Cancer research最新文献

{"title":"A Cyanobacteria-derived RNA aptamer resensitizes prostate cancer to hormone therapy","authors":"Carlos D. Cruz-Hernández, Bethany Smith, Sandrine Billet, Manish Thiruvalluvan, Gabrielle Gonzales, David M. Underhill, Ekihiro Seki, Shelly C. Lu, Neil A. Bhowmick","doi":"10.1158/0008-5472.can-24-4039","DOIUrl":"https://doi.org/10.1158/0008-5472.can-24-4039","url":null,"abstract":"Prostate adenocarcinoma (PCa) resistance to androgen receptor (AR) signaling inhibitor therapy is associated with elevated glutamine (L-Gln). Glutamine sensors, present in conserved riboswitches (glnA), control nitrogen metabolism in many organisms, like cyanobacteria. Iterative in silico modifications of glnA found in Synechococcus elongatus and thermodynamic analysis of a 56mer aptamer resulted in high L-Gln specificity and affinity. The optimized aptamer depleted L-Gln from PCa cells by both L-Gln sequestration and extracellular glutaminase activation, serving as an allosteric activator. Glutamine depletion reduced FOXM1 transcriptional occupancy on the promoter of fibroblast growth factor 8 (FGF8), a known mediator of PCa castration resistance. A point mutation in the binding pocket of the 56mer rendered the aptamer ineffective in L-Gln binding and FGF8 regulation. Accordingly, the L-Gln-depleting aptamer, with demonstrated serum stability, limited the proliferation and promoted cell death of castration-resistant PCa alone and in combination therapy with AR antagonists, enzalutamide and apalutamide, in subcutaneous and orthotopic mouse models. Further selective tumor targeting was achieved by functionalizing gold nanoparticles with either the optimized L-Gln aptamer or the point-mutant aptamer. Castration sensitivity was restored by the L-Gln-depleting aptamer but not by the point-mutant. The functionalized nanoparticle demonstrated superior anti-tumor efficacy in an orthotopic PCa model over the untargeted aptamer. The anti-tumor activity of the aptamer helped support L-Gln as an oncometabolite in PCa that can be targeted to sensitize tumors to hormone therapy.","PeriodicalId":9441,"journal":{"name":"Cancer research","volume":"35 1","pages":""},"PeriodicalIF":11.2,"publicationDate":"2025-04-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143884652","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Combining Spatial Transcriptomics, Pseudotime, and Machine Learning Enables Discovery of Biomarkers for Prostate Cancer","authors":"Martin Smelik, Daniel Diaz-Roncero Gonzalez, Xiaojing An, Rakesh Heer, Lars Henningsohn, Xinxiu Li, Hui Wang, Yelin Zhao, Mikael Benson","doi":"10.1158/0008-5472.can-25-0269","DOIUrl":"https://doi.org/10.1158/0008-5472.can-25-0269","url":null,"abstract":"Early cancer diagnosis is crucial but challenging owing to the lack of reliable biomarkers that can be measured using routine clinical methods. The identification of biomarkers for early detection is complicated by each tumor involving changes in the interactions between thousands of genes. In addition to this staggering complexity, these interactions can vary among patients with the same diagnosis as well as within the same tumor. We hypothesized that reliable biomarkers that can be measured with routine methods could be identified by exploiting three facts: (1) the same tumor can have multiple grades of malignant transformation; (2) these grades and their molecular changes can be characterized using spatial transcriptomics; and (3) these changes can be integrated into models of malignant transformation using pseudotime. Pseudotime models were constructed based on spatial transcriptomic data from three independent prostate cancer studies to prioritize the genes that were most correlated with malignant transformation. The identified genes were associated with cancer grade, copy number aberrations, hallmark pathways, and drug targets, and they encoded candidate biomarkers for prostate cancer in mRNA, immunohistochemistry, and proteomics data from the sera, prostate tissue, and urine of more than 2,000 patients with prostate cancer and controls. Machine learning-based prediction models revealed that the biomarkers in urine had an AUC of 0.92 for prostate cancer and were associated with cancer grade. Overall, this study demonstrates the diagnostic potential of combining spatial transcriptomics, pseudotime, and machine learning for prostate cancer, which should be further tested in prospective studies.","PeriodicalId":9441,"journal":{"name":"Cancer research","volume":"44 1","pages":""},"PeriodicalIF":11.2,"publicationDate":"2025-04-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143884653","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Blocking Nitrosylation Induces Immunogenic Cell Death by Sensitizing NRAS-Mutant Melanoma to MEK Inhibitors","authors":"Jyoti Srivastava, Vipin K. Yadav, Rachel V. Jimenez, Pravin R. Phadatare, Ninad A. Inamdar, Montana M. Young, Antonella Bacchiocchi, Ruth Halaban, Bin Fang, Alvaro de Mingo. Pulido, Kenneth Y. Tsai, Keiran S.M. Smalley, John M. Koomen, Paulo C. Rodriguez, Sanjay Premi","doi":"10.1158/0008-5472.can-24-0693","DOIUrl":"https://doi.org/10.1158/0008-5472.can-24-0693","url":null,"abstract":"Activating NRAS mutations occur in 15-25% of all melanomas. However, this subtype remains refractory to existing therapeutics, including immunotherapy and RAS inhibitors; therefore, identifying innovative treatment strategies is of utmost importance. We investigated the role of nitrosylation, a nitric oxide-induced post-translational modification, in melanoma progression and therapeutic resistance. Inhibiting nitrosylation sensitized NRAS-mutant melanomas to targeted MEK inhibitors (MEKi), leading to sustained downregulation of the ERK-MAPK pathway, along with concomitant de-nitrosylation of NRAS, MEK, ERK, RSK1, and DUSPs. Global nitrosylome profiling using mass-spectrometry revealed nitrosylation of multiple ERK regulators. Gain- and loss-of-function studies confirmed a positive association between nitrosylation and ERK activation. ERK and MEK proteins harbored potential nitrosylation sites, mutation of which abrogated their phosphorylation and inhibited cell growth. The nitrosylome also contained death-associated molecular patterns (DAMPs), factors known to induce immunogenic cell death (ICD). Notably, nitrosylation inhibition combined with MEKi markedly inhibited Nras-mutant melanoma growth in an immunocompetent mouse model. This was accompanied by downregulated MEK-ERK signaling and extracellular release of DAMPs like calreticulin, phospho-eIF2α, and HMGB1, confirming ICD induction. Furthermore, the combination significantly increased the repertoire of CD8+ T cells, dendritic cells (DCs), and macrophages in the tumor microenvironment, which was validated in co-cultures of DCs and T-lymphocytes. In conclusion, the current study demonstrates that nitrosylation inhibition sensitizes NRAS-mutant melanomas to targeted MEKi-induced cell death and causes the release of non-nitrosylated (active) DAMPs that induce a potent anti-melanoma immune response via ICD. These findings highlight potential therapeutic vulnerabilities in the currently untreatable NRAS-mutant melanoma subtype.","PeriodicalId":9441,"journal":{"name":"Cancer research","volume":"45 1","pages":""},"PeriodicalIF":11.2,"publicationDate":"2025-04-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143880703","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Abstract CT092: A phase II basket trial of dual anti-CTLA-4 and anti-PD-1 blockade in rare tumors (DART) SWOG S1609: Vaginal cancers","authors":"Young K. Chae, Josie Czeskleba, Sandip P. Patel, Alex Menter, William Robinson, Nathaniel L. Jones, Murtuza Rampurwala, Aung Naing, Joseph M. Beck, Carolyn Moloney, Liam IL-Young Chung, Christine M. McLeod, Helen X. Chen, Elad Sharon, Sara Threlkel, Megan Othus, Christopher W. Ryan, Charles D. Blanke, Razelle Kurzrock","doi":"10.1158/1538-7445.am2025-ct092","DOIUrl":"https://doi.org/10.1158/1538-7445.am2025-ct092","url":null,"abstract":"Background: SWOG S1609 Dual Anti-CTLA-4 & Anti-PD-1 blockade in Rare Tumors (DART) administered ipilimumab and nivolumab to patients with primary vaginal cancers. Methods: DART is a prospective, open-label, multicenter, multi-cohort phase II clinical trial of ipilimumab (1 mg/kg intravenously) every six weeks plus nivolumab (240 mg intravenously) every two weeks. The trial was carried out by the Early Therapeutics and Rare Cancers Committee (NCI/SWOG) and opened at >1000 sites. Cohort 33 included patients with vagina cancers only. The primary endpoint was objective response rate [ORR, confirmed complete and partial responses (CR and PR, respectively)] (RECISTv1.1), progression-free survival (PFS), and overall survival (OS); clinical benefit rate [CBR: ORR plus stable disease (SD)>6 months] and toxicity were secondary endpoints. Results: Seven evaluable patients (median age, 60 years; performance status 0-1; no prior exposure to immunotherapy) were analyzed (adenocarcinoma, N=3; squamous cell carcinoma (SCC) (N=2); small cell carcinoma and undifferentiated histology (N=1 each). The ORR was 29%: one, CR (undifferentiated) (lasting 14.8 months); one, PR (SCC) (lasting 45.2 months). The CBR was 43% (3/7 patients) (included one adenocarcinoma with 8 months SD). The 6-month PFS rate was 43%; median OS, 11.7 months. Five patients (71.4%) experienced an adverse event (AE); four, a grade 3-4 AE including one patient (14.3%) with elevated liver function tests leading to drug discontinuation. The most common AEs (any grade, at least possibly related to treatment) were cough (42.9%), fever (42.9%) and diarrhea (42.9%). Conclusion: Ipilimumab plus nivolumab in vaginal cancers resulted in an ORR of 29% and CBR of 43% including one CR, one PR and one patient with 8 months of stable disease; the longest response lasted 45.2 months. Further prospective studies exploring the role of both monotherapy and dual immunotherapy in vaginal cancers are warranted. Citation Format: Young K. Chae, Josie Czeskleba, Sandip P. Patel, Alex Menter, William Robinson, Nathaniel L. Jones, Murtuza Rampurwala, Aung Naing, Joseph M. Beck, Carolyn Moloney, Liam IL-Young Chung, Christine M. McLeod, Helen X. Chen, Elad Sharon, Sara Threlkel, Megan Othus, Christopher W. Ryan, Charles D. Blanke, Razelle Kurzrock. A phase II basket trial of dual anti-CTLA-4 and anti-PD-1 blockade in rare tumors (DART) SWOG S1609: Vaginal cancers [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 2 (Late-Breaking, Clinical Trial, and Invited s); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_2): nr CT092.","PeriodicalId":9441,"journal":{"name":"Cancer research","volume":"3 1","pages":""},"PeriodicalIF":11.2,"publicationDate":"2025-04-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143876107","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Abstract LB055: A ketogenic diet sensitizes pancreatic cancer to inhibition of glutamine metabolism","authors":"Omid Hajihassani, Mehrdad Zarei, Asael Roichman, Alexander Loftus, Christina Boutros, Jonathan Hue, Parnian Naji, Jacob A. Boyer, Soubhi Tahhan, Peter Gallagher, William Beegan, James Choi, Shihong Lei, Christine Kim, Moeez Rathore, Faith Nakazzi, Ishan Shah, Kevin Lebo, Helen Cheng, Anusha Mudigonda, Sydney Alibeckoff, Karen Ji, Hallie Graor, Priyashree Sunita, Goutam Dey, Masaru Miyagi, Ali Vaziri-Gohar, Henri Brunengraber, Rui Wang, Peder Lund, Luke Rothermel, Joshua D. Rabinowitz, Jordan M. Winter","doi":"10.1158/1538-7445.am2025-lb055","DOIUrl":"https://doi.org/10.1158/1538-7445.am2025-lb055","url":null,"abstract":"Background: A ketogenic diet, with high fat (90% kCal) and low carbohydrate (5% kCal) intake, induces ketosis [2], altering cancer cell carbon utilization toward the tricarboxylic acid cycle (TCA) [3]. While the overall impact on cancer growth is unclear, most literature suggests an anti-cancer effect. Our hypothesis aims to uncover pancreatic cancer cell adaptations to the ketogenic diet, revealing metabolic vulnerabilities for informed therapeutic strategies. Methods: Mice on a ketogenic or normal diet (control) underwent pancreatic cancer xenograft observation. Tumor metabolites were analyzed with LC/GC-MS, oxidative stress with NAD(P)+/NAD(P)H, and Lipid Peroxidation assays. Western blot assessed enzyme expression. In vitro studies used Seahorse FX Analyzer for mitochondrial function and PicoGreen for cell growth quantification. Ivosidenib and CB839 were used for combination therapies. Result: A ketogenic diet induces a metabolic shift in pancreatic cancer, altering nutrient and metabolite levels in diverse in vivo models. Besides the expected increase in TCA metabolites, heightened amino acid anaplerosis, particularly with glutamine and glutamate, was observed. Examination of the diet's impact on oxidative phosphorylation enzymes revealed increased BDH1 expression, aiding ketone body utilization, and upregulation of cytosolic IDH1 for antioxidant defense. Enzymes involved in glutamine uptake and conversion, like ASCT2 and GLS, showed altered expression. Simultaneously, we explored tumor microenvironment vulnerabilities, detecting a significant increase in reactive oxygen species (ROS) levels, specifically lipid peroxidation, in mice on the ketogenic diet. Given these pancreatic cancer adaptations, we hypothesized that combining therapeutics to elevate ROS levels and target the glutamine pathway would substantially impede tumor growth. To test this, we combined a ketogenic diet with an IDH1 inhibitor for antioxidant defense hindrance and a glutaminase inhibitor to impair mitochondrial function, resulting in a marked reduction in tumor proliferation compared to individual treatments. Conclusion: A ketogenic diet demonstrates a robust anti-tumor effect in various pancreatic cancer mouse models, likely arising from the diminished glucose and increased fatty acid load inherent in the diet. Metabolic adaptation towards an oxidative phosphorylation (OXPHOS) phenotype makes pancreatic cancer especially susceptible to antioxidant and mitochondrial inhibitors, as well as inhibitors of glutamine-metabolizing enzymes. Citation Format: Omid Hajihassani, Mehrdad Zarei, Asael Roichman, Alexander Loftus, Christina Boutros, Jonathan Hue, Parnian Naji, Jacob A. Boyer, Soubhi Tahhan, Peter Gallagher, William Beegan, James Choi, Shihong Lei, Christine Kim, Moeez Rathore, Faith Nakazzi, Ishan Shah, Kevin Lebo, Helen Cheng, Anusha Mudigonda, Sydney Alibeckoff, Karen Ji, Hallie Graor, Priyashree Sunita, Goutam Dey, Masaru Miyagi, Ali Vaziri-Gohar, Henri Brunengrab","PeriodicalId":9441,"journal":{"name":"Cancer research","volume":"34 1","pages":""},"PeriodicalIF":11.2,"publicationDate":"2025-04-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143875713","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Abstract CT223: The building of a cancer vaccine trial platform: The NHS England Cancer Vaccine Launch Pad (CVLP)","authors":"Gareth Griffiths, Victoria Goss, Nicole Keyworth, Daniel Muller, Sam Wilding, Simon Crabb, Emily Shaw, Nicola Chapman-Hart, Max Shen, Patrick Ezeani, Gillian Rosenberg, Peter Johnson","doi":"10.1158/1538-7445.am2025-ct223","DOIUrl":"https://doi.org/10.1158/1538-7445.am2025-ct223","url":null,"abstract":"Background: The CVLP has been established to address the process for generating personalized vaccines at scale, by recruiting suitable patients and supporting accelerated tumor tissue processing. The CVLP is a collaborative project including NHS England, Genomics England, the Department of Health and Social Care, the Office for Life Sciences and the National Institute of Health and Care Research (NIHR) which is being delivered by the Cancer Research UK Southampton Clinical Trials Unit. The CVLP has been designed as a company and trial agnostic program so it can be flexible to the needs of multiple cancer vaccine trials in multiple cancer types. Methods: The CVLP aims to rapidly identify large numbers of cancer patients who could be eligible for trials to expedite evidence for the efficacy of vaccines across multiple types of cancer. To support the identification of participants their tissue samples are processed by a standardised, high quality, expanded pathway, incorporating elements of the NHS Genomic Medicine Service. The primary objective of the CVLP is to determine whether it is feasible to recruit cancer patients to a platform for personalised cancer vaccine trials, whether there is capacity for tumor samples to be analysed within a suitable time frame and if this results in acceptable participation in cancer vaccine clinical trials. Sponsored by NHS England the first trial incorporated within the CVLP is BioNTech BNT122-01 (NCT04486378) investigating the RO7198457 mRNA vaccine in patients with ctDNA-positive, resected Stage II/III colorectal cancer. Results: Between Sep 2023 and Dec 2024, 435 patients have consented to participate in the CVLP from 55 English sites, 96.4% of tissue samples were prepared in the required time frame for testing (average 2.5 days), of which 342 patients proceeded to referral to BNT122-01. We now estimate that approximately 60% of patients across England undergoing colorectal surgery have access to the trial through the CVLP resulting in the UK screening more than 3x the global average for BNT122-01 trial. The CVLP patient pathway from patient identification to entry into available clinical trials has been developed during the feasibility stage which now includes following the steps; i) patients identified by the clinical team managing their care and consented into CVLP; ii) blood and tissue samples (during surgery) collected; iii) samples sent to Cellular Pathology Genomic Centre and Genomic Laboratory Labs to carry out genomic sequencing; iv) sequencing data stored as part of NHS standard of care and the clinical liaison team pairs patients with available research trials. The CVLP has now progressed to onboarding further cancer vaccine trials in other cancer indications. Conclusions: CVLP has met its first feasibility endpoint of recruiting 300 patients and has progressed to onboarding further cancer vaccine trials. Citation Format: Gareth Griffiths, Victoria Goss, Nicole Keyworth, Daniel Muller, Sam Wilding, ","PeriodicalId":9441,"journal":{"name":"Cancer research","volume":"2 1","pages":""},"PeriodicalIF":11.2,"publicationDate":"2025-04-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143875789","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Abstract LB311: Dissecting and targeting EZH2’s non-canonical oncogenic activity in cancers","authors":"Arum Kim, G Greg Wang","doi":"10.1158/1538-7445.am2025-lb311","DOIUrl":"https://doi.org/10.1158/1538-7445.am2025-lb311","url":null,"abstract":"In many human cancer types, expression of Enhancer of Zeste Homolog 2 (EZH2) is well correlated with poorer outcomes. Furthermore, ∼20-25% of patients with diffuse large B-cell lymphoma (DLBCL) contain somatic mutation of EZH2 at the Tyr-646 residue within its catalytic SET domain, leading to EZH2 gain-of- function (GOF). Thus, EZH2 represents a prominent onco-target and small-molecule inhibitors targeting its enzymatic activity are under clinical evaluation, with some (i.e. tazemetostat) FDA-approved for the treatment of lymphoma and epithelial sarcoma. However, these EZH2 enzymatic inhibitors often face issues, such as ineffectiveness or resistance, and new treatment strategies targeting EZH2 are urgently needed. Traditionally, EZH2 is viewed as a catalytic subunit of Polycomb Repressive Complex 2 (PRC2), which induces trimethylation of histone H3 lysine 27 (H3K27me3) for repressing the target gene expression such as tumor-suppressive and immune-related genes. We recently have shown that EZH2’s oncogenic functions go well beyond PRC2 and its enzymatic function for H3K27me3 deposition and has the new PRC2-independent activity (non-canonical) to sustain oncogenesis. We show that the non-canonical function of EZH2 partly rely on transcriptional activation domains (tADs) of EZH2, which physically interacts with oncogene (co)activators, to turn on the oncogenic signaling. Our unpublished data point to increased Myc signaling as well as cancer metabolism enhancement such as lipid metabolism. We demonstrate such non-canonical oncogenic activity of EZH2 in blood cancers (including DLBCL) and solid tumors, which may explain why the current enzymatic inhibitors of EZH2 have rather limited antitumor effect. To develop a more effective therapeutic strategy in which both the canonical and noncanonical activities of EZH2 can be targeted, we employ the Proteolysis Targeting Chimera (PROTAC) technology and developed novel EZH2-targeted PROTAC degraders. EZH2-targeted PROTACs induced the EZH2 degradation and target the aberrant gene expression from both canonical and non-canonical activities of EZH2, leading to more effective, more consistent growth inhibition in tumors, and to a much greater degree when compared to EZH2 methyltransferase inhibitors. Collectively, this work uncovers an unexplored function of EZH2 in sustaining tumorigenesis via enhancing non-canonical oncogenic signaling. Indeed, our data support EZH2 PROTAC to be an attractive therapeutic candidate for cancer treatments. Citation Format: Arum Kim, G Greg Wang. Dissecting and targeting EZH2’s non-canonical oncogenic activity in cancers [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 2 (Late-Breaking, Clinical Trial, and Invited s); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_2): nr LB311.","PeriodicalId":9441,"journal":{"name":"Cancer research","volume":"7 1","pages":""},"PeriodicalIF":11.2,"publicationDate":"2025-04-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143872966","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Abstract LB370: Tumor-infiltrating lymphocytes-derived CD8 clonotypes infiltrate the tumor tissue and mediate tumor regression in glioblastoma","authors":"Lucas C M Arruda, Julia Karbach, Dragan Kiselicki, Hans-Michael Altmannsberger, Evgueni Sinelnikov, Dirk Gustavus, Hans Hoffmeister, Akin Atmaca, Elke Jäger","doi":"10.1158/1538-7445.am2025-lb370","DOIUrl":"https://doi.org/10.1158/1538-7445.am2025-lb370","url":null,"abstract":"Adoptive cell therapy using tumor-infiltrating lymphocytes (TILs) has shown remarkable efficacy in treating melanoma and other \"hot\" tumors characterized by high tumor mutation burden (TMB), a biomarker increasingly recognized for predicting immunotherapy success in solid tumors. However, gliomas show no clear correlation between TMB and immunotherapy efficacy due to the immunosuppressive tumor microenvironment, defective antigen presentation and the restrictive blood-brain barrier, hindering the effectiveness of immunotherapy. We report the successful treatment of a rapidly progressing high-TMB glioblastoma patient with TILs expanded using a defined cytokine cocktail comprising IL-2, IL-15, and IL-21. The therapeutic regimen included lymphodepletion with a single dose of cyclophosphamide prior to TIL intravenous infusion followed by a single dose of IL-2 post-infusion. Remarkably, complete tumor regression was achieved following two TIL infusions administered two weeks apart. Sequential cranial MRI showed complete tumor remission 22 days after the second infusion, with biopsies of the tumor showing complete necrotic tissue transformation. The TIL products were enriched for CD8 T-cells with high IFNg production and CD107a expression. They exhibited dose-dependent, specific cytolytic activity against autologous tumor cell lines but not against an autologous EBV-transformed B-cell line, the allogeneic glioblastoma cell lines U-373 and DBTRG05, or the unrelated Daudi B-cell lymphoma cell line. After TIL infusion, peripheral blood T-cells exhibited TCR downregulation, indicating activation, alongside with increased numbers of effector memory CD8 T-cells and CD4 Th1 and Th17 subtypes, while terminally differentiated CD8 T-cells decreased. A surge in serum IL-6 and sIL-2R levels was seen after each TIL infusion, confirming the strong systemic T-cell activation. Hematological analyses revealed persistent lymphopenia despite the use of reduced conditioning regimen. Surgical tumor samples collected before and after TIL infusions were analyzed by whole-exome sequencing (WES), RNA-seq and T-cell receptor (TCR) next-generation sequencing. WES revealed a high mutation burden (>10/Mb) across all samples, including mutations on EGFR, TP53 and BRCA1/2. Transcriptomic analysis of post-infusion tumor biopsies demonstrated enhanced expression of genes associated with immunological synapse formation and T-cell effector function, in line with the observed clinical response. TCR sequencing demonstrated that TIL-derived CD8 T-cells effectively infiltrated the tumor tissue and were strongly associated with tumor clearance. Hyperexpanded clonotypes within the tumor indicated robust TIL expansion in vivo, highlighting the significant contribution of TIL-derived CD8 T-cell proliferation to tumor control. CD4 T-cells, despite presenting greater TCR diversity than CD8 T-cells within the infused product, showed limited infiltration. This case highlights the potential o","PeriodicalId":9441,"journal":{"name":"Cancer research","volume":"72 1","pages":""},"PeriodicalIF":11.2,"publicationDate":"2025-04-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143875701","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Abstract SY14-03: Exploiting dysregulated ribosomal homeostasis in chromosome 9p21.3 deleted cancers and microsatellite unstable cancers","authors":"Patricia Borck, Isabella Boyle, Kristina Jankovic, Nolan Bick, Kyla Foster, Anthony Lau, Lucy Parker-Burns, Daniel Lubicki, Ashir Borah, Nicholas Lofaso, Sohani Das Sharma, Riya V. Kishen, Joshua Dempster, Francisca Vazquez, Edmond M. Chan","doi":"10.1158/1538-7445.am2025-sy14-03","DOIUrl":"https://doi.org/10.1158/1538-7445.am2025-sy14-03","url":null,"abstract":"Synthetic lethality, a phenomenon in which alterations in two or more genes together induce cell death while changes in either gene alone do not, provides a promising approach for cancer treatment. Indeed, various inhibitors targeting synthetic lethal interactions are approved by the Food and Drug Administration or in clinical trials. Seeking to nominate additional synthetic lethal targets, we analyzed large-scale CRISPR knockout screening data and identified Pelota mRNA surveillance and ribosome rescue factor (PELO) as a promising therapeutic target for two independent and frequently observed molecular subtypes of cancer: biallelic deletion of chromosomal region 9p21.3 (9p21.3-/-) and microsatellite instability-high (MSI-H). Homozygous deletion of chromosomal region 9p21.3 is one of the most frequently observed somatic copy number alterations in human cancers, occurring in approximately 15% of all cancers. Many 9p21.3-/- cancers are associated with poor clinical outcomes including subsets of glioblastoma, mesothelioma, urothelial, pancreatic, esophageal, and non-small cell lung cancers. The primary driver of 9p21.3-/- is thought to be loss of the tumor suppressor cyclin-dependent kinase inhibitor 2A. Additionally, studies have linked the loss of the interferon gene cluster on 9p21.3 to immune evasion and primary resistance to immune checkpoint inhibitors. Extensive deletions of chromosomal regions can provide opportunities for cancer treatment. For instance, PRMT5 and MAT2A were found to be promising targets in 9p21.3-/- cancers due to synthetic lethal interactions with deletions of the 9p21.3 gene methylthioadenosine phosphorylase. While clinical trials are underway examining PRMT5 and MAT2A inhibitors, the frequency and poor outcomes of many 9p21.3−/− cancers underscores the urgent need for additional therapies to treat this diverse group of cancers. Using large-scale functional genomic datasets, we identified PELO as the top preferential dependency in 9p21.3-/- cell lines. We also observed that some cell lines with intact 9p21.3 (9p21.3+) were dependent on PELO for survival. Examining other genomic features, we found that these cells were characterized as MSI-H, a hypermutable state observed in subsets of colon, endometrial, gastric, and ovarian cancers. Indeed, when we compared 9p21.3+/MSI-H and 9p21.3+/microsatellite stable (MSS) cell lines, we found that PELO scored as a strong preferential dependency in MSI-H cell lines, second only to the previously described synthetic lethal target Werner helicase (WRN). To validate these findings, we interrogated the viability effects of PELO knockdown across a panel of cell lines representing 9p21.3+/MSS, 9p21.3-/-/MSS, or 9p21.3+/MSI-H. CRISPR interference (CRISPRi)-mediated PELO knockdown with three distinct guide RNAs impaired the viability of 9p21.3-/-/MSS cell lines and 9p21.3+/MSI-H cell lines, but not 9p21.3+/MSS cell lines. We also sought to validate PELO dependency in tumor organoid models fo","PeriodicalId":9441,"journal":{"name":"Cancer research","volume":"15 1","pages":""},"PeriodicalIF":11.2,"publicationDate":"2025-04-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143875710","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Abstract CT052: A highly selective, brain-penetrant and overcoming G2032R resistance ROS1 inhibitor JYP0322 in NSCLC patients with ROS1 fusion","authors":"Hongyun Zhao, Yanqiu Zhao, Yuxiang Ma, Yan Zhang, Zhangzhou Huang, Ying Cheng, Zhengbo Song, Yongzhong Luo, Juan Li, Wei Wei, Yaling Qi, Binyan Xia, Yuexia Zeng, Jing Lv, Li Zhang","doi":"10.1158/1538-7445.am2025-ct052","DOIUrl":"https://doi.org/10.1158/1538-7445.am2025-ct052","url":null,"abstract":"Background: JYP0322 is a potent, brain-penetrant and highly selective ROS1 inhibitor, demonstrating over 100-fold selectivity for ROS1 compared to TRKA and sub-nanomolar potency against the ROS1 G2032R resistance mutation. JYP0322 is designed to simultaneously address the key clinical challenges including ROS1 resistance mutations, tumor brain metastases while avoiding the off-target neurotoxicity associated with TRK inhibition. Method: The Phase I study (NCT06128148) was designed to evaluate safety, pharmacokinetics (PK), and preliminary clinical efficacy in patients with locally advanced or metastatic ROS1+NSCLC, including both ROS1 TKI pre-treated patients as well as TKI naïve patients. Response was assessed by investigators according to RECIST V1.1. Results: As of December 10, 2024, dose escalation study was conducted across 7 dose levels: 50mg qd, 100mg qd, 200mg qd, 100mg bid, 150mg bid, 200mg bid, 150mg tid and dose expansion stage is ongoing at doses of 100mg bid, 150mg bid and 150mg tid. A total of 73 NSCLC patients were enrolled. No dose-limiting toxicities were observed. The most frequently reported treatment related adverse events (TRAE) were low grade including weight gains (32.9%), hyperglyceridemia (31.5%), hypercholesteremia (26%), and AST elevation (21.9%). Grade 3-5 TRAE occurred in 12.3% patients. Only low grade neurotoxicities (6.8%) occurred. Among 58 efficacy evaluable patients, objective response rates (ORRs) were 85.7% (12/14) for ROS1 TKI naive, 54.5% (12/22) for patients previously received ≥2L systemic therapy and ≥1 prior ROS1 TKIs including 19 patients pre-treated with 2 to 4 ROS1 TKIs (Table). In ROS1 G2032R mutant cancers, ORR was 71.4% (5/7) with 3 patients pre-treated with Lorlatinib. In patients with measurable brain metastasis at baseline, intracranial ORR was 33.3% (2/6) and intracranial DCR was 83.3%. JYP0322 showed significantly brain penetration ability with the brain to plasma ration 1.20. Enrollment in the dose expansion stage is ongoing. Conclusions: JYP0322 had a favorable safety profile with a low incidence of neurotoxicities. It showed highly promising anti-tumor effects in patients with ROS1+NSCLC including both TKI-naïve and TKI pre-treated patients, as well as those with TKI-heavily treated, brain metastases, or harboring ROS1 G2032R mutation. Citation Format: Hongyun Zhao, Yanqiu Zhao, Yuxiang Ma, Yan Zhang, Zhangzhou Huang, Ying Cheng, Zhengbo Song, Yongzhong Luo, Juan Li, Wei Wei, Yaling Qi, Binyan Xia, Yuexia Zeng, Jing Lv, Li Zhang. A highly selective, brain-penetrant and overcoming G2032R resistance ROS1 inhibitor JYP0322 in NSCLC patients with ROS1 fusion [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 2 (Late-Breaking, Clinical Trial, and Invited s); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_2): nr CT052.","PeriodicalId":9441,"journal":{"name":"Cancer research","volume":"29 1","pages":""},"PeriodicalIF":11.2,"publicationDate":"2025-04-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143875719","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}