Pub Date : 2024-03-01Epub Date: 2024-02-14DOI: 10.1080/14728222.2024.2317900
Lang Pan, Istvan Boldogh
Introduction: Pulmonary diseases impose a daunting burden on healthcare systems and societies. Current treatment approaches primarily address symptoms, underscoring the urgency for the development of innovative pharmaceutical solutions. A noteworthy focus lies in targeting enzymes recognizing oxidatively modified DNA bases within gene regulatory elements, given their pivotal role in governing gene expression.
Areas covered: This review delves into the intricate interplay between the substrate-specific binding of 8-oxoguanine DNA glycosylase 1 (OGG1) and epigenetic regulation, with a focal point on elucidating the molecular underpinnings and their biological implications. The absence of OGG1 distinctly attenuates the binding of transcription factors to cis elements, thereby modulating pro-inflammatory or pro-fibrotic transcriptional activity. Through a synergy of experimental insights gained from cell culture studies and murine models, utilizing prototype OGG1 inhibitors (O8, TH5487, and SU0268), a promising panorama emerges. These investigations underscore the absence of cytotoxicity and the establishment of a favorable tolerance profile for these OGG1 inhibitors.
Expert opinion: Thus, the strategic targeting of the active site pocket of OGG1 through the application of small molecules introduces an innovative trajectory for advancing redox medicine. This approach holds particular significance in the context of pulmonary diseases, offering a refined avenue for their management.
导言:肺部疾病给医疗系统和社会带来了沉重的负担。目前的治疗方法主要针对症状,这凸显了开发创新药物解决方案的紧迫性。一个值得关注的焦点是靶向识别基因调控元件中氧化修饰 DNA 碱基的酶,因为它们在调控基因表达方面起着关键作用:本综述深入探讨了 8-氧鸟嘌呤 DNA 糖基化酶 1(OGG1)的底物特异性结合与表观遗传调控之间错综复杂的相互作用,重点是阐明其分子基础及其生物学意义。OGG1 的缺失会明显减弱转录因子与顺式元件的结合,从而调节促炎症或促纤维化的转录活性。利用原型 OGG1 抑制剂(O8、TH5487 和 SU0268)从细胞培养研究和小鼠模型中获得的实验见解,通过协同作用形成了一幅前景广阔的全景图。这些研究强调了这些 OGG1 抑制剂没有细胞毒性,并建立了良好的耐受性特征:因此,通过应用小分子化合物战略性地靶向 OGG1 的活性位点口袋,为推进氧化还原医学的发展开辟了一条创新之路。这种方法对肺部疾病具有特别重要的意义,为肺部疾病的治疗提供了一条完善的途径。
{"title":"The potential for OGG1 inhibition to be a therapeutic strategy for pulmonary diseases.","authors":"Lang Pan, Istvan Boldogh","doi":"10.1080/14728222.2024.2317900","DOIUrl":"10.1080/14728222.2024.2317900","url":null,"abstract":"<p><strong>Introduction: </strong>Pulmonary diseases impose a daunting burden on healthcare systems and societies. Current treatment approaches primarily address symptoms, underscoring the urgency for the development of innovative pharmaceutical solutions. A noteworthy focus lies in targeting enzymes recognizing oxidatively modified DNA bases within gene regulatory elements, given their pivotal role in governing gene expression.</p><p><strong>Areas covered: </strong>This review delves into the intricate interplay between the substrate-specific binding of 8-oxoguanine DNA glycosylase 1 (OGG1) and epigenetic regulation, with a focal point on elucidating the molecular underpinnings and their biological implications. The absence of OGG1 distinctly attenuates the binding of transcription factors to cis elements, thereby modulating pro-inflammatory or pro-fibrotic transcriptional activity. Through a synergy of experimental insights gained from cell culture studies and murine models, utilizing prototype OGG1 inhibitors (O8, TH5487, and SU0268), a promising panorama emerges. These investigations underscore the absence of cytotoxicity and the establishment of a favorable tolerance profile for these OGG1 inhibitors.</p><p><strong>Expert opinion: </strong>Thus, the strategic targeting of the active site pocket of OGG1 through the application of small molecules introduces an innovative trajectory for advancing redox medicine. This approach holds particular significance in the context of pulmonary diseases, offering a refined avenue for their management.</p>","PeriodicalId":12185,"journal":{"name":"Expert Opinion on Therapeutic Targets","volume":" ","pages":"117-130"},"PeriodicalIF":4.6,"publicationDate":"2024-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11111349/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139722209","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-03-01Epub Date: 2024-03-21DOI: 10.1080/14728222.2024.2331015
Prasanna Anjaneyulu Yakkala, Fatima Naaz, Syed Shafi, Ahmed Kamal
Introduction: The pathways like Wingless-related integration (Wnt/β-catenin) and PI3K play an important role in colorectal cancer (CRC) development; however, their roles are distinct in the process of oncogenesis. Despite their differences, these pathways interact through feedback mechanisms and regulate the common effectors both in the upstream and the downstream processes in normal and pathological conditions. Their ability to reciprocally control each other is a primary resistance mechanism for the selective inhibitors in CRC.
Area covered: This review highlights the Wnt/β-catenin and PI3K pathways that are interrelated in CRC, recent advances and some key perspectives in developing inhibitors that could target the tankyrase enzyme and PI3K, apart from a brief description of the potential of dual inhibitors of PI3K and Tankyrases (TNKS).
Expert opinion: Recent research has focused on overcoming the challenges particularly relating to the resistance and efficacy of dual inhibitors targeting PI3K and tankyrase proteins. Despite these challenges, PI3K as well as tankyrases remain promising therapeutic targets for the treatment of solid tumors. The design of potent inhibitors is crucial to effectively block these protein signaling pathways. Moreover, it is essential to explore the potential of dual-target inhibition of other signaling pathways in conjunction with PI3K and tankyrase.
{"title":"PI3K and tankyrase inhibitors as therapeutic targets in colorectal cancer.","authors":"Prasanna Anjaneyulu Yakkala, Fatima Naaz, Syed Shafi, Ahmed Kamal","doi":"10.1080/14728222.2024.2331015","DOIUrl":"10.1080/14728222.2024.2331015","url":null,"abstract":"<p><strong>Introduction: </strong>The pathways like Wingless-related integration (Wnt/β-catenin) and PI3K play an important role in colorectal cancer (CRC) development; however, their roles are distinct in the process of oncogenesis. Despite their differences, these pathways interact through feedback mechanisms and regulate the common effectors both in the upstream and the downstream processes in normal and pathological conditions. Their ability to reciprocally control each other is a primary resistance mechanism for the selective inhibitors in CRC.</p><p><strong>Area covered: </strong>This review highlights the Wnt/β-catenin and PI3K pathways that are interrelated in CRC, recent advances and some key perspectives in developing inhibitors that could target the tankyrase enzyme and PI3K, apart from a brief description of the potential of dual inhibitors of PI3K and Tankyrases (TNKS).</p><p><strong>Expert opinion: </strong>Recent research has focused on overcoming the challenges particularly relating to the resistance and efficacy of dual inhibitors targeting PI3K and tankyrase proteins. Despite these challenges, PI3K as well as tankyrases remain promising therapeutic targets for the treatment of solid tumors. The design of potent inhibitors is crucial to effectively block these protein signaling pathways. Moreover, it is essential to explore the potential of dual-target inhibition of other signaling pathways in conjunction with PI3K and tankyrase.</p>","PeriodicalId":12185,"journal":{"name":"Expert Opinion on Therapeutic Targets","volume":" ","pages":"159-177"},"PeriodicalIF":5.8,"publicationDate":"2024-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140143056","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-03-01Epub Date: 2024-02-19DOI: 10.1080/14728222.2024.2318449
Annarosa Arcangeli, Jessica Iorio, Claudia Duranti
Introduction: Despite great advances, novel therapeutic targets and strategies are still needed, in particular for some carcinomas in the metastatic stage (breast cancer, colorectal cancer, pancreatic ductal adenocarcinoma and the clear cell renal carcinoma). Ion channels may be considered good cancer biomarkers and targets for antineoplastic therapy. These concepts are particularly relevant considering the hERG1 potassium channel as a novel target for antineoplastic therapy.
Areas covered: A great deal of evidence demonstrates that hERG1 is aberrantly expressed in human cancers, in particular in aggressive carcinomas. A relevant cornerstone was the discovery that, in cancer cells, the channel is present in a very peculiar conformation, strictly bound to the β1 subunit of integrin receptors. The hERG1/β1 integrin complex does not occur in the heart. Starting from this evidence, we developed a novel single chain bispecific antibody (scDb-hERG1-β1), which specifically targets the hERG1/β1 integrin complex and exerts antineoplastic effects in preclinical experiments.
Expert opinion: Since hERG1 blockade cannot be pursued for antineoplastic therapy due to the severe cardiac toxic effects (ventricular arrhythmias) that many hERG1 blockers exert, different strategies must be identified to specifically target hERG1 in cancer. The targeting of the hERG1/β1 integrin complex through the bispecific antibody scDb-hERG1-β1 can overcome such hindrances.
{"title":"Targeting the hERG1 and β1 integrin complex for cancer treatment.","authors":"Annarosa Arcangeli, Jessica Iorio, Claudia Duranti","doi":"10.1080/14728222.2024.2318449","DOIUrl":"10.1080/14728222.2024.2318449","url":null,"abstract":"<p><strong>Introduction: </strong>Despite great advances, novel therapeutic targets and strategies are still needed, in particular for some carcinomas in the metastatic stage (breast cancer, colorectal cancer, pancreatic ductal adenocarcinoma and the clear cell renal carcinoma). Ion channels may be considered good cancer biomarkers and targets for antineoplastic therapy. These concepts are particularly relevant considering the hERG1 potassium channel as a novel target for antineoplastic therapy.</p><p><strong>Areas covered: </strong>A great deal of evidence demonstrates that hERG1 is aberrantly expressed in human cancers, in particular in aggressive carcinomas. A relevant cornerstone was the discovery that, in cancer cells, the channel is present in a very peculiar conformation, strictly bound to the β1 subunit of integrin receptors. The hERG1/β1 integrin complex does not occur in the heart. Starting from this evidence, we developed a novel single chain bispecific antibody (scDb-hERG1-β1), which specifically targets the hERG1/β1 integrin complex and exerts antineoplastic effects in preclinical experiments.</p><p><strong>Expert opinion: </strong>Since hERG1 blockade cannot be pursued for antineoplastic therapy due to the severe cardiac toxic effects (ventricular arrhythmias) that many hERG1 blockers exert, different strategies must be identified to specifically target hERG1 in cancer. The targeting of the hERG1/β1 integrin complex through the bispecific antibody scDb-hERG1-β1 can overcome such hindrances.</p>","PeriodicalId":12185,"journal":{"name":"Expert Opinion on Therapeutic Targets","volume":" ","pages":"145-157"},"PeriodicalIF":5.8,"publicationDate":"2024-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139899627","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-03-01Epub Date: 2024-03-04DOI: 10.1080/14728222.2024.2326211
Jaime Gonzalez-Montero, Mauricio Burotto
{"title":"Considerations on the implementation of MAP4K4 inhibitors as cancer treatment.","authors":"Jaime Gonzalez-Montero, Mauricio Burotto","doi":"10.1080/14728222.2024.2326211","DOIUrl":"10.1080/14728222.2024.2326211","url":null,"abstract":"","PeriodicalId":12185,"journal":{"name":"Expert Opinion on Therapeutic Targets","volume":" ","pages":"113-115"},"PeriodicalIF":5.8,"publicationDate":"2024-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139989702","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-01-01Epub Date: 2024-01-23DOI: 10.1080/14728222.2024.2306345
Lin Chen, Tian Fan, Miao Wang, Chun-Yu Zhu, Wang-You Feng, Yu Li, Hong Yang
Background: Ovarian cancer (OC) is the most lethal gynecological tumor, but it currently lacks effective therapeutic targets. CD147, which is overexpressed in OC, plays a crucial role in promoting malignant progression and is associated with poor prognosis in patients. Therefore, CD147 has been identified as a potential therapeutic target. However, there is a limited amount of research on the development of CD147 inhibitors.
Methods: Surface plasmon resonance (SPR) assay and virtual molecular docking analysis were performed to identify potential natural compounds targeting CD147. The anti‑tumor effects of myricetin were evaluated using various assays, including CCK8, Alkaline comet, immunofluorescence and xenograft mouse models. The underlying mechanism was investigated through western blot analysis and lentivirus short hairpin RNA (LV-shRNA) transfection.
Results: Myricetin, a flavonoid commonly found in plants, was discovered to be a potent inhibitor of CD147. Our findings demonstrated that myricetin exhibited a strong affinity for CD147 and down-regulated the protein level of CD147 by facilitating its proteasome-dependent degradation. Additionally, we observed synergistic antitumor effects of myricetin and cisplatin both in vivo and in vitro. Mechanistically, myricetin suppressed the expression of FOXM1 and its downstream DNA damage response (DDR) genes E×O1and BRIP1, thereby enhancing the DDR induced by cisplatin.
Conclusion: Our data demonstrate that myricetin, a natural inhibitor of CD147, may have clinical utility in the treatment of OC due to its ability to increase genomic toxicity when combined with cisplatin.
{"title":"Myricetin, a natural inhibitor of CD147, increases sensitivity of cisplatin in ovarian cancer.","authors":"Lin Chen, Tian Fan, Miao Wang, Chun-Yu Zhu, Wang-You Feng, Yu Li, Hong Yang","doi":"10.1080/14728222.2024.2306345","DOIUrl":"10.1080/14728222.2024.2306345","url":null,"abstract":"<p><strong>Background: </strong>Ovarian cancer (OC) is the most lethal gynecological tumor, but it currently lacks effective therapeutic targets. CD147, which is overexpressed in OC, plays a crucial role in promoting malignant progression and is associated with poor prognosis in patients. Therefore, CD147 has been identified as a potential therapeutic target. However, there is a limited amount of research on the development of CD147 inhibitors.</p><p><strong>Methods: </strong>Surface plasmon resonance (SPR) assay and virtual molecular docking analysis were performed to identify potential natural compounds targeting CD147. The anti‑tumor effects of myricetin were evaluated using various assays, including CCK8, Alkaline comet, immunofluorescence and xenograft mouse models. The underlying mechanism was investigated through western blot analysis and lentivirus short hairpin RNA (LV-shRNA) transfection.</p><p><strong>Results: </strong>Myricetin, a flavonoid commonly found in plants, was discovered to be a potent inhibitor of CD147. Our findings demonstrated that myricetin exhibited a strong affinity for CD147 and down-regulated the protein level of CD147 by facilitating its proteasome-dependent degradation. Additionally, we observed synergistic antitumor effects of myricetin and cisplatin both in vivo and in vitro. Mechanistically, myricetin suppressed the expression of FOXM1 and its downstream DNA damage response (DDR) genes E×O1and BRIP1, thereby enhancing the DDR induced by cisplatin.</p><p><strong>Conclusion: </strong>Our data demonstrate that myricetin, a natural inhibitor of CD147, may have clinical utility in the treatment of OC due to its ability to increase genomic toxicity when combined with cisplatin.</p>","PeriodicalId":12185,"journal":{"name":"Expert Opinion on Therapeutic Targets","volume":" ","pages":"83-95"},"PeriodicalIF":5.8,"publicationDate":"2024-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139485237","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Background: The current study tried to elucidate the regulatory role of tumor cell-derived exosomes (Exos)-circ_0064516 in angiogenesis and growth of cervical cancer.
Research design and methods: Related cirRNAs and downstream target genes were identified through bioinformatics analysis. Exos were isolated from cervical cancer cell line CaSki, followed by co-cultured with human umbilical vein endothelial cells (HUVECs). Then, the roles of circ_0064516, miR-6805-3p, and MAPK1 in migration and angiogenesis of HUVECs were assayed. Furthermore, xenografted tumors were transplanted into nude mice for in vivo validation.
Results: In vitro assay validated highly expressed circ_0064516 in cervical cancer cells. Tumor cell-derived Exos carried circ_0064516 to HUVECs. circ_0064516 increased MAPK1 expression by binding to miR-6805-3p, thus enhancing migration and angiogenesis. Exos containing circ_0064516 also promoted tumorigenesis of cervical cancer cells in nude mice.
Conclusions: We confirmed the oncogenic role of tumor cell-derived Exos carrying circ_0064516 in cervical cancer progression through miR-6805-3p/MAPK1.
{"title":"Tumor cells-derived extracellular vesicles carry circ_0064516 competitively inhibit microRNA-6805-3p and promote cervical cancer angiogenesis and tumor growth.","authors":"Yujue Wang, Yao Xie, Xue Wang, Nian Yang, Zhao Wu, Xun Zhang","doi":"10.1080/14728222.2024.2306353","DOIUrl":"10.1080/14728222.2024.2306353","url":null,"abstract":"<p><strong>Background: </strong>The current study tried to elucidate the regulatory role of tumor cell-derived exosomes (Exos)-circ_0064516 in angiogenesis and growth of cervical cancer.</p><p><strong>Research design and methods: </strong>Related cirRNAs and downstream target genes were identified through bioinformatics analysis. Exos were isolated from cervical cancer cell line CaSki, followed by co-cultured with human umbilical vein endothelial cells (HUVECs). Then, the roles of circ_0064516, miR-6805-3p, and MAPK1 in migration and angiogenesis of HUVECs were assayed. Furthermore, xenografted tumors were transplanted into nude mice for in vivo validation.</p><p><strong>Results: </strong>In vitro assay validated highly expressed circ_0064516 in cervical cancer cells. Tumor cell-derived Exos carried circ_0064516 to HUVECs. circ_0064516 increased MAPK1 expression by binding to miR-6805-3p, thus enhancing migration and angiogenesis. Exos containing circ_0064516 also promoted tumorigenesis of cervical cancer cells in nude mice.</p><p><strong>Conclusions: </strong>We confirmed the oncogenic role of tumor cell-derived Exos carrying circ_0064516 in cervical cancer progression through miR-6805-3p/MAPK1.</p>","PeriodicalId":12185,"journal":{"name":"Expert Opinion on Therapeutic Targets","volume":" ","pages":"97-112"},"PeriodicalIF":4.6,"publicationDate":"2024-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139546084","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-01-01Epub Date: 2024-01-23DOI: 10.1080/14728222.2024.2306341
Christoph Garbers, Juliane Lokau
Introduction: Inflammatory bowel disease (IBD) is an umbrella term that includes different chronic inflammatory diseases of the gastrointestinal tract, most commonly Crohn's disease and ulcerative colitis. IBD affects more than 6 million people worldwide and constitutes not only a debilitating disease for the patients, but also a significant factor for society due to costs for health care and reduced working capacity. Despite the introduction of biologicals for the treatment of IBD, the identification of novel targets that could lead to novel therapeutics is still needed.
Areas covered: In this review, we summarize current knowledge about the interleukin-6 family of cytokines as potential therapeutic targets for improving the therapy of patients with IBD. We discuss cytokines like IL-6 itself for which therapeutics such as inhibitory monoclonal antibodies have already entered the clinics, but also focus on other family members whose therapeutic potential has not been explored yet.
Expert opinion: The different cytokines of the IL-6 family offer multiple therapeutic targets that can potentially be used to treat patients with inflammatory bowel disease, but unwanted side effects like inhibition of epithelial regeneration have to be considered.
{"title":"Cytokines of the interleukin-6 family as emerging targets in inflammatory bowel disease.","authors":"Christoph Garbers, Juliane Lokau","doi":"10.1080/14728222.2024.2306341","DOIUrl":"10.1080/14728222.2024.2306341","url":null,"abstract":"<p><strong>Introduction: </strong>Inflammatory bowel disease (IBD) is an umbrella term that includes different chronic inflammatory diseases of the gastrointestinal tract, most commonly Crohn's disease and ulcerative colitis. IBD affects more than 6 million people worldwide and constitutes not only a debilitating disease for the patients, but also a significant factor for society due to costs for health care and reduced working capacity. Despite the introduction of biologicals for the treatment of IBD, the identification of novel targets that could lead to novel therapeutics is still needed.</p><p><strong>Areas covered: </strong>In this review, we summarize current knowledge about the interleukin-6 family of cytokines as potential therapeutic targets for improving the therapy of patients with IBD. We discuss cytokines like IL-6 itself for which therapeutics such as inhibitory monoclonal antibodies have already entered the clinics, but also focus on other family members whose therapeutic potential has not been explored yet.</p><p><strong>Expert opinion: </strong>The different cytokines of the IL-6 family offer multiple therapeutic targets that can potentially be used to treat patients with inflammatory bowel disease, but unwanted side effects like inhibition of epithelial regeneration have to be considered.</p>","PeriodicalId":12185,"journal":{"name":"Expert Opinion on Therapeutic Targets","volume":" ","pages":"57-65"},"PeriodicalIF":5.8,"publicationDate":"2024-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139466250","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-01-01Epub Date: 2024-02-12DOI: 10.1080/14728222.2024.2316739
Ilan Bruchim, Ilaria Capasso, Ariel Polonsky, Shilhav Meisel, Vanda Salutari, Haim Werner, Domenica Lorusso, Giovanni Scambia, Francesco Fanfani
Introduction: Endometrial cancer (EC) is the only gynecologic malignancy showing increasing trends in incidence and mortality. While standard treatment has been effective primarily for early-stage EC, precision medicine with tailored therapy has revolutionized the management of this disease. Genome sequencing analyses have identified four sub-types of EC. Treatments for primary and metastatic disease can now be tailored more accurately to achieve better oncologic results.
Areas covered: This review provides an overview of the most relevant and updated evidence in the literature regarding EC molecular analysis and its role in risk classification, prognostication, and guidance for tailored and target therapies in early and advanced/metastatic stages. In addition, it provides updated information on optimal surgical management based on molecular classification and highlights key advances and future strategies.
Expert opinion: EC molecular analysis yields the potential of tailoring adjuvant treatment by escalating or deescalating therapy, as shown for POLE-mutated and p53-mutated tumors. Moreover, the expression of specific molecular signatures offers the possibility to employ novel target therapies, such as immune-checkpoint inhibitors that have demonstrated a significant benefit on prognosis. New treatment guidelines are still being established, and ongoing studies are exploring the potential prognostic role of further sub-stratifications of the four molecular classes and treatment options.
{"title":"New therapeutic targets for endometrial cancer: a glimpse into the preclinical sphere.","authors":"Ilan Bruchim, Ilaria Capasso, Ariel Polonsky, Shilhav Meisel, Vanda Salutari, Haim Werner, Domenica Lorusso, Giovanni Scambia, Francesco Fanfani","doi":"10.1080/14728222.2024.2316739","DOIUrl":"10.1080/14728222.2024.2316739","url":null,"abstract":"<p><strong>Introduction: </strong>Endometrial cancer (EC) is the only gynecologic malignancy showing increasing trends in incidence and mortality. While standard treatment has been effective primarily for early-stage EC, precision medicine with tailored therapy has revolutionized the management of this disease. Genome sequencing analyses have identified four sub-types of EC. Treatments for primary and metastatic disease can now be tailored more accurately to achieve better oncologic results.</p><p><strong>Areas covered: </strong>This review provides an overview of the most relevant and updated evidence in the literature regarding EC molecular analysis and its role in risk classification, prognostication, and guidance for tailored and target therapies in early and advanced/metastatic stages. In addition, it provides updated information on optimal surgical management based on molecular classification and highlights key advances and future strategies.</p><p><strong>Expert opinion: </strong>EC molecular analysis yields the potential of tailoring adjuvant treatment by escalating or deescalating therapy, as shown for POLE-mutated and p53-mutated tumors. Moreover, the expression of specific molecular signatures offers the possibility to employ novel target therapies, such as immune-checkpoint inhibitors that have demonstrated a significant benefit on prognosis. New treatment guidelines are still being established, and ongoing studies are exploring the potential prognostic role of further sub-stratifications of the four molecular classes and treatment options.</p>","PeriodicalId":12185,"journal":{"name":"Expert Opinion on Therapeutic Targets","volume":" ","pages":"29-43"},"PeriodicalIF":5.8,"publicationDate":"2024-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139702206","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-01-01Epub Date: 2024-02-06DOI: 10.1080/14728222.2024.2315017
Mattia Galli, Dominick J Angiolillo
{"title":"Role of the P2Y12 receptor on thrombus formation and evolution in therapeutic strategies.","authors":"Mattia Galli, Dominick J Angiolillo","doi":"10.1080/14728222.2024.2315017","DOIUrl":"10.1080/14728222.2024.2315017","url":null,"abstract":"","PeriodicalId":12185,"journal":{"name":"Expert Opinion on Therapeutic Targets","volume":" ","pages":"5-8"},"PeriodicalIF":5.8,"publicationDate":"2024-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139691590","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-01-01Epub Date: 2024-01-26DOI: 10.1080/14728222.2024.2306344
Alessandra Merlini, Martina Rabino, Silvia Brusco, Valeria Pavese, Debora Masci, Dario Sangiolo, Paolo Bironzo, Giorgio Vittorio Scagliotti, Silvia Novello, Lorenzo D'Ambrosio
Introduction: Soft tissue sarcomas are a group of rare, mesenchymal tumors characterized by dismal prognosis in advanced/metastatic stages. Knowledge of their molecular determinants is still rather limited. However, in recent years, epigenetic regulation - the modification of gene expression/function without DNA sequence variation - has emerged as a key player both in sarcomagenesis and sarcoma progression.
Areas covered: Herein, we describe and review the main epigenetic mechanisms involved in chromatin remodeling and their role as disease drivers in different soft tissue sarcoma histotypes, focusing on epithelioid sarcoma, synovial sarcoma, and malignant peripheral nerve sheath tumors. Focusing on chromatin-remodeling complexes, we provide an in-depth on the role of BAF complex alterations in these soft tissue sarcoma histotypes. In parallel, we highlight current state-of-the-art and future perspectives in the development of rational, innovative treatments leveraging on epigenetic dysregulation in soft tissue sarcomas.
Expert opinion: Therapeutic options for metastatic/advanced sarcomas are to date very limited and largely represented by cytotoxic agents, with only modest results. In the continuous attempt to find novel targets and innovative, effective drugs, epigenetic mechanisms represent an emerging and promising field of research, especially for malignant peripheral nerve sheath tumors, epithelioid and synovial sarcoma.
导言:软组织肉瘤是一组罕见的间质肿瘤,其特点是晚期/转移期预后不良。人们对其分子决定因素的了解仍然相当有限。然而,近年来,表观遗传调控--在没有 DNA 序列变异的情况下改变基因表达/功能--已成为肉瘤成因和肉瘤进展的关键因素:在本文中,我们描述并回顾了参与染色质重塑的主要表观遗传学机制及其在不同软组织肉瘤组织类型中作为疾病驱动因素的作用,重点关注上皮样肉瘤、滑膜肉瘤和恶性周围神经鞘瘤。我们以染色质重塑复合物为重点,深入探讨了 BAF 复合物改变在这些软组织肉瘤组织类型中的作用。同时,我们还强调了利用软组织肉瘤表观遗传失调开发合理、创新治疗方法的当前先进水平和未来前景:迄今为止,转移性/晚期肉瘤的治疗方案非常有限,主要以细胞毒药物为主,而且效果一般。在不断尝试寻找新靶点和创新有效药物的过程中,表观遗传学机制是一个新兴且前景广阔的研究领域,尤其是针对恶性周围神经鞘瘤、上皮样肉瘤和滑膜肉瘤。
{"title":"Epigenetic determinants in soft tissue sarcomas: molecular mechanisms and therapeutic targets.","authors":"Alessandra Merlini, Martina Rabino, Silvia Brusco, Valeria Pavese, Debora Masci, Dario Sangiolo, Paolo Bironzo, Giorgio Vittorio Scagliotti, Silvia Novello, Lorenzo D'Ambrosio","doi":"10.1080/14728222.2024.2306344","DOIUrl":"10.1080/14728222.2024.2306344","url":null,"abstract":"<p><strong>Introduction: </strong>Soft tissue sarcomas are a group of rare, mesenchymal tumors characterized by dismal prognosis in advanced/metastatic stages. Knowledge of their molecular determinants is still rather limited. However, in recent years, epigenetic regulation - the modification of gene expression/function without DNA sequence variation - has emerged as a key player both in sarcomagenesis and sarcoma progression.</p><p><strong>Areas covered: </strong>Herein, we describe and review the main epigenetic mechanisms involved in chromatin remodeling and their role as disease drivers in different soft tissue sarcoma histotypes, focusing on epithelioid sarcoma, synovial sarcoma, and malignant peripheral nerve sheath tumors. Focusing on chromatin-remodeling complexes, we provide an in-depth on the role of BAF complex alterations in these soft tissue sarcoma histotypes. In parallel, we highlight current state-of-the-art and future perspectives in the development of rational, innovative treatments leveraging on epigenetic dysregulation in soft tissue sarcomas.</p><p><strong>Expert opinion: </strong>Therapeutic options for metastatic/advanced sarcomas are to date very limited and largely represented by cytotoxic agents, with only modest results. In the continuous attempt to find novel targets and innovative, effective drugs, epigenetic mechanisms represent an emerging and promising field of research, especially for malignant peripheral nerve sheath tumors, epithelioid and synovial sarcoma.</p>","PeriodicalId":12185,"journal":{"name":"Expert Opinion on Therapeutic Targets","volume":" ","pages":"17-28"},"PeriodicalIF":5.8,"publicationDate":"2024-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139485314","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}