Cancer research communications最新文献

{"title":"In Situ Proinflammatory Effects of Dazostinag Alone or with Chemotherapy on the Tumor Microenvironment of Patients with Head and Neck Squamous Cell Carcinoma.","authors":"Richard C Gregory, Neil Lineberry, Alex Parent, Karthik Rajasekaran, Thomas J Ow, Cherie-Ann Nathan, Beryl A Hatton, Wendy Jenkins, Marc Grenley, Connor Burns, Angela Merrell, Jason P Frazier, Jonathan M J Derry, Emily Beirne, Richard A Klinghoffer","doi":"10.1158/2767-9764.CRC-25-0314","DOIUrl":"10.1158/2767-9764.CRC-25-0314","url":null,"abstract":"<p><strong>Purpose: </strong>The tumor microenvironment (TME) is difficult to model in an in vivo cancer research setting. This study leveraged intratumor microdosing using comparative in vivo oncology (CIVO) with spatial profiling to evaluate the effects of the stimulator of interferon genes agonist dazostinag, alone or with chemotherapy, on cellular responses within the native TME of intact human tumors.</p><p><strong>Patients and methods: </strong>This phase 0 study enrolled adult patients with head and neck squamous cell carcinoma (HNSCC) planned for surgical intervention. Intratumoral microdose injections of dazostinag (maximum dose: 1.68 μg in a 0.05 mg/mL solution), alone or combined with various chemotherapies, were delivered via CIVO to tumors 24, 48, 72, or 96 hours prior to resection. Each tumor sample was prepared for analysis using IHC and ISH. Analysis of the microdosed tumors using the GeoMx Digital Spatial Profiler and CosMx Spatial Molecular Imager was performed in one patient.</p><p><strong>Results: </strong>Type 1 IFN signaling was induced with dazostinag alone and in combination with chemotherapy from multiple cell types within the TME, including immune cells. Dazostinag also shifted the polarization of macrophages from an immune-suppressive phenotype to a proinflammatory phenotype at 24 hours after injection. Enrichment of cytotoxic T cells was observed in regions of localized dazostinag exposure, coinciding with increased chemokine (CXCL9) expression. Based on cleaved caspase-3, an apoptosis marker, dazostinag plus chemotherapy increased cellular apoptosis relative to either drug alone.</p><p><strong>Conclusions: </strong>Utilizing CIVO and spatial profiling technology, dazostinag alone and combined with chemotherapy promoted an early proinflammatory response and enhanced chemotherapy-mediated cell death in the native TME of intact human HNSCC tumors.</p><p><strong>Significance: </strong>The CIVO approach demonstrates that dazostinag alone and combined with chemotherapy promotes both proapoptotic and early proinflammatory responses in the native TME of intact human HNSCC tumors, providing clinical evidence for an on-target mechanism of action and rationale for further clinical investigation.</p>","PeriodicalId":72516,"journal":{"name":"Cancer research communications","volume":" ","pages":"1243-1255"},"PeriodicalIF":3.3,"publicationDate":"2025-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144651380","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":"Assessing Racial Disparities in Guideline-Concordant Care and Clinical Outcomes after Surgical Resection of Nonmetastatic Colon Cancer at a Comprehensive Cancer Center.","authors":"Christina I Lee, Sharafudeen D Abubakar, Fan Wu, Hannah M Thompson, Farheen Shah, Michele Waters, Jonathan B Yuval, Hannah Williams, Anisha Luthra, Dana M Omer, Chin-Tung Chen, Julio Garcia-Aguilar, Francisco Sanchez-Vega","doi":"10.1158/2767-9764.CRC-24-0633","DOIUrl":"10.1158/2767-9764.CRC-24-0633","url":null,"abstract":"<p><p>In this study, we examined racial disparities in guideline-concordant care (GCC) and clinical outcomes of patients with colon cancer treated at a single comprehensive cancer center. We analyzed data from self-reported Hispanic, non-Hispanic Black (NHB), and non-Hispanic White (NHW) patients who underwent curative colectomy for stage I to III colon cancer between 2006 and 2021 at Memorial Sloan Kettering Cancer Center. GCC was defined as retrieval of ≥12 lymph nodes and appropriate receipt of adjuvant chemotherapy. Recurrence and overall survival from the time of surgery were compared using the Kaplan-Meier method and the log-rank test. Multivariable analyses were performed using Cox regression. The study included 2,209 patients, with 1,911 NHW, 153 NHB, and 145 Hispanic patients. NHW patients were older, whereas NHB patients had higher percentages of Medicaid coverage, obesity, and lower socioeconomic status. NHB patients more often presented with stage III disease and underwent open surgery. Receipt of GCC was not different by race. NHB patients had the highest 5-year recurrence rate compared with NHW and Hispanic patients (27% vs. 15.7% vs. 15.1%; P = 0.03). NHB race (HR = 1.43; P = 0.07) and low body mass index (HR = 1.98; P = 0.05) were associated with an increased risk of recurrence with marginal significance. NHB race was associated with an increased risk of recurrence in stage I disease (HR = 3.52; P = 0.03). NHB patients had shorter recurrence-free survival, despite standardized quality of care. NHB race was independently associated with an increased risk of recurrence in stage I disease.</p><p><strong>Significance: </strong>This study compares receipt of GCC, disease recurrence, and survival among White, Black, and Hispanic patients with nonmetastatic colon cancer treated at a single comprehensive cancer center with standardized quality of care and comparable access to health care. Black patients had higher rates of recurrence in this study.</p>","PeriodicalId":72516,"journal":{"name":"Cancer research communications","volume":" ","pages":"1171-1179"},"PeriodicalIF":2.0,"publicationDate":"2025-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12272046/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144531339","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":"Plasma Cell-Free Human Papillomavirus DNA and Oral Gargle HPV DNA in Patients with HPV-Related Oropharyngeal Cancer Treated with Radiotherapy.","authors":"Michelle Echevarria, Robin Park, Jimmy J Caudell, Youngchul Kim, George Q Yang, Kedar Kirtane, Ritu Chaudhary, Sunil Kumar, Antonio L Amelio, Anna R Giuliano, Christine H Chung","doi":"10.1158/2767-9764.CRC-25-0180","DOIUrl":"10.1158/2767-9764.CRC-25-0180","url":null,"abstract":"<p><p>Dynamic biomarkers that guide de-escalation strategies in human papillomavirus (HPV)-related oropharyngeal squamous cell carcinoma (OPSCC) remain an unmet need. In this study, we evaluated the kinetics of plasma cell-free HPV (cfHPV) DNA and oral gargle HPV DNA during radiotherapy in patients with low-risk HPV-related OPSCC. Data were obtained from a trial evaluating an adaptive model optimizing radiation fractionation in patients with low-risk (T0-2N0-1M0) HPV-related OPSCC undergoing radiotherapy. The primary objective was to determine whether week 4 plasma cfHPV DNA or oral gargle HPV DNA clearance is associated with reduction of target tumor volume (TTV) at week 4. A total of 325 plasma and 334 oral gargle samples from 50 patients with available baseline samples were analyzed. Higher baseline plasma cfHPV DNA was associated with higher nodal staging (P = 0.002), whereas oral gargle HPV DNA was detected more frequently in the tonsil or soft palate than occult or base of tongue primary tumors (P = 0.039). Week 4 plasma but not oral gargle HPV DNA clearance was associated with higher reduction of TTV at week 4 (P = 0.0063). Whereas week 4 plasma and oral gargle HPV DNA clearance was not associated with progression-free survival, a lower baseline plasma cfHPV DNA was associated with superior progression-free survival (P = 0.027). Week 4 plasma cfHPV DNA clearance aligns with reduction in TTV, and future studies are warranted to determine the role of early plasma cfHPV DNA clearance in biomarker-adapted de-escalation strategies.</p><p><strong>Significance: </strong>Our findings may inform appropriate patient selection for low-risk HPV-related OPSCC based on cfHPV DNA in future deintensification studies, aimed at preventing or minimizing treatment-related toxicities in patients who may have lower risk of recurrence.</p>","PeriodicalId":72516,"journal":{"name":"Cancer research communications","volume":" ","pages":"1194-1202"},"PeriodicalIF":2.0,"publicationDate":"2025-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12281097/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144610451","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 I First-in-Human Study of TRK-950, an IgG1 Antibody Specific to CAPRIN-1, in Patients with Advanced Solid Tumors.","authors":"Philippe A Cassier, Mitesh J Borad, Sunil Sharma, Bertrand Dubois, Christophe Caux, Fumiyoshi Okano, Daniel D Von Hoff, Jean-Yves Blay","doi":"10.1158/2767-9764.CRC-25-0123","DOIUrl":"10.1158/2767-9764.CRC-25-0123","url":null,"abstract":"<p><strong>Purpose: </strong>TRK-950 is a first-in-class humanized antibody targeting cytoplasmic activation/proliferation-associated protein-1, which is strongly expressed on the cell membrane surface in or on most solid tumors but not in or on normal tissues. This first-in-human study investigated the safety profile, pharmacokinetics (PK), and preliminary antitumor activity.</p><p><strong>Patients and methods: </strong>Patients with treatment-refractory, locally advanced, or metastatic solid tumors were enrolled in a dose escalation/expansion study. TRK-950 was administered intravenously weekly for 3 weeks in a 28-day cycle, with doses ranging from 3 to 30 mg/kg. Dose expansion included 10 mg/kg weekly and 30 mg/kg biweekly for colorectal cancer and 10 mg/kg weekly for cholangiocarcinoma. The primary objective of this study was to determine its safety, tolerability, and maximum tolerated dose. The secondary objectives were PK, preliminary antitumor activity, and identification of potential biomarkers.</p><p><strong>Results: </strong>Thirty-six patients received at least one dose of TRK-950. In the dose escalation cohort, the maximum tolerated dose was not reached, and no dose-limiting toxicities were observed up to 30 mg/kg. Common adverse events included abdominal pain, fatigue, constipation, back pain, nausea, and decreased appetite. TRK-950 exhibited a PK profile similar to that of other IgG subclass 1 therapeutic antibodies, with linear PK parameters over the 3 to 30 mg/kg dose range. The best response was stable disease. Notably, one patient with cholangiocarcinoma showed signs of cavitation after approximately 8 months, suggesting potential antitumor activity.</p><p><strong>Conclusions: </strong>TRK-950 is safe and well tolerated, has a favorable PK profile, and should be further investigated as a monotherapy and in combination with standard treatment for various types of solid tumors.</p><p><strong>Significance: </strong>TRK-950, a humanized antibody targeting CAPRIN-1, demonstrated good tolerability, no dose-limiting toxicities, a favorable PK profile, and potential antitumor activity in this first-in-human study. Currently, TRK-950 is undergoing Phase Ib and II trials for various cancers, showing promising development potential.</p>","PeriodicalId":72516,"journal":{"name":"Cancer research communications","volume":" ","pages":"1119-1128"},"PeriodicalIF":2.0,"publicationDate":"2025-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12246539/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144487358","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":"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":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144651379","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":"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}