Pub Date : 2024-11-06DOI: 10.1186/s13046-024-03219-0
Elise Jirovec, Dafne C A Quixabeira, James H A Clubb, Santeri A Pakola, Tatiana Kudling, Victor Arias, Lyna Haybout, Katriina Jalkanen, Tuomo Alanko, Tine Monberg, Amir Khammari, Brigitte Dreno, Inge Marie Svane, Matthew S Block, Daniel A Adamo, Johanna Mäenpää, Claudia Kistler, Suvi Sorsa, Otto Hemminki, Anna Kanerva, João M Santos, Victor Cervera-Carrascon, Akseli Hemminki
Background: A limitation of approved oncolytic viruses is their requirement for intratumoral (i.t.) injection. TILT-123 (igrelimogene litadenorepvec, Ad5/3-E2F-D24-hTNFα-IRES-hIL-2) is a chimeric oncolytic adenovirus suitable for intravenous (i.v.) delivery due to its capsid modification and dual selectivity devices. It is armed with tumor necrosis alpha and interleukin-2 for promoting T-cell activation and lymphocyte trafficking to tumors, thereby enhancing the antitumor immune response. Here, we present the findings after a single i.v. administration of TILT-123 in three phase I dose escalation clinical trials.
Methods: Patients with advanced solid tumors initially received a single i.v. dose of TILT-123 ranging from 3 × 109 to 4 × 1012 viral particles (VP). Blood was collected at baseline, 1, 16, and 192 h (7 days) post-treatment for bioavailability and serum analysis. Tumor biopsies were collected prior to treatment and 7 days post-treatment for analysis of viral presence and immunological effects. Patients did not receive any other cancer therapies during this period.
Results: Across all three trials (TUNIMO, TUNINTIL, and PROTA), 52 total patients were treated with i.v. TILT-123. Overall, TILT-123 was found to be well-tolerated, with no dose-limiting toxicities observed. Post-treatment tumor biopsies showed expression of viral genes, presence of TILT-123 adenovirus proteins or DNA, and changes in immune cell infiltration from baseline. Increased virus dose did not lead to increased virus detection in tumors. Median overall survival was longer in patients with confirmed presence of TILT-123 in post-treatment biopsies (280 versus 190 days, p = 0.0405).
Conclusion: TILT-123 demonstrated safety and significant intratumoral immunomodulation following a single i.v. administration, warranting further investigation.
Trial registrations: TUNIMO-NCT04695327. Registered 4 January 2021, https://clinicaltrials.gov/study/NCT04695327 . TUNINTIL-NCT04217473. Registered 19 December 2019, https://clinicaltrials.gov/study/NCT04217473 . PROTA-NCT05271318. Registered 4 February 2022, https://clinicaltrials.gov/study/NCT05271318 .
{"title":"Single intravenous administration of oncolytic adenovirus TILT-123 results in systemic tumor transduction and immune response in patients with advanced solid tumors.","authors":"Elise Jirovec, Dafne C A Quixabeira, James H A Clubb, Santeri A Pakola, Tatiana Kudling, Victor Arias, Lyna Haybout, Katriina Jalkanen, Tuomo Alanko, Tine Monberg, Amir Khammari, Brigitte Dreno, Inge Marie Svane, Matthew S Block, Daniel A Adamo, Johanna Mäenpää, Claudia Kistler, Suvi Sorsa, Otto Hemminki, Anna Kanerva, João M Santos, Victor Cervera-Carrascon, Akseli Hemminki","doi":"10.1186/s13046-024-03219-0","DOIUrl":"10.1186/s13046-024-03219-0","url":null,"abstract":"<p><strong>Background: </strong>A limitation of approved oncolytic viruses is their requirement for intratumoral (i.t.) injection. TILT-123 (igrelimogene litadenorepvec, Ad5/3-E2F-D24-hTNFα-IRES-hIL-2) is a chimeric oncolytic adenovirus suitable for intravenous (i.v.) delivery due to its capsid modification and dual selectivity devices. It is armed with tumor necrosis alpha and interleukin-2 for promoting T-cell activation and lymphocyte trafficking to tumors, thereby enhancing the antitumor immune response. Here, we present the findings after a single i.v. administration of TILT-123 in three phase I dose escalation clinical trials.</p><p><strong>Methods: </strong>Patients with advanced solid tumors initially received a single i.v. dose of TILT-123 ranging from 3 × 10<sup>9</sup> to 4 × 10<sup>12</sup> viral particles (VP). Blood was collected at baseline, 1, 16, and 192 h (7 days) post-treatment for bioavailability and serum analysis. Tumor biopsies were collected prior to treatment and 7 days post-treatment for analysis of viral presence and immunological effects. Patients did not receive any other cancer therapies during this period.</p><p><strong>Results: </strong>Across all three trials (TUNIMO, TUNINTIL, and PROTA), 52 total patients were treated with i.v. TILT-123. Overall, TILT-123 was found to be well-tolerated, with no dose-limiting toxicities observed. Post-treatment tumor biopsies showed expression of viral genes, presence of TILT-123 adenovirus proteins or DNA, and changes in immune cell infiltration from baseline. Increased virus dose did not lead to increased virus detection in tumors. Median overall survival was longer in patients with confirmed presence of TILT-123 in post-treatment biopsies (280 versus 190 days, p = 0.0405).</p><p><strong>Conclusion: </strong>TILT-123 demonstrated safety and significant intratumoral immunomodulation following a single i.v. administration, warranting further investigation.</p><p><strong>Trial registrations: </strong>TUNIMO-NCT04695327. Registered 4 January 2021, https://clinicaltrials.gov/study/NCT04695327 . TUNINTIL-NCT04217473. Registered 19 December 2019, https://clinicaltrials.gov/study/NCT04217473 . PROTA-NCT05271318. Registered 4 February 2022, https://clinicaltrials.gov/study/NCT05271318 .</p>","PeriodicalId":50199,"journal":{"name":"Journal of Experimental & Clinical Cancer Research","volume":null,"pages":null},"PeriodicalIF":11.4,"publicationDate":"2024-11-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11539705/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142591968","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 : 2024-11-05DOI: 10.1186/s13046-024-03213-6
Maria Laura De Angelis, Federica Francescangeli, Eleonora Aricò, Paola Verachi, Massimo Zucchetti, Cristina Matteo, Elena Petricci, Emanuela Pilozzi, Isabella Orienti, Alessandra Boe, Adriana Eramo, Rachele Rossi, Tiberio Corati, Daniele Macchia, Anna Maria Pacca, Ann Zeuner, Marta Baiocchi
Background: Prevention and treatment of metastatic breast cancer (BC) is an unmet clinical need. The retinoic acid derivative fenretinide (FeR) was previously evaluated in Phase I-III clinical trials but, despite its excellent tolerability and antitumor activity in preclinical models, showed limited therapeutic efficacy due to poor bioavailability. We recently generated a new micellar formulation of FeR, Bionanofenretinide (Bio-nFeR) showing enhanced bioavailability, low toxicity, and strong antitumor efficacy on human lung cancer, colorectal cancer, and melanoma xenografts. In the present study, we tested the effect of Bio-nFeR on a preclinical model of metastatic BC.
Methods: We used BC cell lines for in vitro analyses of cell viability, cell cycle and migratory capacity. For in vivo studies, we used HER2/neu transgenic mice (neuT) as a model of spontaneously metastatic BC. Mice were treated orally with Bio-nFeR and at sacrifice primary and metastatic breast tumors were analyzed by histology and immunohistochemistry. Molecular pathways activated in primary tumors were analyzed by immunoblotting. Stem cell content was assessed by flow cytometry, immunoblotting and functional assays such as colony formation ex vivo and second transplantation assay in immunocompromised mice.
Results: Bio-nFeR inhibited the proliferation and migration of neuT BC cells in vitro and showed significant efficacy against BC onset in neuT mice. Importantly, Bio-nFeR showed the highest effectiveness against metastatic progression, counteracting both metastasis initiation and expansion. The main mechanism of Bio-nFeR action consists of promoting tumor dormancy through a combined induction of antiproliferative signals and inhibition of the mTOR pathway.
Conclusion: The high effectiveness of Bio-nFeR in the neuT model of mammary carcinogenesis, coupled with its low toxicity, indicates this formulation as a potential candidate for the treatment of metastatic BC and for the adjuvant therapy of BC patients at high risk of developing metastasis.
背景:预防和治疗转移性乳腺癌(BC预防和治疗转移性乳腺癌(BC)是一项尚未满足的临床需求。视黄酸衍生物非格列汀(FeR)曾在 I-III 期临床试验中接受过评估,尽管它在临床前模型中具有极佳的耐受性和抗肿瘤活性,但由于生物利用度较低,因此疗效有限。我们最近生成了一种新的铁线肽胶束制剂--Bionanofenretinide(Bio-nFeR),其生物利用度提高,毒性降低,对人类肺癌、结直肠癌和黑色素瘤异种移植物具有很强的抗肿瘤疗效。在本研究中,我们测试了 Bio-nFeR 对转移性 BC 临床前模型的作用:我们使用 BC 细胞系进行细胞活力、细胞周期和迁移能力的体外分析。在体内研究中,我们使用 HER2/neu 转基因小鼠(neuT)作为自发性转移性 BC 的模型。小鼠口服 Bio-nFeR,牺牲时通过组织学和免疫组化对原发性和转移性乳腺肿瘤进行分析。用免疫印迹法分析原发肿瘤中激活的分子通路。干细胞含量通过流式细胞术、免疫印迹法和功能检测(如体内外集落形成和免疫缺陷小鼠第二次移植检测)进行评估:结果:Bio-nFeR 在体外抑制了 neuT BC 细胞的增殖和迁移,对 neuT 小鼠 BC 的发病有显著疗效。重要的是,Bio-nFeR 对转移进展表现出最高的效力,既能抑制转移的发生,也能抑制转移的扩大。Bio-nFeR 的主要作用机制是通过联合诱导抗增殖信号和抑制 mTOR 通路来促进肿瘤休眠:结论:Bio-nFeR 在乳腺癌 neuT 模型中的高效性及其低毒性表明,该制剂是治疗转移性 BC 和辅助治疗高转移风险 BC 患者的潜在候选药物。
{"title":"A nanoencapsulated oral formulation of fenretinide promotes local and metastatic breast cancer dormancy in HER2/neu transgenic mice.","authors":"Maria Laura De Angelis, Federica Francescangeli, Eleonora Aricò, Paola Verachi, Massimo Zucchetti, Cristina Matteo, Elena Petricci, Emanuela Pilozzi, Isabella Orienti, Alessandra Boe, Adriana Eramo, Rachele Rossi, Tiberio Corati, Daniele Macchia, Anna Maria Pacca, Ann Zeuner, Marta Baiocchi","doi":"10.1186/s13046-024-03213-6","DOIUrl":"10.1186/s13046-024-03213-6","url":null,"abstract":"<p><strong>Background: </strong>Prevention and treatment of metastatic breast cancer (BC) is an unmet clinical need. The retinoic acid derivative fenretinide (FeR) was previously evaluated in Phase I-III clinical trials but, despite its excellent tolerability and antitumor activity in preclinical models, showed limited therapeutic efficacy due to poor bioavailability. We recently generated a new micellar formulation of FeR, Bionanofenretinide (Bio-nFeR) showing enhanced bioavailability, low toxicity, and strong antitumor efficacy on human lung cancer, colorectal cancer, and melanoma xenografts. In the present study, we tested the effect of Bio-nFeR on a preclinical model of metastatic BC.</p><p><strong>Methods: </strong>We used BC cell lines for in vitro analyses of cell viability, cell cycle and migratory capacity. For in vivo studies, we used HER2/neu transgenic mice (neuT) as a model of spontaneously metastatic BC. Mice were treated orally with Bio-nFeR and at sacrifice primary and metastatic breast tumors were analyzed by histology and immunohistochemistry. Molecular pathways activated in primary tumors were analyzed by immunoblotting. Stem cell content was assessed by flow cytometry, immunoblotting and functional assays such as colony formation ex vivo and second transplantation assay in immunocompromised mice.</p><p><strong>Results: </strong>Bio-nFeR inhibited the proliferation and migration of neuT BC cells in vitro and showed significant efficacy against BC onset in neuT mice. Importantly, Bio-nFeR showed the highest effectiveness against metastatic progression, counteracting both metastasis initiation and expansion. The main mechanism of Bio-nFeR action consists of promoting tumor dormancy through a combined induction of antiproliferative signals and inhibition of the mTOR pathway.</p><p><strong>Conclusion: </strong>The high effectiveness of Bio-nFeR in the neuT model of mammary carcinogenesis, coupled with its low toxicity, indicates this formulation as a potential candidate for the treatment of metastatic BC and for the adjuvant therapy of BC patients at high risk of developing metastasis.</p>","PeriodicalId":50199,"journal":{"name":"Journal of Experimental & Clinical Cancer Research","volume":null,"pages":null},"PeriodicalIF":11.4,"publicationDate":"2024-11-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11536529/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142576675","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 : 2024-11-04DOI: 10.1186/s13046-024-03214-5
Juliano Tiburcio de Freitas, Varsha Thakur, Kathryn M LaPorte, Vijay S Thakur, Brian Flores, Valentina Caicedo, Chioma G E Ajaegbu, Giuseppe Ingrasci, Zoe M Lipman, Keman Zhang, Hong Qiu, Thomas R Malek, Barbara Bedogni
Background: Immune checkpoint inhibitors (ICI) have dramatically improved the life expectancy of patients with metastatic melanoma. However, about half of the patient population still present resistance to these treatments. We have previously shown Notch1 contributes to a non-inflamed TME in melanoma that reduces the response to ICI. Here, we addressed the therapeutic effects of a novel anti-Notch1 neutralizing antibody we produced, alone and in combination with immune checkpoint inhibition in melanoma models.
Methods: Anti-Notch1 was designed to interfere with ligand binding. Mice were immunized with a peptide encompassing EGF-like repeats 11-15 of human Notch1, the minimal required region that allows ligand binding and Notch1 activation. Positive clones were expanded and tested for neutralizing capabilities. Anti-Notch1-NIC was used to determine whether anti-Notch1 was able to reduce Notch1 cleavage; while anti-SNAP23 and BCAT2 were used as downstream Notch1 and Notch2 targets, respectively. K457 human melanoma cells and the YUMM2.1 and 1.7 syngeneic mouse melanoma cells were used. Cell death after anti-Notch1 treatment was determined by trypan blue staining and compared to the effects of the gamma-secretase inhibitor DBZ. 10 mg/kg anti-Notch1 was used for in vivo tumor growth of YUMM2.1 and 1.7 cells. Tumors were measured and processed for flow cytometry using antibodies against major immune cell populations.
Results: Anti-Notch1 selectively inhibited Notch1 but not Notch2; caused significant melanoma cell death in vitro but did not affect normal melanocytes. In vivo, it delayed tumor growth without evident signs of gastro-intestinal toxicities; and importantly promoted an inflamed TME by increasing the cytotoxic CD8+ T cells while reducing the tolerogenic Tregs and MDSCs, resulting in enhanced efficacy of anti-PD-1.
Conclusions: Anti-Notch1 safely exerts anti-melanoma effects and improves immune checkpoint inhibitor efficacy. Thus, anti-Notch1 could represent a novel addition to the immunotherapy repertoire for melanoma.
{"title":"Notch1 blockade by a novel, selective anti-Notch1 neutralizing antibody improves immunotherapy efficacy in melanoma by promoting an inflamed TME.","authors":"Juliano Tiburcio de Freitas, Varsha Thakur, Kathryn M LaPorte, Vijay S Thakur, Brian Flores, Valentina Caicedo, Chioma G E Ajaegbu, Giuseppe Ingrasci, Zoe M Lipman, Keman Zhang, Hong Qiu, Thomas R Malek, Barbara Bedogni","doi":"10.1186/s13046-024-03214-5","DOIUrl":"10.1186/s13046-024-03214-5","url":null,"abstract":"<p><strong>Background: </strong>Immune checkpoint inhibitors (ICI) have dramatically improved the life expectancy of patients with metastatic melanoma. However, about half of the patient population still present resistance to these treatments. We have previously shown Notch1 contributes to a non-inflamed TME in melanoma that reduces the response to ICI. Here, we addressed the therapeutic effects of a novel anti-Notch1 neutralizing antibody we produced, alone and in combination with immune checkpoint inhibition in melanoma models.</p><p><strong>Methods: </strong>Anti-Notch1 was designed to interfere with ligand binding. Mice were immunized with a peptide encompassing EGF-like repeats 11-15 of human Notch1, the minimal required region that allows ligand binding and Notch1 activation. Positive clones were expanded and tested for neutralizing capabilities. Anti-Notch1-NIC was used to determine whether anti-Notch1 was able to reduce Notch1 cleavage; while anti-SNAP23 and BCAT2 were used as downstream Notch1 and Notch2 targets, respectively. K457 human melanoma cells and the YUMM2.1 and 1.7 syngeneic mouse melanoma cells were used. Cell death after anti-Notch1 treatment was determined by trypan blue staining and compared to the effects of the gamma-secretase inhibitor DBZ. 10 mg/kg anti-Notch1 was used for in vivo tumor growth of YUMM2.1 and 1.7 cells. Tumors were measured and processed for flow cytometry using antibodies against major immune cell populations.</p><p><strong>Results: </strong>Anti-Notch1 selectively inhibited Notch1 but not Notch2; caused significant melanoma cell death in vitro but did not affect normal melanocytes. In vivo, it delayed tumor growth without evident signs of gastro-intestinal toxicities; and importantly promoted an inflamed TME by increasing the cytotoxic CD8<sup>+</sup> T cells while reducing the tolerogenic Tregs and MDSCs, resulting in enhanced efficacy of anti-PD-1.</p><p><strong>Conclusions: </strong>Anti-Notch1 safely exerts anti-melanoma effects and improves immune checkpoint inhibitor efficacy. Thus, anti-Notch1 could represent a novel addition to the immunotherapy repertoire for melanoma.</p>","PeriodicalId":50199,"journal":{"name":"Journal of Experimental & Clinical Cancer Research","volume":null,"pages":null},"PeriodicalIF":11.4,"publicationDate":"2024-11-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11533310/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142570057","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 : 2024-11-01DOI: 10.1186/s13046-024-03217-2
Arianna Giacomini, Sara Taranto, Giorgia Gazzaroli, Jessica Faletti, Davide Capoferri, Raffaella Marcheselli, Margherita Sciumè, Marco Presta, Antonio Sacco, Aldo M Roccaro
Among blood cancers, multiple myeloma (MM) represents the second most common neoplasm and is characterized by the accumulation and proliferation of monoclonal plasma cells within the bone marrow. Despite the last few decades being characterized by the development of different therapeutic strategies against MM, at present such disease is still considered incurable. Although MM is highly heterogeneous in terms of genetic and molecular subtypes, about 67% of MM cases are associated with abnormal activity of the transcription factor c-Myc, which has so far revealed a protein extremely difficult to target. We have recently demonstrated that activation of fibroblast growth factor (FGF) signaling protects MM cells from oxidative stress-induced apoptosis by stabilizing the oncoprotein c-Myc. Accordingly, secretion of FGF ligands and autocrine activation of FGF receptors (FGFR) is observed in MM cells and FGFR3 genomic alterations represent some 15-20% MM cases and are associated with poor outcome. Thus, FGF/FGFR blockade may represent a promising strategy to indirectly target c-Myc in MM. On this basis, the present review aims at providing an overview of recently explored connections between the FGF/FGFR system and c-Myc oncoprotein, sustaining the therapeutic potential of targeting the FGF/FGFR/c-Myc axis in MM by using inhibitors targeting FGF ligands or FGF receptors. Importantly, the provided findings may represent the rationale for using FDA approved FGFR TK inhibitors (i.e. Pemigatinib, Futibatinib, Erdafitinib) for the treatment of MM patients presenting with an aberrant activation of this axis.
在血癌中,多发性骨髓瘤(MM)是第二大常见肿瘤,其特征是骨髓中单克隆浆细胞的聚集和增殖。尽管在过去的几十年里,针对多发性骨髓瘤开发出了不同的治疗策略,但目前这种疾病仍被认为是不治之症。虽然 MM 在遗传和分子亚型方面具有高度异质性,但约 67% 的 MM 病例与转录因子 c-Myc 的异常活性有关,而迄今为止,c-Myc 蛋白仍是一种极难靶向的蛋白质。我们最近证实,成纤维细胞生长因子(FGF)信号的激活可通过稳定肿瘤蛋白 c-Myc 保护 MM 细胞免受氧化应激诱导的细胞凋亡。因此,在 MM 细胞中可观察到成纤维细胞生长因子配体的分泌和成纤维细胞生长因子受体(FGFR)的自分泌激活,FGFR3 基因组改变约占 MM 病例的 15-20%,并与不良预后有关。因此,阻断成纤维细胞生长因子受体/成纤维细胞生长因子受体可能是在 MM 中间接靶向 c-Myc 的一种有前途的策略。在此基础上,本综述旨在概述最近探索的成纤维细胞生长因子/成纤维细胞生长因子受体系统与 c-Myc 肿瘤蛋白之间的联系,通过使用靶向成纤维细胞生长因子配体或成纤维细胞生长因子受体的抑制剂,维持靶向成纤维细胞生长因子/成纤维细胞生长因子受体/c-Myc 轴的治疗潜力。重要的是,这些发现可能是使用 FDA 批准的 FGFR TK 抑制剂(即 Pemigatinib、Futibatinib、Erdafitinib)治疗出现该轴异常激活的 MM 患者的依据。
{"title":"The FGF/FGFR/c-Myc axis as a promising therapeutic target in multiple myeloma.","authors":"Arianna Giacomini, Sara Taranto, Giorgia Gazzaroli, Jessica Faletti, Davide Capoferri, Raffaella Marcheselli, Margherita Sciumè, Marco Presta, Antonio Sacco, Aldo M Roccaro","doi":"10.1186/s13046-024-03217-2","DOIUrl":"10.1186/s13046-024-03217-2","url":null,"abstract":"<p><p>Among blood cancers, multiple myeloma (MM) represents the second most common neoplasm and is characterized by the accumulation and proliferation of monoclonal plasma cells within the bone marrow. Despite the last few decades being characterized by the development of different therapeutic strategies against MM, at present such disease is still considered incurable. Although MM is highly heterogeneous in terms of genetic and molecular subtypes, about 67% of MM cases are associated with abnormal activity of the transcription factor c-Myc, which has so far revealed a protein extremely difficult to target. We have recently demonstrated that activation of fibroblast growth factor (FGF) signaling protects MM cells from oxidative stress-induced apoptosis by stabilizing the oncoprotein c-Myc. Accordingly, secretion of FGF ligands and autocrine activation of FGF receptors (FGFR) is observed in MM cells and FGFR3 genomic alterations represent some 15-20% MM cases and are associated with poor outcome. Thus, FGF/FGFR blockade may represent a promising strategy to indirectly target c-Myc in MM. On this basis, the present review aims at providing an overview of recently explored connections between the FGF/FGFR system and c-Myc oncoprotein, sustaining the therapeutic potential of targeting the FGF/FGFR/c-Myc axis in MM by using inhibitors targeting FGF ligands or FGF receptors. Importantly, the provided findings may represent the rationale for using FDA approved FGFR TK inhibitors (i.e. Pemigatinib, Futibatinib, Erdafitinib) for the treatment of MM patients presenting with an aberrant activation of this axis.</p>","PeriodicalId":50199,"journal":{"name":"Journal of Experimental & Clinical Cancer Research","volume":null,"pages":null},"PeriodicalIF":11.4,"publicationDate":"2024-11-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11529022/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142559274","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 : 2024-10-31DOI: 10.1186/s13046-024-03216-3
Zhe Wang, Hanxue Sun, Jan Provaznik, Thilo Hackert, Margot Zöller
{"title":"Correction: Pancreatic cancer-initiating cell exosome message transfer into noncancer-initiating cells: the importance of CD44v6 in reprogramming.","authors":"Zhe Wang, Hanxue Sun, Jan Provaznik, Thilo Hackert, Margot Zöller","doi":"10.1186/s13046-024-03216-3","DOIUrl":"10.1186/s13046-024-03216-3","url":null,"abstract":"","PeriodicalId":50199,"journal":{"name":"Journal of Experimental & Clinical Cancer Research","volume":null,"pages":null},"PeriodicalIF":11.4,"publicationDate":"2024-10-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11526508/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142548669","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 : 2024-10-22DOI: 10.1186/s13046-024-03180-y
Patrizia Tempora, Silvia D'Amico, Paula Gragera, Verena Damiani, Kamila Krol, Valentina Scaldaferri, Kirti Pandey, Shanzou Chung, Valeria Lucarini, Ezio Giorda, Marco Scarsella, Gabriele Volpe, Marco Pezzullo, Cristiano De Stefanis, Valentina D'Oria, Lorenzo De Angelis, Roberto Giovannoni, Maria Antonietta De Ioris, Ombretta Melaiu, Anthony W Purcell, Franco Locatelli, Doriana Fruci
Background: Checkpoint immunotherapy unleashes tumor control by T cells, but it is undermined in non-immunogenic tumors, e.g. with low MHC class I expression and low neoantigen burden, such as neuroblastoma (NB). Endoplasmic reticulum aminopeptidase 1 (ERAP1) is an enzyme that trims peptides before loading on MHC class I molecules. Inhibition of ERAP1 results in the generation of new antigens able of inducing potent anti-tumor immune responses. Here, we identify a novel non-toxic combinatorial strategy based on genetic inhibition of ERAP1 and administration of the HDAC inhibitor (HDACi) entinostat that increase the immunogenicity of NB, making it responsive to PD-1 therapy.
Methods: CRISPR/Cas9-mediated gene editing was used to knockout (KO) the ERAP1 gene in 9464D NB cells derived from spontaneous tumors of TH-MYCN transgenic mice. The expression of MHC class I and PD-L1 was evaluated by flow cytometry (FC). The immunopeptidome of these cells was studied by mass spectrometry. Cocultures of splenocytes derived from 9464D bearing mice and tumor cells allowed the assessment of the effect of ERAP1 inhibition on the secretion of inflammatory cytokines and activation and migration of immune cells towards ERAP1 KO cells by FC. Tumor cell killing was evaluated by Caspase 3/7 assay and flow cytometry analysis. The effect of ERAP1 inhibition on the immune content of tumors was analyzed by FC, immunohistochemistry and multiple immunofluorescence.
Results: We found that inhibition of ERAP1 makes 9464D cells more susceptible to immune cell-mediated killing by increasing both the recall and activation of CD4+ and CD8+ T cells and NK cells. Treatment with entinostat induces the expression of MHC class I and PD-L1 molecules in 9464D both in vitro and in vivo. This results in pronounced changes in the immunopeptidome induced by ERAP1 inhibition, but also restrains the growth of ERAP1 KO tumors in vivo by remodelling the tumor-infiltrating T-cell compartment. Interestingly, the absence of ERAP1 in combination with entinostat and PD-1 blockade overcomes resistance to PD-1 immunotherapy and increases host survival.
Conclusions: These findings demonstrate that ERAP1 inhibition combined with HDACi entinostat treatment and PD-1 blockade remodels the immune landscape of a non-immunogenic tumor such as NB, making it responsive to checkpoint immunotherapy.
背景:检查点免疫疗法可释放T细胞对肿瘤的控制作用,但对于非免疫原性肿瘤,如MHC I类低表达和新抗原负荷低的肿瘤,如神经母细胞瘤(NB),这种疗法就会受到破坏。内质网氨肽酶 1(ERAP1)是一种在肽载入 MHC I 类分子之前对其进行修饰的酶。抑制 ERAP1 会产生新的抗原,从而诱导有效的抗肿瘤免疫反应。在这里,我们发现了一种新型无毒组合策略,该策略基于对ERAP1的基因抑制和HDAC抑制剂(HDACi)恩替诺司他的施用,可增加NB的免疫原性,使其对PD-1疗法产生反应:方法:利用 CRISPR/Cas9 介导的基因编辑技术敲除(KO)来自 TH-MYCN 转基因小鼠自发性肿瘤的 9464D NB 细胞中的 ERAP1 基因。流式细胞术(FC)评估了 MHC I 类和 PD-L1 的表达。质谱法研究了这些细胞的免疫肽组。将携带 9464D 的小鼠脾脏细胞与肿瘤细胞共培养,可通过 FC 评估 ERAP1 抑制对炎症细胞因子分泌的影响,以及免疫细胞对 ERAP1 KO 细胞的激活和迁移。Caspase 3/7 检测法和流式细胞术分析评估了肿瘤细胞杀伤作用。通过FC、免疫组化和多重免疫荧光分析了抑制ERAP1对肿瘤免疫成分的影响:结果:我们发现,抑制ERAP1会增加CD4+和CD8+T细胞以及NK细胞的召回和活化,从而使9464D细胞更容易受到免疫细胞介导的杀伤。用恩替诺特治疗可诱导 9464D 细胞在体外和体内表达 MHC I 类和 PD-L1 分子。这不仅导致ERAP1抑制诱导的免疫肽组发生明显变化,还通过重塑肿瘤浸润T细胞区系抑制了体内ERAP1 KO肿瘤的生长。有趣的是,ERAP1缺失与恩替诺斯他和PD-1阻断联合使用,可克服对PD-1免疫疗法的耐药性,并提高宿主存活率:这些研究结果表明,ERAP1抑制与HDACi恩替诺司他治疗和PD-1阻断相结合,可重塑NB等非免疫原性肿瘤的免疫格局,使其对检查点免疫疗法产生反应。
{"title":"Combining ERAP1 silencing and entinostat therapy to overcome resistance to cancer immunotherapy in neuroblastoma.","authors":"Patrizia Tempora, Silvia D'Amico, Paula Gragera, Verena Damiani, Kamila Krol, Valentina Scaldaferri, Kirti Pandey, Shanzou Chung, Valeria Lucarini, Ezio Giorda, Marco Scarsella, Gabriele Volpe, Marco Pezzullo, Cristiano De Stefanis, Valentina D'Oria, Lorenzo De Angelis, Roberto Giovannoni, Maria Antonietta De Ioris, Ombretta Melaiu, Anthony W Purcell, Franco Locatelli, Doriana Fruci","doi":"10.1186/s13046-024-03180-y","DOIUrl":"10.1186/s13046-024-03180-y","url":null,"abstract":"<p><strong>Background: </strong>Checkpoint immunotherapy unleashes tumor control by T cells, but it is undermined in non-immunogenic tumors, e.g. with low MHC class I expression and low neoantigen burden, such as neuroblastoma (NB). Endoplasmic reticulum aminopeptidase 1 (ERAP1) is an enzyme that trims peptides before loading on MHC class I molecules. Inhibition of ERAP1 results in the generation of new antigens able of inducing potent anti-tumor immune responses. Here, we identify a novel non-toxic combinatorial strategy based on genetic inhibition of ERAP1 and administration of the HDAC inhibitor (HDACi) entinostat that increase the immunogenicity of NB, making it responsive to PD-1 therapy.</p><p><strong>Methods: </strong>CRISPR/Cas9-mediated gene editing was used to knockout (KO) the ERAP1 gene in 9464D NB cells derived from spontaneous tumors of TH-MYCN transgenic mice. The expression of MHC class I and PD-L1 was evaluated by flow cytometry (FC). The immunopeptidome of these cells was studied by mass spectrometry. Cocultures of splenocytes derived from 9464D bearing mice and tumor cells allowed the assessment of the effect of ERAP1 inhibition on the secretion of inflammatory cytokines and activation and migration of immune cells towards ERAP1 KO cells by FC. Tumor cell killing was evaluated by Caspase 3/7 assay and flow cytometry analysis. The effect of ERAP1 inhibition on the immune content of tumors was analyzed by FC, immunohistochemistry and multiple immunofluorescence.</p><p><strong>Results: </strong>We found that inhibition of ERAP1 makes 9464D cells more susceptible to immune cell-mediated killing by increasing both the recall and activation of CD4<sup>+</sup> and CD8<sup>+</sup> T cells and NK cells. Treatment with entinostat induces the expression of MHC class I and PD-L1 molecules in 9464D both in vitro and in vivo. This results in pronounced changes in the immunopeptidome induced by ERAP1 inhibition, but also restrains the growth of ERAP1 KO tumors in vivo by remodelling the tumor-infiltrating T-cell compartment. Interestingly, the absence of ERAP1 in combination with entinostat and PD-1 blockade overcomes resistance to PD-1 immunotherapy and increases host survival.</p><p><strong>Conclusions: </strong>These findings demonstrate that ERAP1 inhibition combined with HDACi entinostat treatment and PD-1 blockade remodels the immune landscape of a non-immunogenic tumor such as NB, making it responsive to checkpoint immunotherapy.</p>","PeriodicalId":50199,"journal":{"name":"Journal of Experimental & Clinical Cancer Research","volume":null,"pages":null},"PeriodicalIF":11.4,"publicationDate":"2024-10-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11494811/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142512154","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 : 2024-10-21DOI: 10.1186/s13046-024-03211-8
Agata Lichawska-Cieslar, Weronika Szukala, Guillem Ylla, Gabriela Machaj, Faustyna Ploskonka, Iwona Chlebicka, Jacek C Szepietowski, Jolanta Jura
Background: Monocyte Chemotactic Protein 1-Induced Protein 1 (MCPIP1, also called Regnase-1) is a negative modulator of inflammation with tumor-suppressive properties. Mice with keratinocyte-specific deletion of the Zc3h12a gene, encoding MCPIP1, (Mcpip1eKO mice) are more susceptible to the development of epidermal papillomas initiated by 7,12-dimethylbenz[a]-anthracene (DMBA) and promoted by 2-O-tetradecanoylphorbol-13-acetate (TPA).
Methods: The aim of this study was to investigate the MCPIP1 RNase-dependent microRNA (miRNA)‒mRNA regulatory network in chemically induced squamous cell carcinoma (SCC)-like skin papillomas. Next-generation sequencing (NGS) coupled with bioinformatic analysis was used to shortlist the MCPIP1-dependent changes in protein-coding genes and miRNAs. The expression levels of the selected miRNAs were analyzed by quantitative PCR in human keratinocytes with MCPIP1 silencing. Functional studies were performed in human keratinocytes transfected with appropriate miRNA mimics. The DIANA-microT-CDS algorithm and DIANA-TarBase v7 database were used to predict potential target genes and identify the experimentally validated targets of differentially expressed (DE) miRNAs.
Results: RNA sequencing (RNA-Seq) analysis of control and Mcpip1eKO DMBA/TPA-induced papillomas revealed transcriptome changes, with 2400 DE protein-coding genes and 33 DE miRNAs. The expression of miR-223-3p, miR-376c-3p, and miR-139-5p was confirmed to be dependent on MCPIP1 activity in both murine and human models. We showed that MCPIP1 directly regulates the expression of miR-376c-3p via direct cleavage of the corresponding precursor miRNA. The pro-proliferative activity of miR-223-3p, miR-376c-3p, and miR-139-5p was experimentally confirmed in SCC-like keratinocytes. Bioinformatic prediction of the mRNA targets of the DE-miRNAs revealed 416 genes as putative targets of the 18 upregulated miRNAs and 425 genes as putative targets of the 15 downregulated miRNAs. Further analyses revealed the murine interactions that are conserved in humans. Functional analysis indicated that during the development of cutaneous SCC, the most important pathways/processes mediated by the miRNA‒mRNA MCPIP1-dependent network are the regulation of inflammatory processes, epithelial cell proliferation, Wnt signaling, and miRNA transcription.
Conclusions: Loss of MCPIP1 modulates the expression profiles of 33 miRNAs in chemically induced Mcpip1eKO papillomas, and these changes directly affect the miRNA‒mRNA network and the modulation of pathways and processes related to carcinogenesis.
{"title":"MCPIP1 modulates the miRNA‒mRNA landscape in keratinocyte carcinomas.","authors":"Agata Lichawska-Cieslar, Weronika Szukala, Guillem Ylla, Gabriela Machaj, Faustyna Ploskonka, Iwona Chlebicka, Jacek C Szepietowski, Jolanta Jura","doi":"10.1186/s13046-024-03211-8","DOIUrl":"10.1186/s13046-024-03211-8","url":null,"abstract":"<p><strong>Background: </strong>Monocyte Chemotactic Protein 1-Induced Protein 1 (MCPIP1, also called Regnase-1) is a negative modulator of inflammation with tumor-suppressive properties. Mice with keratinocyte-specific deletion of the Zc3h12a gene, encoding MCPIP1, (Mcpip1<sup>eKO</sup> mice) are more susceptible to the development of epidermal papillomas initiated by 7,12-dimethylbenz[a]-anthracene (DMBA) and promoted by 2-O-tetradecanoylphorbol-13-acetate (TPA).</p><p><strong>Methods: </strong>The aim of this study was to investigate the MCPIP1 RNase-dependent microRNA (miRNA)‒mRNA regulatory network in chemically induced squamous cell carcinoma (SCC)-like skin papillomas. Next-generation sequencing (NGS) coupled with bioinformatic analysis was used to shortlist the MCPIP1-dependent changes in protein-coding genes and miRNAs. The expression levels of the selected miRNAs were analyzed by quantitative PCR in human keratinocytes with MCPIP1 silencing. Functional studies were performed in human keratinocytes transfected with appropriate miRNA mimics. The DIANA-microT-CDS algorithm and DIANA-TarBase v7 database were used to predict potential target genes and identify the experimentally validated targets of differentially expressed (DE) miRNAs.</p><p><strong>Results: </strong>RNA sequencing (RNA-Seq) analysis of control and Mcpip1<sup>eKO</sup> DMBA/TPA-induced papillomas revealed transcriptome changes, with 2400 DE protein-coding genes and 33 DE miRNAs. The expression of miR-223-3p, miR-376c-3p, and miR-139-5p was confirmed to be dependent on MCPIP1 activity in both murine and human models. We showed that MCPIP1 directly regulates the expression of miR-376c-3p via direct cleavage of the corresponding precursor miRNA. The pro-proliferative activity of miR-223-3p, miR-376c-3p, and miR-139-5p was experimentally confirmed in SCC-like keratinocytes. Bioinformatic prediction of the mRNA targets of the DE-miRNAs revealed 416 genes as putative targets of the 18 upregulated miRNAs and 425 genes as putative targets of the 15 downregulated miRNAs. Further analyses revealed the murine interactions that are conserved in humans. Functional analysis indicated that during the development of cutaneous SCC, the most important pathways/processes mediated by the miRNA‒mRNA MCPIP1-dependent network are the regulation of inflammatory processes, epithelial cell proliferation, Wnt signaling, and miRNA transcription.</p><p><strong>Conclusions: </strong>Loss of MCPIP1 modulates the expression profiles of 33 miRNAs in chemically induced Mcpip1<sup>eKO</sup> papillomas, and these changes directly affect the miRNA‒mRNA network and the modulation of pathways and processes related to carcinogenesis.</p>","PeriodicalId":50199,"journal":{"name":"Journal of Experimental & Clinical Cancer Research","volume":null,"pages":null},"PeriodicalIF":11.4,"publicationDate":"2024-10-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11492624/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142479518","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}
Background: Clear cell renal cell carcinoma (ccRCC) arises from the renal parenchymal epithelium and is the predominant malignant entity of renal cancer, exhibiting increasing incidence and mortality rates over time. SEC14-like 3 (SEC14L3) has emerged as a compelling target for cancer intervention; nevertheless, the precise clinical implications and molecular underpinnings of SEC14L3 in ccRCC remain elusive.
Methods: By leveraging clinical data and data from the TCGA-ccRCC and GEO datasets, we investigated the association between SEC14L3 expression levels and overall survival rates in ccRCC patients. The biological role and mechanism of SEC14L3 in ccRCC were investigated via in vivo and in vitro experiments. Moreover, siRNA-SEC14L3@PDA@MUC12 nanoparticles (SSPM-NPs) were synthesized and assessed for their therapeutic potential against SEC14L3 through in vivo and in vitro assays.
Results: Our investigation revealed upregulated SEC14L3 expression in ccRCC tissues, and exogenous downregulation of SEC14L3 robustly suppressed the malignant traits of ccRCC cells. Mechanistically, knocking down SEC14L3 facilitated the ubiquitination-mediated degradation of ribosomal protein S3 (RPS3) and augmented IκBα accumulation in ccRCC. This concerted action thwarted the nuclear translocation of P65, thereby abrogating the activation of the nuclear factor kappa B (NFκB) signaling pathway and impeding ccRCC cell proliferation and metastasis. Furthermore, diminished SEC14L3 levels exerted a suppressive effect on NFKB1 expression within the NFκB signaling cascade. NFKB1 functions as a transcriptional regulator capable of binding to the SEC14L3 enhancer and promoter, thereby promoting SEC14L3 expression. Consequently, the inhibition of SEC14L3 expression was further potentiated, thus forming a positive feedback loop. Additionally, we observed that downregulation of SEC14L3 significantly increased the sensitivity of ccRCC cells to sunitinib. The evaluation of SSPM-NPs nanotherapy highlighted its effectiveness in combination with sunitinib for inhibiting ccRCC growth.
Conclusion: Our findings not only underscore the promise of SEC14L3 as a therapeutic target but also unveil an SEC14L3/RPS3/NFκB positive feedback loop that curtails ccRCC progression. Modulating SEC14L3 expression to engage this positive feedback loop might herald novel avenues for ccRCC treatment.
{"title":"SEC14L3 knockdown inhibited clear cell renal cell carcinoma proliferation, metastasis and sunitinib resistance through an SEC14L3/RPS3/NFκB positive feedback loop.","authors":"Ziming Jiang, Guangcan Yang, Guangchun Wang, Jiayi Wan, Yifan Zhang, Wei Song, Houliang Zhang, Jinliang Ni, Haipeng Zhang, Ming Luo, Keyi Wang, Bo Peng","doi":"10.1186/s13046-024-03206-5","DOIUrl":"10.1186/s13046-024-03206-5","url":null,"abstract":"<p><strong>Background: </strong>Clear cell renal cell carcinoma (ccRCC) arises from the renal parenchymal epithelium and is the predominant malignant entity of renal cancer, exhibiting increasing incidence and mortality rates over time. SEC14-like 3 (SEC14L3) has emerged as a compelling target for cancer intervention; nevertheless, the precise clinical implications and molecular underpinnings of SEC14L3 in ccRCC remain elusive.</p><p><strong>Methods: </strong>By leveraging clinical data and data from the TCGA-ccRCC and GEO datasets, we investigated the association between SEC14L3 expression levels and overall survival rates in ccRCC patients. The biological role and mechanism of SEC14L3 in ccRCC were investigated via in vivo and in vitro experiments. Moreover, siRNA-SEC14L3@PDA@MUC12 nanoparticles (SSPM-NPs) were synthesized and assessed for their therapeutic potential against SEC14L3 through in vivo and in vitro assays.</p><p><strong>Results: </strong>Our investigation revealed upregulated SEC14L3 expression in ccRCC tissues, and exogenous downregulation of SEC14L3 robustly suppressed the malignant traits of ccRCC cells. Mechanistically, knocking down SEC14L3 facilitated the ubiquitination-mediated degradation of ribosomal protein S3 (RPS3) and augmented IκBα accumulation in ccRCC. This concerted action thwarted the nuclear translocation of P65, thereby abrogating the activation of the nuclear factor kappa B (NFκB) signaling pathway and impeding ccRCC cell proliferation and metastasis. Furthermore, diminished SEC14L3 levels exerted a suppressive effect on NFKB1 expression within the NFκB signaling cascade. NFKB1 functions as a transcriptional regulator capable of binding to the SEC14L3 enhancer and promoter, thereby promoting SEC14L3 expression. Consequently, the inhibition of SEC14L3 expression was further potentiated, thus forming a positive feedback loop. Additionally, we observed that downregulation of SEC14L3 significantly increased the sensitivity of ccRCC cells to sunitinib. The evaluation of SSPM-NPs nanotherapy highlighted its effectiveness in combination with sunitinib for inhibiting ccRCC growth.</p><p><strong>Conclusion: </strong>Our findings not only underscore the promise of SEC14L3 as a therapeutic target but also unveil an SEC14L3/RPS3/NFκB positive feedback loop that curtails ccRCC progression. Modulating SEC14L3 expression to engage this positive feedback loop might herald novel avenues for ccRCC treatment.</p>","PeriodicalId":50199,"journal":{"name":"Journal of Experimental & Clinical Cancer Research","volume":null,"pages":null},"PeriodicalIF":11.4,"publicationDate":"2024-10-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11490128/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142479520","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 : 2024-10-19DOI: 10.1186/s13046-024-03205-6
Meng Wang, Yong Han, Chao Zhang
Recent progress in elucidating the role of specific antidiuretic hormones in Drosophila models has provided valuable insights into the mechanisms underlying tumor-induced renal dysfunction. Xu et al. identified the mammalian neurokinin 3 receptor (TACR3), a homolog of the G protein-coupled receptor TkR99D in fruit flies, as a potential therapeutic target for alleviating renal tubular dysfunction in mice with malignant neoplasms. Here, we commented on these findings by emphasizing the structural and evolutionary significance of TACR3 and provided an in-depth analysis of cell type specific expression of TACR3 in response to renal injury and expressional dynamics during renal carcinoma progression. The implications of these findings for transforming the therapeutic approaches to renal complications associated with oncological disorders were highlighted. We also acknowledged the limitations of current experimental models in this study and emphasized the necessary clinical validation in the future. These insights could contribute to the advancement of diagnostic and therapeutic strategies for treating tumor-related renal pathologies.
{"title":"Noval insights and therapeutic strategies for tumor-induced kidney pathologies.","authors":"Meng Wang, Yong Han, Chao Zhang","doi":"10.1186/s13046-024-03205-6","DOIUrl":"10.1186/s13046-024-03205-6","url":null,"abstract":"<p><p>Recent progress in elucidating the role of specific antidiuretic hormones in Drosophila models has provided valuable insights into the mechanisms underlying tumor-induced renal dysfunction. Xu et al. identified the mammalian neurokinin 3 receptor (TACR3), a homolog of the G protein-coupled receptor TkR99D in fruit flies, as a potential therapeutic target for alleviating renal tubular dysfunction in mice with malignant neoplasms. Here, we commented on these findings by emphasizing the structural and evolutionary significance of TACR3 and provided an in-depth analysis of cell type specific expression of TACR3 in response to renal injury and expressional dynamics during renal carcinoma progression. The implications of these findings for transforming the therapeutic approaches to renal complications associated with oncological disorders were highlighted. We also acknowledged the limitations of current experimental models in this study and emphasized the necessary clinical validation in the future. These insights could contribute to the advancement of diagnostic and therapeutic strategies for treating tumor-related renal pathologies.</p>","PeriodicalId":50199,"journal":{"name":"Journal of Experimental & Clinical Cancer Research","volume":null,"pages":null},"PeriodicalIF":11.4,"publicationDate":"2024-10-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11490039/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142479519","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}