Cancer research最新文献

{"title":"Abstract LB239: Overcoming resistance to camptothecin-based topoisomerase I inhibitors through a novel core scaffold design strategy","authors":"Xiaodan Fu, Yaozong Li, Qilin Wang, Hui Liu, Dongmei Hu, Qun Dang","doi":"10.1158/1538-7445.am2025-lb239","DOIUrl":"https://doi.org/10.1158/1538-7445.am2025-lb239","url":null,"abstract":"Camptothecin (CPT) derivatives as DNA topoisomerase I (TOPO-1) are widely used to treat various cancers. However, their clinical efficacy was significantly undermined by both inherent resistance and the rapid development of emerging resistance. Although resistance mechanisms are complicated, some key factors are identified such as TOPO-1 mutations and drug efflux. Unfortunately, all clinical stage CPT-derived TOPO-1 inhibitors shared the original CPT core structure, thus little chance to address resistance via structural diversity. In this study, we aimed to discover a novel class of non-CPT core TOPO-1 inhibitors that specifically address the key enzyme mutations thus overcoming resistance to current TOPO-1 drugs in the clinic. Using a Computer-Assisted Drug Design (CADD) approach, a non-CPT core scaffold was designed to specifically improve binding to the clinically relevant R364H mutant. Molecules from the novel scaffold performed very well in our computational model showing significantly improved hydrogen bonding and polar interactions with both wild type and R364H mutated TOPO-1. Cellular assay proved that molecules with predicted enhancements led to a 30-fold improvement in inhibitory potency compared to topotecan in the R364H-mutant cell line. Furthermore, the novel compounds exhibited markedly reduced efflux in the BCRP-overexpressing cell lines, maintaining higher intracellular concentrations and thereby enhancing their anticancer activities. More importantly, compared to irinotecan these molecules demonstrated 50 to 1000-fold higher potency in patient-derived, irinotecan-resistant tumor organoid models, thus successfully addressed tumor resistance to current TOPO-1 inhibitors. In vivo antitumor activity was also validated in various PD animal models. A PCC molecule was identified and moved into IND-enabling development, which shows significant promise as next-generation therapies for cancers overcoming resistant to traditional TOPO-1 inhibitors. Recent breakthrough discoveries of ADCs attracted more attention to TOPO-1 inhibitors, however most if not all payloads targeting TOPO-1 still utilized the original CPT core (e.g. DXD, SN-38). Therefore, it is anticipated that ADC treatment will lead to new resistance, and our novel molecules with a non-CPT core could address future resistance via structure diversity. Citation Format: Xiaodan Fu, Yaozong Li, Qilin Wang, Hui Liu, Dongmei Hu, Qun Dang. Overcoming resistance to camptothecin-based topoisomerase I inhibitors through a novel core scaffold design strategy [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 LB239.","PeriodicalId":9441,"journal":{"name":"Cancer research","volume":"78 1","pages":""},"PeriodicalIF":11.2,"publicationDate":"2025-04-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143876023","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 LB082: Disrupting lipid metabolism in GBM: A systems biology approach to targeting treatment-resistant persister cells and tumor associated myeloid cell-mediated support","authors":"Avirup Chakraborty, Changlin Yang, Diana Feier, Aryeh Silver, Nyla T. Searl, Miruna Anica, Avinash Pittu, Illena West, Olusegun O. Sobanjo, Ethan D. Hodge, Mia K. Engelbart, Srabasti Sengupta, Nagheme Thomas, Christina Von Roemeling, Maryam Rahman, Matthew Sarkisian, Jianping Huang, Jeffrey Harrison, Duane A. Mitchell, Loic P. Deleyrolle","doi":"10.1158/1538-7445.am2025-lb082","DOIUrl":"https://doi.org/10.1158/1538-7445.am2025-lb082","url":null,"abstract":"Introduction: Glioblastoma (GBM) tumors contain distinct cell lineages, including treatment-sensitive cells (TSCs) relying on aerobic glycolysis and treatment-resistant persister cells (TRPCs) dependent on lipid metabolism. Our systems biology-based, spatial multi-omics and multi-targeted approach decodes a critical node in GBM progression, lipid acquisition in TRPCs, and validates this through a retrospective analysis of statin-treated patients, offering clinical insights into the potential benefits of targeting lipid metabolism in high TRPC signature GBM patients. Methods: We performed spatial transcriptomics and proteomics, combined with 3D rendering of the tumor microenvironment (TME) and geospatially resolved single-cell neighborhood analysis of IHC-stained GBM tissues using our custom-developed SNAQ algorithm to investigate the immune microenvironment and lipid distribution specific to TSCs and TRPCs. To characterize lipid dynamics, we employed flow cytometry, time-lapse imaging, and holotomography to track lipid transfer from Tumor-Associated Myeloid Cells (TAMCs) to TRPCs. A critical node for GBM progression was identified through in vivo survival and tumor progression studies that assessed effects of genetic targeting of CCR2 and pharmacological targeting of CSF1R and FABP3. Retrospective analysis was conducted on 4,085 GBM patients to evaluate the effect of statin treatment on GBM outcomes based on their TRPC signature. Results: Our study establishes the skewed accumulation of TAMCs within the TRPC microenvironment through upregulation of the CCL2/7-CCR2 and CSF1-CSF1R pathways. TAMCs actively transfer lipids to TRPCs to fulfill their metabolic demands. Targeting elements responsible for lipid incorporation in TRPCs, such as CCR2, CSF1R, and FABP3 in vivo, resulted in tumor immune microenvironment remodeling, significant tumor growth reduction, and improved survival. This reinforces the critical role of metabolic communications via lipid trafficking in TRPCs as an essential node in GBM progression. Our retrospective study showed that GBM patients with elevated TRPC signatures, typically associated with shorter survival, had no significant survival differences when treated with lipid-lowering statins. This suggests statins may disrupt lipid metabolism in TRPCs, reducing TAMC lipid support and improving patient outcomes. Conclusion: Our study highlights lipid trafficking in TRPCs as a key mechanism in GBM progression, suggesting that targeting TAMC recruitment and lipid acquisition in TRPCs may offer a promising therapy. Additionally, our retrospective analysis highlights the potential of transcriptomic profiling for patient stratification based on TRPC signature expression levels, enabling the identification of patients to benefit from lipid metabolism-targeted therapies. Citation Format: Avirup Chakraborty, Changlin Yang, Diana Feier, Aryeh Silver, Nyla T. Searl, Miruna Anica, Avinash Pittu, Illena West, Olusegun O. Sobanjo, Ethan D. Ho","PeriodicalId":9441,"journal":{"name":"Cancer research","volume":"8 1","pages":""},"PeriodicalIF":11.2,"publicationDate":"2025-04-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143876024","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 6012: PSMA x CD3 T-cell engagers show preclinical efficacy for the treatment of prostate cancer","authors":"Peter Bergqvist, Alaa Amash, Kelly Bullock, Lauren Clifford, Patrick Farber, Jessica Fernandes Scortecci, Ingrid Knarston, Tallie Kuang, Ahn Lee, Amy Lee, Cindy-Lee Crichlow, Franco Li, Matt Mai, Stephanie K. Masterman, Janice Reimer, Eduardo Solano Salgado, Raffi Tonikian, Christopher Williamson, Allison Goodman, Lindsay DeVorkin","doi":"10.1158/1538-7445.am2025-6012","DOIUrl":"https://doi.org/10.1158/1538-7445.am2025-6012","url":null,"abstract":"Prostate-specific membrane antigen (PSMA) is a clinically validated target in metastatic castration-resistant prostate cancer (mCRPC) that is being prosecuted by a number of different modalities in the clinic. CD3 T-cell engagers (TCEs) targeting PSMA have shown promise in preclinical and early clinical studies, but generating a molecule with a therapeutic window that enables efficacious dosing in patients has been a barrier to development. Here, we present preclinical in vitro and in vivo data on novel PSMA x CD3 TCEs developed using our TCE platform. To address the challenges of TCE development for mCRPC, we screened and identified hundreds of diverse PSMA- and CD3-binding antibodies with different affinities, epitopes, and biophysical properties using our proprietary antibody screening platform. From there, we engineered large panels of OrthomabTM PSMA x CD3 bispecifics, varying TCE parameters that impact function. Detailed in vitro functional assessment and biophysical characterization assays were conducted to identify antibodies with promising functional and developability profiles. IgG-like bispecifics comprised of PSMA- and CD3-binding arms with finely tuned affinity for each target were generated. PSMA binding epitopes were assessed using cryo-electron microscopy, and TCE function was measured using in vitro T cell co-culture assays. TCEs binding membrane-proximal epitopes drove optimal immune synapse formation, leading to potent killing of cells expressing high (C4-2) and low (22Rv1) levels of PSMA with EC50 values in the picomolar range. Molecules show target-dependent T-cell activation with no killing of a low PSMA-expressing cell line (DU-145) in vitro. Further, select molecules show robust CD4+/CD8+ T-cell activation and proliferation in the presence of target cells, as well as sustained killing of target cells over time in a repeat challenge assay. Finally, molecules evaluated in vivo in a humanized C4-2 xenograft mouse model demonstrated anti-tumor activity and a favorable IgG-like pharmacokinetic profile. In summary, we engineered and assessed hundreds of PSMA x CD3 TCEs at high-throughput, conducted detailed in vitro functional and biophysical characterization, and identified molecules with promising preclinical in vivo efficacy that supports further evaluation and development towards the clinic. Citation Format: Peter Bergqvist, Alaa Amash, Kelly Bullock, Lauren Clifford, Patrick Farber, Jessica Fernandes Scortecci, Ingrid Knarston, Tallie Kuang, Ahn Lee, Amy Lee, Cindy-Lee Crichlow, Franco Li, Matt Mai, Stephanie K. Masterman, Janice Reimer, Eduardo Solano Salgado, Raffi Tonikian, Christopher Williamson, Allison Goodman, Lindsay DeVorkin. PSMA x CD3 T-cell engagers show preclinical efficacy for the treatment of prostate cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular s); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1): nr","PeriodicalId":9441,"journal":{"name":"Cancer research","volume":"1 1","pages":""},"PeriodicalIF":11.2,"publicationDate":"2025-04-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143857491","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 5016: Enhancing prostate pelvic multimodality data generating with conditional generative models: A Pix2Pix-based approach for MRI-to-PET synthesis","authors":"Ruobing Liu, Shuo Wang, Shibiao Wan, Jieqiong Wang","doi":"10.1158/1538-7445.am2025-5016","DOIUrl":"https://doi.org/10.1158/1538-7445.am2025-5016","url":null,"abstract":"Prostate cancer remains the second leading cause of cancer-related mortality among men globally, underscoring the critical need for early detection of treatment failure and effective assessment of metastatic risk. Positron Emission Tomography (PET), particularly with prostate-specific membrane antigen (PSMA) tracers, has demonstrated superior sensitivity for identifying prostate lesions, including metastases. However, the accessibility of PET imaging is often limited by its high costs and associated radiation exposure. To overcome these challenges, we developed a deep learning model to synthesize PET images from Magnetic Resonance Imaging (MRI) image, facilitating treatment response evaluation.High-resolution T2-weighted MRI and PSMA PET images acquired within a close timeframe were retrieved from 10 prostate cancer patients, who underwent definitive radiotherapy. The PSMA-PET scans were registered to the MRI images within the Eclipse (Varian Medical Systems), and the PET images were cropped to match the same size and resolution of MRI images, resulting in 321 pairs of MRI-PET 2D images. Preprocessing included grayscale transformation, z-score normalization, and pixel value inversion to enhance model learning. A Pix2Pix framework was implemented, employing a U-Net generator and a PatchGAN discriminator. The loss function used consisted of a combination of adversarial loss, to ensure the realism of the generated images, and L1 loss, to maintain pixel-wise consistency between the generated and target images. Model evaluation was performed using leave-one-out-cross-validation (LOOCV), where all slices from one patient was used for testing and the remaining 9 patients for training.The model achieved an average Peak Signal-to-Noise Ratio (PSNR) of 14.55 and a Structural Similarity Index Measure (SSIM) of 0.648. Although these quantitative metrics were moderate, qualitative evaluation demonstrated precise and clinically meaningful localization of lesions, offering utility for aiding physician visualization of high-risk regions.This study highlighted the feasibility of leveraging Pix2Pix-based conditional generative models for synthesizing PET-equivalent images from MRI data as a cost-effective alternative to enhance prostate cancer imaging. Future efforts will focus on expanding the dataset and investigating advanced architectures, including 3D-to-3D generative models and diffusion techniques, to further improve the accuracy of prostate lesion localization and clinical applicability. Citation Format: Ruobing Liu, Shuo Wang, Shibiao Wan, Jieqiong Wang. Enhancing prostate pelvic multimodality data generating with conditional generative models: A Pix2Pix-based approach for MRI-to-PET synthesis [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular s); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1): nr 5016.","PeriodicalId":9441,"journal":{"name":"Cancer research","volume":"64 1","pages":""},"PeriodicalIF":11.2,"publicationDate":"2025-04-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143857539","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 4294: SMCHD1 is a synthetic lethal strategy for cancers with a cancer-testis antigen gene expression signature","authors":"Victor Quereda, Youyou Zhang, Diana Klimaszewska, Stefano Tonin, Theodore Groth, Yanhua Rao, Michael T. McCabe, Benjamin Schwartz, Markus Queisser, Rachel Buxton, Thomas J. Berrodin, Simon Peace","doi":"10.1158/1538-7445.am2025-4294","DOIUrl":"https://doi.org/10.1158/1538-7445.am2025-4294","url":null,"abstract":"SMCHD1 is a component of the structural maintenance of chromosomes (SMC) protein family involved in epigenetic gene silencing of the X chromosome and other autosomal chromosome regions. SMCHD1 encodes an ATPase domain and binds chromatin at both N- and C-term domains to facilitate long-range chromatin interactions. However, the exact mechanism by which it elicits transcriptional silencing remains unknown. We have identified a selective dependency on SMCHD1 in cell lines exhibiting a gene expression signature characterized by high expression of multiple cancer testis antigen (CTA) genes. This CTA signature is observed in multiple cancers with >60% prevalence in Chronic Myeloid Leukemia. Importantly, SMCHD1’s effect on cell growth was independent of its ATPase activity, and a knock-in degron tag phenocopied SMCHD1 KO indicating that the proliferative advantage offered by SMCHD1 might be due to structural SMCHD1 function unrelated with its enzymatic ATPase role. Finally, SMCHD1 depletion led to the upregulation of multiple genes, including a cluster of CTA genes, in sensitive cell lines with the CTA-positive signature, while CTA-negative cell lines remained unaffected. These data confirm that SMCHD1 is a potential therapeutic target for patients with elevated CTA expression, and provides insight to what therapeutic modality would be most effective. Citation Format: Victor Quereda, Youyou Zhang, Diana Klimaszewska, Stefano Tonin, Theodore Groth, Yanhua Rao, Michael T. McCabe, Benjamin Schwartz, Markus Queisser, Rachel Buxton, Thomas J. Berrodin, Simon Peace. SMCHD1 is a synthetic lethal strategy for cancers with a cancer-testis antigen gene expression signature [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular s); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1): nr 4294.","PeriodicalId":9441,"journal":{"name":"Cancer research","volume":"126 1","pages":""},"PeriodicalIF":11.2,"publicationDate":"2025-04-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143857590","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 4836: Re-expression of MHCII in colorectal organoids: Investigating the novel role of EHMT1 in regulating MHCII expression","authors":"Nahla A. Elzefzafy, Louise Tee, Maria Pinna, Neeraj Lal, Gary M. M Middleton, Andrew Beggs","doi":"10.1158/1538-7445.am2025-4836","DOIUrl":"https://doi.org/10.1158/1538-7445.am2025-4836","url":null,"abstract":"Background: Major histocompatibility complex class II is expressed by mature professional antigen-presenting cells, forming a critical part of the innate immune response. However, other cell types, including tumour (tsMHCII), can be induced to express MHCII in response to inflammatory signalling by IFN-g, leading to increased tumour killing. TsMHCII-II expression has been associated with a higher number of tumour-infiltrating CD4 and CD8, with improved progression-free survival (PFS) and overall survival (OS). These observations suggested that increased tsMHCII expression is associated with increased tumour recognition by T cells and enhanced antitumor immunity. However, treatment with IFN-g is not a practical solution due to patient side effects and the finding that a high percentage of tumours have no upregulation of MHCII in response to IFNg stimulation. We have recently shown that EHMT1 is a potential target to upregulate MHCII in a genome wide CRISPR/Cas9 screen. In this study, we aim to 1) investigate a potential non-canonical relationship between EHMT1 and MHC-II expression in a microsatellite stable (MSS) colorectal organoid model 2) Evaluate the ability of organoids that constitutively express MHC-II to prime naïve T cells; and 3) explore pharmacological EHMT1 inhibitors as treatments to enhance MHC-II expression in tumour cells Methods: CRISPR/Cas9 was used to knock down the EHMT1 gene in colorectal organoids, confirmed with Sanger sequencing and Western blot analysis. To investigate the mechanistic differences between these clones and the WT, we carried out a differential gene expression analysis using RNAseq and ChIP-sequencing, focusing on the impact of EHMT1 knockout on whole genomic methylation signatures. Furthermore, we investigated the efficacy of targeting EHMT1 pharmacologically, utilising a selection of EHMT1 inhibitors. Finally, we co-cultured EHMT1-/- clones with allogenic T cells in a mixed lymphocyte reaction (MLR) assay. T cell stimulation was evaluated by assessing CD25, CD69, CD107a, and CD137 Results: In contrast to the wild-type (WT) organoid that showed no response to IFNg stimulation, four EHMT1-/- knockout clones demonstrated upregulated levels of MHCII expression, independent of IFNg. The level of MHCII expression by the clones was correlated with the level of methylated H3K9. Additionally, EHMT inhibitors showed variable efficacy in enhancing MHCII expression in wild-type organoids. Analysis is ongoing to investigate the capability of these clones with constitutively expressed MHCII to process and present tumor antigens to stimulate naïve CD4+ T cells Conclusion: This study reveals a potentially novel role for EHMT1 in modulating the tumour immune response by controlling the expression of MHC-II in colorectal organoids. Future work will focus on assessing the efficacy of combining immune checkpoint inhibitors with EHMT1 inhibitors Citation Format: Nahla A. Elzefzafy, Louise Tee, Maria Pinna, Neeraj Lal, Gary M. ","PeriodicalId":9441,"journal":{"name":"Cancer research","volume":"1 1","pages":""},"PeriodicalIF":11.2,"publicationDate":"2025-04-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143857592","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 2763: Molecular QTL analyses identify functional variants at inherited risk loci in chronic lymphocytic leukemia","authors":"Huihuang Yan, Zhiquan Wang, Mingma Hoel, Cristine Allmer, Chantal McCabe, Daniel O’Brien, Dennis Robinson, James Cerhan, Sameer Parikh, Esteban Braggio, Susan Slager","doi":"10.1158/1538-7445.am2025-2763","DOIUrl":"https://doi.org/10.1158/1538-7445.am2025-2763","url":null,"abstract":"Most disease-associated single-nucleotide polymorphisms (SNPs) identified by genome-wide association studies (GWASs) reside in noncoding regions. There is increasing evidence that they play regulatory roles through epigenetic mechanisms by altering local chromatin state, 3D chromatin structure, and looping interactions. We and others have identified 42 CLL risk loci from GWASs. At 12 risk loci located outside of gene promoters, we previously demonstrated that functional SNPs are highly enriched in enhancers and super-enhancers that mostly target BCL2 family genes and transcriptional regulators. However, the study was limited by using only public epigenomic data generated in lymphoblastoid cell lines (LCL) and normal immune related cell types. To gain a better understanding of how the functional SNPs alter local chromatin state and modulate target gene expression in CLL, we generated RNA-seq data (n=588) and transposase-accessible chromatin with sequencing (ATAC-seq) data (n=69) in CLL tumor B cells. We performed molecular quantitative trait loci (QTL) analysis with index and correlated SNPs (R2 0.5) at 41 risk loci (excluding the HLA locus). The analyses identified cis expression QTLs (eQTLs), within 1Mb of genes’ transcription start site, at 25 risk loci and chromatin accessibility QTLs (caQTLs, within peak) at 11 risk loci, with both eQTLs and caQTLs at 8 risk loci. We identified a total of 54 eGenes, for which the expression is affected by nearby SNPs within 1Mb, including 40 novel eGenes at 16 CLL risk loci not previously reported. Notably, based on publicly available chromosome interaction data from CLL, LCL, and normal B cells, for over 70% of the novel eGenes, their promoters showed looping interactions with the regions carrying the eQTLs. Further, 13 SNPs were identified as both caQTL and eQTL, with the associated novel eGenes including CD81 at 11p15.5, IPCEF1 at 6q25.2, as well as CXXC1 and MBD1 at 18q21.1. The result suggests that these SNPs play a role in altering chromatin accessibility contributed to gene expression variation. At 11p15.5 risk locus, SNP rs2651823 (A/G) represents a novel caQTL and eQTL. The alternative G allele is associated with increased chromatin accessibility and CD81 expression. Hi-C data from GM12878 and CD20+ B cells supported interaction between the open chromatin region carrying rs2651823 and CD81 promoter. CD81 facilitates the trafficking of CD19 to the surface of activated B cells, and CD81-null mice showed impaired immune response. In a mouse model, CD81 contributes to tumor progression and metastasis in Lewis lung carcinoma. In summary, our molecular QTL analysis revealed that functional SNPs, located in CLL risk loci, modulate chromatin accessibility and expression of downstream target genes that could impact CLL risk. Citation Format: Huihuang Yan, Zhiquan Wang, Mingma Hoel, Cristine Allmer, Chantal McCabe, Daniel O’Brien, Dennis Robinson, James Cerhan, Sameer Parikh, Esteban Braggio, Susan Slager. Mol","PeriodicalId":9441,"journal":{"name":"Cancer research","volume":"67 1","pages":""},"PeriodicalIF":11.2,"publicationDate":"2025-04-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143862855","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 5862: Combining circular RNA and a silicon membrane-based cell engineering approach to create CAR-Ts with membrane bound IL-2 and IL-12","authors":"Zhihui Song, Andrew Larocque, Sophia Hirsch, Eleni Rogers, Darby Kreienberg, Jacquelyn Hanson, Alec Barclay, Armon Sharei","doi":"10.1158/1538-7445.am2025-5862","DOIUrl":"https://doi.org/10.1158/1538-7445.am2025-5862","url":null,"abstract":"Engineered immune cell therapies have great potential to revolutionize the treatment of many pathologies such as cancer, autoimmunity and infectious diseases. However, limitations remain in some areas including long manufacturing times, inability to engineer critical cell functions, potential for cell exhaustion, and limited access to the disease site as in the case for solid tumors. Portal has developed a novel implementation of mechanoporation technology using a silicon membrane with pores which enables deformation of the cell and poration of the cell membrane, allowing for diffusion of any cargo, charged or uncharged, into the cell. Mechanoporation is a gentle intracellular delivery technique that preserves cell viability and function (DiTommaso, et al., PNAS 2018). It can shorten manufacturing time and enable the introduction of key therapy-enhancing factors via transient modifications shortly before administration. Portal has established methodology for cytoplasmic introduction of many diverse cargo including mRNA, circular RNA, siRNA, proteins, peptides, and CRISPR RNPs to primary immune cells, including both unstimulated and activated T cells, B cells, NK cells, monocytes and iPSCs. In this work, we demonstrated simultaneous expression of a functional CD19 CAR, membrane bound IL-2 and membrane bound IL-12 through delivery of three circRNAs into activated T cells. They are highly expressed for multiple days while maintaining high viability and ensuring robust in vitro killing. The expression of mbIL2 and mbIL12 not only promotes T cell proliferation but also upregulates CD62L and enhances the cytotoxic function of CAR T cells. At clinical scale, we have demonstrated delivery of RNA to over 1 billion T cells while achieving over 90% expression. Portal’s technology and approach has the potential to further advance immune cell therapy developments, particularly in multiplexed engineering approaches involving simultaneous delivery of multiple cargos. Coupled with Portal’s compatibility with diverse immune cell types and next generation cargos. We believe this simple approach to intracellular delivery can dramatically reduce manufacturing time and cost, easily integrate into existing clinical equipment and enable unique enhancements that underpin a new generation of therapeutics. Citation Format: Zhihui Song, Andrew Larocque, Sophia Hirsch, Eleni Rogers, Darby Kreienberg, Jacquelyn Hanson, Alec Barclay, Armon Sharei. Combining circular RNA and a silicon membrane-based cell engineering approach to create CAR-Ts with membrane bound IL-2 and IL-12 [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular s); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1): nr 5862.","PeriodicalId":9441,"journal":{"name":"Cancer research","volume":"22 1","pages":""},"PeriodicalIF":11.2,"publicationDate":"2025-04-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143857359","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 5158: Establishing novel patient-derived xenograft models for peritoneal metastasis in a racially diverse population","authors":"Vashti Bandy, Adam Khader, Praveen Bhoopathi, Vignesh Vudatha, Arunima Punjala, Jose Trevino, Bhaumik Patel, Leopoldo Fernandez, Savannah Gregg","doi":"10.1158/1538-7445.am2025-5158","DOIUrl":"https://doi.org/10.1158/1538-7445.am2025-5158","url":null,"abstract":"Colorectal cancer (CRC) is highly treatable when localized, but survival drops sharply with metastasis, especially to the peritoneum (PM). CRC PM is particularly resistant to chemotherapy, emphasizing the need for models that replicate disease biology for use in drug discovery. Our study establishes reproducible CRC PM patient-derived xenografts (PDX) from a racially diverse patient population. Patients with CRC PM were recruited for a tissue collection study at a single academic tertiary care center. Tumor samples were collected under sterile conditions and prepared for subcutaneous propagation into NOD.Cg-Prkdcscid/J (NSG) mice. Next, tumor was harvested and reimplanted intraperitoneally into new NSG models. Peritoneal metastasis was induced via 1) Intraperitoneal injection of a single cell suspension or 2) Intraperitoneal tumor implantation via laparotomy. Post-necropsy, peritoneal carcinomatous index (PCI) was calculated and pictures were taken using a cross-polarization technique to allow for PCI scoring by an independent investigator. Collected tumor was processed for histological analysis. We developed four successful intraperitoneal PDX models using CRC PM derived from a 62-year-old non-Hispanic Black female with KRAS G12V mutation and a 60-year-old non-Hispanic White female with KRAS wildtype. Both tumors had microsatellite stability (MSS). All four PDX were representative of the human clinical condition as diffuse peritoneal metastases were found in each. The laparotomy group exhibited a higher tumor burden and PCI compared to the tumor injection group. In histological comparison of PDX to patient tissue, we observed that tumor gland formation and architecture were maintained. Early findings show that CRC PM PDX models can be successfully established from a racially diverse patient population. Intraperitoneal tumor implantation into NSG mice via laparotomy resulted in a higher PCI compared to tumor injection, though the latter may be more reproducible. Cross-polarization imaging optimized tumor visualization and allowed PCI scoring by an independent investigator. These models mimic gross and histologic characteristics of the original patient tumor. Future directions include extensive multi-omic profiling to further characterize each PDX. We aim to expand our PDX library to better represent CRC PM heterogeneity with a focus towards drug development. Citation Format: Vashti Bandy, Adam Khader, Praveen Bhoopathi, Vignesh Vudatha, Arunima Punjala, Jose Trevino, Bhaumik Patel, Leopoldo Fernandez, Savannah Gregg. Establishing novel patient-derived xenograft models for peritoneal metastasis in a racially diverse population [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular s); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1): nr 5158.","PeriodicalId":9441,"journal":{"name":"Cancer research","volume":"64 1","pages":""},"PeriodicalIF":11.2,"publicationDate":"2025-04-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143857543","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 643: Efficacy and safety comparison of CAR-T and blinatumomab immunotherapy as bridge-to-transplant strategy in relapsed/refractory B cell acute lymphoblastic leukemia","authors":"Wenyue Cao, Ningwen Li, Na Wang, Yang Cao","doi":"10.1158/1538-7445.am2025-643","DOIUrl":"https://doi.org/10.1158/1538-7445.am2025-643","url":null,"abstract":"Background: B cell acute lymphoblastic leukemia (B-ALL) remains a therapeutic challenge despite advances. Hematopoietic stem cell transplantation (HSCT) provides a potential cure but is hindered by various limitations. Emerging immunotherapies, including chimeric antigen receptor T cell (CAR-T) therapy and Blinatumomab, have shown potential as bridging strategies to HSCT in relapsed/refractory (R/R) cases. Methods: A retrospective study was conducted at Tongji Hospital from March 2017 to March 2023, involving 36 R/R B-ALL patients who underwent HSCT. Prior to transplantation, 27 patients received CD19/CD22 CAR-T therapy, while 9 received Blinatumomab. Outcomes assessed included the overall survival (OS), progression-free survival (PFS), graft-versus-host disease-free and relapse-free survival (GRFS), and non-relapse mortality (NRM), with comparisons made between treatment groups. Hematopoietic reconstitution and transplant-related complications were also evaluated. Results: The median follow-up time was 28.07 (range: 2.29-92.21) months. The 2-year OS, PFS, GRFS, and NRM of the entire cohort were 76.54%, 54.97%, 40.12%, and 9.93%, respectively. In the CAR-T and the Blinatumomab treatment group before transplantation, the 2-year OS was 73.89% and 88.89% (P=0.862), PFS, was 59.03% and 44.44% (P=0.501), GRFS was 47.86% and 13.89% (P=0.083), and NRM was 8.52% and 11.11% (P=0.713), respectively. Safety profiles were similar with no significant differences observed in hematopoietic reconstitution, infection, the incidence of grade II-IV acute graft-versus-host disease (GVHD) and chronic GVHD incidence between CAR-T and Blinatumomab groups. Conclusion: CAR-T and Blinatumomab therapies demonstrate comparable safety and efficacy as bridging treatments to HSCT in patients with R/R B-ALL. Further studies are needed to optimize these treatment strategies. Citation Format: Wenyue Cao, Ningwen Li, Na Wang, Yang Cao. Efficacy and safety comparison of CAR-T and blinatumomab immunotherapy as bridge-to-transplant strategy in relapsed/refractory B cell acute lymphoblastic leukemia [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 643.","PeriodicalId":9441,"journal":{"name":"Cancer research","volume":"5 1","pages":""},"PeriodicalIF":11.2,"publicationDate":"2025-04-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143862928","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}