":"The development of mesothelin (MSLN) epitope reactive T cells is observed in mice that are immunized with the MSLN vaccine. Engineered T cells expressing MSLN-reactive high-affinity TCR exhibit extraordinary therapeutic effects for invasive pancreatic ductal adenocarcinoma in a mouse model. However, the generation of MSLN-reactive T cells through the introduction of MSLN-deficient thymus and the transplantation of the latter as a cure for cancer treatment have not been tested to date. In the present study, the expression of MSLN was mainly identified in medullary thymic epithelial cells (mTECs) but not in hematopoietic cells, cortical thymic epithelial cells (cTECs), endothelial cells, or fibroblast cells in the thymus. The increasement of activated T cells was observed in MSLN-expressing tumors from MSLN-deficient mice, indicating that MSLN-reactive T cells had developed. Finally, in an AOM-DSS-induced mouse model of colorectal cancer (CRC), transplantation of MSLN-deficient thymus repressed the progression of CRC, accompanied by an increased number of IFNγ-expressing T lymphocytes in the tumors. The data from this study demonstrated that ectopic transplantation of MSLN-deficient thymus induced MSLN-specific antitumor responses to MSLN-expressing tumors, and thus attenuated tumor progression.","PeriodicalId":48943,"journal":{"name":"Cancer Science","volume":" ","pages":""},"PeriodicalIF":5.7,"publicationDate":"2025-01-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143034686","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Treating Hematological Malignancies With OR-2100, an Orally Bioavailable Prodrug of Decitabine. 口服地西他滨前药OR-2100治疗血液系统恶性肿瘤。

IF 5.7 2区医学

Cancer Science Pub Date : 2025-01-21 DOI: 10.1111/cas.16452

Tatsuro Watanabe, Keisuke Kidoguchi, Shinya Kimura

{"title":"Treating Hematological Malignancies With OR-2100, an Orally Bioavailable Prodrug of Decitabine.","authors":"Tatsuro Watanabe, Keisuke Kidoguchi, Shinya Kimura","doi":"10.1111/cas.16452","DOIUrl":"https://doi.org/10.1111/cas.16452","url":null,"abstract":"DNA methylation is an enzyme-driven epigenetic modification that must be precisely regulated to maintain cellular homeostasis. Aberrant methylation status, especially hypermethylation of the promoter sites of tumor-suppressor genes, is observed in human malignancies and is a proven target for cancer therapy. The first-generation DNA demethylating agents, azacitidine and decitabine, are widely used for treating several hematological malignancies. In addition, orally bioavailable prodrugs of azacitidine and decitabine have recently been approved by the FDA. We have developed a silylated derivative of decitabine, OR-2100, which is resistant to degradation by cytidine deaminase and orally bioavailable. It has efficacy against several human hematological malignancies in xenograft mouse models with less hematotoxicity than decitabine. Since DNA demethylating agents are combined with molecularly targeted drugs in clinical use and trials, we think that the less hematotoxic profile of OR-2100 makes it suitable for use as a combination therapy. In this article, we review the therapeutic approach in hematological malignancies with the DNA demethylating agent OR-2100.","PeriodicalId":48943,"journal":{"name":"Cancer Science","volume":" ","pages":""},"PeriodicalIF":5.7,"publicationDate":"2025-01-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143014559","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Molecular Subtyping and Genomic Profiling Expand Precision Medicine in KRAS Wild-Type Pancreatic Cancer. KRAS野生型胰腺癌的分子分型和基因组分析扩展了精准医学。

IF 5.7 2区医学

Cancer Science Pub Date : 2025-01-20 DOI: 10.1111/cas.16456

Dan Su, Yuli Ruan, Yingfei Shi, Dandan Cao, Tong Wu, Tianjiao Dang, Hong Wang, Yaqun Xin, Ming Ma, Hongxue Meng, Chao Liu, Yanqiao Zhang

{"title":"Molecular Subtyping and Genomic Profiling Expand Precision Medicine in KRAS Wild-Type Pancreatic Cancer.","authors":"Dan Su, Yuli Ruan, Yingfei Shi, Dandan Cao, Tong Wu, Tianjiao Dang, Hong Wang, Yaqun Xin, Ming Ma, Hongxue Meng, Chao Liu, Yanqiao Zhang","doi":"10.1111/cas.16456","DOIUrl":"https://doi.org/10.1111/cas.16456","url":null,"abstract":"Pancreatic ductal adenocarcinoma (PDAC) is a highly lethal disease with poor prognosis and limited treatment options. While the majority of PDAC cases harbor KRAS mutations, approximately 8%-10% are KRAS wild-type (KRAS-WT). These KRAS-WT tumors often contain actionable mutations and gene fusions, making them more suitable for precision therapies. Identifying these molecular alterations is crucial for improving outcomes in this subset of patients. This retrospective study involved 34 patients with KRAS-WT PDAC. Genomic profiling was performed using next-generation sequencing (NGS) and RNA sequencing to detect mutations and fusions. Comparative analysis was conducted with TCGA-PAAD data, and immune infiltration was assessed using bioinformatic deconvolution methods. Targetable alterations were identified in multiple pathways. Key mutations included ATM (18%), PIK3CA (15%), and ROS1 (15%), while actionable gene fusions such as CCDC6-RET and ETV6-NTRK3 were present in 10.3% of patients. The gene mutations associated with homologous recombination deficiency (HRD) are predicted to increase sensitivity to platinum-based chemotherapy (p = 0.047). Tumors with epigenetic regulatory genes mutations (e.g., ARID1A, KMT2C/D) exhibited enhanced immune cell infiltration, highlighting potential responsiveness to immune checkpoint inhibitors (ICIs). Kinase fusions (NTRK and RET) were linked to response to larotinib and RET-specific inhibitors, respectively. KRAS-WT PDAC contains actionable mutations and fusions, offering significant potential for targeted and immune-based therapies. Further clinical studies are needed to validate these therapeutic approaches.","PeriodicalId":48943,"journal":{"name":"Cancer Science","volume":" ","pages":""},"PeriodicalIF":5.7,"publicationDate":"2025-01-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143014539","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

A Phase I, First-In-Human Study of CBA-1205, an Anti-DLK1 Monoclonal Antibody, in Patients With Advanced Solid Tumors. 抗dlk1单克隆抗体CBA-1205在晚期实体瘤患者中的I期首次人体研究

IF 5.7 2区医学

Cancer Science Pub Date : 2025-01-20 DOI: 10.1111/cas.16454

Yuki Katsuya, Masafumi Ikeda, Takafumi Koyama, Jun Sato, Mao Okada, Nobuaki Matsubara, Chihiro Kondoh, Toru Mukohara, Kazuo Watanabe, Daisuke Kotani, Yoshimi Ogawa, Shose Taoka, Noboru Yamamoto

{"title":"A Phase I, First-In-Human Study of CBA-1205, an Anti-DLK1 Monoclonal Antibody, in Patients With Advanced Solid Tumors.","authors":"Yuki Katsuya, Masafumi Ikeda, Takafumi Koyama, Jun Sato, Mao Okada, Nobuaki Matsubara, Chihiro Kondoh, Toru Mukohara, Kazuo Watanabe, Daisuke Kotani, Yoshimi Ogawa, Shose Taoka, Noboru Yamamoto","doi":"10.1111/cas.16454","DOIUrl":"https://doi.org/10.1111/cas.16454","url":null,"abstract":"CBA-1205 is a novel humanized antibody targeting delta-like 1 homolog (DLK1) that enhances antibody-dependent cellular cytotoxicity activity. DLK1 overexpression has been reported in various cancer types, such as hepatocellular carcinoma and neuroblastoma. CBA-1205 demonstrates potent antitumor activity in multiple tumor models, making it a potential treatment option for DLK1-expressing cancers. This first-in-human, open-label Phase I study includes three parts. Part 1, the dose-escalation phase, primarily evaluates the safety profile, tolerability, and maximum tolerated dose of CBA-1205. The drug is administered intravenously every 2 weeks in a 28-day cycle. A standard 3 + 3 dose-escalation design was used across seven cohorts. In a cohort of 22 Japanese patients, over 80% had undergone three or more prior treatments. CBA-1205 was well tolerated, with no dose-limiting toxicity observed at doses ranging from 0.1 to 30 mg/kg, the planned highest dose. There were no treatment-related serious adverse events or trial-related deaths. CBA-1205 exposure, as measured by Cmax, AUC0-14, and AUC0-∞, increased in a dose-dependent manner. No serum anti-CBA-1205 antibodies were detected. Serum DLK1 concentrations were found in 6 out of 22 patients. Stable disease for over 6 months was observed in six patients, with progression-free survival ranging from 29 to 144 weeks. CBA-1205 was well tolerated, showing no severe toxicity in patients with advanced or recurrent solid tumors. The favorable safety profile and indications of potential activity support further investigation in Parts 2 and 3 of this Phase I study to evaluate the safety, tolerability, and preliminary efficacy of CBA-1205.","PeriodicalId":48943,"journal":{"name":"Cancer Science","volume":" ","pages":""},"PeriodicalIF":5.7,"publicationDate":"2025-01-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143014497","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0