Cancer research communications最新文献

{"title":"A Phase 1 Safety Study of Evexomostat (SDX-7320) in Patients with Late-Stage Cancer: An Antiangiogenic, Insulin-Sensitizing Drug Conjugate Targeting METAP2.","authors":"Monica M Mita, Alain C Mita, Bradley J Carver, James M Shanahan, Benjamin A Mayes, Pierre J Dufour, David Browning, Alfred Anderson-Villaluz, John S Petersen, David J Turnquist, Peter Cornelius","doi":"10.1158/2767-9764.CRC-24-0627","DOIUrl":"10.1158/2767-9764.CRC-24-0627","url":null,"abstract":"<p><strong>Purpose: </strong>To investigate the safety and tolerability of evexomostat (SDX-7320) in patients with late-stage cancer.</p><p><strong>Patients and methods: </strong>This phase 1 dose-escalation safety study used an accelerated titration followed by a 3 + 3 design on 7- or 14-day administration, with dose expansion at the recommended phase 2 dose in 32 patients with late-stage, solid tumors. Measurements included standard assessments of safety, tolerability, target engagement in whole blood, plasma levels of protein biomarkers, and drug exposure. Tumor response was measured using RECIST v.1.1.</p><p><strong>Results: </strong>Thirty-two patients were dosed with evexomostat (SDX-7320), starting at 1.7 mg/m2 once per week and escalated to 65 mg/m2 (once every 2 weeks, 28 days/cycle). Dose escalation and expansion confirmed the maximum tolerated dose at 49 mg/m2 once every 2 weeks with reversible thrombocytopenia as the dose-limiting toxicity. Most treatment-emergent adverse events were of grade 1 or 2 in severity and nonserious, with no grade 5 adverse events. Eighty percent of patients (n = 20/25 evaluable) had stable disease, and the average treatment duration was 87 days (3.1 cycles). Key angiogenic biomarkers VEGF-C and bFGF (FGF2) improved in response to evexomostat. Patients with baseline insulin resistance (i.e., fasting insulin >20 µU/mL; n = 11) exhibited significant decreased fasting insulin after treatment. Decreases in leptin were observed in 27/31 patients (87%), whereas adiponectin increased in 28/31 patients (90%). Plasma lipid profiles showed increased high-density lipoprotein (HDL) and decreased low-density lipoprotein (LDL) cholesterol.</p><p><strong>Conclusions: </strong>Evexomostat (SDX-7320) was well-tolerated with prolonged stable disease and metastatic control in an open-label, phase I safety study. Improvements were observed in angiogenic and metabolic biomarkers.</p><p><strong>Significance: </strong>Obesity and insulin resistance are known to promote tumor growth and accelerate the mortality of patients with cancer. Evexomostat is a novel antiangiogenic and antimetastatic drug candidate which also has insulin-sensitizing and antiobesity properties that is being developed for use in combination with standard-of-care therapies for obese patients with cancer.</p>","PeriodicalId":72516,"journal":{"name":"Cancer research communications","volume":" ","pages":"1008-1017"},"PeriodicalIF":2.0,"publicationDate":"2025-06-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12183619/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144188615","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"High-Throughput Drug Screening of Clear Cell Ovarian Cancer Organoids Reveals Vulnerability to Proteasome Inhibitors and Dinaciclib and Identifies AGR2 as a Therapeutic Target.","authors":"Takuma Yoshimura, Takashi Kamatani, Aki Ookubo, Mio Takahashi, Manabu Itoh, Toshiki Ebisudani, Yohei Masugi, Tomomi Toyonaga, Junko Hamamoto, Keiko Saotome, Kensuke Sakai, Tomoko Yoshihama, Nobuko Moritoki, Shinsuke Shibata, Hiroyuki Yasuda, Toshiro Sato, Taka-Aki Sato, Daisuke Aoki, Wataru Yamagami, Tatsuhiko Tsunoda, Tatsuyuki Chiyoda","doi":"10.1158/2767-9764.CRC-25-0024","DOIUrl":"10.1158/2767-9764.CRC-25-0024","url":null,"abstract":"<p><p>There are currently no effective treatments available for clear cell ovarian cancer (CCC). In this study, we aimed to identify effective drugs for CCC through high-throughput drug screening (HTDS) using ovarian cancer organoids and determine novel therapeutic targets based on the biological characteristics of CCC through omics analysis. An ovarian cancer organoid biobank was established, and HTDS was conducted using CCC organoids based on libraries of 361 and 4,560 compounds. The efficacy of the identified drugs was verified in in vitro and in vivo experiments using a patient-derived organoid xenograft mouse model. Transcriptome analysis was performed to identify genes related to the pathways targeted by the identified drugs in CCC and to assess their potential as therapeutic targets. Proteasome inhibitors and dinaciclib were extracted using HTDS and shown to inhibit tumorigenesis in vitro and in vivo. CCC, like multiple myeloma, exhibited activated endoplasmic reticulum (ER) stress and unfolded protein response (UPR), and treatment with proteasome inhibitors further enhanced ER stress and UPR, ultimately leading to cell death. Transcriptome analysis identified anterior gradient-2 (AGR2) as a key gene involved in UPR in CCC. CRISPR knockout of AGR2 suppressed cell proliferation, increased sensitivity to proteasome inhibitors, and reversed platinum resistance in CCC. AGR2 knockout also upregulated Schlafen 11, contributing to platinum sensitivity. ER stress and the UPR are activated in CCC, and proteasome inhibitors disrupt this balance, ultimately leading to cell death. AGR2 may serve as a potential therapeutic target in CCC.</p><p><strong>Significance: </strong>Proteasome inhibitors and dinaciclib are identified as effective drugs for CCC. CCC has a high basal UPR, and proteasome inhibition may disrupt this balance. AGR2 is involved in the UPR of CCC, and inhibiting AGR2 further enhances the UPR and confers platinum sensitivity, making it a potential therapeutic target.</p>","PeriodicalId":72516,"journal":{"name":"Cancer research communications","volume":" ","pages":"1018-1033"},"PeriodicalIF":2.0,"publicationDate":"2025-06-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144210329","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Phase II Study Evaluating the Efficacy of Niraparib and Dostarlimab (TSR-042) in Patients with Recurrent/Metastatic Head and Neck Squamous Cell Carcinoma.","authors":"Olga Zamulko, Vidhya Karivedu, Muhammad Kashif Riaz, Ilaina Monroe, Audrey Romano, Rachel Mulanda, Nicky Kurtzweil, Allie Forsythe, Casey L Allen, Nusrat Harun, Jianmin Pan, Shesh Rai, Dalia El-Gamal, Trisha M Wise-Draper","doi":"10.1158/2767-9764.CRC-25-0192","DOIUrl":"10.1158/2767-9764.CRC-25-0192","url":null,"abstract":"<p><strong>Purpose: </strong>Recurrent/metastatic head and neck squamous cell carcinoma (R/M HNSCC) portends a poor prognosis. DNA pathway repair mutations in HNSCC are associated with higher tumor mutational burden rates and immune checkpoint inhibitor response. PARP inhibitors (PARPi) induce ssDNA breaks and are efficacious in cancers with DNA repair defects. Thus, we designed a single-arm, open-label, phase II clinical trial to evaluate the combination of niraparib and dostarlimab in patients with R/M HNSCC.</p><p><strong>Patients and methods: </strong>Patients with R/M HNSCC were treated with niraparib and dostarlimab until disease progression or unacceptable toxicity. The primary endpoint was the overall response rate and clinical benefit assessed by RECIST version 1.1. Using Simon's two-step minimax design, 14 patients were planned to enroll in the first stage with a goal of overall clinical benefit of 50%.</p><p><strong>Results: </strong>Ten patients were enrolled. The majority were White males with a median age of 62.5. One patient had a PD-L1 combined positive score >20, a high tumor mutational burden, a BRCA1 rearrangement, and an ATRX splice site mutation. Nine patients previously failed anti-PD-1/PD-L1 therapy. The best overall response rate was 10%, with a 20% clinical benefit (1 partial response, 1 stable disease). The trial was terminated early for futility as the goal clinical benefit could not be reached. At a median follow-up of 10.13 months, the median progression-free survival was 3.8 months, and the median overall survival was 10.1 months. The most common grade 3 or higher treatment-related adverse events were thrombocytopenia and hypertension.</p><p><strong>Conclusions: </strong>The combination of niraparib and dostarlimab did not achieve the primary endpoint of clinical benefit, but activity may be improved with biomarker-driven treatment and selected patients.</p><p><strong>Significance: </strong>Patients with R/M HNSCC that progress on PD-1 inhibitors have poor prognoses. PARPis cause ssDNA breaks that accumulate in cells with mutations in DNA damage repair pathways, leading to synthetic lethality. However, PARPi also inhibits glycogen synthase kinase-3β activity, leading to upregulated PD-L1, which is abrogated by PD-1 inhibitors. In this study, we combine niraparib (PARPi) with dostarlimab (anti-PD-L1) to evaluate clinical benefit in patients with R/M HNSCC.</p>","PeriodicalId":72516,"journal":{"name":"Cancer research communications","volume":" ","pages":"939-944"},"PeriodicalIF":2.0,"publicationDate":"2025-06-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12146980/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144082579","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Real-world Data on Risk Factors for Emergency Department Visits to Treat Outpatient Chemotherapy-Associated Toxicities.","authors":"Sanja Karovic, Erik Dvergsten, Chiara Pierattini, Ana Barac, Lauren Fay, Timothy L Cannon, Kathleen K Harnden, Jeanny B Aragon-Ching, Raymund S Cuevo, Michael L Maitland, John F Deeken","doi":"10.1158/2767-9764.CRC-24-0631","DOIUrl":"10.1158/2767-9764.CRC-24-0631","url":null,"abstract":"<p><p>The Centers for Medicare & Medicaid Services Hospital Outpatient Quality Reporting Program's OP-35 rule penalizes health systems that have a higher-than-expected rate of emergency department (ED) visits or inpatient admissions for 10 potentially preventable conditions within 30 days of receiving chemotherapy. Identifying patients at risk for toxicities and resultant acute care could lead to reducing the rate of such events, improving patient care, and reducing costs. We identified patients with cancer seen in the ED at our institution between January 1, 2018, and December 31, 2021, for one of the OP-35 toxicities who had received chemotherapy within the previous 30 days and analyzed demographic factors using zero-truncated Poisson regression. We further analyzed comorbid conditions for risk factors by matching by demographics and cancer type a cohort of patients without ED visits due to OP-35 events. A total of 1,618 patients were identified. The most frequent events were pain, sepsis, and fever. Thirty-nine percent had two or more visits during the study, and among those patients, the most frequent cancer types were gastrointestinal (32%) and breast (22%) cancers. Race, age, and sex were associated with an increased risk of events. In the matched cohort analysis, five comorbidities were statistically significant (P < 0.05) with event risk: history of coagulopathy/pulmonary emboli, myocardial infarction, cardiac arrhythmias, depression, and weight loss (concordance = 0.58). Forty-seven percent of patients with an event had at least one of these five comorbidities. Future interventions may concentrate on resources to monitor patients based on the risk assessment established in this study.</p><p><strong>Significance: </strong>Cardiovascular comorbidities, cancer cachexia, and depression were associated with increased risk for ED visits due to OP-35 events throughout cancer treatment. Future interventions may concentrate on resources to monitor patients based on the risk assessment established in this real-world data study.</p>","PeriodicalId":72516,"journal":{"name":"Cancer research communications","volume":" ","pages":"973-980"},"PeriodicalIF":2.0,"publicationDate":"2025-06-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12169210/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144217698","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Targeting the Glucose-Insulin Link in Head and Neck Squamous Cell Carcinoma Induces Cytotoxic Oxidative Stress and Inhibits Cancer Growth.","authors":"Simbarashe Mazambani, Seong-Ho Park, Joshua H Choe, An H Nguyen, Bok-Soon Lee, Ji Yun Jeong, Shin Yup Lee, Chul-Ho Kim, Yea-In Park, Joselyn Padilla, Jiyoung Lee, Dinesh Thotala, Tae Gyu Oh, Pankaj K Singh, Hoon Hur, Junho K Hur, Jung-Whan Kim, Tae Hoon Kim","doi":"10.1158/2767-9764.CRC-23-0506","DOIUrl":"10.1158/2767-9764.CRC-23-0506","url":null,"abstract":"<p><p>Head and neck squamous cell carcinoma (HNSCC) remains a clinically challenging malignancy with limited targeted therapy options and poor patient outcomes. Thus, identifying unique dependencies, including HNSCC-specific metabolic reprogramming, is imperative for improving treatment strategies for this disease. In this study, we show that HNSCC relies on elevated glucose transporter 1 (GLUT1)-mediated glucose uptake to support redox homeostasis and tumor growth. Analyses of GLUT1 expression data in tumors and cancer cell lines reveal significant upregulation of GLUT1 in HNSCC relative to both normal tissue and other cancer subtypes and that high GLUT1 expression correlates with poorer clinical outcomes. Using a basal epithelial layer-specific GLUT1-knockout mouse model, we demonstrate that GLUT1 ablation in HNSCC cells of origin markedly attenuates tumor initiation and progression, implicating the necessity of GLUT1 in HNSCC tumorigenesis. Building on this observation, combining pharmacologic inhibition of GLUT1 with pro-oxidants such as vitamin C and auranofin induces potent cytotoxicity in vitro and in vivo, partly by precipitating oxidative stress. We further observe that insulin signaling is required to sustain glucose uptake and redox homeostasis, as insulin receptor knockdown decreases proliferation and increases reactive oxygen species levels. Together, these results suggest that although GLUT1 overexpression is a key driver of glucose uptake, insulin signaling also contributes to the metabolic and oncogenic pathways underlying HNSCC progression. Consequently, strategies that co-target GLUT1 and insulin signaling to restrict glucose flux may synergize with pro-oxidant therapies, offering a promising therapeutic avenue for HNSCC.</p><p><strong>Significance: </strong>Enhanced GLUT1 expression and oncogenic insulin signaling drive elevated glucose uptake in HNSCC, which contribute to the maintenance of redox homeostasis and tumor growth. Disrupting both glucose uptake and redox balance may offer a promising therapeutic approach.</p>","PeriodicalId":72516,"journal":{"name":"Cancer research communications","volume":" ","pages":"921-938"},"PeriodicalIF":2.0,"publicationDate":"2025-06-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12141995/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144082630","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"First-in-Human Study to Evaluate the Safety and Efficacy of Anti-GDF15 Antibody AZD8853 in Patients with Advanced/Metastatic Solid Tumors.","authors":"Benedito A Carneiro, Olumide B Gbolahan, Albiruni Abdul Abdul Razak, John F Hilton, Arthur W Lambert, John Hood, Michael Pluta, Veronique Bragulat, Elhan Sanai, Rakesh Kumar, Duncan I Jodrell, Patricia M LoRusso","doi":"10.1158/2767-9764.CRC-24-0565","DOIUrl":"10.1158/2767-9764.CRC-24-0565","url":null,"abstract":"<p><strong>Purpose: </strong>Growth and differentiation factor 15 (GDF15) is overexpressed in multiple solid tumors and is thought to exert immunosuppressive effects in the tumor microenvironment. AZD8853 is an anti-GDF15 mAb.</p><p><strong>Patients and methods: </strong>This first-in-human, phase I/IIa, open-label study (NCT05397171) assessed AZD8853 monotherapy in previously treated patients with advanced/metastatic microsatellite-stable colorectal cancer and urothelial carcinoma. The primary objective was safety including dose-limiting toxicities. Secondary objectives included efficacy, pharmacokinetics, and pharmacodynamics (PD), including free serum GDF15. Exploratory objectives included biomarkers of clinical activity and effects on cancer cachexia.</p><p><strong>Results: </strong>During dose escalation, 16 patients received AZD8853 300 mg (n = 3), 1,000 mg (n = 6), or 3,000 mg (n = 7) intravenously every 3 weeks; 15 patients had microsatellite-stable colorectal cancer; and one patient had urothelial carcinoma. By June 6, 2023, all patients had discontinued treatment. Thirteen (81.3%) patients had treatment-emergent adverse events (TEAE); most commonly diarrhea (31.3%), abdominal pain (31.3%), and decreased appetite (25%). Eight (50.0%) patients had grade ≥3 TEAEs, and six (37.5%) had serious TEAEs, none treatment related. There were no dose-limiting toxicities. The best response per RECIST v1.1 was stable disease in five (31.3%) patients and disease progression in 11 (68.8%) patients. AZD8853 showed linear pharmacokinetics with a half-life of 5 to 10 days, supporting every 3 weeks dosing. AZD8853 suppression of GDF15 was transient. There was no evidence of ctDNA clearance or dose-dependent changes in peripheral T cells. Changes in body weight showed no apparent trends.</p><p><strong>Conclusions: </strong>AZD8853 was well tolerated; however, no objective responses or PD effects were seen, and GDF15 suppression was not sustained. The study was terminated after dose escalation.</p><p><strong>Significance: </strong>GDF15 is upregulated in the tumor microenvironment and suppresses antitumor immune responses. In this first-in-human trial, the anti-GDF15 antibody AZD8853 was well tolerated in previously treated patients with advanced/metastatic solid tumors, but no objective responses or PD effects were seen and GDF15 suppression was not sustained.</p>","PeriodicalId":72516,"journal":{"name":"Cancer research communications","volume":" ","pages":"896-905"},"PeriodicalIF":2.0,"publicationDate":"2025-06-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12127903/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144042521","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Cisplatin-Induced APE2 Overexpression Disrupts MYH9 Function and Causes Hearing Loss.","authors":"Qingzhu Wang, Eric E Irons, Wanying Zhang, Fangfang Zhao, Meng-Han Chang, Esther Dai, Joelle Jeon, Hanna Hong, Rie Maeda, Minseo Kim, Kylin A Emhoff, Mei Yin, Belinda B Willard, Qing Y Zheng, Richard A Prayson, Jordan Beach, Jennifer S Yu, Bohua Hu, Jianjun Zhao, Jianhong Lin","doi":"10.1158/2767-9764.CRC-24-0506","DOIUrl":"10.1158/2767-9764.CRC-24-0506","url":null,"abstract":"<p><p>Cisplatin remains a cornerstone chemotherapy for many solid tumors but is limited by dose-limiting toxicities, including nephrotoxicity, peripheral neuropathy, and ototoxicity-the latter of which disproportionately affects pediatric patients and lacks effective prevention strategies. Although therapeutic approaches to mitigate cisplatin-induced toxicity are urgently needed, the underlying mechanisms driving organ-specific injury remain incompletely understood. We previously identified apurinic/apyrimidinic endonuclease (APE) 2 as a critical mediator of cisplatin-induced acute kidney injury through disruption of mitochondrial integrity. In this study, we extend these findings to cisplatin-induced hearing loss (C-HL). We demonstrate that cisplatin selectively induces APE2, but not APE1, overexpression in murine and human outer hair cells. Using an inducible, outer hair cell-specific APE2 transgenic mouse model, we show that APE2 overexpression alone is sufficient to cause high-frequency hearing loss, accompanied by hair cell loss and stereocilia disorganization visualized by electron microscopy. Mechanistically, we identified a direct interaction between APE2 and MYH9, mapped the critical MYH9-binding domains, and demonstrated that APE2 knockdown preserved mitochondrial metabolism and protected cochlear cells from cisplatin-induced apoptosis. Notably, APE2 depletion activated an ATR-p53 signaling axis, promoting nuclear p53 localization and suppressing mitochondrial apoptotic pathways. Together, these findings reveal a noncanonical, APE2-dependent mechanism driving C-HL and suggest that targeting APE2 may offer a novel therapeutic strategy to prevent cisplatin-induced ototoxicity.</p><p><strong>Significance: </strong>These results reveal an unexpected role of APE2 via its interaction with MYH9, emphasizing the therapeutic promise of targeting APE2 for preventing C-HL in patients with cancer.</p>","PeriodicalId":72516,"journal":{"name":"Cancer research communications","volume":" ","pages":"994-1007"},"PeriodicalIF":2.0,"publicationDate":"2025-06-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12179588/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144217697","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Repurposing Amiodarone for Bladder Cancer Treatment.","authors":"Francisco J Roa, Maria Roubelakis, Konstantinos Paschidis, Nils C H van Creij, Florian Handle, Manousos Makridakis, Shaman Narayanasamy, Irina-Afrodita Balaur, Aggeliki Tserga, Antonia Vlahou, Frédéric R Santer, Per-Sonne Holm, Michele Hoffmann, Martin Puhr, Marika Mokou, Maria Frantzi, Reinhard Schneider, Agnieszka Latosinska, Harald Mischak, Venkata Satagopam, Zoran Culig, Renate Pichler","doi":"10.1158/2767-9764.CRC-24-0433","DOIUrl":"10.1158/2767-9764.CRC-24-0433","url":null,"abstract":"<p><p>Cisplatin-based neoadjuvant chemotherapy followed by radical cystectomy is the main treatment for muscle-invasive bladder cancer (MIBC). However, low survival rates highlight the necessity for new therapeutic strategies. Drug repurposing has emerged as a promising approach in cancer treatment, with various studies proposing the use of existing drugs for the treatment of bladder cancer. In this context, we previously established an in silico repurposing strategy using patient omics signatures, identifying drugs and compounds with the potential to reverse nonmuscle-invasive bladder cancer (NMIBC) to less aggressive subtypes. In the present study, we expanded our in silico approach to verify a list of compounds with potential antitumor activity against MIBC. We investigated the efficacy of the predicted candidates in a group of different bladder cancer cell lines, including NMIBC and MIBC. The most potent compound for decreasing cell viability was amiodarone, an antiarrhythmic drug widely used in the field of cardiology. Amiodarone reduced cell proliferation and colony formation capacity, with a stronger effect on the most aggressive invasive models, validating our repurposing pipeline. The drug additionally induced cell death and inhibited the activity of mTOR and its target protein S6, suggesting that the anticancer effect of the drug is, in part, mediated by inhibition of the mTOR signaling pathway. Furthermore, the administration of amiodarone in a xenograft MIBC mouse model reduced tumor growth without inducing toxicity. Altogether, we demonstrated that amiodarone is a potential repurposed drug for bladder cancer, which might be especially effective in MIBC.</p><p><strong>Significance: </strong>Treatment of advanced bladder cancer remains a therapeutic challenge in urological oncology. In order to make more drugs available to patients in the future, we identified amiodarone, a repurposed drug used in cardiology as a compound that inhibits bladder cancer in vitro and in vivo.</p>","PeriodicalId":72516,"journal":{"name":"Cancer research communications","volume":" ","pages":"906-920"},"PeriodicalIF":2.0,"publicationDate":"2025-06-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12134865/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144054487","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"NLRP3 Inflammasome Activation Expands the Immunosuppressive Myeloid Stroma and Antagonizes the Therapeutic Benefit of STING Activation in Glioblastoma.","authors":"Spencer T Lea, Chao-Hsien Chen, Jun Wei, Ivana William, Inés Lopez Del Castillo, Michael A Curran","doi":"10.1158/2767-9764.CRC-23-0189","DOIUrl":"10.1158/2767-9764.CRC-23-0189","url":null,"abstract":"<p><p>Glioblastoma (GBM) is the most common and deadly primary brain malignancy and is clinically refractory to immunotherapy. Active NLRP3 inflammasome signaling and IL-1β secretion have been observed in GBM, and NLRP3-driven myeloid-derived suppressor cell (MDSC) recruitment can mediate cancer immune evasion. Agonists of the cytosolic double-stranded DNA-sensing stimulator of IFN gene (STING) pathway can mediate proinflammatory conversion of cancer MDSCs; however, secretion of the NLRP3 products IL-1β and IL-18 has also been observed in certain myeloid populations following STING activation. In this study, we aimed to determine both the potential mechanistic synergy between STING and NLRP3 agonists, and the effects of this innate immune combination on the GBM tumor immune landscape. We find that STING activation does not prime pro-IL-1β expression for activated NLRP3 inflammasome secretion. In subcutaneous GL261 GBM, we show that NLRP3 activation expands the immunosuppressive myeloid stroma primarily via granulocytic MDSC recruitment and antagonizes the benefit of STING activation. In brain GL261, we find that NLRP3 activation expands granulocytic MDSCs but does not antagonize the therapeutic benefit of STING activation. Finally, we report that mesenchymal subtype GBM tumors have elevated neutrophil, IL-1β, and NLRP3 gene expression, a setting where our data suggest that NLRP3 activation could counteract STING agonists.</p><p><strong>Significance: </strong>NLRP3 inflammasome signaling, which suppresses antitumor immunity in some cancers, has been observed in GBM tissues. NLRP3 activation in GBM induces granulocyte-dependent tumor immunosuppression and antagonizes the therapeutic efficacy of STING activation.</p>","PeriodicalId":72516,"journal":{"name":"Cancer research communications","volume":" ","pages":"960-972"},"PeriodicalIF":2.0,"publicationDate":"2025-06-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12163576/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144082575","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Creation and Characterization of a Breast Cancer Tissue Microarray Including Black and White Patients from Florida and Hispanic Patients from Puerto Rico and Florida.","authors":"Abigail E Lantz, Edna R Gordián, Marilin Rosa, Marileana Rodríguez-Ruíz, Joseph O Johnson, Ryan Gebert, Allison Bahr, Dung Tsa Chen, Julie Dutil, Jiannong Li, José A Oliveras Torres, Harold I Saavedra, Steven A Eschrich, Idhaliz Flores, William D Cress","doi":"10.1158/2767-9764.CRC-24-0650","DOIUrl":"10.1158/2767-9764.CRC-24-0650","url":null,"abstract":"<p><p>Breast cancer is a leading cause of cancer-related mortality among women worldwide and is known to have higher mortality among women with African ancestry. Herein, we describe the creation and characterization of a multiethnic breast cancer tissue microarray (ME-BrTMA) representing tumors from non-Hispanic White (n = 41), non-Hispanic Black (NHB; n = 45), and Hispanic patients from Puerto Rico (n = 36) and Florida (n = 52). This ME-BrTMA comprises five blocks with a total of 610 cores: 371 breast cancer tumor cores, 93 breast stromal cores, 96 normal breast tissue cores, 30 non-breast cancer tumor cores, and 20 cores representing normal tissues. Initial characterization of the ME-BrTMA includes standard IHC staining of well-characterized clinical biomarkers, including the estrogen hormone receptors and progesterone hormone receptors, HER2, and Ki-67, interpreted by the coauthoring pathologist (Marilin Rosa). The IHC results indicated good but imperfect alignment with clinical diagnoses. Cores from breast cancer tumors from the NHB cohort most frequently scored negative for estrogen receptor (63%, P < 0.005) and progesterone receptor (80%, P < 0.005) and most frequently have high expression of the Ki-67 proliferation marker (38%, P < 0.05). Prediction Analysis of Microarray 50 (PAM50) analysis using RNA from secondary patient blocks showed that the NHB group also most frequently scored in the basal-like category (61%, P < 0.05). Taken together, the initial characterization of the ME-BrTMA suggests that it may serve as a representative resource to understand the underlying biology of breast cancer and its relationship to patient outcomes.</p><p><strong>Significance: </strong>The ME-BrTMA described herein provides a resource that may serve as a tool to understand the underlying biology of breast cancer.</p>","PeriodicalId":72516,"journal":{"name":"Cancer research communications","volume":" ","pages":"804-813"},"PeriodicalIF":2.0,"publicationDate":"2025-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12082392/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144013528","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}