Cancer research communications最新文献

{"title":"Epidemiologic Features and Age-Related Differences in Management among Patients with Gastrointestinal Stromal Tumors in Japan: A National Cancer Registry Study.","authors":"Hidekazu Hirano, Yoichi Naito, Toshirou Nishida, Takahiro Higashi, Tomoyuki Satake, Chigusa Morizane, Akira Kawai","doi":"10.1158/2767-9764.CRC-25-0074","DOIUrl":"10.1158/2767-9764.CRC-25-0074","url":null,"abstract":"<p><p>Data on the epidemiology of gastrointestinal stromal tumor (GIST) and differences in its management according to age group are limited in Japan. We aimed to conduct an epidemiologic evaluation and describe age-related differences in management using data from Japan's National Cancer Registry. We analyzed National Cancer Registry data of 21,426 patients with GIST between 2016 and 2019. We compared information on demographics, treatment, and prognosis across three age groups: pediatric and adolescent young adult (PAYA; ≤39 years), adult (40-74 years), and geriatric (≥75 years). Crude and age-adjusted annual incidences of GIST were 4.23 and 4.20 per 100,000 population, respectively. Regional variations in average age-adjusted annual incidence were observed among prefectures. The most common primary organs were stomach (72%), followed by the small intestine (21%). Geriatric patients represented 33% of the total population. Relative to PAYA and adult patients, geriatric patients were less likely to undergo surgery in the nonmetastatic setting (PAYA, 93%; adult, 93%; and geriatric, 87%; P < 0.001) or to receive chemotherapy in the metastatic setting (PAYA, 90%; adult, 87%; and geriatric, 61%; P < 0.001). Geriatric patients showed poorer 2-year overall survival relative to PAYA and adult patients in the nonmetastatic (PAYA, 98.5%; adult, 97.2%; and geriatric, 89.2%; P < 0.001) and metastatic (PAYA, 92.9%; adult, 79.2%; and geriatric, 54.7%; P < 0.001) settings. Geriatric patients comprised one third of the study population and were associated with less active treatment and an unfavorable prognosis.</p><p><strong>Significance: </strong>This is the first report presenting comprehensive Japanese epidemiologic data on GIST at a national level.</p>","PeriodicalId":72516,"journal":{"name":"Cancer research communications","volume":" ","pages":"1235-1242"},"PeriodicalIF":3.3,"publicationDate":"2025-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12304871/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144651379","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":"The XPO1 Inhibitor Eltanexor Modulates the Wnt/β-Catenin Signaling Pathway to Reduce Colorectal Cancer Tumorigenesis.","authors":"Andrew E Evans, Sahida Afroz, Alexa Magstadt, Anup Kasi, Dan A Dixon","doi":"10.1158/2767-9764.CRC-25-0052","DOIUrl":"10.1158/2767-9764.CRC-25-0052","url":null,"abstract":"<p><p>Colorectal cancer is the second leading cause of cancer-related death in the United States and high-risk individuals face a notably higher likelihood of developing colorectal cancer based on their genetic background. Hence, there is a compelling need for innovative chemopreventive treatments aimed at minimizing colorectal cancer tumorigenesis. Exportin 1 (XPO1; also referred to as CRM1) plays a pivotal role in transporting proteins from the nucleus to the cytoplasm. Various cancers overexpress XPO1, including colorectal cancer, and selective inhibitors of nuclear export compounds, such as eltanexor (KPT-8602), have been developed to target XPO1. Eltanexor demonstrates fewer adverse effects than its precursors and is currently under evaluation in phase I/II clinical trials. This research evaluates eltanexor as a chemopreventive agent for colorectal cancer. Our findings indicate that eltanexor treatment inhibits expression of the common chemoprevention target in colorectal cancer, COX-2. This occurs by eltanexor-dependent reduction of Wnt/β-catenin signaling. Furthermore, XPO1 inhibition leads to forkhead transcription factor O subfamily member 3a nuclear retention, which can modulate β-catenin/TCF transcriptional activity. The in vivo oral treatment of eltanexor to Apcmin/+ mice (a mouse model for familial adenomatosis polyposis) was well tolerated and reduced tumor burden by approximately threefold, along with decreased tumor size. Drug sensitivity assays using organoids from Apcmin/+ mice tumors showed increased sensitivity to eltanexor compared with wild-type organoids. Collectively, these findings highlight XPO1 as a potent target for colorectal cancer chemoprevention.</p><p><strong>Significance: </strong>In this study, we show the XPO1 inhibitor eltanexor acts as an effective colorectal cancer chemopreventive agent both in vivo and in vitro. This occurs by reducing COX-2 expression by modulating the Wnt/β-catenin signaling pathway. Collectively, these findings highlight XPO1 as a potent target for colorectal cancer chemoprevention.</p>","PeriodicalId":72516,"journal":{"name":"Cancer research communications","volume":" ","pages":"1140-1154"},"PeriodicalIF":2.0,"publicationDate":"2025-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12260813/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144556041","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":"Assessing MC1R Variants in Lentigo Maligna Melanoma within the Utah Population.","authors":"Amanda Jiang, Annabelle Huntsman, Carly Becker, Bing-Jian Feng, Kayla Marks, Jessica Donigan, Keith L Duffy, Alice Frigerio, Douglas Grossman, Deborah W Neklason, Robert L Judson-Torres, Dekker C Deacon","doi":"10.1158/2767-9764.CRC-25-0263","DOIUrl":"10.1158/2767-9764.CRC-25-0263","url":null,"abstract":"<p><p>Lentigo maligna (LM) and lentigo maligna melanoma (LMM) arise from chronically sun-damaged skin. LM/LMM incidence continues to increase, particularly in Utah, where melanoma rates are twice the national average. The melanocortin-1 receptor (MC1R) has been studied in melanocyte pigmentation and DNA repair but has yet to be thoroughly investigated in LM/LMM. We investigated allele and genotype frequencies of germline MC1R variants among 175 Utah patients diagnosed with LM/LMM and 402 Utah reference individuals. The comparative analysis demonstrated an increased frequency of the D294H allele (0.046; P = 0.0042) and a decreased frequency of the V60L allele (0.074; P = 0.034) in patients with LM/LMM. The LM/LMM group demonstrated a higher OR compared with the Utah reference group associated with R151C homozygosity compared with heterozygous R151C [OR = 5.6; 95% confidence interval (CI), 0.98-32; P = 0.052] and R151C homozygosity compared with wild type (OR = 5.7; 95% CI, 1.1-30; P = 0.042). D294H heterozygosity was strongly associated with LM/LMM (OR = 3.8; 95% CI, 1.3-11; P = 0.014). Conversely, V60L heterozygosity was less strongly associated with LM/LMM (OR = 0.52; 95% CI, 0.26-1.1; P = 0.072). Stratified analyses showed no significant differences in age or gender across the key MC1R variants studied. These data highlight significant differences in MC1R allele frequencies in patients with LM/LMM, demonstrating that D294H is associated with increased LM/LMM risk, whereas the V60L variant is inversely associated with risk. This study provides the first comprehensive analysis of specific high-risk MC1R variants in patients with LM/LMM in Utah.</p><p><strong>Significance: </strong>Our study is the first comprehensive analysis of MC1R germline variants in patients with LM/LMM in Utah, a region with an exceptionally high melanoma incidence. We draw new risk associations in LM/LMM, identifying an increased risk with the D294H and R151C variants. We also describe a novel inverse association for V60L, warranting further investigation. This study contributes to improved targeted risk stratification and an increased understanding of an understudied melanoma subtype.</p>","PeriodicalId":72516,"journal":{"name":"Cancer research communications","volume":" ","pages":"1228-1234"},"PeriodicalIF":3.3,"publicationDate":"2025-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12301710/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144651378","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":"Dual Role of NRF2 in Pancreatic Precursor Lesions.","authors":"Shu Ichimiya, Sung Shin Ahn, Maya S Dixon, John P O'Sullivan, Lela C DeVine, Alex Chen, Takeo Yamamoto, Yoshinao Oda, Masafumi Nakamura, Iok In Christine Chio","doi":"10.1158/2767-9764.CRC-25-0107","DOIUrl":"10.1158/2767-9764.CRC-25-0107","url":null,"abstract":"<p><p>Pancreatic ductal adenocarcinoma (PDA) arises from distinct precursor lesions, primarily pancreatic intraepithelial neoplasia (PanIN) and intraductal papillary mucinous neoplasm (IPMN). Unlike PanIN, IPMN is a cystic lesion detectable by imaging, providing an opportunity for early intervention. However, the molecular determinants guiding the formation of PanIN versus IPMN remain poorly understood. In this study, we uncover a previously unrecognized role for nuclear factor erythroid 2-related factor 2 (NRF2), a master regulator of redox homeostasis, in dictating pancreatic precursor lesion fate. Although NRF2 is known to promote PanIN formation and sustain PDA, we found that active NRF2 levels are significantly lower in human IPMN compared with PanIN and PDA. Using a conditional NRF2 knockout mouse model, we demonstrate that NRF2 loss significantly increases IPMN-like cystic tumor formation in KRASG12D-mutant pancreatic epithelium, revealing an unexpected suppressive role of NRF2 in IPMN development. Mechanistically, NRF2 suppresses IPMN formation through redox-independent transcriptional repression of SAM pointed domain-containing Ets transcription factor and MUC6, key markers of IPMN. These findings establish NRF2 as a lesion-specific regulator of pancreatic tumorigenesis, providing new molecular insights into PDA progression and potential biomarkers for early detection and risk stratification.</p><p><strong>Significance: </strong>This study reveals a context-dependent role of NRF2 in pancreatic tumorigenesis, promoting PanIN progression while suppressing IPMN formation. These findings provide new insights into early lesion heterogeneity and highlight NRF2 status as a potential biomarker for risk stratification in pancreatic cancer.</p>","PeriodicalId":72516,"journal":{"name":"Cancer research communications","volume":" ","pages":"945-959"},"PeriodicalIF":2.0,"publicationDate":"2025-06-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12158068/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144129590","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":"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":"An Acrolein-Based Drug Delivery System Enables Tumor-Specific Sphingosine-1-Phosphate Targeting in Breast Cancer without Lymphocytopenia.","authors":"Masayuki Nagahashi, Miki Komatsu, Sayaka Urano, Mamiko Kuroiwa, Yuria Takahashi, Koji Morimoto, Ambara R Pradipta, Katsunori Tanaka, Yasuo Miyoshi","doi":"10.1158/2767-9764.CRC-25-0023","DOIUrl":"10.1158/2767-9764.CRC-25-0023","url":null,"abstract":"<p><p>We developed a novel FTY720 prodrug (pro-FTY) that specifically inhibits sphingosine-1-phosphate signaling in cancer cells using a novel drug delivery system that reacts with acrolein. Our objective was to evaluate the efficacy and safety of pro-FTY in preclinical experiments. Ten breast cancer cell lines, two multidrug-resistant cell lines, and one normal mammary cell line were used to compare the IC50 values of pro-FTY with those of other drugs. Patient-derived organoids (PDO) were established and utilized for IC50 value comparisons. Drug efficacy was tested in mice bearing either syngeneic 4T1 cell tumors or patient-derived xenograft tumors, and blood analysis (including mass spectrometry) was performed. FTY720 and pro-FTY inhibited the survival of all breast cancer cell lines, including multidrug-resistant cells resistant to paclitaxel or doxorubicin. Unlike pro-FTY, FTY720 inhibited the survival of normal breast cell lines, suggesting that pro-FTY does not affect normal breast cells. Pro-FTY showed reproducible activity against multidrug-resistant PDOs, whereas paclitaxel and doxorubicin did not. Mass spectrometric analysis of pro-FTY-treated mice showed that FTY720 accumulated in tumors but was barely detectable in blood. Importantly, lymphocytopenia occurred in FTY720-treated mice but not in pro-FTY-treated mice. Furthermore, intravenous pro-FTY treatment significantly suppressed tumor growth in mice bearing patient-derived xenograft tumors generated from multidrug-resistant PDOs. In conclusion, pro-FTY inhibited breast cancer, including multidrug-resistant breast cancer, while avoiding lymphocytopenia, highlighting its clinical potential.</p><p><strong>Significance: </strong>Pro-FTY selectively inhibits sphingosine-1-phosphate signaling in cancer cells using a novel acrolein-responsive drug delivery system that reacts with acrolein. Pro-FTY does not inhibit normal cell growth, thus avoiding lymphocytopenia. Pro-FTY is effective against multidrug-resistant breast cancer with a unique mechanism of action, highlighting its translational and therapeutic potential.</p>","PeriodicalId":72516,"journal":{"name":"Cancer research communications","volume":"5 6","pages":"981-993"},"PeriodicalIF":2.0,"publicationDate":"2025-06-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12174973/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144318861","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":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12188421/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144210329","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":"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":"Histone Deacetylase Inhibitors Target DNA Replication Regulators and Replication Stress in Ewing Sarcoma Cells.","authors":"Stacia L Koppenhafer, Elizabeth L Geary, Mary V Thomas, Emma E Croushore, Jessica A O Zimmerman, Jenna M Gedminas, Dawn E Quelle, Rebecca D Dodd, David J Gordon","doi":"10.1158/2767-9764.CRC-25-0058","DOIUrl":"10.1158/2767-9764.CRC-25-0058","url":null,"abstract":"<p><p>Histone deacetylases (HDAC) regulate diverse pathways in cancer cells. Previously, we identified that Ewing sarcoma tumors, which are caused by a translocation between the EWSR1 and FLI1 genes (EWS::FLI1), are sensitive to drugs that target DNA replication, including the RRM1 and RRM2 subunits of ribonucleotide reductase, and the ATR-checkpoint kinase 1 (CHK1)-WEE1 signaling pathway. In this study, we identified that multiple HDAC inhibitors, including fimepinostat, romidepsin, and panobinostat, downregulate the levels of the RRM1, RRM2, CHK1, and WEE1 proteins in Ewing sarcoma cells and impair DNA replication. Moreover, transcriptome analyses identified that HDAC inhibitors downregulate the expression of multiple components of the prereplication complex, including the minichromosome maintenance complex 2-7 (MCM2-7) proteins and CDT1, that are essential for genomic DNA replication. Additionally, proteomic studies identified that HDAC inhibitors also downregulate the level of the BRD4 protein, a BET bromodomain protein that regulates both the transcriptional program of the EWS::FLI1 oncoprotein and DNA replication. Overall, these results provide novel insight into the molecular mechanisms by which HDAC inhibitors target cancer cells, regulate DNA replication, and inhibit the cellular response to DNA replication stress.</p><p><strong>Significance: </strong>In this work, we identify that HDAC inhibitors broadly disrupt DNA replication and the response to replication stress in Ewing sarcoma cells by downregulating RRM1, RRM2, CHK1, and WEE1. Notably, HDAC inhibitors also reduce MCM2-7 proteins, which are essential for prereplication complex helicase function in replication initiation and elongation, and CDT1, which loads MCM2-7 onto DNA.</p>","PeriodicalId":72516,"journal":{"name":"Cancer research communications","volume":" ","pages":"1034-1048"},"PeriodicalIF":2.0,"publicationDate":"2025-06-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12202856/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144251115","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}