OncoTargets and therapy最新文献

{"title":"Synergistic Effect of Ubiquitin-Specific Protease 14 and Poly(ADP-Ribose) Glycohydrolase Co-Inhibition in BRCA1-Mutant, Poly(ADP-Ribose) Polymerase Inhibitor-Resistant Triple-Negative Breast Cancer Cells","authors":"Pisong Li, Xiaoyu Zhu, Hui Qu, Zhongbin Han, Xingyu Yao, Yuan Wei, Baijun Li, Hongshen Chen","doi":"10.2147/ott.s463217","DOIUrl":"https://doi.org/10.2147/ott.s463217","url":null,"abstract":"<strong>Purpose:</strong> The clinical benefits of poly(ADP-ribose) polymerase (PARP) inhibitors are limited to triple-negative breast cancer (TNBC) with BRCA deficiency due to primary and acquired resistance. Thus, there is a pressing need to develop alternative treatment regimens to target BRCA-mutated TNBC tumors that are resistant to PARP inhibition. Similar to PARP, poly(ADP-ribose) glycohydrolase (PARG) plays a role in DNA replication and repair. However, there are conflicting reports on the vulnerability of BRCA1-deficient tumor cells to PARG inhibition. This study aims to investigate the synergistically lethal effect of the PARG inhibitor COH34 and the ubiquitin-specific protease (USP) 14 inhibitor IU1-248 and the underlying mechanisms in BRCA1-mutant, PARP inhibitor-resistant TNBC cells.<br/><strong>Methods:</strong> The cytotoxicity of PARG inhibition alone or in combination with USP14 inhibition in the BRCA-mutant, PARP inhibitor-resistant TNBC cell lines, HCC1937 and SUM149PT, was analyzed using cell viability and proliferation assays and flow cytometry. The molecular mechanisms underlying the synergistic effects of IU1-248 and COH34 were evaluated by immunofluorescence staining, DNA repair reporter assays and Western blot analysis.<br/><strong>Results:</strong> It was found that HCC1937 and SUM149PT cells exhibited moderate responsiveness to PARG inhibition alone. To the best of our knowledge, this research is the first to demonstrate that the combination of IU1-248 and COH34 produces synergistic effects against TNBC cells in the same setting. Mechanistically, the blockade of USP14 by IU1-248 was shown to increase DNA damage and promote error-prone non-homologous end joining (NHEJ), as evidenced by the accumulation of γH2AX and 53BP1 in the nucleus and the activation of a reporter assay. Additionally, it was demonstrated that the inhibition of NHEJ repair activity attenuates the synergistic effects of concomitant PARG and USP14 inhibition. IU1-248 promotes NHEJ repair through the downregulation of the expression of c-Myc.<br/><strong>Conclusion:</strong> USP14 inhibition may be a plausible strategy for expanding the utility of PARG inhibitors in TNBC in BRCA-mutant, PARP inhibitor-resistant settings.<br/><br/><strong>Keywords:</strong> PARG, USP14, NHEJ, c-Myc, BRCA, triple-negative breast cancer<br/>","PeriodicalId":19534,"journal":{"name":"OncoTargets and therapy","volume":null,"pages":null},"PeriodicalIF":4.0,"publicationDate":"2024-09-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142197059","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Familial Acute Promyelocytic Leukemia: A Case Report and Review of the Literature.","authors":"Mingqi Yang, Lian Bai, Yunju Ma, Xuanqi Cao, Qingya Cui, Depei Wu, Xiaowen Tang","doi":"10.2147/OTT.S482781","DOIUrl":"10.2147/OTT.S482781","url":null,"abstract":"<p><p>Acute promyelocytic leukemia (APL) is characterized by a reciprocal translocation t (15;17) (q24;q21), which leads to the fusion of PML and RARα genes known as <i>PML-RARα</i> fusion. A few cases of potentially hereditary leukemia-related genes in APL have been reported, but no instances of familial aggregation of APL have been documented. Here, we describe a family in whom two members successively affected by APL。The potential familial association observed in these two cases of APL highlights the need for further investigation and more definitive genetic lineage tracing in order to understand the genetic basis of this disease.</p>","PeriodicalId":19534,"journal":{"name":"OncoTargets and therapy","volume":null,"pages":null},"PeriodicalIF":2.7,"publicationDate":"2024-09-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11380871/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142157185","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Implications of the Receptor Tyrosine Kinase Axl in Gastric Cancer Progression [Retraction].","authors":"","doi":"10.2147/OTT.S493699","DOIUrl":"https://doi.org/10.2147/OTT.S493699","url":null,"abstract":"<p><p>[This retracts the article DOI: 10.2147/OTT.S257606.].</p>","PeriodicalId":19534,"journal":{"name":"OncoTargets and therapy","volume":null,"pages":null},"PeriodicalIF":2.7,"publicationDate":"2024-08-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11370778/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142126316","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"RAB43 Promotes Gastric Cancer Cell Proliferation and Metastasis via Regulating the PI3K/AKT Signaling Pathway [Retraction].","authors":"","doi":"10.2147/OTT.S493691","DOIUrl":"https://doi.org/10.2147/OTT.S493691","url":null,"abstract":"<p><p>[This retracts the article DOI: 10.2147/OTT.S237356.].</p>","PeriodicalId":19534,"journal":{"name":"OncoTargets and therapy","volume":null,"pages":null},"PeriodicalIF":2.7,"publicationDate":"2024-08-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11370889/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142126317","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"TRIM11 Promotes Proliferation, Migration, Invasion and EMT of Gastric Cancer by Activating β-Catenin Signaling [Retraction].","authors":"","doi":"10.2147/OTT.S493697","DOIUrl":"https://doi.org/10.2147/OTT.S493697","url":null,"abstract":"<p><p>[This retracts the article DOI: 10.2147/OTT.S289922.].</p>","PeriodicalId":19534,"journal":{"name":"OncoTargets and therapy","volume":null,"pages":null},"PeriodicalIF":2.7,"publicationDate":"2024-08-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11370760/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142126320","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Safety and Efficacy of Gefitinib Administration After Osimertinib-Induced Interstitial Lung Disease: A Six-Case Series.","authors":"Kaoruko Shimbu, Kakeru Hisakane, Naohiro Kadoma, Shunichi Nishima, Kenichiro Atsumi, Masahiro Seike, Takashi Hirose","doi":"10.2147/OTT.S475836","DOIUrl":"10.2147/OTT.S475836","url":null,"abstract":"<p><strong>Purpose: </strong>Osimertinib, a third-generation epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor, is the standard treatment for patients with non-small cell lung cancer harboring EGFR mutations. Although the frequency of osimertinib-induced interstitial lung disease (osi-ILD) is high, the optimal cancer treatment after osi-ILD has not been established. This time, we focused on the safety and efficacy of gefitinib following osi-ILD.</p><p><strong>Case presentation: </strong>We experienced six cases (five women and one man; median age: 74 years) in which gefitinib was administered after osi-ILD. All six cases had grade 2 or higher osi-ILD and required steroid treatment. The computed tomography imaging pattern of osi-ILD revealed organizing pneumonia in three cases, diffuse alveolar damage in two cases, and hypersensitivity pneumonia in one case. Eastern Cooperative Oncology Group performance status was 1 in four cases, 2 in one case, and 3 in one case. EGFR mutation status was exon 19 deletion in two cases and exon 21 L858R in four cases. Only one patient experienced recurrence of ILD after receiving gefitinib. The best response to gefitinib was partial response in two cases and stable disease in three cases; one case was not evaluable. The median progression-free survival after treatment with gefitinib was 190 days (95% confidence interval: 33-328).</p><p><strong>Conclusion: </strong>The treatment with gefitinib after the development of osi-ILD was safe and effective. Gefitinib may be a promising option for patients who recovered from severe osi-ILD.</p>","PeriodicalId":19534,"journal":{"name":"OncoTargets and therapy","volume":null,"pages":null},"PeriodicalIF":2.7,"publicationDate":"2024-08-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11371895/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142133390","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Tumor-Homing Antibody-Cytokine Fusions for Cancer Therapy.","authors":"Eleonora Prodi, Dario Neri, Roberto De Luca","doi":"10.2147/OTT.S480787","DOIUrl":"10.2147/OTT.S480787","url":null,"abstract":"<p><p>Recombinant cytokine products have emerged as a promising avenue in cancer therapy due to their capacity to modulate and enhance the immune response against tumors. However, their clinical application is significantly hindered by systemic toxicities already at low doses, thus preventing escalation to therapeutically active regimens. One promising approach to overcoming these limitations is using antibody-cytokine fusion proteins (also called immunocytokines). These biopharmaceuticals leverage the targeting specificity of antibodies to deliver cytokines directly to the tumor microenvironment, thereby reducing systemic exposure and enhancing the therapeutic index. This review comprehensively examines the development and potential of antibody-cytokine fusion proteins in cancer therapy. It explores the molecular characteristics that influence the performance of these fusion proteins, and it highlights key findings from preclinical and clinical studies, illustrating the potential of immunocytokines to improve treatment outcomes in cancer patients. Recent advancements in the field, such as novel engineering strategies and combination strategies to enhance the efficacy and safety of immunocytokines, are also discussed. These innovations offer new opportunities to optimize this class of biotherapeutics, making them a more viable and effective option for cancer treatment. As the field continues to evolve, understanding the critical factors that influence the performance of immunocytokines will be essential for successfully translating these therapies into clinical practice.</p>","PeriodicalId":19534,"journal":{"name":"OncoTargets and therapy","volume":null,"pages":null},"PeriodicalIF":2.7,"publicationDate":"2024-08-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11368152/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142120296","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"KRAS^G12C Inhibitors in Non-Small Cell Lung Cancer: A Review.","authors":"Min Tang, Yijun Wu, Xiufeng Bai, You Lu","doi":"10.2147/OTT.S473368","DOIUrl":"10.2147/OTT.S473368","url":null,"abstract":"<p><p>Rat sarcoma virus (<i>RAS</i>) GTPase is one of the most important drivers of non-small cell lung cancer (NSCLC). <i>RAS</i> has three different isoforms (Harvey rat sarcoma viral oncogene homolog [<i>HRAS]</i>, Kirsten rat sarcoma viral oncogene homolog [<i>KRAS]</i> and Neuroblastoma ras viral oncogene homolog [<i>NRAS</i>]), of which <i>KRAS</i> is most commonly mutated in NSCLC. The mutated KRAS protein was historically thought to be \"undruggable\" until the development of KRAS^G12C inhibitors. In this review, from the aspect of brain metastasis, we aim to provide an overview of the advances in therapies that target KRAS^G12C, the limitations of the current treatments, and future prospects in patients with <i>KRAS</i> p.G12C mutant NSCLC.</p>","PeriodicalId":19534,"journal":{"name":"OncoTargets and therapy","volume":null,"pages":null},"PeriodicalIF":2.7,"publicationDate":"2024-08-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11352592/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142110366","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"A Multidisciplinary Approach to Improve the Management of Immune-Checkpoint Inhibitor-Related Pneumonitis.","authors":"Monica Valente, Maura Colucci, Virginia Vegni, Valentina Croce, Cristiana Bellan, Giulia Rossi, Giulia Gibilisco, Francesco Frongia, Raffaella Guazzo, Claudia Ghiribelli, Elena Bargagli, Vinno Savelli, Matteo Ravara, Tommaso Sani, Elena Simonetti, Michele Maio, Luana Calabrò, Anna Maria Di Giacomo","doi":"10.2147/OTT.S470892","DOIUrl":"10.2147/OTT.S470892","url":null,"abstract":"<p><strong>Purpose: </strong>Treatment with immune-checkpoint inhibitors (ICIs) can be associated with a wide spectrum of immune-related adverse events (irAEs). Among irAEs, immune-mediated pneumonitis (im-PN) is a rare but potentially life-threatening side effect. TPrompt multidisciplinary diagnosis and effective management of im-PN may be essential to avoid severe complications and allowing resumation of therapy.</p><p><strong>Patients and methods: </strong>We collected a case series of skin (melanoma, cutaneous squamous cell carcinoma-CSCC), lung, and mesothelioma cancer patients (pts), treated with ICI at the Center for Immuno-Oncology University Hospital of Siena, Italy, and diagnosed with im-PN. Clinical and radiologic data were thoroughly collected, as well as bronchoalveolar lavage (BAL) samples; im-PN was graded using CTCAE v. 5.0. Radiological patterns were reported according to the <i>F</i>leischner Society classification.</p><p><strong>Results: </strong>From January 2014 to February 2023, 1004 patients with melanoma (522), CSCC (42), lung (342) or mesothelioma (98) were treated with ICI (619 monotherapy; 385 combination). Among treated patients, 24 (2%) developed an im-PN and 58% were symptomatic. Im-PN were classified as grades G1 (10) and G2 (14). Prompt steroid treatment led to complete resolution of im-PN in 21 patients, with a median time to resolution of 14 weeks (range: 0.4-51). Twelve patients resumed ICI therapy once fully-recovered and 2 experienced a recurrence that completely resolved with steroids after resumption of treatment. Three radiologic patterns were identified: organizational pneumonia-like (67%), pulmonary eosinophilia (29%), and hypersensitivity pneumonitis (4%). Furthermore, BAL analysis performed in 8 (33%) patients showed an inflammatory lymphocytic infiltrate, predominantly consisting of foam cell-like macrophage infiltrates in 6 cases. Notably, transmission electron microscopy evaluation performed in 2 patients revealed a scenario suggestive of a drug-mediated toxicity.</p><p><strong>Conclusion: </strong>Im-PN is a rare but challenging side effect of ICI therapy, with variable time of onset and with heterogeneous clinical and radiological presentations. A multidisciplinary assessment is mandatory to optimize the clinical management of im-PN.</p>","PeriodicalId":19534,"journal":{"name":"OncoTargets and therapy","volume":null,"pages":null},"PeriodicalIF":2.7,"publicationDate":"2024-08-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11346482/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142073500","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"TRIM31 Promotes Glioma Proliferation and Invasion Through Activating NF-κB Pathway [Retraction].","authors":"","doi":"10.2147/OTT.S491281","DOIUrl":"https://doi.org/10.2147/OTT.S491281","url":null,"abstract":"<p><p>[This retracts the article DOI: 10.2147/OTT.S183625.].</p>","PeriodicalId":19534,"journal":{"name":"OncoTargets and therapy","volume":null,"pages":null},"PeriodicalIF":2.7,"publicationDate":"2024-08-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11345454/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142073501","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}