Neoplasia最新文献

{"title":"L-methionine promotes CD8+ T cells killing hepatocellular carcinoma by inhibiting NR1I2/PCSK9 signaling","authors":"Chengsha Yuan ,&nbsp;Changpeng Hu ,&nbsp;Huyue Zhou,&nbsp;Wuyi Liu,&nbsp;Wenjing Lai,&nbsp;Yafeng Liu,&nbsp;Yue Yin,&nbsp;Guobing Li,&nbsp;Rong Zhang","doi":"10.1016/j.neo.2025.101160","DOIUrl":"10.1016/j.neo.2025.101160","url":null,"abstract":"<div><h3>Background</h3><div>Liver cancer has consistently high incidence and mortality rates among malignant tumors. PCSK9, a target for hypercholesterolemia therapy, has recently been identified as an inhibitor of anti-tumor immunity, and targeting PCSK9 effectively inhibits tumor progression. However, small molecule inhibitors are lacking due to its flat protein structure.</div></div><div><h3>Methods</h3><div>PCSK9 transcription inhibitor screening was conducted using a PCSK9 promoter-driven td-Tomato plasmid. Quantitative real-time PCR and immunoblotting were employed to assess the effect of L-methionine on PCSK9 expression in HCC cell lines. Co-culture experiments were performed to evaluate the impact of L-methionine on CD8⁺ T cell-mediated killing of liver cancer cells. RNA sequencing, CUT&amp;Tag, gene editing, and luciferase reporter assays were utilized to identify the transcription factor regulating PCSK9. Additionally, liver cancer xenograft and spontaneous liver cancer mouse models were used to evaluate the anti-cancer efficacy of L-methionine.</div></div><div><h3>Results</h3><div>Our study identified L-methionine, an essential amino acid, as a transcriptional inhibitor of PCSK9. The optimal dose of L-methionine to inhibit PCSK9 expression and enhance CD8⁺ T cell-mediated killing of liver cancer cells <em>in vitro</em> is 50 μM. Furthermore, intraperitoneal injection of 5 mg/kg/day of L-methionine significantly inhibited tumor growth in both liver cancer xenograft and spontaneous liver cancer mouse models. Mechanistically, we identified NR1I2 as a key transcription factor for PCSK9 and their crucial binding site was TGCACCCTGACAC. L-methionine inhibits PCSK9 transcription by downregulating NR1I2.</div></div><div><h3>Conclusions</h3><div>This work demonstrates that L-methionine promotes CD8⁺ T cell-mediated killing of hepatocellular carcinoma by inhibiting NR1I2/PCSK9 signaling. Our study introduces a novel and convenient approach to inhibit PCSK9 and provides a theoretical basis for the rational supplementation of L-methionine in liver cancer patients.</div></div>","PeriodicalId":18917,"journal":{"name":"Neoplasia","volume":"64 ","pages":"Article 101160"},"PeriodicalIF":4.8,"publicationDate":"2025-03-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143725300","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}

{"title":"High dose acetaminophen re-polarizes CD11b+ cells in the tumor microenvironment towards an activated macrophage phenotype","authors":"Allyn Bryan ,&nbsp;Madison Isbell ,&nbsp;Pavani Pingali ,&nbsp;Lauren May ,&nbsp;Syed A. Shah ,&nbsp;Adam Khader ,&nbsp;Andrea Galabow ,&nbsp;Madelyn Lorenz ,&nbsp;Jennifer Koblinski ,&nbsp;Won Sok Lee ,&nbsp;Rebecca K Martin ,&nbsp;Bhaumik Patel ,&nbsp;Joseph Landry ,&nbsp;Alex Neuwelt","doi":"10.1016/j.neo.2025.101155","DOIUrl":"10.1016/j.neo.2025.101155","url":null,"abstract":"<div><h3>Objective</h3><div>High dose acetaminophen (AAP) has demonstrated promising results in early phase clinical trials for treatment of advanced malignancies. When administered concurrently with the CYP2E1 inhibitor fomepizole, AAP can be dose-escalated 100-fold relative to standard dosing without liver toxicity and without compromising anti-tumor activity.</div></div><div><h3>Methods and analysis</h3><div>The current study used a 23-plex flow cytometry panel to study AAP-induced changes in the tumor immune microenvironment of syngeneic mouse breast tumors. Effects of AAP on macrophage function and antigen presentation, alone and in combination with PD-1 antibodies, were evaluated.</div></div><div><h3>Results</h3><div>Findings demonstrated that the vast majority of CD45+ cells in the triple negative breast cancer model are CD11b+ cells of the innate immune system. The CD11b+ cells in the tumor micro-environment of vehicle-treated mice were mostly comprised of GR1+ myeloid derived suppressor cells. On the other hand, the CD11b+ cells in the high dose AAP-treated mice were mostly of the activated macrophage phenotype (F4/80+CD80+MHCII+). In vitro studies were performed to better understand AAP effects on macrophage function. It was demonstrated that AAP enhances phagocytosis as well as antigen presentation by macrophages to antigen-reactive T-cells. These effects are amplified when PD-1 antibodies are combined with AAP in the in vitro antigen presentation assay. Furthermore, AAP has synergistic anti-tumor activity in vivo when combined with PD-1 antibody therapy, an effect that is macrophage dependent.</div></div><div><h3>Conclusion</h3><div>The present study demonstrates profound AAP-induced changes in the tumor immune microenvironment including the differentiation of CD11b+ cells towards an activated “M1” macrophage phenotype.</div></div>","PeriodicalId":18917,"journal":{"name":"Neoplasia","volume":"64 ","pages":"Article 101155"},"PeriodicalIF":4.8,"publicationDate":"2025-03-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143734624","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}

{"title":"MTFR1 phosphorylation-activated adaptive mitochondrial fusion is essential for colon cancer cell survival during glucose deprivation","authors":"Nan Zhang,&nbsp;Lu Dong,&nbsp;Sifan Liu,&nbsp;Tingting Ning,&nbsp;Shengtao Zhu","doi":"10.1016/j.neo.2025.101159","DOIUrl":"10.1016/j.neo.2025.101159","url":null,"abstract":"<div><h3>Background</h3><div>Mitochondrial dynamics are essential for maintaining cellular function under metabolic stress. However, their role in colon cancer's response to glucose deprivation remains poorly understood.</div></div><div><h3>Methods</h3><div>The role of the mitochondrial protein MTFR1 in colon cancer proliferation was evaluated using CCK-8 and colony formation assays. Mass spectrometry identified MTFR1-interacting proteins and phosphorylation sites. Mitochondrial morphology was examined with Mitotracker staining, and mitochondrial function was evaluated using MitoSOX, JC-1 staining, and the Seahorse cell mitochondrial stress test.</div></div><div><h3>Results</h3><div>We observed that MTFR1 is highly expressed in colon cancer cells and interacts with NEK1 under glucose deprivation. This interaction induces phosphorylation of MTFR1 at serine 119, which promotes mitochondrial fusion and supports mitochondrial function. Consequently, enhanced oxidative phosphorylation improves cellular tolerance to glucose deprivation.</div></div><div><h3>Conclusions</h3><div>Our findings highlight the importance of MTFR1 in modulating mitochondrial dynamics and its potential impact on colon cancer cell survival under metabolic stress. These results suggest that MTFR1 serine 119 could be a key regulator of colon cancer cell metabolism and a potential therapeutic target for enhancing cancer cell response to metabolic challenges.</div></div>","PeriodicalId":18917,"journal":{"name":"Neoplasia","volume":"63 ","pages":"Article 101159"},"PeriodicalIF":4.8,"publicationDate":"2025-03-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143682611","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}

{"title":"Comprehensive mapping elucidates high risk genotypes in primary metastatic breast cancer","authors":"Tobias Berg ,&nbsp;Lise Ahlborn ,&nbsp;Maj-Britt Jensen ,&nbsp;Ann Søegaard Knoop ,&nbsp;Bent Ejlertsen ,&nbsp;Maria Rossing","doi":"10.1016/j.neo.2025.101162","DOIUrl":"10.1016/j.neo.2025.101162","url":null,"abstract":"<div><div>Among women with primary metastatic breast cancer (pMBC), around 5 % of women with primary invasive breast cancer, high-risk mutations associated with disease progression and poor prognosis is shown. The heterogeneity and clinical implications of these genomic alterations remains to be fully elucidated. We performed comprehensive gene mapping on 211 tumors of women diagnosed with pMBC at Rigshospitalet 2014-2021. After DNA purification 203 tumor samples were eligible for analysis. Median age in our cohort was 69 years, 68 % were ER-positive/HER2-negative, 23 % HER2-positive and 9 % triple-negative. A high tumor mutational burden (TMB), shown in 10 %, was in univariable analysis associated with a poor prognosis and a median overall survival of 5.3 months (95 % CI, 2.5-51.3) but no significant association after adjusting for subtype and age. 65 % of tumors had an actionable biomarker, including a <em>PIK3CA</em> mutation in 39 %. <em>TP53</em> mutations were found in 33 % of tumors and were associated with an increased risk of death (adjusted HR: 1.60, 95 % CI; 1.07-2.40). We have found that for women with pMBC, the disease is driven by several targetable genetic mutations across subtypes, however our results suggest a reduced prognostic value of TMB for this complex patient group. Taken together, our findings substantiate the value of early genomic profiling to actively identify women that may be eligible for a more individualized treatment scheme.</div></div>","PeriodicalId":18917,"journal":{"name":"Neoplasia","volume":"63 ","pages":"Article 101162"},"PeriodicalIF":4.8,"publicationDate":"2025-03-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143682612","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}

{"title":"Expression of the cholesterol transporter SR-B1 in melanoma cells facilitates inflammatory signaling leading to reduced cholesterol synthesis","authors":"Oliver Eckel ,&nbsp;Madalina A. Mirea ,&nbsp;Anna Gschwendtner ,&nbsp;Martina Pistek ,&nbsp;Katharina Kinslechner ,&nbsp;Clemens Röhrl ,&nbsp;Herbert Stangl ,&nbsp;Markus Hengstschläger ,&nbsp;Mario Mikula","doi":"10.1016/j.neo.2025.101154","DOIUrl":"10.1016/j.neo.2025.101154","url":null,"abstract":"<div><div>Scavenger receptor class B type 1 (SR-B1) is a cholesterol transporter, abundantly expressed in human melanoma, yet its precise role for melanoma progression is not fully understood. This study investigates the involvement of SR-B1 in cholesterol homeostasis of tumor cells and its implications for potential therapy. We found that SR-B1 depletion in melanoma cells does not alter total cholesterol levels, but induces cholesterol biosynthesis. This effect was characterized by an increased expression of HMG-CoA reductase (HMGCR), a rate limiting enzyme of cholesterol biosynthesis. Notably, further analyses indicated that this regulation occurs at the post-translational level, mediated via the hypoxia-inducible factor (HIF) signaling pathway. Importantly, we identified SR-B1 as a transporter of the lipid hormone sphingosine-1-phosphate (S1P) and we found that S1P exposure leads to HIF1A up-regulation. Finally, we used a pluripotent stem cell-derived skin organoid model to show that targeting SR-B1 in combination with targeted melanoma therapy can lead to increased apoptosis and suppressed proliferation of transplanted tumor cells. Our study shows that functional SR-B1 is linked to inflammatory signaling, which reduces cholesterol synthesis, while enabling melanoma cell survival during chemotherapy treatment.</div></div>","PeriodicalId":18917,"journal":{"name":"Neoplasia","volume":"63 ","pages":"Article 101154"},"PeriodicalIF":4.8,"publicationDate":"2025-03-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143682610","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}

{"title":"Anti-PD1 prolongs the response of PI3K and farnesyl transferase inhibition in HRAS- and PIK3CA-mutant head and neck cancers","authors":"Dinesh Babu Manikandan ,&nbsp;Sankar Jagadeeshan ,&nbsp;Sooraj Mathukkada ,&nbsp;Raghda Abu Shareb ,&nbsp;Manu Prasad ,&nbsp;Liju Vijaya Steltar Belsamma ,&nbsp;Divyasree Marripati ,&nbsp;Noga Erez ,&nbsp;Monica Wainer ,&nbsp;Amit Geva ,&nbsp;Danielle Raviv ,&nbsp;Irit Allon ,&nbsp;Luc GT Morris ,&nbsp;Gloria H Su ,&nbsp;Hai Wang ,&nbsp;Ari J Rosenberg ,&nbsp;Linda Kessler ,&nbsp;Francis Burrows ,&nbsp;Moshe Elkabets","doi":"10.1016/j.neo.2025.101157","DOIUrl":"10.1016/j.neo.2025.101157","url":null,"abstract":"<div><h3>Background</h3><div>Tipifarnib, a farnesyl transferase inhibitor, has shown promising response in the treatment of <em>HRAS</em>-mutant HNSCC in the clinic, and in combination with a PI3K inhibitor in <em>PIK3CA</em>-mutant mouse models; however, the involvement of antitumor immunity in the efficacy of tipifarnib has not yet been investigated. This study aimed to evaluate the involvement of antitumor immunity in the efficacy of tipifarnib in <em>HRAS</em>- or <em>PIK3CA</em>-mutant HPV-positive and HPV-negative head and neck cancer murine models.</div></div><div><h3>Methods</h3><div>To investigate the role of antitumor immunity, we compared the efficacy of tipifarnib in immune-intact C57BL/6 mice and immunodeficient NSG mice. Histopathological analyses were conducted to evaluate PD-L1 expression and the activation of key signaling pathways. Additionally, the synergistic potential of tipifarnib with the PI3Kα inhibitor alpelisib (BYL719) was assessed <em>in vitro</em> and <em>in vivo</em>. Immunohistochemical analysis was performed to examine the infiltration of CD8⁺ <em>T</em> cells, and anti-PD1 treatment was tested to evaluate its potential to prolong progression-free survival.</div></div><div><h3>Results</h3><div>In the HPV-positive <em>HRAS</em>-mutant HNSCC model, the antitumor efficacy of tipifarnib was primarily dependent on CD8⁺ <em>T</em> cell activity, whereas in HPV-negative cancers, the contribution of antitumor immunity was less pronounced. Tipifarnib treatment upregulated PD-L1 expression, potentially inhibiting T cell antitumor activity and inducing hyperactivation of the AKT pathway, which mitigated MAPK inhibition and promoted cell proliferation. Blocking the PI3K pathway with alpelisib demonstrated synergistic antitumor effects in all models. The combination of tipifarnib and alpelisib exhibited greater efficacy in immune-intact mice than in immunodeficient mice, and was accompanied by increased CD8⁺ <em>T</em> cell infiltration. Adding anti-PD1 treatment to the tipifarnib/alpelisib combination further prolonged progression-free survival in tumor-bearing mice.</div></div><div><h3>Conclusion</h3><div>These findings underscore the critical role of antitumor immunity, particularly CD8⁺ <em>T</em> cell activity, in the efficacy of tipifarnib alone and in combination with alpelisib. The triple combination of tipifarnib, alpelisib, and anti-PD1 treatment showed superior antitumor activity and extended survival in preclinical models, suggesting its potential as a therapeutic strategy for HNSCC patients with <em>HRAS</em>- and <em>PIK3CA</em>-mutation.</div></div>","PeriodicalId":18917,"journal":{"name":"Neoplasia","volume":"63 ","pages":"Article 101157"},"PeriodicalIF":4.8,"publicationDate":"2025-03-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143674768","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}

{"title":"Kv11.1-dependent senescence activates a lethal immune response via tumor necrosis factor alpha","authors":"Maedeh Vakili Saatloo ,&nbsp;Davide Delisi ,&nbsp;Najmeh Eskandari ,&nbsp;Carsten Krieg ,&nbsp;Saverio Gentile","doi":"10.1016/j.neo.2025.101148","DOIUrl":"10.1016/j.neo.2025.101148","url":null,"abstract":"<div><div>Understanding the complex relationship between cancer and immune surveillance is essential for leveraging the immune system to control tumor growth. In our study, we discovered that activating the Kv11.1 potassium channel in ER+ breast cancer cells induces a senescent phenotype, which in turn triggers a potent immune response against these senescent cells. Specifically, we found that the senescence-associated secretory phenotype (SASP) plays a crucial role in activating CD4+ <em>T</em>-helper 1 (Th1) cells and memory T cell phenotypes. This activation led to the release of tumor necrosis factor-alpha (TNFα), which induced the death of senescent breast cancer cells, independent of their resistance to endocrine therapy. Our findings suggest that Kv11.1 channel-induced cellular senescence in ER+ breast cancer cells is a key mechanism in immune surveillance, driving a lethal immune response through TNFα. These results highlight the potential immunomodulatory role of Kv11.1 activation in ER-positive breast cancer and provide a foundation for future therapeutic investigations.</div></div>","PeriodicalId":18917,"journal":{"name":"Neoplasia","volume":"63 ","pages":"Article 101148"},"PeriodicalIF":4.8,"publicationDate":"2025-03-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143674769","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}

{"title":"Targeting BARD1 suppresses a Myc-dependent transcriptional program and tumor growth in pancreatic ductal adenocarcinoma","authors":"Sohum Patel ,&nbsp;Eleanor Jenkins ,&nbsp;Rutuj P Kusurkar ,&nbsp;Sherry Lee ,&nbsp;Wei Jiang ,&nbsp;Avinoam Nevler ,&nbsp;Matthew McCoy ,&nbsp;Michael J Pishvaian ,&nbsp;Rosalie C Sears ,&nbsp;Jonathan R Brody ,&nbsp;Charles J Yeo ,&nbsp;Aditi Jain","doi":"10.1016/j.neo.2025.101152","DOIUrl":"10.1016/j.neo.2025.101152","url":null,"abstract":"<div><div>Pancreatic ductal adenocarcinoma (PDAC) remains one of the deadliest cancers demanding better and more effective therapies. BARD1 or BRCA1-Associated -Ring Domain-1 plays a pivotal role in homologous recombination repair (HRR). However, its function and the underlying molecular mechanisms in PDAC are still not fully elucidated. Here, we demonstrate that BARD1 is overexpressed in PDAC and its genetic inhibition suppresses c-Myc and disrupts c-Myc dependent transcriptional program. Mechanistically, BARD1 stabilizes c-Myc through ubiquitin–proteasome system by regulating FBXW7. Importantly, targeting BARD1 using either siRNAs or CRISPR/Cas9 deletion blocks PDAC growth <em>in vitro</em> and <em>in vivo</em>, without any signs of toxicity to mice. Using a focused drug library of 477 DNA damage response compounds, we also found that BARD1 inhibition enhances therapeutic efficacy of several clinically relevant agents (fold changes ≥4), including PARPi, in HRR proficient PDAC cells. These data uncover BARD1 as an attractive therapeutic target for HRR proficient PDAC.</div></div>","PeriodicalId":18917,"journal":{"name":"Neoplasia","volume":"63 ","pages":"Article 101152"},"PeriodicalIF":4.8,"publicationDate":"2025-03-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143632197","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}

{"title":"Granulocyte-macrophage colony-stimulating factor for newly diagnosed glioblastoma","authors":"Caineng Cao ,&nbsp;Le Wang ,&nbsp;Feng Jiang ,&nbsp;Qifeng Jin ,&nbsp;Ting Jin ,&nbsp;Shuang Huang ,&nbsp;Qiaoying Hu ,&nbsp;Yuanyuan Chen ,&nbsp;Yongfeng Piao ,&nbsp;Yonghong Hua ,&nbsp;Xinglai Feng ,&nbsp;Yi Zhou ,&nbsp;Xiaozhong Chen","doi":"10.1016/j.neo.2025.101156","DOIUrl":"10.1016/j.neo.2025.101156","url":null,"abstract":"<div><h3>Background</h3><div>There is a clear need to improve the efficiency of therapeutic strategy for patients with newly diagnosed glioblastoma (GBM). The purpose of this study was to evaluate the feasibility of hypofractionated intensity-modulated radiation therapy (IMRT), temozolomide and granulocyte-macrophage colony-stimulating factor (GM-CSF) for patients with newly diagnosed GBM.</div></div><div><h3>Methods</h3><div>Patients were treated with hypofractionated IMRT (15 × 3.5Gy to the high-risk region and 15 × 3.0Gy to the low-risk region), temozolomide (75 mg per square meter of body-surface area per day, from 1 week before the beginning of radiotherapy to the last day of radiotherapy) and GM-CSF [200μg (equivalent to 125 μg/m² calculated dose) subcutaneously injected daily for 2 weeks, starting from the second week of radiotherapy]. The primary endpoint was 6-month progression free survival (PFS).</div></div><div><h3>Results</h3><div>Between June 2016 and Feburary 2020, 41 patients were enrolled. During concomitant chemoradiotherapy, no grade 3 or 4 hematologic toxicities were observed and grade 3 non-hematologic toxicities were documented in 5 patients (12.2 %) due to GM-CSF. All patients completed both radiotherapy and concomitant temozolomide as planned. Only five patients (12.2 %) discontinued concomitant GM-CSF because of toxicity. At a median follow-up of 33.1 months (IQR 23.0-51.2), the 6-month PFS rate was 68.3 % (95 % CI: 54.0-82.6). The median overall survival of all patients was 16.7 months (95 % CI: 10.5-22.9). Compared with pre-GM-CSF, the concentrations of TNF-α (<em>p</em> = 1.9615E-10) and IL-18 (<em>p</em> = 6.8467E-8) were increased after GM-CSF, while the proportion of CD19 (<em>p</em> = 0.000015), the concentrations of IgG (<em>p</em> = 0.000015) and CXCL12 (<em>p</em> = 0.000257) were decreased.</div></div><div><h3>Conclusions</h3><div>The combination of hypofractionated IMRT, temozolomide and GM-CSF for GBM was feasible and safe.</div></div><div><h3>Trial Registration</h3><div>ClinicalTrials.gov Identifier: NCT02663440.</div></div>","PeriodicalId":18917,"journal":{"name":"Neoplasia","volume":"63 ","pages":"Article 101156"},"PeriodicalIF":4.8,"publicationDate":"2025-03-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143632214","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}

{"title":"Targeting PAR1 activation in JAK2V617F-driven philadelphia-negative myeloproliferative neoplasms: Unraveling its role in thrombosis and disease progression","authors":"İldeniz USLU-BIÇAK ,&nbsp;Meliha NALÇACI ,&nbsp;Selçuk SÖZER","doi":"10.1016/j.neo.2025.101153","DOIUrl":"10.1016/j.neo.2025.101153","url":null,"abstract":"<div><div>Philadelphia chromosome-negative myeloproliferative neoplasms (Ph^-MPNs) are clonal disorders marked by high morbidity and mortality, driven by uncontrolled myeloid proliferation from hematopoietic stem/progenitor cells (HSCs) and associated with a significant risk of thrombosis. This study explored the relationship between <em>JAK2</em>V617F and protease-activated receptor 1 (PAR1) by examining <em>PAR1</em> expression and activation across various hematopoietic stem/progenitor cell (HSPC) subgroups, assessing their contribution to the hypercoagulable state in Ph^-MPNs.</div><div>We investigated the effects of thrombin, a PAR1 antagonist (vorapaxar), and a JAK2 inhibitor (ruxolitinib) on Ph^-MPN cells. Mononuclear cells (MNCs) were isolated from Ph-MPN patients (<em>n</em> = 18), cord blood (CB) samples (<em>n</em> = 5) and healthy volunteers (<em>n</em> = 11). Specific subpopulations were sorted and analyzed for PAR1 expression and <em>JAK2</em>V617F status using qRT-PCR. <em>PAR1</em> expression changes, along with other PAR pathway-related genes, were assessed post-treatment.</div><div>Our results revealed that most PAR1⁺ cells (∼95 %) co-expressed CD34⁺, with a smaller JAK2V617F⁺ PAR1⁺ population lacking CD34. PAR1 expression was significantly higher in Ph-MPN MNCs compared to CB (<em>p</em> = 0.0005), particularly in EMP, HSC/EPC, and EPC subsets. Thrombin treatment reduced surface PAR1 expression, while PAR1 antagonist treatment further decrease the expression level. Combined PAR1 antagonist and ruxolitinib treatment significantly downregulated <em>PAR1</em> expression (<em>p</em> &lt; 0.0001), and several PAR-pathway-related genes were notably downregulated after treatment.</div><div>This study highlights that elevated PAR1 expression in primitive hematopoietic subpopulations is linked to disease progression and thrombosis in Ph^-MPNs, suggesting PAR1 as a potential therapeutic target. Combining PAR1 antagonists with JAK2 inhibitors shows promise in reducing PAR1 expression and mitigating thrombotic events in Ph^-MPN patients.</div></div>","PeriodicalId":18917,"journal":{"name":"Neoplasia","volume":"63 ","pages":"Article 101153"},"PeriodicalIF":4.8,"publicationDate":"2025-03-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143620539","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}