2f:I[703058,["/_next/static/immutable/chunks/3bhq_5eh1d760.js","/_next/static/immutable/chunks/1855-ogyi8eh4.js","/_next/static/immutable/chunks/2pfsjpn6k6zlg.js","/_next/static/immutable/chunks/26c7v3_3uwnwu.js","/_next/static/immutable/chunks/25a3ozcrvi1ff.js","/_next/static/immutable/chunks/2r4wx50nvjh_4.js","/_next/static/immutable/chunks/23fsw06hsi5b1.js","/_next/static/immutable/chunks/06_yt270h41rg.js","/_next/static/immutable/chunks/3ezsiz-7shkna.js","/_next/static/immutable/chunks/20x2y96ldu5wx.js","/_next/static/immutable/chunks/2lxntcm3pd1_h.js","/_next/static/immutable/chunks/00dgco8irq3jw.js","/_next/static/immutable/chunks/00nwe-kq0rboc.js","/_next/static/immutable/chunks/2051ffx3xzio9.js"],"PaperListPageClient"] 30:T535,Idiopathic pulmonary fibrosis (IPF) is a progressive and fatal interstitial lung disease marked by aberrant fibroblast activation, resulting in excessive proliferation, survival, and accumulation of extracellular matrix (ECM). A critical barrier to developing effective therapies for IPF is the limited understanding of druggable molecular regulators that control fibroblast activation. In this study, we identify the proto-oncogene MYCN as a key driver upregulated in dysregulated fibroblasts from IPF lungs. Mechanistically, we show that TGFα induces MYCN expression via the profibrotic transcription factor Wilms tumor 1 (WT1). Notably, the knockdown of MYCN significantly attenuated fibroblast proliferation, survival, and ECM production. We further show that MYCN positively regulates the mitotic kinase, Polo-like kinase (PLK1), and that pharmacological inhibition of PLK1 using volasertib reduced expression of MYCN, WT1, and PLK1 and mitigated fibroblast activation. In vivo, volasertib treatment attenuated fibroblast activation and collagen deposition during TGFα-induced pulmonary fibrosis. Together, these findings identify a pathogenic role for the WT1-MYCN-PLK1 axis in fibroblast activation and provide proof-of-concept evidence supporting PLK1 inhibition with volasertib as a potential therapeutic strategy for IPF.31:T546,Idiopathic pulmonary fibrosis (IPF) is a progressive and fatal interstitial lung disease marked by aberrant fibroblast activation, resulting in excessive proliferation, survival, and accumulation of extracellular matrix (ECM). A critical barrier to developing effective therapies for IPF is the limited understanding of druggable molecular regulators that control fibroblast activation. In this study, we identify the proto-oncogene MYCN as a key driver upregulated in dysregulated fibroblasts from IPF lungs. Mechanistically, we show that TGFα induces MYCN expression via the profibrotic transcription factor Wilms tumor 1 (WT1). Notably, the knockdown of MYCN significantly attenuated fibroblast proliferation, survival, and ECM production. We further show that MYCN positively regulates the mitotic kinase, Polo-like kinase (PLK1), and that pharmacological inhibition of PLK1 using volasertib reduced expression of MYCN, WT1, and PLK1 and mitigated fibroblast activation. In vivo, volasertib treatment attenuated fibroblast activation and collagen deposition during TGFα-induced pulmonary fibrosis. Together, these findings identify a pathogenic role for the WT1-MYCN-PLK1 axis in fibroblast activation and provide proof-of-concept evidence supporting PLK1 inhibition with volasertib as a potential therapeutic strategy for IPF.32:T72d,Recessive dystrophic epidermolysis bullosa (RDEB) is an epithelial fragility disease primarily affecting the skin and caused by variants in the COL7A1 gene. Individuals with RDEB are predisposed to develop highly aggressive cutaneous squamous cell carcinomas (SCC) which represent the most common cause of premature death. There is a lack of effective prevention or treatment options for patients with RDEB-SCC. To evaluate the anti-tumor activity and safety of the polo-like kinase-1 (PLK1) inhibitor, rigosertib, two investigator initiated open-label, single arm phase 2 studies were opened in Europe and the United States and enrolled five RDEB patients diagnosed with locally advanced and/or metastatic SCCs that had failed prior standard of care. Using a common protocol, patients were offered either oral or intravenous administration of rigosertib with consultation from the treating physician. Patients were monitored with clinical photography, biopsy, PET-CT scans and quality of life questionnaires over the 12 months duration of the trial. Pharmacokinetics of drug absorption was monitored in 4 patients. Patients on intravenous or oral therapy showed anti-tumor efficacy with acceptable toxicity and two patients had a complete response within six months of treatment. Quality of life was not negatively impacted by treatment and drug absorption exceeded previous patient populations presumably due to the relatively high dosing in an underweight patient cohort. These data identify rigosertib as a promising drug therapy for RDEB-SCC where there is a substantial unmet need, absence of approved therapies and where tumors arise on the background of a unique fibrotic and inflammatory environment characterized by germline mutations in COL7A1 that promote development of homogenous primary tumors with aberrant PLK1 activity.33:Tae5,Abstract Background Recessive dystrophic epidermolysis bullosa (RDEB) is an epithelial fragility disease primarily affecting the skin and is caused by variants in the COL7A1 gene. Individuals with RDEB are predisposed to develop highly aggressive cutaneous squamous cell carcinomas (SCCs) which are the most common cause of premature death. There is a lack of effective prevention or treatment options for patients with RDEB-SCC. Objectives To evaluate the antitumour activity and safety of the polo-like kinase-1 (PLK1) inhibitor, rigosertib, two investigator-initiated open-label, single-arm phase II studies were opened in Europe and the USA and enrolled five patients with RDEB diagnosed with locally advanced and/or metastatic SCCs whose disease had not previously responded successfully to standard care. Methods Using a common protocol, patients were offered either oral or intravenous (IV) administration of rigosertib with consultation from the treating physician. Patients were monitored with clinical photography, biopsy, positron emission tomography/computed tomography scans and quality of life (QoL) questionnaires over the 12-month duration of the trial. The pharmacokinetics of drug absorption was monitored in four patients. Results Antitumour efficacy with acceptable toxicity was seen in patients on IV or oral therapy and two patients had a complete response within 6 months of treatment. Their QoL was not negatively impacted by treatment and drug absorption exceeded that seen in previous patient populations presumably due to the relatively high dosing in a cohort of underweight patients. Conclusions These data identify rigosertib as a promising drug therapy for patients with RDEB-SCC where there is a substantial unmet need, absence of approved therapies and where tumours arise on a background of a unique fibrotic and inflammatory environment characterized by germline mutations in COL7A1 that promote the development of homogenous primary tumours with aberrant PLK1 activity. An author video to accompany this article is available online. 25:[[["$","script","0",{"type":"application/ld+json","dangerouslySetInnerHTML":{"__html":"{\"@context\":\"https://schema.org\",\"@type\":\"CollectionPage\",\"name\":\"PLK1 Inhibitor: modality Research & Clinical Takeaways\",\"description\":\"Explore peer-reviewed papers on PLK1 Inhibitor (modality). 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Lung cellular and molecular physiology","methods":"","results":"","abstract":"$30","keywords":["Fibroblasts","Idiopathic pulmonary fibrosis","MYCN proto-oncogene","Polo-like kinase 1","Volasertib"],"pubmed_id":"41481275","conclusions":"","publication_date":"2026-01-02T00:00:00"},"crossref":{"DOI":"10.1152/ajplung.00204.2025","URL":"https://doi.org/10.1152/ajplung.00204.2025","ISSN":["1040-0605","1522-1504"],"link":[{"URL":"https://journals.physiology.org/doi/pdf/10.1152/ajplung.00204.2025","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"page":null,"type":"journal-article","issue":null,"score":1,"title":["PLK1 Inhibition by Volasertib Suppresses Key Transcriptional Regulators Underlying Fibroblast Activation and Pulmonary Fibrosis"],"author":[{"given":"Priyanka","family":"Singh","sequence":"first","affiliation":[{"name":"University of Cincinnati College of Medicine"}]},{"given":"Pradeep Kumar","family":"Patel","sequence":"additional","affiliation":[{"name":"University of Cincinnati College of Medicine"}]},{"given":"Rajesh K.","family":"Kasam","sequence":"additional","affiliation":[{"name":"University of Cincinnati College of Medicine"}]},{"given":"Ryan","family":"Lawson","sequence":"additional","affiliation":[{"name":"University of Cincinnati College of Medicine"}]},{"given":"Harshavardhana Haresamudram","family":"Ediga","sequence":"additional","affiliation":[{"name":"University of Cincinnati College of Medicine"}]},{"given":"Anil G.","family":"Jegga","sequence":"additional","affiliation":[{"name":"Cincinnati Children's Hospital Medical Center"}]},{"given":"Satish K","family":"Madala","sequence":"additional","affiliation":[]}],"funder":[{"id":[{"id":"10.13039/100000050","id-type":"DOI","asserted-by":"publisher"}],"DOI":"10.13039/100000050","name":"HHS | NIH | National Heart, Lung, and Blood Institute","award":["1R01 HL134801"],"award-info":[{"award-number":["1R01 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Fibrosis","value_numeric":null},{"paper_doi":"10.1152/ajplung.00204.2025","tag_type":"generic","value":"volasertib","value_numeric":null},{"paper_doi":"10.1152/ajplung.00204.2025","tag_type":"impact_flag","value":"limited_evidence","value_numeric":null},{"paper_doi":"10.1152/ajplung.00204.2025","tag_type":"modality","value":"PLK1 Inhibitor","value_numeric":null},{"paper_doi":"10.1152/ajplung.00204.2025","tag_type":"study_design","value":"Preclinical Study","value_numeric":null},{"paper_doi":"10.1152/ajplung.00204.2025","tag_type":"warning","value":"Abstract does not report sample size, species, or effect sizes.","value_numeric":null},{"paper_doi":"10.1152/ajplung.00204.2025","tag_type":"warning","value":"In vivo results are from a TGFα-induced pulmonary fibrosis model, not patients.","value_numeric":null},{"paper_doi":"10.1152/ajplung.00204.2025","tag_type":"warning","value":"Preclinical design; not classifiable under standard clinical study types.","value_numeric":null}],"summaries":{"what_studied":"A preclinical study mapped the WT1–MYCN–PLK1 pathway driving fibroblast activation in idiopathic pulmonary fibrosis and tested PLK1 inhibition with volasertib. Experiments included in vitro fibroblast assays and an in vivo TGFα‑induced pulmonary fibrosis model, assessing proliferation, survival, ECM production, and collagen deposition.","key_result":"Volasertib reduced expression of MYCN, WT1, and PLK1, mitigated fibroblast activation in vitro, and attenuated fibroblast activation and collagen deposition in a TGFα‑induced pulmonary fibrosis model in vivo. MYCN knockdown also decreased fibroblast proliferation, survival, and ECM production.","limitations":"Findings are limited to in vitro systems and an in vivo TGFα‑induced fibrosis model rather than human clinical studies. The abstract reports no sample sizes, species, effect sizes, or duration of treatment.","practice_takeaway":"PLK1 inhibition with volasertib shows antifibrotic activity in preclinical IPF models, highlighting the WT1–MYCN–PLK1 axis as a druggable target. This does not change clinical care; clinical trials are needed to assess safety and efficacy in patients."}},{"doi":"10.1093/bjd/ljaf205","pmid":"40439508","title":"Efficacy and safety of rigosertib in patients with recessive dystrophic epidermolysis bullosa-associated advanced/metastatic cutaneous squamous cell carcinoma","journal_title":"British Journal of Dermatology","journal_issn":"0007-0963","published_at":"2025-05-29T00:00:00.000Z","url":"https://doi.org/10.1093/bjd/ljaf205","source_score":45,"is_retracted":false,"is_open_access":true,"raw_metadata":{"ooir":{"day":"2025-06-27","doi":"10.1093/bjd/ljaf205","days":"30","issn":"0007-0963","rank":"5","field":"Clinical Medicine","score":"45","category":"Dermatology","categories":["Dermatology"],"_categories":["Dermatology"]},"pubmed":{"doi":"10.1093/bjd/ljaf205","title":"Efficacy and Safety of Rigosertib in Patients with Recessive Dystrophic Epidermolysis Bullosa Associated Advanced/Metastatic Cutaneous Squamous Cell Carcinoma.","journal":"The British journal of dermatology","methods":"","results":"Patients on intravenous or oral therapy showed anti-tumor efficacy with acceptable toxicity and two patients had a complete response within six months of treatment. Quality of life was not negatively impacted by treatment and drug absorption exceeded previous patient populations presumably due to the relatively high dosing in an underweight patient cohort.","abstract":"$32","keywords":[],"pubmed_id":"40439508","conclusions":"","publication_date":"2025-05-29T00:00:00"},"crossref":{"DOI":"10.1093/bjd/ljaf205","URL":"https://doi.org/10.1093/bjd/ljaf205","ISSN":["0007-0963","1365-2133"],"link":[{"URL":"https://academic.oup.com/bjd/advance-article-pdf/doi/10.1093/bjd/ljaf205/63398152/ljaf205.pdf","content-type":"application/pdf","content-version":"am","intended-application":"syndication"},{"URL":"https://academic.oup.com/bjd/advance-article-pdf/doi/10.1093/bjd/ljaf205/63398152/ljaf205.pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"page":null,"type":"journal-article","issue":null,"score":1,"title":["Efficacy and safety of rigosertib in patients with recessive dystrophic epidermolysis 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,"}]},{"given":"Lauren","family":"Banner","sequence":"additional","affiliation":[{"name":"Department of Dermatology and Cutaneous Biology, Thomas Jefferson University , Philadelphia, PA ,"}]},{"given":"Michael","family":"Alexander","sequence":"additional","affiliation":[{"name":"Department of Pharmacology, Physiology and Cancer Biology, Sidney Kimmel Medical College, Thomas Jefferson University , Philadelphia, PA ,"}]},{"given":"Linda","family":"Hosler","sequence":"additional","affiliation":[{"name":"Jefferson Clinical Research Institute, Sidney Kimmel Medical College, Thomas Jefferson University , Philadelphia, PA ,"}]},{"given":"Henry","family":"Yang","sequence":"additional","affiliation":[{"name":"Department of Dermatology and Cutaneous Biology, Thomas Jefferson University , Philadelphia, PA ,"}]},{"given":"Matthew","family":"Parris","sequence":"additional","affiliation":[{"name":"Onconova Therapeutics Inc. , Newtown, PA 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Treatment showed anti-tumor activity with acceptable toxicity, quality of life was not negatively affected, and drug absorption exceeded prior populations.","limitations":"Extremely small sample (n=5) and uncontrolled, open-label design without a comparator. Heterogeneous administration (oral vs IV), and pharmacokinetics were assessed in only four patients.","practice_takeaway":"Rigosertib produced signals of efficacy with tolerable safety in RDEB-associated advanced/metastatic cutaneous SCC after standard care failure, including two complete responses by six months. 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