Cancer research communications最新文献

{"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 (AML) ≥ 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":"https://doi.org/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 mutant AML, we evaluated the clinical activity of TP-0903 in combination with decitabine.</p><p><strong>Methods: </strong>This was a multicenter, open-label, Phase 1b/2 substudy of the 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 aged ≥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 1-21 with decitabine 20 mg/m2 on days 1-10 for up to three 28-day induction cycles, followed by up to 30 maintenance cycles in which the decitabine was reduced to days 1-5. 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/CRi/CRh) 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 months 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>","PeriodicalId":72516,"journal":{"name":"Cancer research communications","volume":" ","pages":""},"PeriodicalIF":2.0,"publicationDate":"2025-06-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144487357","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Phase 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":"https://doi.org/10.1158/2767-9764.CRC-25-0123","url":null,"abstract":"<p><strong>Purpose: </strong>TRK-950 is a first-in-class humanized antibody targeting CAPRIN-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 and preliminary antitumor activity.</p><p><strong>Patients and methods: </strong>Patients with treatment refractory, locally advanced or metastatic solid tumors were enrolled in dose escalation/expansion study. TRK-950 was administered intravenously weekly for three weeks in a 28 day cycle, with doses ranging from 3-30 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 MTD. The secondary objectives were pharmacokinetics, preliminary antitumor activity, and identification of potential biomarkers.</p><p><strong>Results: </strong>36 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 IgG1 therapeutic antibodies, with linear PK parameters over the 3-30 mg/kg dose range. The best response was stable disease. Notably, one cholangiocarcinoma patient showed signs of cavitation after approximately eight 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>","PeriodicalId":72516,"journal":{"name":"Cancer research communications","volume":" ","pages":""},"PeriodicalIF":2.0,"publicationDate":"2025-06-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144487358","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":"Uncovering novel lncRNAs linked to melanoma growth and migration with CRISPR-inhibition screening.","authors":"Stavroula Petroulia, Kathryn Hockemeyer, Shashank Tiwari, Pietro Berico, Sama Shamloo, Seyedeh Elnaz Banijamali, Eleazar Vega-Saenz de Miera, Yixiao Gong, Palaniraja Thandapani, Eric Wang, Jeffrey L Schloßhauer, Aristotelis Tsirigos, Iman Osman, Ioannis Aifantis, Jochen Imig","doi":"10.1158/2767-9764.CRC-24-0416","DOIUrl":"https://doi.org/10.1158/2767-9764.CRC-24-0416","url":null,"abstract":"<p><p>Melanoma being one of the most common and deadliest skin cancers, has been rising since the past decade. Patients at advanced stages of the disease have very poor prognoses, as opposed to at the earlier stages. Nowadays the standard-of-care of advanced melanoma is resection followed by immune checkpoint inhibition based immunotherapy. However, a substantial proportion of patients either do not respond or develop resistances. This underscores a need for novel approaches and therapeutic targets as well as a better understanding of the mechanisms of melanoma pathogenesis. Long non-coding RNAs (lncRNAs) comprise a poorly characterized class of functional players and promising targets in promoting malignancy. Certain lncRNAs have been identified to play integral roles in melanoma progression and drug resistances, however systematic screens to uncover novel functional lncRNAs are scarce. Here, we profile differentially expressed lncRNAs in patient derived short-term metastatic cultures and BRAF- MEK-inhibition resistant cells. We conduct a focused growth-related CRISPR-inhibition screen of overexpressed lncRNAs, validate and functionally characterize lncRNA hits with respect to cellular growth, invasive capacities and apoptosis in vitro as well as the transcriptomic impact of our lead candidate the novel lncRNA XLOC_030781. In sum, we extend the current knowledge of ncRNAs and their potential relevance on melanoma.</p>","PeriodicalId":72516,"journal":{"name":"Cancer research communications","volume":" ","pages":""},"PeriodicalIF":2.0,"publicationDate":"2025-06-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144478042","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":"Racial disparities in analgesic and psychiatric medication use during end-of-life care in advanced-stage colorectal cancer: A Retrospective Cohort Study.","authors":"John M Allen, Olga M Trejos Kweyete, Yi Guo, Jiang Bian, Xiwei Lou, Sherise C Rogers, Lisa Scarton, David L DeRemer, Diana J Wilkie","doi":"10.1158/2767-9764.CRC-25-0164","DOIUrl":"https://doi.org/10.1158/2767-9764.CRC-25-0164","url":null,"abstract":"<p><p>This study examined racial and ethnic disparities in the use of analgesic and psychiatric medications during end-of-life care among Medicare beneficiaries with advanced-stage colorectal cancer. Using the SEER-Medicare linked database from 2005 to 2017, we identified 28,212 patients with stage IV colorectal cancer who died within one year of diagnosis. Multivariable logistic regression models were used to assess differences in medication use by race and ethnicity. Compared to non-Hispanic White patients, Black patients had significantly lower odds of opioid use (adjusted odds ratio [aOR]: 0.86; 95% confidence interval [CI]: 0.80-0.93) and overall analgesic use, while Hispanic patients had higher use of opioids (aOR: 1.12; 95% CI: 1.03-1.22) and non-opioid analgesics (aOR: 1.22; 95% CI: 1.06-1.40). Asian patients had increased non-opioid use (aOR: 1.71; 95% CI: 1.44-2.03) and decreased skeletal muscle relaxant use (aOR: 0.59; 95% CI: 0.43-0.82). Across all minority groups, psychiatric medication use was consistently lower than in non-Hispanic White patients. These disparities persisted after adjusting for demographic, clinical, and socioeconomic factors. Findings highlight the urgent need for equitable, culturally responsive symptom management strategies to improve the quality of end-of-life care in this population.</p>","PeriodicalId":72516,"journal":{"name":"Cancer research communications","volume":" ","pages":""},"PeriodicalIF":2.0,"publicationDate":"2025-06-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144327895","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":"Defining non-small cell lung cancer tumor microenvironment changes at primary and acquired immune checkpoint inhibitor resistance using clinical and real-world data.","authors":"Lang Ho Lee, Xin Xu, Thanos Mourikis, Fanying Tang, Lauren Fairchild, Lexiang Ji, Angelo L Grauel, Joel P Wagner, Sebastian Szpakowski, Marc R Pelletier, Lisa Kattenhorn, Laurent Sansregret, Carlotta Costa, Claudia Bossen, Heather Burks, Anna F Farago, Jincheng Wu","doi":"10.1158/2767-9764.CRC-24-0605","DOIUrl":"https://doi.org/10.1158/2767-9764.CRC-24-0605","url":null,"abstract":"<p><p>Immune checkpoint inhibitors (ICIs) have demonstrated clinical efficacy in non-small cell lung cancer (NSCLC) and extensive research has been conducted to explore biomarkers predictive of ICI response. However, the impact of ICI on the tumor and tumor microenvironment (TME) at primary and acquired resistance states is understudied due to the difficulty of collecting tissue biopsies at disease progression. In this study, we leveraged clinical and real-world data to study ICI resistance. Data used in this work consist of treatment outcome information and tissue RNA-Seq data from advanced-stage NSCLC cohorts from three sources: Tempus RWE database (3 cohorts), one cohort from CANOPY-1 (NCT03631199), a phase 3 clinical trial in 1L NSCLC, and one cohort curated from the academic initiative Stand Up 2 Cancer (SU2C). Our results indicate higher interferon gamma (IFNγ) and T cell exhaustion in patients' tumors at acquired resistance and low levels of B cell and dendritic cells (DC) expression at primary resistance. The lower B cell and DC levels may be primarily driven by prior treatment with a platinum-based chemotherapy regimen. Baseline transcriptomics data additionally suggest that innate immune cells may play an anti-tumor role in PD-L1<1% patients, whereas IFNγ and T cell inflammation are more predictive of ICI treatment outcome in PD-L1<1% patients. Conclusions: Our study suggests a clear divergence of the TME in patients with primary vs. acquired resistance, and a potential role of myeloid cells in the PD-L1 negative population. These findings shed light on potential next-generation therapies to overcome ICI resistance.</p>","PeriodicalId":72516,"journal":{"name":"Cancer research communications","volume":" ","pages":""},"PeriodicalIF":2.0,"publicationDate":"2025-06-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144251105","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":"Genetic ancestry, Intrinsic Tumor Subtypes, and Breast Cancer Survival in Latin American Women.","authors":"Daniela Alves da Quinta, Darío Rocha, Cristian Yáñez, Renata Binato, Sheila Coelho Soares-Lima, Xiaosong Huang, Daiana Ganiewich, Valentina A Zavala, Monica Sans, Alejandra Lopez-Vazquez, Jael Quintero, Olivia Valenzuela, Antonio Quintero-Ramos, Alicia Del Toro-Arreola, Mauricio Cerda, Katherine Marcelain, Susanne Crocamo, Maria Aparecida Nagai, Dirce M Carraro, Marcia Maria Chiquitelli Marques, Jorge Gómez, Nora Artagaveytia, Adrian Daneri-Navarro, Bettina G Müller, Javier Retamales, Carlos Velazquez, Elmer A Fernández, Osvaldo L Podhajcer, Eliana Abdelhay, Ricardo A Verdugo, Andrea S Llera, Laura Fejerman","doi":"10.1158/2767-9764.CRC-25-0014","DOIUrl":"https://doi.org/10.1158/2767-9764.CRC-25-0014","url":null,"abstract":"<p><p>This study investigates the relationship between genetic ancestry, breast cancer subtypes, and survival outcomes among 951 locally advanced breast cancer cases from Argentina, Brazil, Chile, Mexico, and Uruguay, participating in the Molecular Profile of Breast Cancer Study (MPBCS). Array-based genotyping and ADMIXTURE analysis was used for genetic ancestry evaluation. Breast cancer subtypes were defined by immunohistochemistry and the gene expression-based PAM50 algorithm. The distribution of genetic ancestry, including European (EUR), Indigenous American (IA), African (AFR), and East Asian components, revealed a heterogeneous genetic admixture across countries, with the highest IA ancestry observed in Chile (30.9%) and Mexico (30.8%). Testing the relationship between genetic ancestry and breast cancer subtypes demonstrated that a 10% increase in EUR ancestry was significantly associated with a 14% decrease in the odds of developing HER2-enriched (HER2E) breast cancer, after adjustment by age, nodal status, and the AFR component (adj.p= 0.021, Luminal A as reference). Accordingly, a 10% increase in IA ancestry was associated to a 21% increase in the probability of having HER2E breast cancer (adj.p=0.022). IA ancestry also significantly increased overall survival after adjustment by age, nodal status, and AFR ancestry, although this result is controversial and may be impacted by the size and heterogeneity of the MPBCS cohort. Our research confirms previous findings of a high prevalence of HER2-dependent breast tumors among Hispanic/Latina women and strengthen the hypotheses of the existence of either population-specific genetic variant(s) or of other ancestry-correlated factors that impact HER2 expression in breast cancer consistently across different Latin American regions.</p>","PeriodicalId":72516,"journal":{"name":"Cancer research communications","volume":" ","pages":""},"PeriodicalIF":2.0,"publicationDate":"2025-06-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144236014","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":"Protein-level analysis of differential response to chemotherapy in triple negative breast cancer identifies CYP1B1 as a biomarker for chemotherapy resistance.","authors":"F Scott Heinemann, Paul D Gershon","doi":"10.1158/2767-9764.CRC-25-0034","DOIUrl":"https://doi.org/10.1158/2767-9764.CRC-25-0034","url":null,"abstract":"<p><p>Resistance to chemotherapy is a critical challenge in triple negative breast cancer (TNBC). In this study, the proteomes of pretreatment core biopsy samples from 16 TNBC patients with differential response to neoadjuvant chemotherapy (NAC) were analyzed by nanoLC-MS/MS to identify biomarkers of intrinsic chemotherapy resistance. This led to the identification of cytochrome P450, family 1, subfamily B, polypeptide 1 (CYP1B1) and 71 additional proteins as significantly more abundant in chemoresistant than chemosensitive TNBC. Immunohistochemical analysis of 80 TNBC confirmed an association between elevated tumor cell CYP1B1 and residual cancer burden class 2/3 disease after NAC in T cell-excluded (TCE) TNBC (P <0.01), but not in T cell-infiltrated TNBC. The frequency of complete pathologic response in TCE-TNBC with elevated CYP1B1 was 18% versus 56% in TCE-TNBC with low CYP1B1 and 75% in T cell-infiltrated TNBC. Retrospective review of the chemotherapy regimens suggested that TCE-TNBC with elevated CYP1B1 were particularly resistant to doxorubicin/cyclophosphamide. This study is the first to associate resistance to neoadjuvant chemotherapy in TNBC with elevated CYP1B1.</p>","PeriodicalId":72516,"journal":{"name":"Cancer research communications","volume":" ","pages":""},"PeriodicalIF":2.0,"publicationDate":"2025-06-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144251116","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":"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":"https://doi.org/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 (RNR), and the ATR-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 pre-replication complex (pre-RC), including the 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>","PeriodicalId":72516,"journal":{"name":"Cancer research communications","volume":" ","pages":""},"PeriodicalIF":2.0,"publicationDate":"2025-06-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144251115","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":"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":"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}