Agents that target PD-1 and PD-L1 have been developed in the treatment of bladder cancer (BC). However, the diversity of immune cell infiltration in non-muscle-invasive BC (NMIBC) and the dynamics of the microenvironment as it progresses to muscle-invasive/metastatic disease remains unknown. To assess tumor immune activity, hierarchical clustering was applied to 159 BC samples based on cellular positivity for the defined immune cellular markers (CD3/CD4/CD8/FOXP3/CD20/PD-1/PD-L1/LAG3/TIGIT), divided into two clusters. There was a "hot cluster" (25%) consisting of patients with a high expression of these markers and a "cold cluster" (75%) comprising those without. The expression of CD39, CD44, CD68, CD163, IDO1, and Ki67 was significantly higher in tumors in the hot cluster. Immunologically, high-grade T1 tumors were significantly hotter, whereas tumors that had progressed to muscle invasion turned cold. However, a certain number of high-grade NMIBC patients were in the cold cluster, and these patients had a significantly higher risk of disease progression. Using an externally available TCGA dataset, RB1 and TP53 alterations were more frequently observed in TCGA hot cluster; rather FGFR3, KDM6A, and KMT2A alterations were common in TCGA cold/intermediate cluster. Analyses of recurrent tumors after BCG therapy revealed that tumor immune activity was widely maintained before and after treatment, and high FGFR3 expression was detected after recurrence in tumors initially classified into the cold cluster. Collectively, we revealed the dynamics of the tumor microenvironment in BC as a whole and identified candidate molecules as therapeutic targets for recurrent NMIBC, e.g., after BCG therapy.
针对 PD-1 和 PD-L1 的药物已被开发用于治疗膀胱癌(BC)。然而,非肌层浸润性膀胱癌(NMIBC)中免疫细胞浸润的多样性以及膀胱癌发展为肌层浸润性/转移性疾病时微环境的动态变化仍然未知。为了评估肿瘤免疫活性,研究人员对 159 个 BC 样本进行了分层聚类,根据细胞对定义的免疫细胞标记物(CD3/CD4/CD8/FOXP3/CD20/PD-1/PD-L1/LAG3/TIGIT)的阳性率将其分为两个群组。一个 "热群"(25%)是这些标记物高表达的患者,另一个 "冷群"(75%)是没有这些标记物表达的患者。热群肿瘤中 CD39、CD44、CD68、CD163、IDO1 和 Ki67 的表达明显较高。从免疫学角度看,高级别 T1 肿瘤明显偏热,而进展到肌肉侵犯的肿瘤则偏冷。然而,一定数量的高级别NMIBC患者属于冷群组,这些患者的疾病进展风险明显更高。利用外部提供的TCGA数据集,RB1和TP53的改变在TCGA热群中更为常见;而FGFR3、KDM6A和KMT2A的改变则常见于TCGA冷群/中间群。对卡介苗治疗后复发肿瘤的分析表明,肿瘤免疫活性在治疗前后广泛维持,在最初归入冷簇的肿瘤中,复发后检测到了高表达的FGFR3。总之,我们揭示了整个 BC 肿瘤微环境的动态变化,并确定了候选分子作为复发性 NMIBC(如卡介苗治疗后)的治疗靶点。
{"title":"Tumor immune microenvironment dynamics and outcomes of prognosis in non-muscle-invasive bladder cancer.","authors":"Rei Kamitani, Nobuyuki Tanaka, Tadatsugu Anno, Tetsushi Murakami, Tsukasa Masuda, Yota Yasumizu, Toshikazu Takeda, Shinya Morita, Takeo Kosaka, Shuji Mikami, Kazuhiro Matsumoto, Mototsugu Oya","doi":"10.1111/cas.16333","DOIUrl":"https://doi.org/10.1111/cas.16333","url":null,"abstract":"<p><p>Agents that target PD-1 and PD-L1 have been developed in the treatment of bladder cancer (BC). However, the diversity of immune cell infiltration in non-muscle-invasive BC (NMIBC) and the dynamics of the microenvironment as it progresses to muscle-invasive/metastatic disease remains unknown. To assess tumor immune activity, hierarchical clustering was applied to 159 BC samples based on cellular positivity for the defined immune cellular markers (CD3/CD4/CD8/FOXP3/CD20/PD-1/PD-L1/LAG3/TIGIT), divided into two clusters. There was a \"hot cluster\" (25%) consisting of patients with a high expression of these markers and a \"cold cluster\" (75%) comprising those without. The expression of CD39, CD44, CD68, CD163, IDO1, and Ki67 was significantly higher in tumors in the hot cluster. Immunologically, high-grade T1 tumors were significantly hotter, whereas tumors that had progressed to muscle invasion turned cold. However, a certain number of high-grade NMIBC patients were in the cold cluster, and these patients had a significantly higher risk of disease progression. Using an externally available TCGA dataset, RB1 and TP53 alterations were more frequently observed in TCGA hot cluster; rather FGFR3, KDM6A, and KMT2A alterations were common in TCGA cold/intermediate cluster. Analyses of recurrent tumors after BCG therapy revealed that tumor immune activity was widely maintained before and after treatment, and high FGFR3 expression was detected after recurrence in tumors initially classified into the cold cluster. Collectively, we revealed the dynamics of the tumor microenvironment in BC as a whole and identified candidate molecules as therapeutic targets for recurrent NMIBC, e.g., after BCG therapy.</p>","PeriodicalId":48943,"journal":{"name":"Cancer Science","volume":" ","pages":""},"PeriodicalIF":5.7,"publicationDate":"2024-10-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142478526","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}
Germline pathogenic variants (PVs) are pivotal in gynecological oncology. We focused on the prevalence, clinicopathological features, and survival impact of homologous recombination repair (HRR) PVs in patients with epithelial ovarian cancer (EOC). This was a multicenter retrospective cohort study, and 1248 patients with EOC were registered. Eligible patients (n = 1112) underwent germline DNA analysis for 26 cancer predisposition genes, including nine HRR-related genes, such as BRCA1/2, BRIP1, PALB2, RAD51C/D, and ATM. The associations between clinicopathological factors and HRR-related PVs were examined. Kaplan-Meier and Cox regression analyses were conducted. Among 1091 analyzed patients, 153 (14.0%) carried PVs and 140 (12.8%) were HRR-related. HRR-PV-positive status significantly correlated with serous carcinoma (22.9% vs. 4.8%, P < 0.0001) and advanced disease (18.5% vs. 5.9%, P < 0.0001). The HRR-PV-positive group exhibited higher prevalence of personal breast (12.9%) and familial breast/ovarian (29.2%) cancer history. HRR status independently improved overall survival in stage III/IV disease (P = 0.04) but not progression-free survival. HRR-related germline PVs exhibit distinct clinicopathological features with survival implications. Variants were significantly associated with serous carcinoma and advanced disease, underscoring the importance of genetic testing to develop individualized EOC treatment strategies. Considering the study period (2000-2019), the limited use of bevacizumab and poly (ADP-ribose) polymerase inhibitors as maintenance therapy should be recognized.
{"title":"Prevalence and outcomes of germline pathogenic variants of homologous recombination repair genes in ovarian cancer.","authors":"Maiko Miwa, Masakazu Kitagawa, Yuka Asami, Mayumi Kobayashi-Kato, Takafumi Watanabe, Aiko Ogasawara, Kengo Hiranuma, Hisamori Kato, Motonobu Saito, Yohei Miyagi, Tomoyasu Kato, Hiroshi Yoshida, Yukihide Momozawa, Takashi Kohno, Kouya Shiraishi, Kosei Hasegawa","doi":"10.1111/cas.16367","DOIUrl":"https://doi.org/10.1111/cas.16367","url":null,"abstract":"<p><p>Germline pathogenic variants (PVs) are pivotal in gynecological oncology. We focused on the prevalence, clinicopathological features, and survival impact of homologous recombination repair (HRR) PVs in patients with epithelial ovarian cancer (EOC). This was a multicenter retrospective cohort study, and 1248 patients with EOC were registered. Eligible patients (n = 1112) underwent germline DNA analysis for 26 cancer predisposition genes, including nine HRR-related genes, such as BRCA1/2, BRIP1, PALB2, RAD51C/D, and ATM. The associations between clinicopathological factors and HRR-related PVs were examined. Kaplan-Meier and Cox regression analyses were conducted. Among 1091 analyzed patients, 153 (14.0%) carried PVs and 140 (12.8%) were HRR-related. HRR-PV-positive status significantly correlated with serous carcinoma (22.9% vs. 4.8%, P < 0.0001) and advanced disease (18.5% vs. 5.9%, P < 0.0001). The HRR-PV-positive group exhibited higher prevalence of personal breast (12.9%) and familial breast/ovarian (29.2%) cancer history. HRR status independently improved overall survival in stage III/IV disease (P = 0.04) but not progression-free survival. HRR-related germline PVs exhibit distinct clinicopathological features with survival implications. Variants were significantly associated with serous carcinoma and advanced disease, underscoring the importance of genetic testing to develop individualized EOC treatment strategies. Considering the study period (2000-2019), the limited use of bevacizumab and poly (ADP-ribose) polymerase inhibitors as maintenance therapy should be recognized.</p>","PeriodicalId":48943,"journal":{"name":"Cancer Science","volume":" ","pages":""},"PeriodicalIF":5.7,"publicationDate":"2024-10-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142394490","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}
Liquid biopsy (LB) is an essential tool for obtaining tumor-derived materials with minimum invasion. Bile has been shown to contain much higher free nucleic acid levels than blood plasma and can be collected through endoscopic procedures. Therefore, bile possesses high potential as a source of tumor derived cell-free DNA (cfDNA) for bile duct cancers. In this study, we show that a multigene panel for plasma LB can also be applied to bile cfDNA for comparing driver gene mutation detection in other sources (plasma and tumor tissues of the corresponding patients). We collected cfDNA samples from the bile of 24 biliary tract cancer cases. These included 17 cholangiocarcinomas, three ampullary carcinoma, two pancreatic cancers, one intraductal papillary mucinous carcinoma, and one insulinoma. Seventeen plasma samples were obtained from the corresponding patients before surgical resection and subjected to the LiquidPlex multigene panel LB system. We applied a machine learning approach to classify possible tumor-derived variants among the prefiltered variant calls by a LiquidPlex analytical package with high fidelity. Among the 17 cholangiocarcinomas, we could detect cancer driver mutations in the bile of 10 cases using the LiquidPlex system. Of the biliary tract cancer cases examined with this method, 13 (54%) and 4 (17%) resulted in positive cancer driver mutation detection in the bile and plasma cfDNAs, respectively. These results suggest that bile is a more reliable source for LB than plasma for multigene panel analyses of biliary tract cancers.
{"title":"Usefulness of multigene liquid biopsy of bile for identifying driver genes of biliary duct cancers.","authors":"Shin Ito, Mika Ando, Shuichi Aoki, Satoshi Soma, Jie Zhang, Naohiro Hirano, Ryosuke Kashiwagi, Keigo Murakami, Shingo Yoshimachi, Hideaki Sato, Akiko Kusaka, Masahiro Iseki, Koetsu Inoue, Masamichi Mizuma, Kiyoshi Kume, Kei Nakagawa, Atsushi Masamune, Naoki Asano, Jun Yasuda, Michiaki Unno","doi":"10.1111/cas.16365","DOIUrl":"https://doi.org/10.1111/cas.16365","url":null,"abstract":"<p><p>Liquid biopsy (LB) is an essential tool for obtaining tumor-derived materials with minimum invasion. Bile has been shown to contain much higher free nucleic acid levels than blood plasma and can be collected through endoscopic procedures. Therefore, bile possesses high potential as a source of tumor derived cell-free DNA (cfDNA) for bile duct cancers. In this study, we show that a multigene panel for plasma LB can also be applied to bile cfDNA for comparing driver gene mutation detection in other sources (plasma and tumor tissues of the corresponding patients). We collected cfDNA samples from the bile of 24 biliary tract cancer cases. These included 17 cholangiocarcinomas, three ampullary carcinoma, two pancreatic cancers, one intraductal papillary mucinous carcinoma, and one insulinoma. Seventeen plasma samples were obtained from the corresponding patients before surgical resection and subjected to the LiquidPlex multigene panel LB system. We applied a machine learning approach to classify possible tumor-derived variants among the prefiltered variant calls by a LiquidPlex analytical package with high fidelity. Among the 17 cholangiocarcinomas, we could detect cancer driver mutations in the bile of 10 cases using the LiquidPlex system. Of the biliary tract cancer cases examined with this method, 13 (54%) and 4 (17%) resulted in positive cancer driver mutation detection in the bile and plasma cfDNAs, respectively. These results suggest that bile is a more reliable source for LB than plasma for multigene panel analyses of biliary tract cancers.</p>","PeriodicalId":48943,"journal":{"name":"Cancer Science","volume":" ","pages":""},"PeriodicalIF":5.7,"publicationDate":"2024-10-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142394492","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}
CX3CR1 functions as the specific receptor for the chemokine CX3CL1, demonstrating expression across a broad spectrum of immune cells. This underscores its pivotal role in communication and response mechanisms within the immune system. Upon engagement with CX3CL1, CX3CR1 initiates a cascade of downstream signaling pathways that regulate various biological functions. In the context of tumor progression, the intricate and inhibitory nature of the tumor microenvironment presents a significant challenge to current clinical treatment techniques. This review aims to comprehensively explore the tumor-destructive potential shown by CX3CR1+CD8+ T cells. Simultaneously, it investigates the promising prospects of utilizing CX3CR1 in future tumor immunotherapies.
{"title":"CX3CR1<sup>+</sup>CD8<sup>+</sup> T cells: Key players in antitumor immunity.","authors":"Jiajin Ma, Yue Wu, Shaoxian Wu, Zhang Fang, Lujun Chen, Jingting Jiang, Xiao Zheng","doi":"10.1111/cas.16359","DOIUrl":"https://doi.org/10.1111/cas.16359","url":null,"abstract":"<p><p>CX3CR1 functions as the specific receptor for the chemokine CX3CL1, demonstrating expression across a broad spectrum of immune cells. This underscores its pivotal role in communication and response mechanisms within the immune system. Upon engagement with CX3CL1, CX3CR1 initiates a cascade of downstream signaling pathways that regulate various biological functions. In the context of tumor progression, the intricate and inhibitory nature of the tumor microenvironment presents a significant challenge to current clinical treatment techniques. This review aims to comprehensively explore the tumor-destructive potential shown by CX3CR1<sup>+</sup>CD8<sup>+</sup> T cells. Simultaneously, it investigates the promising prospects of utilizing CX3CR1 in future tumor immunotherapies.</p>","PeriodicalId":48943,"journal":{"name":"Cancer Science","volume":" ","pages":""},"PeriodicalIF":5.7,"publicationDate":"2024-10-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142394487","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}
Lack of tumor-reactive cytotoxic T lymphocytes (CTLs) limits the antitumor efficacy of immune checkpoint inhibitors (ICIs). CD40 agonists have been expected to overcome this limitation by generating tumor-reactive CTLs. However, the clinical efficacy of CD40 agonistic antibodies is not as good as in non-clinical studies. The novel human CD40 (hCD40) agonist KHK2840 is a fully human anti-CD40 IgG2 agonistic antibody that is Fc-engineered to minimize complement-dependent cytotoxicity and antibody-dependent cellular cytotoxicity. Compared to other hCD40 agonists, KHK2840 exhibited the most potent hCD40 agonistic signal in tumor-bearing hCD40 transgenic mice and human peripheral blood B cells. Moreover, KHK2840 enhanced the antitumor efficacy of the antiprogrammed cell death 1 antibody and paclitaxel. Comprehensive immune profiling revealed that the antitumor immune response of the triple combination involved tumor-draining lymph nodes in addition to tumor microenvironments. This suggests that a coordinated antitumor immune response between tumors and lymph nodes may underlie the synergistic antitumor efficacy of the triple combination therapy. Finally, a toxicology study in cynomolgus monkeys demonstrated that KHK2840 activated the CD40 signal with tolerable toxicological properties. These results indicate that KHK2840 is a novel and potent hCD40 agonistic antibody for cancer immunotherapy, which is expected to augment the antitumor efficacy of ICIs and chemotherapy.
{"title":"The novel and potent CD40 agonist KHK2840 augments the antitumor efficacy of anti-PD-1 antibody and paclitaxel.","authors":"Chiaki Kobayashi, Minami Suzuki-Imaizumi, Yasuko Sakaguchi, Toshihiko Ishii, Maiko Adachi, Ayumi Kaneda, Ritsuko Ebihara, Masato Saito, Takeshi Uemori, Kiyotoshi Mori","doi":"10.1111/cas.16366","DOIUrl":"https://doi.org/10.1111/cas.16366","url":null,"abstract":"<p><p>Lack of tumor-reactive cytotoxic T lymphocytes (CTLs) limits the antitumor efficacy of immune checkpoint inhibitors (ICIs). CD40 agonists have been expected to overcome this limitation by generating tumor-reactive CTLs. However, the clinical efficacy of CD40 agonistic antibodies is not as good as in non-clinical studies. The novel human CD40 (hCD40) agonist KHK2840 is a fully human anti-CD40 IgG2 agonistic antibody that is Fc-engineered to minimize complement-dependent cytotoxicity and antibody-dependent cellular cytotoxicity. Compared to other hCD40 agonists, KHK2840 exhibited the most potent hCD40 agonistic signal in tumor-bearing hCD40 transgenic mice and human peripheral blood B cells. Moreover, KHK2840 enhanced the antitumor efficacy of the antiprogrammed cell death 1 antibody and paclitaxel. Comprehensive immune profiling revealed that the antitumor immune response of the triple combination involved tumor-draining lymph nodes in addition to tumor microenvironments. This suggests that a coordinated antitumor immune response between tumors and lymph nodes may underlie the synergistic antitumor efficacy of the triple combination therapy. Finally, a toxicology study in cynomolgus monkeys demonstrated that KHK2840 activated the CD40 signal with tolerable toxicological properties. These results indicate that KHK2840 is a novel and potent hCD40 agonistic antibody for cancer immunotherapy, which is expected to augment the antitumor efficacy of ICIs and chemotherapy.</p>","PeriodicalId":48943,"journal":{"name":"Cancer Science","volume":" ","pages":""},"PeriodicalIF":5.7,"publicationDate":"2024-10-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142394491","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}
Koki Takagi, Ariunbuyan Sukhbaatar, Yohei Inaba, Shiro Mori, Tetsuya Kodama
The combination of radiotherapy and immunotherapy is a promising approach that has been shown in clinical trials to improve significantly survival and response rates compared with monotherapy against solid tumor. Since anti-CTLA-4 antibodies block immunosuppressive signals mainly in the lymph nodes (LNs), efficient drug delivery to the lymphatic system is desirable. However, the immune checkpoint inhibitors, especially anti-CTLA-4 are currently administered intravenously (i.v.), resulting in limited efficacy in controlling solid tumor and inhibiting metastases, and the method of administration has not been optimized. Here, we show that a combination of local radiotherapy and administration of anti-CTLA-4 antibodies using a lymphatic drug delivery system (LDDS) suppresses solid tumor and metastases. We compared the efficacy of LDDS-based immunotherapy or radioimmunotherapy with i.v. administration in a solid-tumor model created by subcutaneous inoculation into LN-swollen mice with osteosarcoma cells. Tumor-bearing mice were divided into various groups (no treatment, immunotherapy [i.v. or LDDS], radiotherapy, and radioimmunotherapy [i.v. or LDDS]) and were observed for 28 days. Immunotherapy was administered with a cumulative dose of 10 mg/kg of anti-CTLA-4 monoclonal antibody, and radiotherapy was administered with a cumulative 8 Gy of fractionated X-ray irradiation. For immunotherapy alone, LDDS provided slight tumor growth inhibition but did not inhibit distant metastasis. For radioimmunotherapy, however, tumor growth was delayed and distant metastasis was suppressed compared with radiotherapy alone. In particular, the LDDS group achieved a high tumor-suppressive effect with T cell-mediated immune activity, indicating the efficacy of LDDS in radioimmunotherapy.
{"title":"A combination of lymphatic drug delivery of anti-CTLA-4 antibody and local radiotherapy for solid-tumor treatment.","authors":"Koki Takagi, Ariunbuyan Sukhbaatar, Yohei Inaba, Shiro Mori, Tetsuya Kodama","doi":"10.1111/cas.16369","DOIUrl":"https://doi.org/10.1111/cas.16369","url":null,"abstract":"<p><p>The combination of radiotherapy and immunotherapy is a promising approach that has been shown in clinical trials to improve significantly survival and response rates compared with monotherapy against solid tumor. Since anti-CTLA-4 antibodies block immunosuppressive signals mainly in the lymph nodes (LNs), efficient drug delivery to the lymphatic system is desirable. However, the immune checkpoint inhibitors, especially anti-CTLA-4 are currently administered intravenously (i.v.), resulting in limited efficacy in controlling solid tumor and inhibiting metastases, and the method of administration has not been optimized. Here, we show that a combination of local radiotherapy and administration of anti-CTLA-4 antibodies using a lymphatic drug delivery system (LDDS) suppresses solid tumor and metastases. We compared the efficacy of LDDS-based immunotherapy or radioimmunotherapy with i.v. administration in a solid-tumor model created by subcutaneous inoculation into LN-swollen mice with osteosarcoma cells. Tumor-bearing mice were divided into various groups (no treatment, immunotherapy [i.v. or LDDS], radiotherapy, and radioimmunotherapy [i.v. or LDDS]) and were observed for 28 days. Immunotherapy was administered with a cumulative dose of 10 mg/kg of anti-CTLA-4 monoclonal antibody, and radiotherapy was administered with a cumulative 8 Gy of fractionated X-ray irradiation. For immunotherapy alone, LDDS provided slight tumor growth inhibition but did not inhibit distant metastasis. For radioimmunotherapy, however, tumor growth was delayed and distant metastasis was suppressed compared with radiotherapy alone. In particular, the LDDS group achieved a high tumor-suppressive effect with T cell-mediated immune activity, indicating the efficacy of LDDS in radioimmunotherapy.</p>","PeriodicalId":48943,"journal":{"name":"Cancer Science","volume":" ","pages":""},"PeriodicalIF":5.7,"publicationDate":"2024-10-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142394486","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}
Joo Young Na, Juyeun Jeon, Ki Young Huh, Kyung-Sang Yu, Sangmi Lee, Jaehyun Eom, Jinhyung Ahn, Weon-Kyoo You, Jaeseong Oh
ABL001/CTX-009 is a bispecific antibody targeting delta-like ligand-4 and vascular endothelial growth factor A. In this study, we developed a population pharmacokinetic (PK) model of ABL001/CTX-009 in patients with solid tumors. A total of 712 plasma concentrations from 30 patients with relapsed or refractory solid tumors were collected from a phase 1 study (NCT03292783). A population PK model was developed using a nonlinear mixed-effect method and was evaluated by graphical and numerical methods. Using the model, the steady-state concentrations were simulated to compare weight-based and fixed-dose regimens and to find optimal dosing intervals. The PK of ABL001/CTX-009 was well described by a two-compartment model with a parallel first-order and Michaelis-Menten elimination kinetics. Body weight was selected as a significant covariate on V1. Model evaluation results suggested that the model was adequate and robust with good precision. Simulations after administrations of fixed or weight-based doses showed similar plasma concentrations. Additionally, 10 mg/kg for every other week and 15 mg/kg for every three-week administration showed comparable plasma concentrations. In conclusion, the model well described the plasma concentrations of ABL001/CTX-009 in patients with solid tumors. The simulation suggested that weight-based dose and fixed dose can provide equivalent systemic exposure.
{"title":"Population pharmacokinetic model of ABL001/CTX-009 (anti-VEGF/DLL4) in adult cancer patients with solid tumor.","authors":"Joo Young Na, Juyeun Jeon, Ki Young Huh, Kyung-Sang Yu, Sangmi Lee, Jaehyun Eom, Jinhyung Ahn, Weon-Kyoo You, Jaeseong Oh","doi":"10.1111/cas.16363","DOIUrl":"https://doi.org/10.1111/cas.16363","url":null,"abstract":"<p><p>ABL001/CTX-009 is a bispecific antibody targeting delta-like ligand-4 and vascular endothelial growth factor A. In this study, we developed a population pharmacokinetic (PK) model of ABL001/CTX-009 in patients with solid tumors. A total of 712 plasma concentrations from 30 patients with relapsed or refractory solid tumors were collected from a phase 1 study (NCT03292783). A population PK model was developed using a nonlinear mixed-effect method and was evaluated by graphical and numerical methods. Using the model, the steady-state concentrations were simulated to compare weight-based and fixed-dose regimens and to find optimal dosing intervals. The PK of ABL001/CTX-009 was well described by a two-compartment model with a parallel first-order and Michaelis-Menten elimination kinetics. Body weight was selected as a significant covariate on V1. Model evaluation results suggested that the model was adequate and robust with good precision. Simulations after administrations of fixed or weight-based doses showed similar plasma concentrations. Additionally, 10 mg/kg for every other week and 15 mg/kg for every three-week administration showed comparable plasma concentrations. In conclusion, the model well described the plasma concentrations of ABL001/CTX-009 in patients with solid tumors. The simulation suggested that weight-based dose and fixed dose can provide equivalent systemic exposure.</p>","PeriodicalId":48943,"journal":{"name":"Cancer Science","volume":" ","pages":""},"PeriodicalIF":5.7,"publicationDate":"2024-10-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142394489","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}
Our understanding of neoadjuvant treatment with microtubule inhibitors (MTIs) for triple negative breast cancer (TNBC) remains limited. To advance our understanding of the role of breast cancer driver genes' mutational status with pathological complete response (pCR; ypT0/isypN0) prediction and to identify distinct gene sets for MTIs like eribulin and paclitaxel, we carried out targeted genomic (n = 50) and whole transcriptomic profiling (n = 64) of TNBC tumor samples from the Japan Breast Cancer Research Group 22 (JBCRG-22) clinical trial. Lower PIK3CA, PTEN, and HRAS mutations were found in homologous recombination deficiency (HRD)-high (HRD score ≥ 42) tumors with higher pCR rates. When HRD-high tumors were stratified by tumor BRCA mutation status, the pCR rates in BRCA2-mutated tumors were higher (83% vs. 36%). Transcriptomic profiling of TP53-positive tumors identified downregulation of FGFR2 (false discovery rate p value = 2.07e-7), which was also the only common gene between HRD-high and -low tumors with pCR/quasi-pCR treated with paclitaxel and eribulin combined with carboplatin, respectively. Differential enrichment analysis of the HRD-high group posttreatment tumors revealed significant correlation (p = 0.006) of the glycan degradation pathway. FGFR2 expression and the differentially enriched pathways play a role in the response and resistance to MTIs containing carboplatin treatment in TNBC patients.
{"title":"Genomic and transcriptomic profiling of pre- and postneoadjuvant chemotherapy triple negative breast cancer tumors.","authors":"Tomomi Nishimura, Ravi Velaga, Norikazu Masuda, Kosuke Kawaguchi, Shuji Kawaguchi, Masahiro Takada, Yurina Maeshima, Sunao Tanaka, Yuichiro Kikawa, Takayuki Kadoya, Hiroko Bando, Rikiya Nakamura, Yutaka Yamamoto, Takayuki Ueno, Hiroyuki Yasojima, Hiroshi Ishiguro, Satoshi Morita, Shinji Ohno, Hironori Haga, Fumihiko Matsuda, Seishi Ogawa, Masakazu Toi","doi":"10.1111/cas.16339","DOIUrl":"https://doi.org/10.1111/cas.16339","url":null,"abstract":"<p><p>Our understanding of neoadjuvant treatment with microtubule inhibitors (MTIs) for triple negative breast cancer (TNBC) remains limited. To advance our understanding of the role of breast cancer driver genes' mutational status with pathological complete response (pCR; ypT0/isypN0) prediction and to identify distinct gene sets for MTIs like eribulin and paclitaxel, we carried out targeted genomic (n = 50) and whole transcriptomic profiling (n = 64) of TNBC tumor samples from the Japan Breast Cancer Research Group 22 (JBCRG-22) clinical trial. Lower PIK3CA, PTEN, and HRAS mutations were found in homologous recombination deficiency (HRD)-high (HRD score ≥ 42) tumors with higher pCR rates. When HRD-high tumors were stratified by tumor BRCA mutation status, the pCR rates in BRCA2-mutated tumors were higher (83% vs. 36%). Transcriptomic profiling of TP53-positive tumors identified downregulation of FGFR2 (false discovery rate p value = 2.07e-7), which was also the only common gene between HRD-high and -low tumors with pCR/quasi-pCR treated with paclitaxel and eribulin combined with carboplatin, respectively. Differential enrichment analysis of the HRD-high group posttreatment tumors revealed significant correlation (p = 0.006) of the glycan degradation pathway. FGFR2 expression and the differentially enriched pathways play a role in the response and resistance to MTIs containing carboplatin treatment in TNBC patients.</p>","PeriodicalId":48943,"journal":{"name":"Cancer Science","volume":" ","pages":""},"PeriodicalIF":5.7,"publicationDate":"2024-10-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142394488","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}
Accurate estimation of tumor mutational burden (TMB) as a predictor of responsiveness to immune checkpoint inhibitors in gene panel assays requires an adequate panel size. The current calculations of TMB only consider coding regions, while most of gene panel assays interrogate non-coding regions. Leveraging the non-coding regions is a potential solution to address this panel size limitation. However, the impact of including non-coding regions on the accuracy of TMB estimates remains unclear. This study investigated the validity of leveraging non-coding regions to supplement panel size using the OncoGuide NCC Oncopanel System (NOP). The aim of this study was to evaluate test performance against orthogonal assays and the association with responsiveness to immune checkpoint inhibitors was not included in the evaluation. We compared TMB status and values between TMB calculated only from coding regions (NOP-coding) and from both coding and non-coding regions (NOP-overall) using whole exome sequencing (WES) and FoundationOne®CDx (F1CDx) assay. Our findings revealed that NOP-overall significantly improved the overall percent agreement (OPA) with TMB status compared with NOP-coding for both WES (OPA: 96.7% vs. 73.3%, n = 30) and F1CDx (OPA: 90.0% vs. 73.3%). Additionally, the mean difference in TMB values compared with WES was lower for NOP-overall (3.55 [95% CI: 0.98-6.13]) than for NOP-coding (6.22 [95% CI: 3.73-8.70]). These results exemplify the utility of incorporating non-coding regions to maintain accurate TMB estimates in small-sized panels.
{"title":"Leveraging non-coding regions to guarantee the accuracy of small-sized panel-based tumor mutational burden estimates.","authors":"Takahiro Nishino, Mio Yumura, Kuniko Sunami, Takashi Kubo, Hitoshi Ichikawa, Tomoyo Yasuda, Eisaku Furukawa, Momoko Nagai, Yasushi Yatabe, Mamoru Kato, Takashi Kohno","doi":"10.1111/cas.16342","DOIUrl":"https://doi.org/10.1111/cas.16342","url":null,"abstract":"<p><p>Accurate estimation of tumor mutational burden (TMB) as a predictor of responsiveness to immune checkpoint inhibitors in gene panel assays requires an adequate panel size. The current calculations of TMB only consider coding regions, while most of gene panel assays interrogate non-coding regions. Leveraging the non-coding regions is a potential solution to address this panel size limitation. However, the impact of including non-coding regions on the accuracy of TMB estimates remains unclear. This study investigated the validity of leveraging non-coding regions to supplement panel size using the OncoGuide NCC Oncopanel System (NOP). The aim of this study was to evaluate test performance against orthogonal assays and the association with responsiveness to immune checkpoint inhibitors was not included in the evaluation. We compared TMB status and values between TMB calculated only from coding regions (NOP-coding) and from both coding and non-coding regions (NOP-overall) using whole exome sequencing (WES) and FoundationOne®CDx (F1CDx) assay. Our findings revealed that NOP-overall significantly improved the overall percent agreement (OPA) with TMB status compared with NOP-coding for both WES (OPA: 96.7% vs. 73.3%, n = 30) and F1CDx (OPA: 90.0% vs. 73.3%). Additionally, the mean difference in TMB values compared with WES was lower for NOP-overall (3.55 [95% CI: 0.98-6.13]) than for NOP-coding (6.22 [95% CI: 3.73-8.70]). These results exemplify the utility of incorporating non-coding regions to maintain accurate TMB estimates in small-sized panels.</p>","PeriodicalId":48943,"journal":{"name":"Cancer Science","volume":" ","pages":""},"PeriodicalIF":5.7,"publicationDate":"2024-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142330535","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}
Alternative splicing generates cancer-specific transcripts and is now recognized as a hallmark of cancer. However, the critical oncogenic spliceosome-related proteins involved in triple-negative breast cancer (TNBC) remain elusive. Here, we explored the expression pattern of spliceosome-related proteins in TNBC, non-TNBC, and normal breast tissues from The Cancer Genome Atlas breast cancer (TCGA-BRCA) cohort, revealing higher expression of nearly half of spliceosome-related proteins in TNBC than their counterparts. Among these TNBC-specific spliceosome-related proteins, the expression of SNRPB2 was associated with poor prognosis in patients with TNBC. In TNBC cells, the knockdown of SNRPB2 strongly suppressed cell proliferation and invasion and induced cell cycle arrest. Mechanistically, transcriptome data showed that SNRPB2 knockdown inactivated E2F1 signaling, which regulated the cell cycle. We further validated the downregulation of several cell cycle genes in SNRPB2 knockdown cells. Moreover, the analysis showed that SNRPB2 knockdown triggered the alteration of many alternative splicing events, most of which were skipping of exon. In TNBC cells, it was found that SNRPB2 knockdown led to the skipping of exon 6 in MDM4 pre-mRNA, generating MDM4-S transcript and downregulating MDM4 protein expression. More importantly, downregulation of MDM4 decreased retinoblastoma 1 (Rb1) protein expression, which is a target of MDM4 and a regulator of E2F1 signaling. In summary, the current study revealed an SNRPB2/MDM4/Rb axis in promoting the progression of TNBC, providing novel insights and novel targets for combating TNBC.
{"title":"SNRPB2 promotes triple-negative breast cancer progression by controlling alternative splicing of MDM4 pre-mRNA.","authors":"Shiyi Yu, Yue Si, Jianzhong Yu, Chengyang Jiang, Fei Cheng, Miao Xu, Zhehao Fan, Fangchen Liu, Chang Liu, Ying Wang, Ning Wang, Chenxu Liu, Caili Bi, Haibo Sun","doi":"10.1111/cas.16356","DOIUrl":"https://doi.org/10.1111/cas.16356","url":null,"abstract":"<p><p>Alternative splicing generates cancer-specific transcripts and is now recognized as a hallmark of cancer. However, the critical oncogenic spliceosome-related proteins involved in triple-negative breast cancer (TNBC) remain elusive. Here, we explored the expression pattern of spliceosome-related proteins in TNBC, non-TNBC, and normal breast tissues from The Cancer Genome Atlas breast cancer (TCGA-BRCA) cohort, revealing higher expression of nearly half of spliceosome-related proteins in TNBC than their counterparts. Among these TNBC-specific spliceosome-related proteins, the expression of SNRPB2 was associated with poor prognosis in patients with TNBC. In TNBC cells, the knockdown of SNRPB2 strongly suppressed cell proliferation and invasion and induced cell cycle arrest. Mechanistically, transcriptome data showed that SNRPB2 knockdown inactivated E2F1 signaling, which regulated the cell cycle. We further validated the downregulation of several cell cycle genes in SNRPB2 knockdown cells. Moreover, the analysis showed that SNRPB2 knockdown triggered the alteration of many alternative splicing events, most of which were skipping of exon. In TNBC cells, it was found that SNRPB2 knockdown led to the skipping of exon 6 in MDM4 pre-mRNA, generating MDM4-S transcript and downregulating MDM4 protein expression. More importantly, downregulation of MDM4 decreased retinoblastoma 1 (Rb1) protein expression, which is a target of MDM4 and a regulator of E2F1 signaling. In summary, the current study revealed an SNRPB2/MDM4/Rb axis in promoting the progression of TNBC, providing novel insights and novel targets for combating TNBC.</p>","PeriodicalId":48943,"journal":{"name":"Cancer Science","volume":" ","pages":""},"PeriodicalIF":5.7,"publicationDate":"2024-09-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142330538","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}