The intrinsic oncogenic mechanisms and properties of the tumor microenvironment (TME) have been extensively investigated. Primary features of the TME include metabolic reprogramming, hypoxia, chronic inflammation, and tumor immunosuppression. Previous studies suggest that senescence-associated secretory phenotypes that mediate intercellular information exchange play a role in the dynamic evolution of the TME. Specifically, hypoxic adaptation, metabolic dysregulation, and phenotypic shifts in immune cells regulated by cellular senescence synergistically contribute to the development of an immunosuppressive microenvironment and chronic inflammation, thereby promoting the progression of tumor events. This review provides a comprehensive summary of the processes by which cellular senescence regulates the dynamic evolution of the tumor-adapted TME, with focus on the complex mechanisms underlying the relationship between senescence and changes in the biological functions of tumor cells. The available findings suggest that components of the TME collectively contribute to the progression of tumor events. The potential applications and challenges of targeted cellular senescence-based and combination therapies in clinical settings are further discussed within the context of advancing cellular senescence-related research.
{"title":"Cellular senescence and metabolic reprogramming: Unraveling the intricate crosstalk in the immunosuppressive tumor microenvironment","authors":"Fusheng Zhang, Junchen Guo, Shengmiao Yu, Youwei Zheng, Meiqi Duan, Liang Zhao, Yihan Wang, Zhi Yang, Xiaofeng Jiang","doi":"10.1002/cac2.12591","DOIUrl":"10.1002/cac2.12591","url":null,"abstract":"<p>The intrinsic oncogenic mechanisms and properties of the tumor microenvironment (TME) have been extensively investigated. Primary features of the TME include metabolic reprogramming, hypoxia, chronic inflammation, and tumor immunosuppression. Previous studies suggest that senescence-associated secretory phenotypes that mediate intercellular information exchange play a role in the dynamic evolution of the TME. Specifically, hypoxic adaptation, metabolic dysregulation, and phenotypic shifts in immune cells regulated by cellular senescence synergistically contribute to the development of an immunosuppressive microenvironment and chronic inflammation, thereby promoting the progression of tumor events. This review provides a comprehensive summary of the processes by which cellular senescence regulates the dynamic evolution of the tumor-adapted TME, with focus on the complex mechanisms underlying the relationship between senescence and changes in the biological functions of tumor cells. The available findings suggest that components of the TME collectively contribute to the progression of tumor events. The potential applications and challenges of targeted cellular senescence-based and combination therapies in clinical settings are further discussed within the context of advancing cellular senescence-related research.</p>","PeriodicalId":9495,"journal":{"name":"Cancer Communications","volume":"44 9","pages":"929-966"},"PeriodicalIF":20.1,"publicationDate":"2024-07-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/cac2.12591","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141598537","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Sangyeop Hyun, Youngmin Han, Jae Yun Moon, Young-Ah Suh, Won-Gun Yun, Wooil Kwon, Jong-Eun Lee, Daeun Kim, Ja-Lok Ku, Jin-Young Jang, Daechan Park
<p>Patient-derived xenograft (PDX) models have been used to explore therapeutic opportunities for pancreatic ductal adenocarcinoma (PDAC) [<span>1</span>]. Although original tumor characteristics are altered by cancer-stromal interactions in a PDX-specific manner [<span>2</span>], the implications of clonal evolution from PDAC tumors to PDX are largely unknown.</p><p>In this study, we have conducted a comprehensive genomic analysis using 36 patient-matched PDAC tumor and PDX samples (Figure 1A). The detailed methods regarding this study are described in the Supplementary Materials. The clinical information is summarized in Supplementary Table S1. To compare the somatic mutation profiles of PDAC tumors and PDX, 33 whole exome sequencing data were analyzed by using matched patient blood as a normal control. The proportion of PDX samples with Kirsten Rat Sarcoma Viral Oncogene Homolog (<i>KRAS</i>), Tumor Protein P53 (<i>TP53</i>), Mothers Against Decapentaplegic Homolog 4 (<i>SMAD4</i>), and cyclin-dependent kinase inhibitor 2A (<i>CDKN2A</i>) mutations increased compared to PDAC tumors, indicating that cancerous clones evolved in PDX from primary tumors (Supplementary Table S2-S5, Figure 1B) [<span>3</span>]. Specifically, the frequency of the <i>KRAS</i> G12D mutation increased during PDX establishment, suggesting that this mutation could be responsible for driving clonal evolution in PDX models (Supplementary Table S2). Next, we observed the high correlation of the variant allele frequencies (VAFs) of commonly mutated genes between matched PDAC tumors and PDX in pairwise comparison (Figure 1C), indicating that the overall mutation rate was conserved during PDX construction. When VAFs were compared at the gene level, VAFs of driver genes significantly increased in PDX compared to primary tumors (Figure 1D). Copy number variation (CNV) profiles of protein-coding genes were also similar between the matched samples (Figure 1E, Supplementary Figure S1), while the copy numbers of driver genes became more evident in PDX compared to primary tumors (Figure 1F). Clonality analysis showed that subclones of primary tumors evolved as monoclonal or polyclonal patterns in matched PDX (Supplementary Figure S2). Despite the lack of investigations into clonal evolution over passages, these results suggest that molecular subtypes of PDX could deviate from PDAC tumors via clonal evolution during PDX model construction.</p><p>To investigate whether conventional PDAC subtyping is applicable to PDX, the molecular subtypes defined by Bailey <i>et al.</i> [<span>5</span>] were assigned to PDAC tumors and PDX. PDAC tumors were clearly clustered according to the Bailey gene signatures, showing the worst prognosis of patients with the squamous subtype as previously reported (Figure 1G). However, PDX clustering based on the Bailey gene signatures exhibited 61% (22/36) conflicting subtypes between the matched PDAC tumor and PDX samples (Supplementary Table S6). In particular
{"title":"Defining and tracing subtypes of patient-derived xenograft models in pancreatic ductal adenocarcinoma","authors":"Sangyeop Hyun, Youngmin Han, Jae Yun Moon, Young-Ah Suh, Won-Gun Yun, Wooil Kwon, Jong-Eun Lee, Daeun Kim, Ja-Lok Ku, Jin-Young Jang, Daechan Park","doi":"10.1002/cac2.12585","DOIUrl":"10.1002/cac2.12585","url":null,"abstract":"<p>Patient-derived xenograft (PDX) models have been used to explore therapeutic opportunities for pancreatic ductal adenocarcinoma (PDAC) [<span>1</span>]. Although original tumor characteristics are altered by cancer-stromal interactions in a PDX-specific manner [<span>2</span>], the implications of clonal evolution from PDAC tumors to PDX are largely unknown.</p><p>In this study, we have conducted a comprehensive genomic analysis using 36 patient-matched PDAC tumor and PDX samples (Figure 1A). The detailed methods regarding this study are described in the Supplementary Materials. The clinical information is summarized in Supplementary Table S1. To compare the somatic mutation profiles of PDAC tumors and PDX, 33 whole exome sequencing data were analyzed by using matched patient blood as a normal control. The proportion of PDX samples with Kirsten Rat Sarcoma Viral Oncogene Homolog (<i>KRAS</i>), Tumor Protein P53 (<i>TP53</i>), Mothers Against Decapentaplegic Homolog 4 (<i>SMAD4</i>), and cyclin-dependent kinase inhibitor 2A (<i>CDKN2A</i>) mutations increased compared to PDAC tumors, indicating that cancerous clones evolved in PDX from primary tumors (Supplementary Table S2-S5, Figure 1B) [<span>3</span>]. Specifically, the frequency of the <i>KRAS</i> G12D mutation increased during PDX establishment, suggesting that this mutation could be responsible for driving clonal evolution in PDX models (Supplementary Table S2). Next, we observed the high correlation of the variant allele frequencies (VAFs) of commonly mutated genes between matched PDAC tumors and PDX in pairwise comparison (Figure 1C), indicating that the overall mutation rate was conserved during PDX construction. When VAFs were compared at the gene level, VAFs of driver genes significantly increased in PDX compared to primary tumors (Figure 1D). Copy number variation (CNV) profiles of protein-coding genes were also similar between the matched samples (Figure 1E, Supplementary Figure S1), while the copy numbers of driver genes became more evident in PDX compared to primary tumors (Figure 1F). Clonality analysis showed that subclones of primary tumors evolved as monoclonal or polyclonal patterns in matched PDX (Supplementary Figure S2). Despite the lack of investigations into clonal evolution over passages, these results suggest that molecular subtypes of PDX could deviate from PDAC tumors via clonal evolution during PDX model construction.</p><p>To investigate whether conventional PDAC subtyping is applicable to PDX, the molecular subtypes defined by Bailey <i>et al.</i> [<span>5</span>] were assigned to PDAC tumors and PDX. PDAC tumors were clearly clustered according to the Bailey gene signatures, showing the worst prognosis of patients with the squamous subtype as previously reported (Figure 1G). However, PDX clustering based on the Bailey gene signatures exhibited 61% (22/36) conflicting subtypes between the matched PDAC tumor and PDX samples (Supplementary Table S6). In particular","PeriodicalId":9495,"journal":{"name":"Cancer Communications","volume":"44 8","pages":"921-925"},"PeriodicalIF":20.1,"publicationDate":"2024-07-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/cac2.12585","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141562645","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Michael Schnekenburger, Anne Lorant, Sruthi Reddy Gajulapalli, Ridhika Rajora, Jin-Young Lee, Aloran Mazumder, Haeun Yang, Christo Christov, Hyoung Jin Kang, Bernard Pirotte, Marc Diederich
<p>Chronic myeloid leukemia (CML) is a lethal hematopoietic malignancy with a global incidence primarily attributed to the <i>breakpoint cluster region-Abelson</i> (BCR-ABL1) fusion oncogene in over 95% of cases. The introduction of tyrosine kinase inhibitors (TKIs) has revolutionized CML management; however, a subset of patients encounters challenges such as resistance and relapse, hindering the achievement of complete remission. Overcoming these challenges in CML also requires addressing persistent leukemia stem cells (LSCs) with inherent resistance mechanisms. Key regulators of LSC metabolism, proliferation, and survival, as well as genetic and epigenetic alterations, provide potential targets [<span>1</span>].</p><p>In this study, leveraging in silico analysis (methods and descriptions of other assays are in the Supplementary file) of LSCs from CML patients at diagnosis, we demonstrated enrichment in pathways predominantly associated with proliferation, oxidative phosphorylation (OXPHOS), and metabolism, concurrently with a decrease in immune response pathways (Figure 1A). Similarly, genes negatively impacting proliferation in CML cell lines, when depleted by CRISPR, were enriched in processes related to OXPHOS, metabolism, and proliferation, mirroring the enrichment observed in LSCs (Figure 1B) [<span>2</span>].</p><p>Sirtuins (SIRTs) are nicotinamide adenine dinucleotide (NAD)<sup>+</sup>-dependent histone deacetylases. SIRT1 and SIRT2 modulate key signaling proteins impacting metabolism, survival, and stress response [<span>3</span>]. Overexpression of SIRT1 and SIRT2 was observed in various cancers, including leukemia (Supplementary Figure S1A) [<span>4, 5</span>]. However, our analysis of CML patients revealed variability in the expression levels of SIRT1 and SIRT2 across datasets (Supplementary Figure S1B). Given the relatively small sample sizes, we recognized the limitations of relying solely on single gene expression data, as it may not fully capture the functional relevance of SIRT1/2 in CML. In response to this limitation, we expanded our analysis to identify broader gene expression patterns associated with SIRT1/2. Specifically, we identified a CML-related network comprising 180 co-regulated transcriptional targets associated with SIRT1/2 enriched in genes relevant to leukemia (Figure 1C, Supplementary Figure S1C-E). To quantify their collective impact, we consolidated the expression of all transcripts in the SIRT1/2 regulon into a unified score, referred to as the SIRT1-2 regulon score. This score effectively discriminated between healthy hematopoietic stem cells and LSCs from CML patients at diagnosis (Figure 1D), indicating the collective impact of SIRT1 and SIRT2 on the disease.</p><p>Given the complementary roles of SIRT1 and 2 in regulating metabolic and survival pathways and their potential to compensate for each other's loss of function [<span>3</span>], we postulated that exploiting metabolic vulnerabilities in LSCs throu
{"title":"Dual inhibition of sirtuins 1 and 2: reprogramming metabolic energy dynamics in chronic myeloid leukemia as an immunogenic anticancer strategy","authors":"Michael Schnekenburger, Anne Lorant, Sruthi Reddy Gajulapalli, Ridhika Rajora, Jin-Young Lee, Aloran Mazumder, Haeun Yang, Christo Christov, Hyoung Jin Kang, Bernard Pirotte, Marc Diederich","doi":"10.1002/cac2.12590","DOIUrl":"10.1002/cac2.12590","url":null,"abstract":"<p>Chronic myeloid leukemia (CML) is a lethal hematopoietic malignancy with a global incidence primarily attributed to the <i>breakpoint cluster region-Abelson</i> (BCR-ABL1) fusion oncogene in over 95% of cases. The introduction of tyrosine kinase inhibitors (TKIs) has revolutionized CML management; however, a subset of patients encounters challenges such as resistance and relapse, hindering the achievement of complete remission. Overcoming these challenges in CML also requires addressing persistent leukemia stem cells (LSCs) with inherent resistance mechanisms. Key regulators of LSC metabolism, proliferation, and survival, as well as genetic and epigenetic alterations, provide potential targets [<span>1</span>].</p><p>In this study, leveraging in silico analysis (methods and descriptions of other assays are in the Supplementary file) of LSCs from CML patients at diagnosis, we demonstrated enrichment in pathways predominantly associated with proliferation, oxidative phosphorylation (OXPHOS), and metabolism, concurrently with a decrease in immune response pathways (Figure 1A). Similarly, genes negatively impacting proliferation in CML cell lines, when depleted by CRISPR, were enriched in processes related to OXPHOS, metabolism, and proliferation, mirroring the enrichment observed in LSCs (Figure 1B) [<span>2</span>].</p><p>Sirtuins (SIRTs) are nicotinamide adenine dinucleotide (NAD)<sup>+</sup>-dependent histone deacetylases. SIRT1 and SIRT2 modulate key signaling proteins impacting metabolism, survival, and stress response [<span>3</span>]. Overexpression of SIRT1 and SIRT2 was observed in various cancers, including leukemia (Supplementary Figure S1A) [<span>4, 5</span>]. However, our analysis of CML patients revealed variability in the expression levels of SIRT1 and SIRT2 across datasets (Supplementary Figure S1B). Given the relatively small sample sizes, we recognized the limitations of relying solely on single gene expression data, as it may not fully capture the functional relevance of SIRT1/2 in CML. In response to this limitation, we expanded our analysis to identify broader gene expression patterns associated with SIRT1/2. Specifically, we identified a CML-related network comprising 180 co-regulated transcriptional targets associated with SIRT1/2 enriched in genes relevant to leukemia (Figure 1C, Supplementary Figure S1C-E). To quantify their collective impact, we consolidated the expression of all transcripts in the SIRT1/2 regulon into a unified score, referred to as the SIRT1-2 regulon score. This score effectively discriminated between healthy hematopoietic stem cells and LSCs from CML patients at diagnosis (Figure 1D), indicating the collective impact of SIRT1 and SIRT2 on the disease.</p><p>Given the complementary roles of SIRT1 and 2 in regulating metabolic and survival pathways and their potential to compensate for each other's loss of function [<span>3</span>], we postulated that exploiting metabolic vulnerabilities in LSCs throu","PeriodicalId":9495,"journal":{"name":"Cancer Communications","volume":"44 8","pages":"915-920"},"PeriodicalIF":20.1,"publicationDate":"2024-07-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/cac2.12590","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141554217","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Rolf F. Barth, Gong Wu, Maria da Graca H. Vicente, John C Grecula, Nilendu Gupta
<p>This is the <i>third</i> Editorial/Commentary that one of us (R. F. Barth) has written relating to boron neutron capture therapy (BNCT) [<span>1, 2</span>]. For those readers who are unfamiliar with BNCT we would refer them to several recent comprehensive reviews [<span>3-5</span>]. The <i>second</i> Editorial ended on a hopeful note that with the introduction of accelerator-based neutron sources (ABNSs), BNCT would enter into the mainstream of radiation therapy [<span>2</span>]. This indeed has happened most notably in Japan, where BNCT now is being used to treat patients with recurrent tumors of the head and neck region, high-grade gliomas, meningiomas and melanomas. Similarly, there has been great interest in China, as indicated by an impressive number of publications coming from both of them [<span>4, 6, 7</span>]. In contrast to the active programs in Asia, there has been no recent clinical activity relating to BNCT in the United States and Europe. Hopefully, however, after many delays, a clinical program will be initiated in the near future in Finland using an ABNS to treat patients with recurrent tumors of the head and neck region. The obvious question is why there hasn't been interest in BNCT by clinicians in the United States and Europe? In this Editorial, we will address this question and hopefully make a convincing case for the further development of BNCT as a cancer treatment modality.</p><p>Why has it been so difficult to develop new boron delivery agents for BNCT? Very simply put, the requirements for such agents are very challenging [<span>3, 5</span>]. These include (1) delivery of ∼20-30 µg <sup>10</sup>B/g tumor; (2) high (>1) tumor:normal tissue and tumor:blood boron concentration ratios during irradiation; and (3) rapid clearance of boron from normal tissues while persisting in the tumor during neutron irradiation. The intracellular localization of <sup>10</sup>B in tumor cells is also important, and ideally, the closer to the nucleus, the better. To date, only two boron delivery agents have met many but not all of these requirements: a boron-containing derivative of phenylalanine, known as boronophenylalanine (BPA), and a polyhedral borane, known as sodium borocaptate (BSH). Finally, a major challenge in the development of effective boron delivery agents is their localization in all parts of the tumor and within all tumor cells. As reported by Elowitz et al. [<span>8</span>] and Goodman et al. [<span>9</span>], there was considerable variability in the boron concentrations of both BPA [<span>8</span>] and BSH [<span>9</span>] in multiple tissue samples taken from the same tumor. This would be especially true in brain tumors, since the blood-brain barrier limits trans-vascular entry of high-molecular weight boron delivery agents (>100 Da) into the tumor.</p><p>Many classes of boron-containing delivery agents have been proposed, and these broadly can be divided into low-molecular weight agents, such as amino acids, pep
{"title":"Boron neutron capture therapy of cancer: where do we stand now?","authors":"Rolf F. Barth, Gong Wu, Maria da Graca H. Vicente, John C Grecula, Nilendu Gupta","doi":"10.1002/cac2.12581","DOIUrl":"10.1002/cac2.12581","url":null,"abstract":"<p>This is the <i>third</i> Editorial/Commentary that one of us (R. F. Barth) has written relating to boron neutron capture therapy (BNCT) [<span>1, 2</span>]. For those readers who are unfamiliar with BNCT we would refer them to several recent comprehensive reviews [<span>3-5</span>]. The <i>second</i> Editorial ended on a hopeful note that with the introduction of accelerator-based neutron sources (ABNSs), BNCT would enter into the mainstream of radiation therapy [<span>2</span>]. This indeed has happened most notably in Japan, where BNCT now is being used to treat patients with recurrent tumors of the head and neck region, high-grade gliomas, meningiomas and melanomas. Similarly, there has been great interest in China, as indicated by an impressive number of publications coming from both of them [<span>4, 6, 7</span>]. In contrast to the active programs in Asia, there has been no recent clinical activity relating to BNCT in the United States and Europe. Hopefully, however, after many delays, a clinical program will be initiated in the near future in Finland using an ABNS to treat patients with recurrent tumors of the head and neck region. The obvious question is why there hasn't been interest in BNCT by clinicians in the United States and Europe? In this Editorial, we will address this question and hopefully make a convincing case for the further development of BNCT as a cancer treatment modality.</p><p>Why has it been so difficult to develop new boron delivery agents for BNCT? Very simply put, the requirements for such agents are very challenging [<span>3, 5</span>]. These include (1) delivery of ∼20-30 µg <sup>10</sup>B/g tumor; (2) high (>1) tumor:normal tissue and tumor:blood boron concentration ratios during irradiation; and (3) rapid clearance of boron from normal tissues while persisting in the tumor during neutron irradiation. The intracellular localization of <sup>10</sup>B in tumor cells is also important, and ideally, the closer to the nucleus, the better. To date, only two boron delivery agents have met many but not all of these requirements: a boron-containing derivative of phenylalanine, known as boronophenylalanine (BPA), and a polyhedral borane, known as sodium borocaptate (BSH). Finally, a major challenge in the development of effective boron delivery agents is their localization in all parts of the tumor and within all tumor cells. As reported by Elowitz et al. [<span>8</span>] and Goodman et al. [<span>9</span>], there was considerable variability in the boron concentrations of both BPA [<span>8</span>] and BSH [<span>9</span>] in multiple tissue samples taken from the same tumor. This would be especially true in brain tumors, since the blood-brain barrier limits trans-vascular entry of high-molecular weight boron delivery agents (>100 Da) into the tumor.</p><p>Many classes of boron-containing delivery agents have been proposed, and these broadly can be divided into low-molecular weight agents, such as amino acids, pep","PeriodicalId":9495,"journal":{"name":"Cancer Communications","volume":"44 8","pages":"889-892"},"PeriodicalIF":20.1,"publicationDate":"2024-07-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/cac2.12581","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141554216","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Boron neutron capture therapy (BNCT) is a cancer treatment modality based on the nuclear capture and fission reactions that occur when boron-10, a stable isotope, is irradiated with neutrons of the appropriate energy to produce boron-11 in an unstable form, which undergoes instantaneous nuclear fission to produce high-energy, tumoricidal alpha particles. The primary purpose of this review is to provide an update on the first drug used clinically, sodium borocaptate (BSH), by the Japanese neurosurgeon Hiroshi Hatanaka to treat patients with brain tumors and the second drug, boronophenylalanine (BPA), which first was used clinically by the Japanese dermatologist Yutaka Mishima to treat patients with cutaneous melanomas. Subsequently, BPA has become the primary drug used as a boron delivery agent to treat patients with several types of cancers, specifically brain tumors and recurrent tumors of the head and neck region. The focus of this review will be on the initial studies that were carried out to define the pharmacokinetics and pharmacodynamics of BSH and BPA and their biodistribution in tumor and normal tissues following administration to patients with high-grade gliomas and their subsequent clinical use to treat patients with high-grade gliomas. First, we will summarize the studies that were carried out in Japan with BSH and subsequently at our own institution, The Ohio State University, and those of several other groups. Second, we will describe studies carried out in Japan with BPA and then in the United States that have led to its use as the primary drug that is being used clinically for BNCT. Third, although there have been intense efforts to develop new and better boron delivery agents for BNCT, none of these have yet been evaluated clinically. The present report will provide a guide to the future clinical evaluation of new boron delivery agents prior to their clinical use for BNCT.
{"title":"Evaluation of sodium borocaptate (BSH) and boronophenylalanine (BPA) as boron delivery agents for neutron capture therapy (NCT) of cancer: an update and a guide for the future clinical evaluation of new boron delivery agents for NCT","authors":"Rolf F. Barth, Nilendu Gupta, Shinji Kawabata","doi":"10.1002/cac2.12582","DOIUrl":"10.1002/cac2.12582","url":null,"abstract":"<p>Boron neutron capture therapy (BNCT) is a cancer treatment modality based on the nuclear capture and fission reactions that occur when boron-10, a stable isotope, is irradiated with neutrons of the appropriate energy to produce boron-11 in an unstable form, which undergoes instantaneous nuclear fission to produce high-energy, tumoricidal alpha particles. The primary purpose of this review is to provide an update on the first drug used clinically, sodium borocaptate (BSH), by the Japanese neurosurgeon Hiroshi Hatanaka to treat patients with brain tumors and the second drug, boronophenylalanine (BPA), which first was used clinically by the Japanese dermatologist Yutaka Mishima to treat patients with cutaneous melanomas. Subsequently, BPA has become the primary drug used as a boron delivery agent to treat patients with several types of cancers, specifically brain tumors and recurrent tumors of the head and neck region. The focus of this review will be on the initial studies that were carried out to define the pharmacokinetics and pharmacodynamics of BSH and BPA and their biodistribution in tumor and normal tissues following administration to patients with high-grade gliomas and their subsequent clinical use to treat patients with high-grade gliomas. <i>First</i>, we will summarize the studies that were carried out in Japan with BSH and subsequently at our own institution, The Ohio State University, and those of several other groups. <i>Second</i>, we will describe studies carried out in Japan with BPA and then in the United States that have led to its use as the primary drug that is being used clinically for BNCT. <i>Third</i>, although there have been intense efforts to develop new and better boron delivery agents for BNCT, none of these have yet been evaluated clinically. The present report will provide a guide to the future clinical evaluation of new boron delivery agents prior to their clinical use for BNCT.</p>","PeriodicalId":9495,"journal":{"name":"Cancer Communications","volume":"44 8","pages":"893-909"},"PeriodicalIF":20.1,"publicationDate":"2024-07-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/cac2.12582","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141554218","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Shuqui Qin, Jin Li, Aiping Zhou, Yanqiao Zhang, Xianglin Yuan, Liangjun Zhu, Baoli Qin, Shan Zeng, Lin Shen, Ying Yuan, Weibo Wang, Jun Liang, Xianwen Zhang, Feng Ye, Ping Chen, Huaizhang Wang, Zhenyan Yu, Lu Yue, Yong Fang, Jianping Xiong, Jianwei Yang, Yiye Wan, Xianli Yin, Wenling Wang, Nong Xu, Xiaohong Wang, Zemin Xiao, Huafang Su, Ying Wang, Kangsheng Gu, Shuiping Tu, Zishu Wang, Bo Liu, Xiaohua Hu, Weixian Liu, Xiaofeng Li
<p>Primary chemotherapy options for colorectal cancer (CRC) involve four key drugs: fluorouracils (5-FU), oxaliplatin, irinotecan and raltitrexed. The first-line regimen consists of 5-FU and leucovorin combined with oxaliplatin (FOLFOX), while the second-line regimen involves 5-FU and leucovorin combined with irinotecan (FOLFIRI) for metastatic CRC (mCRC) in China [<span>1</span>]. Efficacy findings for FOLFOX and FOLFIRI as first-line treatments reported overall response rates (ORRs) of 54% and 56%, with median progression-free survival (mPFS) of 8.0 and 8.5 months, respectively. In the second-line setting, ORRs decreased to 15% and 4%, with mPFS of 4.2 and 2.5 months, respectively, possibly indicating induced drug resistance due to repeated 5-FU infusions in both first-line and second-line treatments [<span>2</span>]. Our present research was a prospective, non-interventional clinical trial conducted in 58 centers across China. The design and procedures are shown in the Supplementary Material. From April 2018 to March 2021, a total of 1,067 mCRC patients were enrolled for second-line treatment with raltitrexed plus irinotecan (SALIRI regimen) following unsuccessful 5-FU combined with platinum-based drug treatment, of whom 1,066 were included in the full analysis set (FAS) and 1,042 in the per-protocol set (PPS). The demographics, baseline and clinical characteristics of the patients are detailed in Supplementary Table S1.</p><p>The primary outcome revealed a mPFS of 7.3 months (range: 0.8-40.7, 95% confidence interval [CI]: 7.0-7.6) and a median overall survival (mOS) of 17.8 months (range: 1.4-47.3, 95% CI: 17.0-19.2) in both the FAS and PPS cohorts (Figure 1A-D, Supplementary Table S2).</p><p>Regarding secondary outcomes, mPFS and mOS were 5.8 (range: 0.8-34.5) and 17.0 (range: 1.8-47.3) months in the SALIRI group (<i>n</i> = 268), whereas in the SALIRI + targeted therapy (TAR; <i>n</i> = 795), including cetuximab (<i>n</i> = 103), bevacizumab (<i>n</i> = 678) or post-cetuximab + bevacizumab (<i>n</i> = 9) or the other targeted drug group (<i>n</i> = 5), mPFS and mOS were 7.6 (range: 0.8-40.7) and 18.1 (range: 1.4-40.7) months. A significant difference only in OS was found between SALIRI and the SALIRI + TAR groups (<i>P</i> = 0.045) (Figure 1E-F).</p><p>Subsequently, the ORR and disease control rate (DCR) for the entire cohort were 19.5% and 84.2%, respectively. The best tumor response comprised 1 patient achieving a complete response (0.1%), 207 with partial responses (19.4%), 690 attaining stable disease (64.7%) and 144 experiencing progressive disease (13.5%). However, in the SALIRI + TAR group, the ORR and DCR were 20.9% (95% CI: 18.1-23.9) and 85.8% (95% CI: 83.2-88.1), whereas in the SALIRI group, the ORR and DCR were 15.7% (95% CI: 11.5-20.6) and 80.6% (95% CI: 75.4-85.2), respectively (Supplementary Table S2).</p><p>In addition, an exploration of PFS and OS among patients with diverse genotypes, including mutation states of rat sarco
{"title":"SALIRI-based (raltitrexed plus irinotecan) therapy as a second-line treatment for patients with metastatic colorectal cancer (SALLY): A prospective, multicenter, non-interventional, registry study","authors":"Shuqui Qin, Jin Li, Aiping Zhou, Yanqiao Zhang, Xianglin Yuan, Liangjun Zhu, Baoli Qin, Shan Zeng, Lin Shen, Ying Yuan, Weibo Wang, Jun Liang, Xianwen Zhang, Feng Ye, Ping Chen, Huaizhang Wang, Zhenyan Yu, Lu Yue, Yong Fang, Jianping Xiong, Jianwei Yang, Yiye Wan, Xianli Yin, Wenling Wang, Nong Xu, Xiaohong Wang, Zemin Xiao, Huafang Su, Ying Wang, Kangsheng Gu, Shuiping Tu, Zishu Wang, Bo Liu, Xiaohua Hu, Weixian Liu, Xiaofeng Li","doi":"10.1002/cac2.12586","DOIUrl":"10.1002/cac2.12586","url":null,"abstract":"<p>Primary chemotherapy options for colorectal cancer (CRC) involve four key drugs: fluorouracils (5-FU), oxaliplatin, irinotecan and raltitrexed. The first-line regimen consists of 5-FU and leucovorin combined with oxaliplatin (FOLFOX), while the second-line regimen involves 5-FU and leucovorin combined with irinotecan (FOLFIRI) for metastatic CRC (mCRC) in China [<span>1</span>]. Efficacy findings for FOLFOX and FOLFIRI as first-line treatments reported overall response rates (ORRs) of 54% and 56%, with median progression-free survival (mPFS) of 8.0 and 8.5 months, respectively. In the second-line setting, ORRs decreased to 15% and 4%, with mPFS of 4.2 and 2.5 months, respectively, possibly indicating induced drug resistance due to repeated 5-FU infusions in both first-line and second-line treatments [<span>2</span>]. Our present research was a prospective, non-interventional clinical trial conducted in 58 centers across China. The design and procedures are shown in the Supplementary Material. From April 2018 to March 2021, a total of 1,067 mCRC patients were enrolled for second-line treatment with raltitrexed plus irinotecan (SALIRI regimen) following unsuccessful 5-FU combined with platinum-based drug treatment, of whom 1,066 were included in the full analysis set (FAS) and 1,042 in the per-protocol set (PPS). The demographics, baseline and clinical characteristics of the patients are detailed in Supplementary Table S1.</p><p>The primary outcome revealed a mPFS of 7.3 months (range: 0.8-40.7, 95% confidence interval [CI]: 7.0-7.6) and a median overall survival (mOS) of 17.8 months (range: 1.4-47.3, 95% CI: 17.0-19.2) in both the FAS and PPS cohorts (Figure 1A-D, Supplementary Table S2).</p><p>Regarding secondary outcomes, mPFS and mOS were 5.8 (range: 0.8-34.5) and 17.0 (range: 1.8-47.3) months in the SALIRI group (<i>n</i> = 268), whereas in the SALIRI + targeted therapy (TAR; <i>n</i> = 795), including cetuximab (<i>n</i> = 103), bevacizumab (<i>n</i> = 678) or post-cetuximab + bevacizumab (<i>n</i> = 9) or the other targeted drug group (<i>n</i> = 5), mPFS and mOS were 7.6 (range: 0.8-40.7) and 18.1 (range: 1.4-40.7) months. A significant difference only in OS was found between SALIRI and the SALIRI + TAR groups (<i>P</i> = 0.045) (Figure 1E-F).</p><p>Subsequently, the ORR and disease control rate (DCR) for the entire cohort were 19.5% and 84.2%, respectively. The best tumor response comprised 1 patient achieving a complete response (0.1%), 207 with partial responses (19.4%), 690 attaining stable disease (64.7%) and 144 experiencing progressive disease (13.5%). However, in the SALIRI + TAR group, the ORR and DCR were 20.9% (95% CI: 18.1-23.9) and 85.8% (95% CI: 83.2-88.1), whereas in the SALIRI group, the ORR and DCR were 15.7% (95% CI: 11.5-20.6) and 80.6% (95% CI: 75.4-85.2), respectively (Supplementary Table S2).</p><p>In addition, an exploration of PFS and OS among patients with diverse genotypes, including mutation states of rat sarco","PeriodicalId":9495,"journal":{"name":"Cancer Communications","volume":"44 8","pages":"910-914"},"PeriodicalIF":20.1,"publicationDate":"2024-07-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/cac2.12586","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141554219","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Anjali Chander, Jacopo Iacovacci, Aize Pellon, Rhadika Kataria, Anita Grigoriadis, John Maher, Cynthia Sears, Gilad Bachrach, Teresa Guerrero Urbano, Mary Lei, Imran Petkar, Anthony Kong, Tony Ng, Ester Orlandi, Nicola Alessandro Iacovelli, Loris De Cecco, Mara Serena Serafini, David Moyes, Tiziana Rancati, Miguel Reis Ferreira
<p>Head and neck squamous cell carcinoma (HNSCC) is a devastating disease. Despite morbid treatment, 5-year survival rates remain poor (28%-67%) [<span>1</span>]. There is a significant knowledge gap regarding how the microbiota may impact HNSCC treatment efficacy [<span>2</span>]. We used microbiome data from two independent cohorts to test and validate the hypothesis that oral bacteria are associated with HNSCC prognosis and in vitro models to investigate mechanistic underpinnings. Methods are detailed in Supplementary Materials.</p><p>We first explored associations between the relative abundance (RA) of bacterial genera and overall survival (OS) time in 155 patients with mucosal HNSCC available in the Cancer Microbiome Atlas (TCMA, Supplementary Table S1, Supplementary Text). The distribution of bacterial genera is shown in Supplementary Figure S1. Linear stepwise and Cox regression modeling evaluated associations between these genera and OS/DSS. Only <i>Fusobacterium</i> detectability was associated with both better OS (hazard ratio [HR] = 0.35, 95% confidence interval [CI] = 0.15-0.83], <i>P</i> = 0.018, Supplementary Figure S2A) and better disease-specific survival (DSS; 0.28 [0.15-0.83], <i>P</i> = 0.031, Supplementary Figure S2B). Kaplan-Meier survival analysis mirrored these results (Figure 1A-B). Additionally, <i>Fusobacterium</i> was more abundant in tumors compared to normal tissue (Supplementary Figure S3A-B), whereas a cognate Gram-negative oral commensal anaerobe, <i>Prevotella</i>, was not (Supplementary Figure S3C-D). Receiver operating characteristic (ROC) analysis identified a <i>Fusobacterium</i> RA cutoff of 0.016 (specificity: 92.7%; sensitivity: 28.8%). Patients with RA above the threshold had better OS and DSS (Supplementary Figure S4).</p><p>Next, we questioned whether any particular <i>Fusobacterium</i> species were associated with survival. Patients were stratified into groups with detectable and undetectable species (Supplementary Figure S5). In Cox regression, only <i>Fusobacterium nucleatum</i> detectability was significantly associated with OS (HR: 0.43 [95% CI: 0.19-0.97], <i>p</i> = 0.042; Supplementary Figure S6). Kaplan-Meier modeling showed that <i>F. nucleatum</i> detectability was associated with improved OS (<i>P</i> <0.001, Supplementary Figure S7A), with a trend for improved DSS (<i>P</i> = 0.096, Supplementary Figure S7B).</p><p>In multivariate Cox modeling with established predictors of survival (disease stage, smoking and Human Papilloma Virus [HPV] status), both <i>Fusobacterium</i> and <i>F. nucleatum</i> detectability were strongly associated with OS (<i>P</i> < 0.001 for both, Supplementary Figures S8A/S9A) and DSS (<i>P</i> < 0.001 and <i>P</i> = 0.015 for each respectively, Supplementary Figures S8B/S9B).</p><p>To test the validity of these results, we evaluated whether the abundance of <i>Fusobacterium</i> was also predictive of treatment efficacy in the separate MicroLearner cohort (<i>
为了检验所观察到的F. nucleatum对OSCC细胞毒性的影响是否是菌株特异性的、细胞系特异性的，而不是口腔共生厌氧菌的一般特性，我们将多个OSCC细胞系（TR146、HN5和HSC-3）与两种F. nucleatum菌株或口腔普雷沃特氏菌（MOI = 100）中的一种共培养，并评估它们对OSCC存活率的影响（图1E），用水晶紫测定法进行验证（补充图S14）。口腔念珠菌与F. nucleatum一样，是一种口腔共生革兰氏阴性厌氧菌。P.oralis感染不会影响OSCC的存活率，而两种F.nucleatum菌株都会降低OSCC的存活率。我们接下来询问了其他镰刀菌是否会导致 OSCC 死亡。我们测试了MOI为100的牙周病镰刀菌对OSCC培养物的影响，发现它对OSCC的杀伤作用与核酸镰刀菌类似（图1F）。在较低的 MOI（0.5-5）下，两个物种对 OSCC 的杀伤力也总体相似，并随着 MOI 的增加而增加（补充图 S15）。这些结果表明，在系统发育上与F. nucleatum接近的其他镰刀菌，而不是所有口腔共生革兰氏阴性厌氧菌都能导致OSCC死亡。我们接下来想知道OSCC死亡是由表面蛋白介导还是由分泌化合物/代谢物介导（图1G）。首先，用活的或热灭活的（inFnuc）F. nucleatum 感染 OSCC 细胞，评估 OSCC 的存活率。我们还检测了F. nucleatum培养上清液是否足以导致OSCC死亡。F. nucleatum上清液能杀死OSCC，而新鲜培养基不能。与生长肉汤相比，在新鲜肉汤中洗涤的 F. nucleatum 的共培养会显著减少 OSCC 的杀伤力，这表明共培养中上清液的持续产生。另外，我们使用了透孔插入物来防止 F. nucleatum 与 OSCC 直接接触，同时允许任何分泌分子在它们之间自由移动（补充图 S16）。在透孔复制品中观察到了明显的细胞杀伤作用，当 F. nucleatum 与 OSCC 直接接触时杀伤作用更强，这可能是因为与透孔复制品相比，直接接触共培养的局部浓度更高。虽然结直肠癌研究表明核酸酵母菌有助于肿瘤进展和耐药性，但这些细菌并不是正常肠道微生物群的常见成分，而它们却是正常口腔微生物群的常见成分[4]。以往的研究通常认为，肿瘤中镰刀菌（我们也检测到了）的丰度越高，表明其致癌作用越大[5]。然而，我们的研究结果表明，它的存在可能会提高 HNSCC 的治疗效果。总之，我们的初步研究表明，镰刀菌积极决定着 HNSCC 的生存结果。正在进行的研究将验证其作为HNSCC预测性生物标志物的作用，并剖析镰刀菌导致HNSCC死亡的机制。Miguel Reis Ferreira、Anjali Chander、Aize Pellon 和 David Moyes 设计了实验。Jacopo Iacovacci 和 Tiziana Rancati 设计并分析了 MicroLearner 研究数据。Miguel Reis Ferreira、Anjali Chander 和 Jacopo Iacovacci 分析数据。Jacopo Iacovacci、Rhadika Kataria、Anita Grigoriadis、David Moyes 和 Tiziana Rancati 为数据分析提供支持。Anjali Chander、Jacopo Iacovacci、Tiziana Rancati 和 Miguel Reis Ferreira 审核了结果、解释了数据并撰写了手稿。Anjali Chander、Jacopo Iacovacci、Aize Pellon、Rhadika Kataria、Anita Grigoriadis、John Maher、Cynthia Sears、Gilad Bachrach、Teresa Guerrero Urbano、Mary Lei、Imran Petkar、Anthony Kong、Tony Ng、Ester Orlandi、Nicola Alessandro Iacovelli、Loris De Cecco、Mara Serena Serafini、David Moyes、Tiziana Rancati 和 Miguel Reis Ferreira 对手稿的重要思想内容进行了严格审阅，并批准了最终版本。米格尔-雷斯-费雷拉对手稿的最终内容负主要责任。所有作者都审阅并批准了最终稿件的提交。作者声明不存在利益冲突：Guys癌症慈善机构（MRF）Guys癌症慈善机构（MRF）英国癌症研究中心通过伦敦市癌症中心（MRF）Fondazione Regionale per la Ricerca Biomedica，资助编号2721017（JI）.MicroLearner头颈癌和前列腺癌放疗患者微生物组观察研究已在ClinicalTrials.gov上注册（编号：NCT03294122），并获得当地伦理委员会批准（编号INT 11/17）。
{"title":"Fusobacterium is toxic for head and neck squamous cell carcinoma and its presence may determine a better prognosis","authors":"Anjali Chander, Jacopo Iacovacci, Aize Pellon, Rhadika Kataria, Anita Grigoriadis, John Maher, Cynthia Sears, Gilad Bachrach, Teresa Guerrero Urbano, Mary Lei, Imran Petkar, Anthony Kong, Tony Ng, Ester Orlandi, Nicola Alessandro Iacovelli, Loris De Cecco, Mara Serena Serafini, David Moyes, Tiziana Rancati, Miguel Reis Ferreira","doi":"10.1002/cac2.12588","DOIUrl":"10.1002/cac2.12588","url":null,"abstract":"<p>Head and neck squamous cell carcinoma (HNSCC) is a devastating disease. Despite morbid treatment, 5-year survival rates remain poor (28%-67%) [<span>1</span>]. There is a significant knowledge gap regarding how the microbiota may impact HNSCC treatment efficacy [<span>2</span>]. We used microbiome data from two independent cohorts to test and validate the hypothesis that oral bacteria are associated with HNSCC prognosis and in vitro models to investigate mechanistic underpinnings. Methods are detailed in Supplementary Materials.</p><p>We first explored associations between the relative abundance (RA) of bacterial genera and overall survival (OS) time in 155 patients with mucosal HNSCC available in the Cancer Microbiome Atlas (TCMA, Supplementary Table S1, Supplementary Text). The distribution of bacterial genera is shown in Supplementary Figure S1. Linear stepwise and Cox regression modeling evaluated associations between these genera and OS/DSS. Only <i>Fusobacterium</i> detectability was associated with both better OS (hazard ratio [HR] = 0.35, 95% confidence interval [CI] = 0.15-0.83], <i>P</i> = 0.018, Supplementary Figure S2A) and better disease-specific survival (DSS; 0.28 [0.15-0.83], <i>P</i> = 0.031, Supplementary Figure S2B). Kaplan-Meier survival analysis mirrored these results (Figure 1A-B). Additionally, <i>Fusobacterium</i> was more abundant in tumors compared to normal tissue (Supplementary Figure S3A-B), whereas a cognate Gram-negative oral commensal anaerobe, <i>Prevotella</i>, was not (Supplementary Figure S3C-D). Receiver operating characteristic (ROC) analysis identified a <i>Fusobacterium</i> RA cutoff of 0.016 (specificity: 92.7%; sensitivity: 28.8%). Patients with RA above the threshold had better OS and DSS (Supplementary Figure S4).</p><p>Next, we questioned whether any particular <i>Fusobacterium</i> species were associated with survival. Patients were stratified into groups with detectable and undetectable species (Supplementary Figure S5). In Cox regression, only <i>Fusobacterium nucleatum</i> detectability was significantly associated with OS (HR: 0.43 [95% CI: 0.19-0.97], <i>p</i> = 0.042; Supplementary Figure S6). Kaplan-Meier modeling showed that <i>F. nucleatum</i> detectability was associated with improved OS (<i>P</i> <0.001, Supplementary Figure S7A), with a trend for improved DSS (<i>P</i> = 0.096, Supplementary Figure S7B).</p><p>In multivariate Cox modeling with established predictors of survival (disease stage, smoking and Human Papilloma Virus [HPV] status), both <i>Fusobacterium</i> and <i>F. nucleatum</i> detectability were strongly associated with OS (<i>P</i> < 0.001 for both, Supplementary Figures S8A/S9A) and DSS (<i>P</i> < 0.001 and <i>P</i> = 0.015 for each respectively, Supplementary Figures S8B/S9B).</p><p>To test the validity of these results, we evaluated whether the abundance of <i>Fusobacterium</i> was also predictive of treatment efficacy in the separate MicroLearner cohort (<i>","PeriodicalId":9495,"journal":{"name":"Cancer Communications","volume":"44 8","pages":"879-883"},"PeriodicalIF":20.1,"publicationDate":"2024-07-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/cac2.12588","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141544578","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Sung Hee Choi, Jay Thomas Myers, Suzanne Louise Tomchuck, Melissa Bonner, Saada Eid, Daniel Tyler Kingsley, Kristen Ashley VanHeyst, Seong-Jin Kim, Byung-Gyu Kim, Alex Yee-Chen Huang
<p>Osteosarcoma is an aggressive malignant bone sarcoma common among children, adolescents, and young adults. Approximately 20% of patients present with pulmonary metastasis, and an additional 40% develop pulmonary osteosarcoma later. The survival outcome in patients with recurrent osteosarcoma and pulmonary osteosarcoma has not improved over many decades [<span>1</span>]. Transforming growth factor-β (TGF-β) is a potent immunosuppressive molecule in the osteosarcoma tumor microenvironment (TME) known to suppress the function of cytotoxic T cells and natural killer (NK) cells and correlates with high-grade osteosarcoma and pulmonary osteosarcoma [<span>2</span>]. Vactosertib (TEW-7197) is a highly selective and potent small molecule inhibitor against Type 1 TGF-β Receptor (activin receptor-like kinase 5; ALK5) [<span>3</span>]. Vactosertib is orally available and has 10 times the potency of galunisertib (IC50 = 11×10<sup>−3</sup> µmol/L vs. 11×10<sup>−2</sup> µmol/L) when tested in 4T1 [<span>4</span>], and is well tolerated with a manageable safety profile in adults, representing an attractive option in osteosarcoma [<span>3</span>].</p><p>TGF-β1 levels correlate with overall survival in osteosarcoma patients (Figure 1A). Vactosertib directly suppressed mouse osteosarcoma and human osteosarcoma cell line growth in a dose-dependent manner, with an IC50 of 0.79-2.1 µmol/L (Figure 1B). Vactosertib (1 × 10<sup>−1</sup> µmol/L) completely suppressed the TGF-β signaling intermediate, p-Smad2, in mouse osteosarcoma and human osteosarcoma cells (Figure 1C). In contrast, other TGF-β1 inhibitors, SB431542 and galunisertib, exhibited an IC50 of 2.05 × 10<sup>3</sup> µmol/L and 12 µmol/L, respectively, and they were not able to suppress p-Smad2 at 1 × 10<sup>−1</sup> µmol/L in SAOS2 cells (Supplementary Figure S1A-B). Vactosertib (1 × 10<sup>−1</sup> µmol/L) treated SAOS2 cells displayed 35 upregulated and 72 downregulated genes, including decreased expression of Ephrin-2 (EFNB2), IL-11, and prostate transmembrane protein androgen induced1 (PMEPA1) which were all associated with osteosarcoma progression and metastasis (Supplementary Figure S2A) [<span>5</span>]. Gene Set Enrichment Analysis (GSEA) revealed 14 down-regulated gene sets, including Wnt Beta-catenin signaling, TGF-β1 and mammalian target of rapamycin complex 1 (mTORC1) signaling (Supplementary Figure S2B), with Myelocytomatosis (MYC) target genes among the most inhibited (Supplementary Figure S2B-C).</p><p>SAOS2 treated with TGF-β1 (5 ng/mL) alone most significantly increased c-Myc target genes, and vactosertib co-treatment with TGF-β1 significantly suppressed the same c-Myc target gene sets (Figure 1D). Expression of individual c-Myc target genes was independently confirmed using real-time reverse transcription-polymerase chain reaction (RT-PCR) (Supplementary Figure S2D). TGF-β1 (5 ng/ml) treatment alone also significantly increased c-Myc protein expression in SAOS2 cells, while a low dose of
{"title":"Oral transforming growth factor-beta receptor 1 inhibitor vactosertib promotes osteosarcoma regression by targeting tumor proliferation and enhancing anti-tumor immunity","authors":"Sung Hee Choi, Jay Thomas Myers, Suzanne Louise Tomchuck, Melissa Bonner, Saada Eid, Daniel Tyler Kingsley, Kristen Ashley VanHeyst, Seong-Jin Kim, Byung-Gyu Kim, Alex Yee-Chen Huang","doi":"10.1002/cac2.12589","DOIUrl":"10.1002/cac2.12589","url":null,"abstract":"<p>Osteosarcoma is an aggressive malignant bone sarcoma common among children, adolescents, and young adults. Approximately 20% of patients present with pulmonary metastasis, and an additional 40% develop pulmonary osteosarcoma later. The survival outcome in patients with recurrent osteosarcoma and pulmonary osteosarcoma has not improved over many decades [<span>1</span>]. Transforming growth factor-β (TGF-β) is a potent immunosuppressive molecule in the osteosarcoma tumor microenvironment (TME) known to suppress the function of cytotoxic T cells and natural killer (NK) cells and correlates with high-grade osteosarcoma and pulmonary osteosarcoma [<span>2</span>]. Vactosertib (TEW-7197) is a highly selective and potent small molecule inhibitor against Type 1 TGF-β Receptor (activin receptor-like kinase 5; ALK5) [<span>3</span>]. Vactosertib is orally available and has 10 times the potency of galunisertib (IC50 = 11×10<sup>−3</sup> µmol/L vs. 11×10<sup>−2</sup> µmol/L) when tested in 4T1 [<span>4</span>], and is well tolerated with a manageable safety profile in adults, representing an attractive option in osteosarcoma [<span>3</span>].</p><p>TGF-β1 levels correlate with overall survival in osteosarcoma patients (Figure 1A). Vactosertib directly suppressed mouse osteosarcoma and human osteosarcoma cell line growth in a dose-dependent manner, with an IC50 of 0.79-2.1 µmol/L (Figure 1B). Vactosertib (1 × 10<sup>−1</sup> µmol/L) completely suppressed the TGF-β signaling intermediate, p-Smad2, in mouse osteosarcoma and human osteosarcoma cells (Figure 1C). In contrast, other TGF-β1 inhibitors, SB431542 and galunisertib, exhibited an IC50 of 2.05 × 10<sup>3</sup> µmol/L and 12 µmol/L, respectively, and they were not able to suppress p-Smad2 at 1 × 10<sup>−1</sup> µmol/L in SAOS2 cells (Supplementary Figure S1A-B). Vactosertib (1 × 10<sup>−1</sup> µmol/L) treated SAOS2 cells displayed 35 upregulated and 72 downregulated genes, including decreased expression of Ephrin-2 (EFNB2), IL-11, and prostate transmembrane protein androgen induced1 (PMEPA1) which were all associated with osteosarcoma progression and metastasis (Supplementary Figure S2A) [<span>5</span>]. Gene Set Enrichment Analysis (GSEA) revealed 14 down-regulated gene sets, including Wnt Beta-catenin signaling, TGF-β1 and mammalian target of rapamycin complex 1 (mTORC1) signaling (Supplementary Figure S2B), with Myelocytomatosis (MYC) target genes among the most inhibited (Supplementary Figure S2B-C).</p><p>SAOS2 treated with TGF-β1 (5 ng/mL) alone most significantly increased c-Myc target genes, and vactosertib co-treatment with TGF-β1 significantly suppressed the same c-Myc target gene sets (Figure 1D). Expression of individual c-Myc target genes was independently confirmed using real-time reverse transcription-polymerase chain reaction (RT-PCR) (Supplementary Figure S2D). TGF-β1 (5 ng/ml) treatment alone also significantly increased c-Myc protein expression in SAOS2 cells, while a low dose of ","PeriodicalId":9495,"journal":{"name":"Cancer Communications","volume":"44 8","pages":"884-888"},"PeriodicalIF":20.1,"publicationDate":"2024-07-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/cac2.12589","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141544579","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Jian Xiao, Shuqing Cao, Jiawei Wang, Pengyu Li, Quan Cheng, Xinyi Zhou, Jiacheng Dong, Yuan Li, Xinyu Zhao, Zekuan Xu, Li Yang
Background
Lymph node metastasis (LNM) is the primary mode of metastasis in gastric cancer (GC). However, the precise mechanisms underlying this process remain elusive. Tumor cells necessitate lipid metabolic reprogramming to facilitate metastasis, yet the role of lipoprotein lipase (LPL), a pivotal enzyme involved in exogenous lipid uptake, remains uncertain in tumor metastasis. Therefore, the aim of this study was to investigate the presence of lipid metabolic reprogramming during LNM of GC as well as the role of LPL in this process.
Methods
Intracellular lipid levels were quantified using oil red O staining, BODIPY 493/503 staining, and flow cytometry. Lipidomics analysis was employed to identify alterations in intracellular lipid composition following LPL knockdown. Protein expression levels were assessed through immunohistochemistry, Western blotting, and enzyme-linked immunosorbent assays. The mouse popliteal LNM model was utilized to investigate differences in LNM. Immunoprecipitation and mass spectrometry were employed to examine protein associations. In vitro phosphorylation assays and Phos-tag sodium dodecyl-sulfate polyacrylamide gel electrophoresis assays were conducted to detect angiopoietin-like protein 4 (ANGPTL4) phosphorylation.
Results
We identified that an elevated intracellular lipid level represents a crucial characteristic of node-positive (N+) GC and further demonstrated that a high-fat diet can expedite LNM. LPL was found to be significantly overexpressed in N+ GC tissues and shown to facilitate LNM by mediating dietary lipid uptake within GC cells. Leptin, an obesity-related hormone, intercepted the effect exerted by ANGPTL4/Furin on LPL cleavage. Circulating leptin binding to the leptin receptor could induce the activation of inositol-requiring enzyme-1 (IRE1) kinase, leading to the phosphorylation of ANGPTL4 at the serine 30 residue and subsequently reducing its binding affinity with LPL. Moreover, our research revealed that LPL disrupted lipid homeostasis by elevating intracellular levels of arachidonic acid, which then triggered the cyclooxygenase-2/prostaglandin E2 (PGE2) pathway, thereby promoting tumor lymphangiogenesis.
Conclusions
Leptin-induced phosphorylation of ANGPTL4 facilitates LPL-mediated lipid uptake and consequently stimulates the production of PGE2, ultimately facilitating LNM in GC.
{"title":"Leptin-mediated suppression of lipoprotein lipase cleavage enhances lipid uptake and facilitates lymph node metastasis in gastric cancer","authors":"Jian Xiao, Shuqing Cao, Jiawei Wang, Pengyu Li, Quan Cheng, Xinyi Zhou, Jiacheng Dong, Yuan Li, Xinyu Zhao, Zekuan Xu, Li Yang","doi":"10.1002/cac2.12583","DOIUrl":"10.1002/cac2.12583","url":null,"abstract":"<div>\u0000 \u0000 \u0000 <section>\u0000 \u0000 <h3> Background</h3>\u0000 \u0000 <p>Lymph node metastasis (LNM) is the primary mode of metastasis in gastric cancer (GC). However, the precise mechanisms underlying this process remain elusive. Tumor cells necessitate lipid metabolic reprogramming to facilitate metastasis, yet the role of lipoprotein lipase (LPL), a pivotal enzyme involved in exogenous lipid uptake, remains uncertain in tumor metastasis. Therefore, the aim of this study was to investigate the presence of lipid metabolic reprogramming during LNM of GC as well as the role of LPL in this process.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Methods</h3>\u0000 \u0000 <p>Intracellular lipid levels were quantified using oil red O staining, BODIPY 493/503 staining, and flow cytometry. Lipidomics analysis was employed to identify alterations in intracellular lipid composition following LPL knockdown. Protein expression levels were assessed through immunohistochemistry, Western blotting, and enzyme-linked immunosorbent assays. The mouse popliteal LNM model was utilized to investigate differences in LNM. Immunoprecipitation and mass spectrometry were employed to examine protein associations. In vitro phosphorylation assays and Phos-tag sodium dodecyl-sulfate polyacrylamide gel electrophoresis assays were conducted to detect angiopoietin-like protein 4 (ANGPTL4) phosphorylation.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Results</h3>\u0000 \u0000 <p>We identified that an elevated intracellular lipid level represents a crucial characteristic of node-positive (N+) GC and further demonstrated that a high-fat diet can expedite LNM. LPL was found to be significantly overexpressed in N+ GC tissues and shown to facilitate LNM by mediating dietary lipid uptake within GC cells. Leptin, an obesity-related hormone, intercepted the effect exerted by ANGPTL4/Furin on LPL cleavage. Circulating leptin binding to the leptin receptor could induce the activation of inositol-requiring enzyme-1 (IRE1) kinase, leading to the phosphorylation of ANGPTL4 at the serine 30 residue and subsequently reducing its binding affinity with LPL. Moreover, our research revealed that LPL disrupted lipid homeostasis by elevating intracellular levels of arachidonic acid, which then triggered the cyclooxygenase-2/prostaglandin E2 (PGE2) pathway, thereby promoting tumor lymphangiogenesis.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Conclusions</h3>\u0000 \u0000 <p>Leptin-induced phosphorylation of ANGPTL4 facilitates LPL-mediated lipid uptake and consequently stimulates the production of PGE2, ultimately facilitating LNM in GC.</p>\u0000 </section>\u0000 </div>","PeriodicalId":9495,"journal":{"name":"Cancer Communications","volume":"44 8","pages":"855-878"},"PeriodicalIF":20.1,"publicationDate":"2024-07-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/cac2.12583","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141490968","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Disitamab vedotin (DV; RC48-ADC) is an antibody-drug conjugate comprising a human epidermal growth factor receptor 2 (HER2)-directed antibody, linker and monomethyl auristatin E. Preclinical studies have shown that DV demonstrated potent antitumor activity in preclinical models of breast, gastric, and ovarian cancers with different levels of HER2 expression. In this pooled analysis, we report the safety and efficacy of DV in patients with HER2-overexpression and HER2-low advanced breast cancer (ABC).
Methods
In the phase I dose-escalation study (C001 CANCER), HER2-overexpression ABC patients received DV at doses of 0.5-2.5 mg/kg once every two weeks (Q2W) until unacceptable toxicity or progressive disease. The dose range, safety, and pharmacokinetics (PK) were determined. The phase Ib dose-range and expansion study (C003 CANCER) enrolled two cohorts: HER2-overexpression ABC patients receiving DV at doses of 1.5-2.5 mg/kg Q2W, with the recommended phase 2 dose (RP2D) determined, and HER2-low ABC patients receiving DV at doses of 2.0 mg/kg Q2W to explore the efficacy and safety of DV in HER2-low ABC.
Results
Twenty-four patients with HER2-overexpression ABC in C001 CANCER, 46 patients with HER2-overexpression ABC and 66 patients with HER2-low ABC in C003 CANCER were enrolled. At 2.0 mg/kg RP2D Q2W, the confirmed objective response rates were 42.9% (9/21; 95% confidence interval [CI]: 21.8%-66.0%) and 33.3% (22/66; 95% CI: 22.2%-46.0%), with median progression-free survival (PFS) of 5.7 months (95% CI: 5.3-8.4 months) and 5.1 months (95% CI: 4.1-6.6 months) for HER2-overexpression and HER2-low ABC, respectively. Common (≥5%) grade 3 or higher treatment-emergent adverse events included neutrophil count decreased (17.6%), gamma-glutamyl transferase increased (13.2%), asthenia (11.0%), white blood cell count decreased (9.6%), peripheral neuropathy such as hypoesthesia (5.9%) and neurotoxicity (0.7%), and pain (5.9%).
Conclusion
DV demonstrated promising efficacy in HER2-overexpression and HER2-low ABC, with a favorable safety profile at 2.0 mg/kg Q2W.
{"title":"Disitamab vedotin, a HER2-directed antibody-drug conjugate, in patients with HER2-overexpression and HER2-low advanced breast cancer: a phase I/Ib study","authors":"Jiayu Wang, Yunjiang Liu, Qingyuan Zhang, Wei Li, Jifeng Feng, Xiaojia Wang, Jianmin Fang, Yiqun Han, Binghe Xu","doi":"10.1002/cac2.12577","DOIUrl":"10.1002/cac2.12577","url":null,"abstract":"<div>\u0000 \u0000 \u0000 <section>\u0000 \u0000 <h3> Background</h3>\u0000 \u0000 <p>Disitamab vedotin (DV; RC48-ADC) is an antibody-drug conjugate comprising a human epidermal growth factor receptor 2 (HER2)-directed antibody, linker and monomethyl auristatin E. Preclinical studies have shown that DV demonstrated potent antitumor activity in preclinical models of breast, gastric, and ovarian cancers with different levels of HER2 expression. In this pooled analysis, we report the safety and efficacy of DV in patients with HER2-overexpression and HER2-low advanced breast cancer (ABC).</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Methods</h3>\u0000 \u0000 <p>In the phase I dose-escalation study (C001 CANCER), HER2-overexpression ABC patients received DV at doses of 0.5-2.5 mg/kg once every two weeks (Q2W) until unacceptable toxicity or progressive disease. The dose range, safety, and pharmacokinetics (PK) were determined. The phase Ib dose-range and expansion study (C003 CANCER) enrolled two cohorts: HER2-overexpression ABC patients receiving DV at doses of 1.5-2.5 mg/kg Q2W, with the recommended phase 2 dose (RP2D) determined, and HER2-low ABC patients receiving DV at doses of 2.0 mg/kg Q2W to explore the efficacy and safety of DV in HER2-low ABC.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Results</h3>\u0000 \u0000 <p>Twenty-four patients with HER2-overexpression ABC in C001 CANCER, 46 patients with HER2-overexpression ABC and 66 patients with HER2-low ABC in C003 CANCER were enrolled. At 2.0 mg/kg RP2D Q2W, the confirmed objective response rates were 42.9% (9/21; 95% confidence interval [CI]: 21.8%-66.0%) and 33.3% (22/66; 95% CI: 22.2%-46.0%), with median progression-free survival (PFS) of 5.7 months (95% CI: 5.3-8.4 months) and 5.1 months (95% CI: 4.1-6.6 months) for HER2-overexpression and HER2-low ABC, respectively. Common (≥5%) grade 3 or higher treatment-emergent adverse events included neutrophil count decreased (17.6%), gamma-glutamyl transferase increased (13.2%), asthenia (11.0%), white blood cell count decreased (9.6%), peripheral neuropathy such as hypoesthesia (5.9%) and neurotoxicity (0.7%), and pain (5.9%).</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Conclusion</h3>\u0000 \u0000 <p>DV demonstrated promising efficacy in HER2-overexpression and HER2-low ABC, with a favorable safety profile at 2.0 mg/kg Q2W.</p>\u0000 </section>\u0000 </div>","PeriodicalId":9495,"journal":{"name":"Cancer Communications","volume":"44 7","pages":"833-851"},"PeriodicalIF":20.1,"publicationDate":"2024-06-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11260767/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141466388","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
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