Lauren Polyakov, Angelina Lim, Alexandra Meyer, Aubree Mades, Joshua Ni, Ryan Cooper, Shirley Ye, Ryutaro Kajihara, Takaaki Oba, Leslie Contreras, Eihab Abdelfatah, Joy Sarkar, Junko Matsuzaki, Ming Li, Rajeev Sharma, Brahm H Segal, Robert C Hsu, Hongbin Chen, Jorge Nieva, Fumito Ito
{"title":"Impact of Glucocorticoids on Immune Checkpoint Inhibitor Efficacy and Circulating Biomarkers in Non-Small Cell Lung Cancer Patients.","authors":"Lauren Polyakov, Angelina Lim, Alexandra Meyer, Aubree Mades, Joshua Ni, Ryan Cooper, Shirley Ye, Ryutaro Kajihara, Takaaki Oba, Leslie Contreras, Eihab Abdelfatah, Joy Sarkar, Junko Matsuzaki, Ming Li, Rajeev Sharma, Brahm H Segal, Robert C Hsu, Hongbin Chen, Jorge Nieva, Fumito Ito","doi":"10.1158/2767-9764.CRC-25-0051","DOIUrl":"10.1158/2767-9764.CRC-25-0051","url":null,"abstract":"<p><p>Corticosteroids are frequently prescribed to patients with non-small cell lung cancer (NSCLC) for palliation of cancer-related symptoms; however, the potential impact of baseline steroid use on immune checkpoint inhibitor (ICI) therapy and its underlying mechanisms remain unclear. In this study, we evaluated clinical outcomes of 277 patients with NSCLC treated with ICI therapy at two academic institutions. Twenty-one patients (8%) were taking steroids at the start of ICIs. Patients on baseline steroids had a lower overall response rate with markedly shorter progression-free survival and overall survival compared with those not receiving steroids. In multivariate analysis, steroid use was the only significant independent risk factor for disease progression and mortality in both independent cohorts, Roswell Park Comprehensive Cancer Center (n = 88) and University of Southern California (n = 189). A baseline peripheral blood neutrophil-to-lymphocyte ratio <5 was a strong prognostic indicator; however, the prognostic value of neutrophil-to-lymphocyte ratio was absent in patients receiving steroids. Additionally, the baseline frequency of circulating CX3CR1+CD8+ T cells was substantially lower in patients on steroids. Using a bedside-to-bench approach, we found that concurrent steroid use significantly decreased antitumor efficacy of anti-PD-1 therapy and attenuated the increase of CX3CR1+CD8+ T cells in mice bearing MC38 tumors whereas discontinuation of steroid at the start of treatment did not make a negative impact on survival. Collectively, baseline steroid use was associated with worse outcomes and decreased frequency of circulating differentiated effector T cells in patients with NSCLC. Caution should be taken when interpreting the results from circulating immune-related biomarkers in patients on steroids.</p><p><strong>Significance: </strong>The impact of corticosteroids, widely prescribed for palliation of cancer-related symptoms, on ICI therapy remains unclear. This study shows that baseline steroid use is a negative independent prognostic factor in patients with NSCLC undergoing ICI therapy and provides insights into the decreased T-cell effector differentiation and utility of predictive blood-based markers by steroids.</p>","PeriodicalId":72516,"journal":{"name":"Cancer research communications","volume":"5 7","pages":"1082-1094"},"PeriodicalIF":2.0,"publicationDate":"2025-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12232904/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144577040","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}
Eric D Eisenmann, Ronan Swords, Ying Huang, Shelley Orwick, Daelynn Buelow, Nicole Abbott, Mitch Phelps, Joshua Zeidner, Matthew C Foster, Tara L Lin, Maria R Baer, Yazan F Madanat, Tibor Kovacsovics, Robert Redner, Zeina Al-Mansour, Bhavana Bhatnagar, Mona Stefanos, Molly Martycz, Franchesca Druggan, Timothy L Chen, Ashley O Yocum, Uma Borate, Brian J Druker, Amy Burd, Ross L Levine, John C Byrd, Sharyn D Baker, Alice S Mims
{"title":"A Phase 1b/2 Study of TP-0903 and Decitabine Targeting Mutant TP53 and/or Complex Karyotype in Patients with Untreated Acute Myeloid Leukemia ≥Age 60 Years.","authors":"Eric D Eisenmann, Ronan Swords, Ying Huang, Shelley Orwick, Daelynn Buelow, Nicole Abbott, Mitch Phelps, Joshua Zeidner, Matthew C Foster, Tara L Lin, Maria R Baer, Yazan F Madanat, Tibor Kovacsovics, Robert Redner, Zeina Al-Mansour, Bhavana Bhatnagar, Mona Stefanos, Molly Martycz, Franchesca Druggan, Timothy L Chen, Ashley O Yocum, Uma Borate, Brian J Druker, Amy Burd, Ross L Levine, John C Byrd, Sharyn D Baker, Alice S Mims","doi":"10.1158/2767-9764.CRC-25-0091","DOIUrl":"10.1158/2767-9764.CRC-25-0091","url":null,"abstract":"<p><strong>Purpose: </strong>Older patients who have acute myeloid leukemia (AML) with mutant TP53 and/or complex karyotype have a dismal prognosis and lack treatment options. Having previously demonstrated that TP-0903, a multikinase inhibitor, has compelling preclinical activity in drug-resistant AML, including TP53-mutated AML, we evaluated the clinical activity of TP-0903 in combination with decitabine.</p><p><strong>Patients and methods: </strong>This was a multicenter, open-label, phase 1b/2 substudy of Beat AML Master Trial (ClinicalTrials.gov: NCT03013998). The phase 1b portion used a 3 + 3 design, and the phase 2 portion used a Simon two-stage design. Eligible patients ages ≥60 years who had newly diagnosed AML with mutations in TP53 and/or complex karyotype (≥3 cytogenetic abnormalities) received either 37 mg (group 1) or 25 mg (group 2) TP-0903 orally on days 1 to 21 with decitabine 20 mg/m2 on days 1 to 10 for up to three 28-day induction cycles, followed by up to 30 maintenance cycles in which decitabine dosing was reduced to days 1 to 5. The primary endpoint was complete remission (CR) by the end of six cycles of treatment.</p><p><strong>Results: </strong>The overall composite remission rate (CR/CR with incomplete count recovery/CR with hematologic improvement) was 33.3% in group 1 and 50.0% in group 2, with CR rates of 13.3% and 25%, respectively. The median overall survival for groups 1 and 2 was 7.6 and 7.5 months, respectively.</p><p><strong>Conclusions: </strong>The combination of TP-0903 and decitabine was reasonably tolerated and had activity in this patient population. Further research and novel treatment strategies are necessary to improve outcomes for patients with these high-risk subtypes of AML.</p><p><strong>Significance: </strong>Treatment options for AML with mutant TP53 and/or complex karyotype are limited. In a phase 1b/2 clinical trial, TP-0903, a multikinase inhibitor, was well-tolerated and had activity comparable with other emerging therapies. Our results suggest that TP-0903 may offer insight and serve as a benchmark for the development of future agents leveraging similar strategies or scaffolds to improve outcomes in these intractable subtypes of AML.</p>","PeriodicalId":72516,"journal":{"name":"Cancer research communications","volume":" ","pages":"1129-1139"},"PeriodicalIF":2.0,"publicationDate":"2025-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12257073/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144487357","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}
Margarita Cariolou, Sofia Christakoudi, Marc J Gunter, Alicia K Heath, Amy Berrington de González, Doris S M Chan, David C Muller, Konstantinos K Tsilidis
{"title":"Adiposity Status Close to Diagnosis and Its Association with Prostate Cancer Survival in the UK Biobank.","authors":"Margarita Cariolou, Sofia Christakoudi, Marc J Gunter, Alicia K Heath, Amy Berrington de González, Doris S M Chan, David C Muller, Konstantinos K Tsilidis","doi":"10.1158/2767-9764.CRC-25-0124","DOIUrl":"10.1158/2767-9764.CRC-25-0124","url":null,"abstract":"<p><p>Substantial evidence links higher adiposity to prostate cancer development. The relationship between adiposity and outcomes after a prostate cancer diagnosis, however, is unclear. This study aimed to investigate the association between adiposity measured close to prostate cancer diagnosis and all-cause and prostate cancer-specific mortality in a prospective cohort study. Cox regression analyses estimated HRs and 95% confidence intervals (CI) for mortality in 3,760 men in the UK Biobank who had first primary prostate cancer and complete data on body mass index (BMI), waist circumference, hip circumference, waist-to-hip ratio (measured up to 2 years before or up to 5 years after diagnosis), and on covariates (diagnosis age and year, smoking, Townsend deprivation index, exercise, sedentary activities, and alcohol). The waist-to-height ratio and body fat percentage (assessed by bioelectrical impedance) were also evaluated as adiposity measures. Each 5-U increment in pre- or post-diagnosis BMI (N = 3,760) was associated with a 30% (95% CI, 1.18-1.44) higher rate of all-cause mortality (deaths = 680), a 33% (95% CI, 1.15-1.52) higher rate of prostate cancer-specific mortality (deaths = 331), and a 28% (95% CI, 1.12-1.47) higher rate of non-prostate cancer mortality (deaths = 347). Positive associations of similar magnitude were observed for separate analyses by pre- and post-diagnosis BMI and for waist and hip circumference, waist-to-hip ratio, waist-to-height ratio, and body fat percentage. Obesity assessed close to prostate cancer diagnosis is associated with higher mortality. More studies are needed to strengthen the evidence and clarify the mechanisms behind the observed associations.</p><p><strong>Significance: </strong>Patients with prostate cancer might improve their chances of survival by avoiding obesity.</p>","PeriodicalId":72516,"journal":{"name":"Cancer research communications","volume":" ","pages":"1155-1170"},"PeriodicalIF":2.0,"publicationDate":"2025-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12264726/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144509813","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}
Ya-Yun Cheng, Beth L Worley, Zaineb Javed, Amal T Elhaw, Priscilla W Tang, Sarah Al-Saad, Shriya Kamlapurkar, Sierra R White, Apoorva Uboveja, Karthikeyan Mythreye, Katherine M Aird, Traci A Czyzyk, Nadine Hempel
{"title":"Loss of Predicted Cell Adhesion Molecule MPZL3 Promotes EMT in Ovarian Cancer.","authors":"Ya-Yun Cheng, Beth L Worley, Zaineb Javed, Amal T Elhaw, Priscilla W Tang, Sarah Al-Saad, Shriya Kamlapurkar, Sierra R White, Apoorva Uboveja, Karthikeyan Mythreye, Katherine M Aird, Traci A Czyzyk, Nadine Hempel","doi":"10.1158/2767-9764.CRC-24-0591","DOIUrl":"10.1158/2767-9764.CRC-24-0591","url":null,"abstract":"<p><p>Myelin protein zero-like 3 (MPZL3) is an immunoglobulin-containing transmembrane protein with predicted cell adhesion molecule function. Loss of 11q23, in which the MPZL3 gene resides, is frequently observed in cancer. Yet the role and consequences of altered MPZL3 expression have not been explored in tumor development and progression. We addressed this in ovarian cancer, in which both MPZL3 amplification and deletions are observed in respective subsets of high-grade serous specimens. Whereas high and low MPZL3-expressing populations are similarly observed in primary ovarian tumors from an independent patient cohort, metastatic omental tumors largely display decreased MPZL3 expression, suggesting that MPZL3 loss is associated with metastatic progression. MPZL3 knockdown leads to an increase in EMT gene expression in OVCAR4 and OVCA433 cell lines, a transcript signature that is associated with poor patient outcomes. MPZL3 promotes homotypic cancer cell adhesion, and decreasing MPZL3 expression enhances invasion and clearance of mesothelial cell monolayers. Conversely, MPZL3 loss abrogates cell-cycle progression and proliferation, with cells adopting senescence features. This was associated with decreased sensitivity to cisplatin and reduced DNA damage and apoptosis in response to treatment in OVCAR4 cells. Our study suggests that decreased expression of the predicted adhesion molecule MPZL3 is associated with low proliferation but increased metastatic potential during ovarian cancer tumor progression.</p><p><strong>Significance: </strong>This work presents novel findings that decreased expression of the potential cell adhesion molecule MPZL3 is a phenotype of ovarian cancer progression and metastasis.</p>","PeriodicalId":72516,"journal":{"name":"Cancer research communications","volume":" ","pages":"1180-1193"},"PeriodicalIF":2.0,"publicationDate":"2025-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144593052","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}
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
{"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}
Philippe A Cassier, Mitesh J Borad, Sunil Sharma, Bertrand Dubois, Christophe Caux, Fumiyoshi Okano, Daniel D Von Hoff, Jean-Yves Blay
{"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}
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
{"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":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144610451","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}
Andrew E Evans, Sahida Afroz, Alexa Magstadt, Anup Kasi, Dan A Dixon
{"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}
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
{"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}
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
{"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}