Pub Date : 2024-06-16DOI: 10.1016/j.bbcan.2024.189138
Binyumeng Jiang , Ahmed Elkashif , Jonathan A. Coulter , Nicholas J. Dunne , Helen O. McCarthy
Head and neck cancer (HNSCC) is the 8th most common cancer in the UK, with incidence increasing due to lifestyle factors such as tobacco and alcohol abuse. HNSCC is an immune-suppressive disease characterised by impaired cytokine secretion and dysregulation of immune infiltrate. As such, immunotherapy is a potential treatment option, with therapeutic cancer vaccination demonstrating the greatest potential. The success of cancer vaccination is dependent on informed antigen selection: an ideal antigen must be either tumour-specific or tumour-associated, as well as highly immunogenic. Stratification of the patient population for antigen expression and validated biomarkers are also vital. This review focuses on the latest developments in immunotherapy, specifically the development of therapeutic vaccines, and highlights successes, potential drawbacks and areas for future development. Immunotherapy approaches considered for HNSCC include monoclonal antibodies (mAb), Oncolytic viral (OV) therapies, Immune Checkpoint Inhibitors (ICIs) and cancer vaccines.
{"title":"Immunotherapy for HPV negative head and neck squamous cell carcinoma","authors":"Binyumeng Jiang , Ahmed Elkashif , Jonathan A. Coulter , Nicholas J. Dunne , Helen O. McCarthy","doi":"10.1016/j.bbcan.2024.189138","DOIUrl":"10.1016/j.bbcan.2024.189138","url":null,"abstract":"<div><p>Head and neck cancer (HNSCC) is the 8th most common cancer in the UK, with incidence increasing due to lifestyle factors such as tobacco and alcohol abuse. HNSCC is an immune-suppressive disease characterised by impaired cytokine secretion and dysregulation of immune infiltrate. As such, immunotherapy is a potential treatment option, with therapeutic cancer vaccination demonstrating the greatest potential. The success of cancer vaccination is dependent on informed antigen selection: an ideal antigen must be either tumour-specific or tumour-associated, as well as highly immunogenic. Stratification of the patient population for antigen expression and validated biomarkers are also vital. This review focuses on the latest developments in immunotherapy, specifically the development of therapeutic vaccines, and highlights successes, potential drawbacks and areas for future development. Immunotherapy approaches considered for HNSCC include monoclonal antibodies (mAb), Oncolytic viral (OV) therapies, Immune Checkpoint Inhibitors (ICIs) and cancer vaccines.</p></div>","PeriodicalId":8782,"journal":{"name":"Biochimica et biophysica acta. Reviews on cancer","volume":null,"pages":null},"PeriodicalIF":9.7,"publicationDate":"2024-06-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.sciencedirect.com/science/article/pii/S0304419X24000696/pdfft?md5=bdc7cbe790355737e7d62382e69fc496&pid=1-s2.0-S0304419X24000696-main.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141413692","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}
Pub Date : 2024-06-15DOI: 10.1016/j.bbcan.2024.189136
Niharika, Lina Ureka, Ankan Roy, Samir Kumar Patra
SRY (Sex Determining Region) box 2 (SOX2) is an essential transcription factor that plays crucial roles in activating genes involved in pre- and post-embryonic development, adult tissue homeostasis, and lineage specifications. SOX2 maintains the self-renewal property of stem cells and is involved in the generation of induced pluripotency stem cells. SOX2 protein contains a particular high-mobility group domain that enables SOX2 to achieve the capacity to participate in a broad variety of functions. The information about the involvement of SOX2 with gene regulatory elements, signaling networks, and microRNA is gradually emerging, and the higher expression of SOX2 is functionally relevant to various cancer types. SOX2 facilitates the oncogenic phenotype via cellular proliferation and enhancement of invasive tumor properties. Evidence are accumulating in favor of three dimensional (higher order) folding of chromatin and epigenetic control of the SOX2 gene by chromatin modifications, which implies that the expression level of SOX2 can be modulated by epigenetic regulatory mechanisms, specifically, via DNA methylation and histone H3 modification. In view of this, and to focus further insights into the roles SOX2 plays in physiological functions, involvement of SOX2 during development, precisely, the advances of our knowledge in pre- and post-embryonic development, and interactions of SOX2 in this scenario with various signaling pathways in tumor development and cancer progression, its potential as a therapeutic target against many cancers are summarized and discussed in this article.
{"title":"Dissecting SOX2 expression and function reveals an association with multiple signaling pathways during embryonic development and in cancer progression","authors":"Niharika, Lina Ureka, Ankan Roy, Samir Kumar Patra","doi":"10.1016/j.bbcan.2024.189136","DOIUrl":"10.1016/j.bbcan.2024.189136","url":null,"abstract":"<div><p>SRY (Sex Determining Region) box 2 (SOX2) is an essential transcription factor that plays crucial roles in activating genes involved in pre- and post-embryonic development, adult tissue homeostasis, and lineage specifications. SOX2 maintains the self-renewal property of stem cells and is involved in the generation of induced pluripotency stem cells. SOX2 protein contains a particular high-mobility group domain that enables SOX2 to achieve the capacity to participate in a broad variety of functions. The information about the involvement of SOX2 with gene regulatory elements, signaling networks, and microRNA is gradually emerging, and the higher expression of SOX2 is functionally relevant to various cancer types. SOX2 facilitates the oncogenic phenotype via cellular proliferation and enhancement of invasive tumor properties. Evidence are accumulating in favor of three dimensional (higher order) folding of chromatin and epigenetic control of the SOX2 gene by chromatin modifications, which implies that the expression level of SOX2 can be modulated by epigenetic regulatory mechanisms, specifically, via DNA methylation and histone H3 modification. In view of this, and to focus further insights into the roles SOX2 plays in physiological functions, involvement of SOX2 during development, precisely, the advances of our knowledge in pre- and post-embryonic development, and interactions of SOX2 in this scenario with various signaling pathways in tumor development and cancer progression, its potential as a therapeutic target against many cancers are summarized and discussed in this article.</p></div>","PeriodicalId":8782,"journal":{"name":"Biochimica et biophysica acta. Reviews on cancer","volume":null,"pages":null},"PeriodicalIF":11.2,"publicationDate":"2024-06-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141332722","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-06-14DOI: 10.1016/j.bbcan.2024.189137
Tian-Qi Zhang , Qian-Yu Lv , Wei-Lin Jin
Cancer is a profoundly dynamic, heterogeneous and aggressive systemic ailment, with a coordinated evolution of various types of tumor niches. Hypoxia plays an indispensable role in the tumor micro-ecosystem, drastically enhancing the plasticity of cancer cells, fibroblasts and immune cells and orchestrating intercellular communication. Hypoxia-induced signals, particularly hypoxia-inducible factor-1α (HIF-1α), drive the reprogramming of genetic, transcriptional, and proteomic profiles. This leads to a spectrum of interconnected processes, including augmented survival of cancer cells, evasion of immune surveillance, metabolic reprogramming, remodeling of the extracellular matrix, and the development of resistance to conventional therapeutic modalities like radiotherapy and chemotherapy. Here, we summarize the latest research on the multifaceted effects of hypoxia, where a multitude of cellular and non-cellular elements crosstalk with each other and co-evolve in a synergistic manner. Additionally, we investigate therapeutic approaches targeting hypoxic niche, encompassing hypoxia-activated prodrugs, HIF inhibitors, nanomedicines, and combination therapies. Finally, we discuss some of the issues to be addressed and highlight the potential of emerging technologies in the treatment of cancer.
{"title":"The cellular-centered view of hypoxia tumor microenvironment: Molecular mechanisms and therapeutic interventions","authors":"Tian-Qi Zhang , Qian-Yu Lv , Wei-Lin Jin","doi":"10.1016/j.bbcan.2024.189137","DOIUrl":"10.1016/j.bbcan.2024.189137","url":null,"abstract":"<div><p>Cancer is a profoundly dynamic, heterogeneous and aggressive systemic ailment, with a coordinated evolution of various types of tumor niches. Hypoxia plays an indispensable role in the tumor micro-ecosystem, drastically enhancing the plasticity of cancer cells, fibroblasts and immune cells and orchestrating intercellular communication. Hypoxia-induced signals, particularly hypoxia-inducible factor-1α (HIF-1α), drive the reprogramming of genetic, transcriptional, and proteomic profiles. This leads to a spectrum of interconnected processes, including augmented survival of cancer cells, evasion of immune surveillance, metabolic reprogramming, remodeling of the extracellular matrix, and the development of resistance to conventional therapeutic modalities like radiotherapy and chemotherapy. Here, we summarize the latest research on the multifaceted effects of hypoxia, where a multitude of cellular and non-cellular elements crosstalk with each other and co-evolve in a synergistic manner. Additionally, we investigate therapeutic approaches targeting hypoxic niche, encompassing hypoxia-activated prodrugs, HIF inhibitors, nanomedicines, and combination therapies. Finally, we discuss some of the issues to be addressed and highlight the potential of emerging technologies in the treatment of cancer.</p></div>","PeriodicalId":8782,"journal":{"name":"Biochimica et biophysica acta. Reviews on cancer","volume":null,"pages":null},"PeriodicalIF":11.2,"publicationDate":"2024-06-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141332723","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-06-06DOI: 10.1016/j.bbcan.2024.189125
Li Niu , Ting Chen , Aodan Yang , Xiwen Yan , Feng Jin , Ang Zheng , Xinyue Song
Tertiary lymphoid structures (TLS) can reflect cancer prognosis and clinical outcomes in various tumour tissues. Tumour-associated macrophages (TAMs) are indispensable components of the tumour microenvironment and play crucial roles in tumour development and immunotherapy. TAMs are associated with TLS induction via the modulation of the T cell response, which is a major component of the TLS. Despite their important roles in cancer immunology, the subtypes of TAMs that influence TLS and their correlation with prognosis are not completely understood. Here, we provide novel insights into the role of TAMs in regulating TLS formation. Furthermore, we discuss the prognostic value of these TAM subtypes and TLS, as well as the current antitumour therapies for inducing TLS. This study highlights an entirely new field of TLS regulation that may lead to the development of an innovative perspective on immunotherapy for cancer treatment.
三级淋巴结构(TLS)可反映各种肿瘤组织的癌症预后和临床结果。肿瘤相关巨噬细胞(TAMs)是肿瘤微环境不可或缺的组成部分,在肿瘤发生发展和免疫治疗中发挥着关键作用。TAMs 通过调节 T 细胞反应与 TLS 诱导有关,而 T 细胞反应是 TLS 的主要组成部分。尽管TAMs在癌症免疫学中发挥着重要作用,但影响TLS的TAMs亚型及其与预后的相关性还不完全清楚。在这里,我们对 TAMs 在调节 TLS 形成中的作用提出了新的见解。此外,我们还讨论了这些 TAM 亚型和 TLS 的预后价值,以及目前诱导 TLS 的抗肿瘤疗法。这项研究凸显了 TLS 调节的全新领域,可能会为癌症治疗的免疫疗法带来创新性的发展前景。
{"title":"Macrophages and tertiary lymphoid structures as indicators of prognosis and therapeutic response in cancer patients","authors":"Li Niu , Ting Chen , Aodan Yang , Xiwen Yan , Feng Jin , Ang Zheng , Xinyue Song","doi":"10.1016/j.bbcan.2024.189125","DOIUrl":"10.1016/j.bbcan.2024.189125","url":null,"abstract":"<div><p>Tertiary lymphoid structures (TLS) can reflect cancer prognosis and clinical outcomes in various tumour tissues. Tumour-associated macrophages (TAMs) are indispensable components of the tumour microenvironment and play crucial roles in tumour development and immunotherapy. TAMs are associated with TLS induction via the modulation of the T cell response, which is a major component of the TLS. Despite their important roles in cancer immunology, the subtypes of TAMs that influence TLS and their correlation with prognosis are not completely understood. Here, we provide novel insights into the role of TAMs in regulating TLS formation. Furthermore, we discuss the prognostic value of these TAM subtypes and TLS, as well as the current antitumour therapies for inducing TLS. This study highlights an entirely new field of TLS regulation that may lead to the development of an innovative perspective on immunotherapy for cancer treatment.</p></div>","PeriodicalId":8782,"journal":{"name":"Biochimica et biophysica acta. Reviews on cancer","volume":null,"pages":null},"PeriodicalIF":11.2,"publicationDate":"2024-06-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141294024","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-06-06DOI: 10.1016/j.bbcan.2024.189126
Zhixiang Hu , Xinyi Guo , Ziteng Li , Zhiqiang Meng , Shenglin Huang
Neoantigen-based therapy is a promising approach that selectively activates the immune system of the host to recognize and eradicate cancer cells. Preliminary clinical trials have validated the feasibility, safety, and immunogenicity of personalized neoantigen-directed vaccines, enhancing their effectiveness and broad applicability in immunotherapy. While many ongoing oncological trials concentrate on neoantigens derived from mutations, these targets do not consistently provoke an immune response in all patients harboring the mutations. Additionally, tumors like ovarian cancer, which have a low tumor mutational burden (TMB), may be less amenable to mutation-based neoantigen therapies. Recent advancements in next-generation sequencing and bioinformatics have uncovered a rich source of neoantigens from non-canonical RNAs associated with transposable elements (TEs). Considering the substantial presence of TEs in the human genome and the proven immunogenicity of TE-derived neoantigens in various tumor types, this review investigates the latest findings on TE-derived neoantigens, examining their clinical implications, challenges, and unique advantages in enhancing tumor immunotherapy.
{"title":"The neoantigens derived from transposable elements – A hidden treasure for cancer immunotherapy","authors":"Zhixiang Hu , Xinyi Guo , Ziteng Li , Zhiqiang Meng , Shenglin Huang","doi":"10.1016/j.bbcan.2024.189126","DOIUrl":"10.1016/j.bbcan.2024.189126","url":null,"abstract":"<div><p>Neoantigen-based therapy is a promising approach that selectively activates the immune system of the host to recognize and eradicate cancer cells. Preliminary clinical trials have validated the feasibility, safety, and immunogenicity of personalized neoantigen-directed vaccines, enhancing their effectiveness and broad applicability in immunotherapy. While many ongoing oncological trials concentrate on neoantigens derived from mutations, these targets do not consistently provoke an immune response in all patients harboring the mutations. Additionally, tumors like ovarian cancer, which have a low tumor mutational burden (TMB), may be less amenable to mutation-based neoantigen therapies. Recent advancements in next-generation sequencing and bioinformatics have uncovered a rich source of neoantigens from non-canonical RNAs associated with transposable elements (TEs). Considering the substantial presence of TEs in the human genome and the proven immunogenicity of TE-derived neoantigens in various tumor types, this review investigates the latest findings on TE-derived neoantigens, examining their clinical implications, challenges, and unique advantages in enhancing tumor immunotherapy.</p></div>","PeriodicalId":8782,"journal":{"name":"Biochimica et biophysica acta. Reviews on cancer","volume":null,"pages":null},"PeriodicalIF":11.2,"publicationDate":"2024-06-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141289035","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-05-26DOI: 10.1016/j.bbcan.2024.189123
Lucy C. Picard, Fenella J. Rich, Diane N. Kenwright, Aaron J. Stevens
Bacillus Calmette-Guérin (BCG) treatment for non-muscle invasive bladder cancer (NMIBC) is an established immunotherapeutic, however, a significant portion of patients do not respond to treatment. Despite extensive research into the therapeutic mechanism of BCG, gaps remain in our understanding. This review specifically focuses on the epigenomic contributions in the immune microenvironment, in the context of BCG treatment for NMIBC. We also summarise the current understanding of NMIBC epigenetic characteristics, and discuss how future targeted strategies for BCG therapy should incorporate epigenomic biomarkers in conjunction with genomic biomarkers.
{"title":"Epigenetic changes associated with Bacillus Calmette-Guerin (BCG) treatment in bladder cancer","authors":"Lucy C. Picard, Fenella J. Rich, Diane N. Kenwright, Aaron J. Stevens","doi":"10.1016/j.bbcan.2024.189123","DOIUrl":"10.1016/j.bbcan.2024.189123","url":null,"abstract":"<div><p>Bacillus Calmette-Guérin (BCG) treatment for non-muscle invasive bladder cancer (NMIBC) is an established immunotherapeutic, however, a significant portion of patients do not respond to treatment. Despite extensive research into the therapeutic mechanism of BCG, gaps remain in our understanding. This review specifically focuses on the epigenomic contributions in the immune microenvironment, in the context of BCG treatment for NMIBC. We also summarise the current understanding of NMIBC epigenetic characteristics, and discuss how future targeted strategies for BCG therapy should incorporate epigenomic biomarkers in conjunction with genomic biomarkers.</p></div>","PeriodicalId":8782,"journal":{"name":"Biochimica et biophysica acta. Reviews on cancer","volume":null,"pages":null},"PeriodicalIF":11.2,"publicationDate":"2024-05-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.sciencedirect.com/science/article/pii/S0304419X24000544/pdfft?md5=5bd9a2538bf1d665304cded2d8d6a283&pid=1-s2.0-S0304419X24000544-main.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141162850","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}
Pub Date : 2024-05-25DOI: 10.1016/j.bbcan.2024.189124
M. Kciuk , A. Gielecińska , Ż. Kałuzińska-Kołat , E.B. Yahya , R. Kontek
Apoptosis has traditionally been regarded as the desired cell death pathway activated by chemotherapeutic drugs due to its controlled and non-inflammatory nature. However, recent discoveries of alternative cell death pathways have paved the way for immune-stimulatory treatment approaches in cancer. Ferroptosis (dependent on iron) and cuproptosis (dependent on copper) hold promise for selective cancer cell targeting and overcoming drug resistance. Copper ionophores and iron-bearing nano-drugs show potential for clinical therapy as single agents and as adjuvant treatments. Here we review up-to-date evidence for the involvement of metal ion-dependent cell death pathways in the cytotoxicity of classical chemotherapeutic agents (alkylating agents, topoisomerase inhibitors, antimetabolites, and mitotic spindle inhibitors) and their combinations with cuproptosis and ferroptosis inducers, indicating the prospects, advantages, and obstacles of their use.
{"title":"Ferroptosis and cuproptosis: Metal-dependent cell death pathways activated in response to classical chemotherapy – Significance for cancer treatment?","authors":"M. Kciuk , A. Gielecińska , Ż. Kałuzińska-Kołat , E.B. Yahya , R. Kontek","doi":"10.1016/j.bbcan.2024.189124","DOIUrl":"10.1016/j.bbcan.2024.189124","url":null,"abstract":"<div><p>Apoptosis has traditionally been regarded as the desired cell death pathway activated by chemotherapeutic drugs due to its controlled and non-inflammatory nature. However, recent discoveries of alternative cell death pathways have paved the way for immune-stimulatory treatment approaches in cancer. Ferroptosis (dependent on iron) and cuproptosis (dependent on copper) hold promise for selective cancer cell targeting and overcoming drug resistance. Copper ionophores and iron-bearing nano-drugs show potential for clinical therapy as single agents and as adjuvant treatments. Here we review up-to-date evidence for the involvement of metal ion-dependent cell death pathways in the cytotoxicity of classical chemotherapeutic agents (alkylating agents, topoisomerase inhibitors, antimetabolites, and mitotic spindle inhibitors) and their combinations with cuproptosis and ferroptosis inducers, indicating the prospects, advantages, and obstacles of their use.</p></div>","PeriodicalId":8782,"journal":{"name":"Biochimica et biophysica acta. Reviews on cancer","volume":null,"pages":null},"PeriodicalIF":11.2,"publicationDate":"2024-05-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.sciencedirect.com/science/article/pii/S0304419X24000556/pdfft?md5=e522af3f11fb9f2662348ecfe1234e20&pid=1-s2.0-S0304419X24000556-main.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141158651","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}
Pub Date : 2024-05-25DOI: 10.1016/j.bbcan.2024.189120
Roberto Ronca , Claudiu T. Supuran
Carbonic anhydrases (CAs), are metallo-enzymes implicated in several pathophysiological processes where tissue pH regulation is required. CA IX is a tumor-associated CA isoform induced by hypoxia and involved in the adaptation of tumor cells to acidosis. Indeed, several tumor-driving pathways can induce CA IX expression, and this in turn has been associated to cancer cells invasion and metastatic features as well as to induction of stem-like features, drug resistance and recurrence. After its functional and structural characterization CA IX targeting approaches have been developed to inhibit its activity in neoplastic tissues, and to date this field has seen an incredible acceleration in terms of therapeutic options and biological readouts. Small molecules inhibitors, hybrid/dual targeting drugs, targeting antibodies and adoptive (CAR-T based) cell therapy have been developed at preclinical level, whereas a sulfonamide CA IX inhibitor and an antibody entered Phase Ib/II clinical trials for the treatment and imaging of different solid tumors. Here recent advances on CA IX biology and pharmacology in cancer, and its therapeutic targeting will be discussed.
碳酸酐酶(CA)是一种金属酶,与多种需要调节组织 pH 值的病理生理过程有关。CA IX 是一种肿瘤相关的 CA 异构体,由缺氧诱导,参与肿瘤细胞对酸中毒的适应。事实上,几种肿瘤驱动途径都能诱导 CA IX 的表达,而这反过来又与癌细胞的侵袭和转移特征以及诱导干样特征、耐药性和复发有关。在对 CA IX 进行功能和结构表征后,人们开发出了抑制其在肿瘤组织中活性的靶向方法。小分子抑制剂、混合/双靶向药物、靶向抗体和收养(基于 CAR-T 的)细胞疗法已在临床前水平开发出来,而磺胺 CA IX 抑制剂和抗体已进入 Ib/II 期临床试验,用于不同实体瘤的治疗和成像。本文将讨论癌症中 CA IX 生物学和药理学的最新进展及其治疗靶点。
{"title":"Carbonic anhydrase IX: An atypical target for innovative therapies in cancer","authors":"Roberto Ronca , Claudiu T. Supuran","doi":"10.1016/j.bbcan.2024.189120","DOIUrl":"10.1016/j.bbcan.2024.189120","url":null,"abstract":"<div><p>Carbonic anhydrases (CAs), are metallo-enzymes implicated in several pathophysiological processes where tissue pH regulation is required. CA IX is a tumor-associated CA isoform induced by hypoxia and involved in the adaptation of tumor cells to acidosis. Indeed, several tumor-driving pathways can induce CA IX expression, and this in turn has been associated to cancer cells invasion and metastatic features as well as to induction of stem-like features, drug resistance and recurrence. After its functional and structural characterization CA IX targeting approaches have been developed to inhibit its activity in neoplastic tissues, and to date this field has seen an incredible acceleration in terms of therapeutic options and biological readouts. Small molecules inhibitors, hybrid/dual targeting drugs, targeting antibodies and adoptive (CAR-T based) cell therapy have been developed at preclinical level, whereas a sulfonamide CA IX inhibitor and an antibody entered Phase Ib/II clinical trials for the treatment and imaging of different solid tumors. Here recent advances on CA IX biology and pharmacology in cancer, and its therapeutic targeting will be discussed.</p></div>","PeriodicalId":8782,"journal":{"name":"Biochimica et biophysica acta. Reviews on cancer","volume":null,"pages":null},"PeriodicalIF":11.2,"publicationDate":"2024-05-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.sciencedirect.com/science/article/pii/S0304419X24000519/pdfft?md5=6d3ac5790309de74d9844f45f2d450f2&pid=1-s2.0-S0304419X24000519-main.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141158645","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}
Pub Date : 2024-05-23DOI: 10.1016/j.bbcan.2024.189121
Zheng Zhang , Zhen Gang Lv , Miao Lu , Haifeng Li , Jiahua Zhou
The autonomic nerve system (ANS) innervates organs and tissues throughout the body and maintains functional balance among various systems. Further investigations have shown that excessive activation of ANS not only causes disruption of homeostasis, but also may promote tumor formation. In addition, the dynamic interaction between nerve and tumor cells in the tumor microenvironment also regulate tumor progression. On the one hand, nerves are passively invaded by tumor cells, that is, perineural invasion (PNI). On the other hand, compared with normal tissues, tumor tissues are subject to more abundant innervation, and nerves can influence tumor progression through regulating tumor proliferation, metastasis and drug resistance. A large number of studies have shown that nerve-tumor crosstalk, including PNI and innervation, is closely related to the prognosis of patients, and contributes to the formation of cancer pain, which significantly deteriorates the quality of life for patients. These findings suggest that nerve-tumor crosstalk represents a potential target for anti-tumor therapies and the management of cancer pain in the future. In this review, we systematically describe the mechanism by which nerve-tumor crosstalk regulates tumorigenesis and progression.
{"title":"Nerve-tumor crosstalk in tumor microenvironment: From tumor initiation and progression to clinical implications","authors":"Zheng Zhang , Zhen Gang Lv , Miao Lu , Haifeng Li , Jiahua Zhou","doi":"10.1016/j.bbcan.2024.189121","DOIUrl":"10.1016/j.bbcan.2024.189121","url":null,"abstract":"<div><p>The autonomic nerve system (ANS) innervates organs and tissues throughout the body and maintains functional balance among various systems. Further investigations have shown that excessive activation of ANS not only causes disruption of homeostasis, but also may promote tumor formation. In addition, the dynamic interaction between nerve and tumor cells in the tumor microenvironment also regulate tumor progression. On the one hand, nerves are passively invaded by tumor cells, that is, perineural invasion (PNI). On the other hand, compared with normal tissues, tumor tissues are subject to more abundant innervation, and nerves can influence tumor progression through regulating tumor proliferation, metastasis and drug resistance. A large number of studies have shown that nerve-tumor crosstalk, including PNI and innervation, is closely related to the prognosis of patients, and contributes to the formation of cancer pain, which significantly deteriorates the quality of life for patients. These findings suggest that nerve-tumor crosstalk represents a potential target for anti-tumor therapies and the management of cancer pain in the future. In this review, we systematically describe the mechanism by which nerve-tumor crosstalk regulates tumorigenesis and progression.</p></div>","PeriodicalId":8782,"journal":{"name":"Biochimica et biophysica acta. Reviews on cancer","volume":null,"pages":null},"PeriodicalIF":11.2,"publicationDate":"2024-05-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141142156","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-05-23DOI: 10.1016/j.bbcan.2024.189122
Louay Abo Qoura , Konstantin V. Balakin , Robert M. Hoffman , Vadim S. Pokrovsky
Cancer cells are addicted to L-methionine (L-Met) and have a much greater requirement for L-Met than normal cells due to excess transmethylation, termed the Hoffman effect. By targeting this vulnerability through dietary restriction of L-Met, researchers have been able to achieve promising results in inhibiting tumor growth and eradicating cancer cells. Methioninase (EC 4.4.1.11; METase) catalyzes the transformation of L-Met into α-ketobutyrate, ammonia, and methanethiol. The use of METase was initially limited due to its poor stability in vivo, high immunogenicity, and enzyme-induced inactivating antibodies. These issues could be partially resolved by PEGylation, encapsulation in erythrocytes, and various site-directed mutagenesis. The big breakthrough came when it was discovered that METase is effectively administered orally. The enzyme L-asparaginase is approved by the FDA for treatment of acute lymphoblastic leukemia. METase has more potential as a therapeutic since addiction to L-Met is a general and fundamental hallmark of cancer.
{"title":"The potential of methioninase for cancer treatment","authors":"Louay Abo Qoura , Konstantin V. Balakin , Robert M. Hoffman , Vadim S. Pokrovsky","doi":"10.1016/j.bbcan.2024.189122","DOIUrl":"10.1016/j.bbcan.2024.189122","url":null,"abstract":"<div><p>Cancer cells are addicted to L-methionine (L-Met) and have a much greater requirement for L-Met than normal cells due to excess transmethylation, termed the Hoffman effect. By targeting this vulnerability through dietary restriction of L-Met, researchers have been able to achieve promising results in inhibiting tumor growth and eradicating cancer cells. Methioninase (EC 4.4.1.11; METase) catalyzes the transformation of L-Met into α-ketobutyrate, ammonia, and methanethiol. The use of METase was initially limited due to its poor stability <em>in vivo</em>, high immunogenicity, and enzyme-induced inactivating antibodies. These issues could be partially resolved by PEGylation, encapsulation in erythrocytes, and various site-directed mutagenesis. The big breakthrough came when it was discovered that METase is effectively administered orally. The enzyme L-asparaginase is approved by the FDA for treatment of acute lymphoblastic leukemia. METase has more potential as a therapeutic since addiction to L-Met is a general and fundamental hallmark of cancer.</p></div>","PeriodicalId":8782,"journal":{"name":"Biochimica et biophysica acta. Reviews on cancer","volume":null,"pages":null},"PeriodicalIF":11.2,"publicationDate":"2024-05-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141132673","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}