tbuckley/cabot-search huggingface dataset:
Abstract 847: Small circular RNA for cancer immunotherapy
Authors: Xiang Liu
Journal: Cancer Research (2025)

Abstract Introduction: Messenger RNA (mRNA) has emerged as a novel vaccine platform and has proven highly effective during the pandemic. This platform had also found application in the development of cancer vaccines. Despite the encouraging outcomes observed in early-phase clinical trials, certain concerns are still associated with current mRNA-based cancer vaccines such as limited stability, suboptimal tumor therapy potency and durability, and limited safety. Here, we report novel highly stable antigen-encoding small circular mRNA (circRNA) vaccines that elicit potent and durable T cell responses for robust tumor immunotherapy. Method: Small circRNAs comprise minimal elements: codon-optimized peptide antigen-encoding RNA, a short IRES, and a Kozak consensus sequence that recruits ribosomes for peptide translation. Using MHC-I-restricted ovalbumin257-264 (OVA257-264 or SIINFEKL) as a model antigen, we prepared circRNA as follows: 1) circularizing 5’-phosphate-RNA using T4 RNA ligases and complementary 30-mer DNA splints, 2) removing linear/lariat RNA and DNA using DNase I and exonuclease T or RNase R, 3) purification to remove immunostimulatory small DNA/RNA fragments, enzymes, and nucleotides, and 4) verification by Sanger sequencing and gel electrophoresis. Results: Compared to modified mRNA and current long circRNA, small circRNA shows superior stability, minimal protein kinase R activation, and low cytotoxicity. This allows small circRNA vaccines to sustain efficient antigen translation over an extended period while activating pattern recognition receptors for innate immunostimulation. Relative to several modified mRNAs, nanocarrier-delivered small circRNA vaccines show superior safety and elicit up to 10-fold antigen-specific T cells, accounting for 25%-75% total peripheral CD8+ T cells over 6 months in mice. circRNA vaccines are applicable for various major histocompatibility complex I/II-restricted tumor and viral (neo)antigens to elicit CD8+ and CD4+ T cell responses, in young adult and immunosenescentaged mice. In mice, mono-/multi-valent circRNA vaccines plus immune checkpoint blockade reduced tumor immunosuppression and eradicated multiple tumors, including B16F10, MC38, TC1, and immunotherapy-resistant BrafV600E melanoma. Overall, small circRNA vaccines represent a promising advancement in the field of tumor immunotherapy, offering optimal stability, safety, and the potential to generate potent and enduring immune responses against a variety of tumors. Citation Format: Xiang Liu. Small circular RNA for cancer immunotherapy [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 847.
Abstract 601: Momordicine-I treatment reduces the triple negative breast cancer growth and alters the M2 phenotype of macrophages in tumor microenvironment
Authors: Ruchi A. Patel, Ellen T. Tran, Kousik Kesh, Ratna B. Ray
Journal: Cancer Research (2025)

Abstract Triple negative breast cancer (TNBC) is an aggressive form of breast cancer with a worse prognosis. The goal of this study is to examine whether Momordicine-I (M-I), a key bioactive compound from Momordica charantia, displays an anti-cancer activity and the potential mechanism. We treated human and mouse TNBC cell lines, MDA-MB-231 and 4T1, with M-I in a dose-dependent manner for 48 hr. We observed a significant inhibition of cell growth. To understand the potential mechanism, we treated these cells with vehicle or M-I and cell lysates were prepared after 48 hr. We found that M-I inhibited pSTAT3, cyclinD1 and c-Myc expression in M-I treated cells. We next evaluated the anti-tumor efficacy of M-I in orthotopic breast cancer mouse model. MDA-MB-231 cells were implanted into the mammary fat pad of nude mice. Tumor bearing (∼80 mm3 in volume) mice were divided into two groups. One group received M-I (30 mg/kg/day) and the other group received vehicle as a control. Tumor volumes were significantly reduced in the M-I treated group compared to the control group. Our previous study showed that M-I treatment alters macrophage phenotype in a different cancer model. We next examined the status of tumor associated macrophages (TAMs) in TNBC tumors. TAMs are mainly considered M2-like macrophages, which plays a crucial role in mediating the interaction between tumor cells and the immune cells. To examine the specific TAM polarization in vivo, RNA from control and treated tumors was analyzed for macrophage polarization using specific primers. Since nude mice contain macrophages, we examined the status of Arg1 and IRF-4 (M2 marker) from the tumor treated with vehicle or M-I. We found a significant reduction in treated tumors. We also performed an in vitro experiment where conditioned media of 4T1 cells with or without M-I treatment were incubated with immortalized bone marrow derived mouse macrophages (iMac) cells and examined the expression of several macrophage markers. We observed that M-I treatment significantly reduced M2 phenotype of iMac cells. Co-culture experiment with or without M-I treated MDA-MB-231 cells with PMA treated THP-1 displayed downregulation of Arg1 and IL-10 expression. Our data demonstrates that M-I has potential as a candidate for TNBC therapy and inhibits the M2 polarization of macrophages. Further work is underway using 4T1 mouse model to understand M-I mediated tumor growth inhibition. Citation Format: Ruchi A. Patel, Ellen T. Tran, Kousik Kesh, Ratna B. Ray. Momordicine-I treatment reduces the triple negative breast cancer growth and alters the M2 phenotype of macrophages in tumor microenvironment [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 601.
Abstract 2330: The Jekyll and Hyde of DARC: Balancing prognosis and metastasis in breast cancer
Authors: Joyeeta Talukdar, Trayambak Srivastava, Ruby Dhar, Subhradip Karmakar
Journal: Cancer Research (2025)

Abstract Background: DARC, a decoy receptor for chemokines, is implicated in breast cancer progression. Understanding its interplay with key molecular markers and its impact on tumor behaviour is crucial for developing targeted therapies. Methodology: This study employed a multi-faceted approach, including immunohistochemistry, quantitative PCR, and bioinformatical analysis of publicly available datasets (TCGA and METABRIC). The DARC, CCL8, c-MYC, ALDH1, and CHEK2 expression patterns were analyzed in breast cancer tissues. Correlation analyses and survival analyses were performed to assess the prognostic significance of these markers. Results: Our findings revealed a positive correlation between DARC and CCL8 expression, suggesting a potential role of DARC in promoting tumor cell migration and invasion through CCL8 signalling. Additionally, elevated DARC expression was associated with increased c-MYC, ALDH1, and CHEK2 levels, indicating its potential involvement in tumor cell proliferation, stemness, and chemoresistance. Bioinformatical analysis further corroborated these findings and identified DARC as a potential prognostic biomarker. Conclusion: These results highlight the complex interplay between DARC and key molecular markers in breast cancer. Targeting DARC may offer a novel therapeutic strategy to inhibit tumor progression and improve patient outcomes. Further validation studies are warranted to elucidate the precise mechanisms underlying DARC-mediated tumorigenesis. Citation Format: Joyeeta Talukdar, Trayambak Srivastava, Ruby Dhar, Subhradip Karmakar. The Jekyll and Hyde of DARC: Balancing prognosis and metastasis in breast cancer [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 2330.
Abstract 1479: Defining the interplay between DNAPKcs and shieldin during chromosomal break repair
Authors: Kaela Makins, Metztli Cisneros-Aguirre, Felicia Lopezcolorado, Jeremy M. Stark
Journal: Cancer Research (2025)

Abstract Chromosomal DNA double strand breaks (DSBs) are the effective lesion of cancer radiotherapy and other cancer therapeutics, such as topoisomerase 2 poisons. Understanding how cancer cells repair DSBs can provide insight into cancer cell resistance to these therapeutics, as well as inform development approaches to improve cancer sensitivity. DSB repair is also significant for cancer biology because aberrant repair of DSBs can cause mutations and chromosomal rearrangements that drive cancer. Repair of DSBs occurs through several pathways, including non-homologous end joining (NHEJ). DNA-PKcs (DNA-dependent protein kinase) promotes NHEJ, inhibits HDR, and is an emerging drug target with kinase inhibitors in oncology clinical trials. DNA-PKcs phosphorylates itself and other DNA damage response proteins and promotes long-range DSB end synapsis to facilitate NHEJ. Another protein complex implicated in long-range DSB end synapsis is Shieldin, which includes the proteins 53BP1, RIF1 (Rap1-interacting factor 1), and other factors. Shieldin is critical for NHEJ to promote class switch recombination, which is a programmed DSB repair event during antibody maturation. However, the role of Shieldin in NHEJ repair outside this context remains poorly understood. Indeed, a specific gap in knowledge is the functional interplay between how DNA-PKcs and Shieldin promote synapsis of DSB ends to favor NHEJ. To study end joining outcomes, I use Cas9 reporter assays to measure end joining frequencies via flow cytometry. These reporter assays are chromosomally integrated into human HEK293 cells. Additionally, I examine end joining junctions using deep sequencing to compare parental HEK293 cell junctions between wild-type and 53BP1-knockout or RIF1-knockout cell lines. This PCR-based approach allows me to categorize junction types into four categories: No Indels, Insertions, Deletions, and Complex Indels. My studies indicate that RIF1 and 53BP1 are genetic modifiers of DNA-PKcs function during DSB repair. I will present our current efforts to address this gap in knowledge. Citation Format: Kaela Makins, Metztli Cisneros-Aguirre, Felicia Lopezcolorado, Jeremy M. Stark. Defining the interplay between DNAPKcs and shieldin during chromosomal break repair [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 1479.
Abstract 1407: Alterations of <i>EIF1AX</i> and carboplatin treatment induce non-canonical translation initiation in ovarian cancer
Authors: Jermaine Austin, Subin Myoong, Natalia Badnarek, Sridevi Challa
Journal: Cancer Research (2025)

Abstract Ovarian cancer (OvCa) is the deadliest gynecologic malignancy with high mortality due to chemoresistance. High grade serous ovarian cancer (HGSOC) is the most common subtype of ovarian cancer. The standard of care for women with HGSOC is cytoreductive surgery and chemotherapy using carboplatin, which causes DNA damage and oxidative stress. Despite aggressive treatment strategies, most patients with high grade HGSOC relapse. We recently demonstrated that post-translational modification of ribosomal proteins affects mRNA translation and protein homeostasis in ovarian cancer cells by regulating polysome formation and stress granule assembly. In this study we aim to understand the role of errors in translation initiation in chemoresistance in ovarian cancers. Eukaryotic Initiation Factor 1A X-linked (EIF1AX) is an essential eukaryotic initiation factor (eIF) that is responsible for both scanning and recognizing the canonical start codon on mRNA transcripts: Adenosine-Uracil-Guanine (AUG). Genetic alterations in EIF1AX are frequently observed in several cancers including low grade ovarian serous carcinoma (LGSOC) and high grade ovarian serous carcinoma (HGSOC). Using luciferase reporter assays, we have observed that EIF1AX ablation and carboplatin treatment in epithelial ovarian cancer cells increases translational initiation from the non-canonical start codon Uracil-Uracil-Guanine (UUG). We have also observed that EIF1AX knockdown specifically decreases the growth of carboplatin-resistant ovarian cancer cells, whereas depletion of EIF1AX enhances the growth of carboplatin-sensitive ovarian cancer cells. Moreover, EIF1AX knockdown sensitizes ovarian cancer cells to carboplatin treatment. Collectively, our results suggest that EIF1AX ablation and carboplatin treatment result in increased non-canonical translation and play a role in chemoresponses in ovarian cancers. Citation Format: Jermaine Austin, Subin Myoong, Natalia Badnarek, Sridevi Challa. Alterations of EIF1AX and carboplatin treatment induce non-canonical translation initiation in ovarian cancer [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 1407.
Abstract 927: Tumor-initiating stem cells utilize the immunomodulatory ligand CD80 to promote Treg expansion and cancer relapse
Authors: Jennifer L. Good, Weijie Guo, Jingyun Luan, Benjamin T. Nicholson, Yuxuan Miao
Journal: Cancer Research (2025)

Abstract Although immunotherapy has been a key innovation in cancer treatment, tumor relapse still poses a major challenge for many patients. Recent research has shown that cancer relapse can be caused by a special group of cancer cells enriched with stemness signatures that survive treatments and repopulate tumors. These cells are referred to as tumor-initiating stem cells (tSCs). The mechanisms by which tSCs survive immunotherapy to drive cancer relapse are still unclear. Using a spontaneous squamous cell carcinoma (SCC) mouse model, we found that tSCs have elevated expression of CD80, a surface molecule that provides co-stimulation to T cells. Notably, the loss of CD80 expression on SCC cells led to diminished tumor growth by blunting the expansion of intratumoral regulatory T cells (Tregs). This interaction between epithelial stem cell and Treg cells can also be found during wound repair where CD80 expression by hair follicle stem cells promotes expansion of Tregs in the wound bed. Interestingly, we found that CD80 on epithelial stem cells facilitates Treg expansion by an unconventional mechanism in which the Foxp3 can be directly induced in preactivated tumor infiltrating CD4+ T cells. Collectively, this study reveals a unique mechanism by which tSCs may sculpt an immunosuppressive niche to evade killing and facilitate tumor relapse. Citation Format: Jennifer L. Good, Weijie Guo, Jingyun Luan, Benjamin T. Nicholson, Yuxuan Miao. Tumor-initiating stem cells utilize the immunomodulatory ligand CD80 to promote Treg expansion and cancer relapse [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 927.
Abstract 1247: Characterizing the evolution of osimertinib resistance in EGFR mutated non-small cell lung cancer
Authors: Mina N. Dinh, Jinling Wu, Masahiro Hitomi, Maximilian Strobl, Jacob G. Scott
Journal: Cancer Research (2025)

Abstract Osimertinib is a 3rd generation EGFR inhibitor and the newest FDA approved adjuvant therapy for non-small cell lung cancer (NSCLC) with EGFR exon 19 deletions or exon 21 L858R mutation. Although the drug can yield impressive initial responses, the majority of patients eventually progress due to the evolution of resistance. While the molecular mechanisms underlying resistance have been well studied, little is known about the ecological and evolutionary laws that govern the creation and subsequent expansion of these mutant populations. How frequently are different evolutionary routes taken and to what degree is evolution repeatable? To study the repeatability of osimertinib resistance evolution, we conducted a large-scale evolution experiment aimed at characterizing the distribution of resistant states that emerge, along with the pathways and vulnerabilities associated with their development. In our experimental design, we evolve PC-9, an EGFR-mutated NSCLC cell line to osimertinib independently 10 times (evolutionary replicates) for 10 cycles (serial passages). We also evolved 6 control replicates that undergo no treatment. At the end of the experiment, we will employ a multi-faceted approach to studying the resistance phenotype: 1) IC50 against osimertinib; 2) bulk RNA-seq; 3) DNA/mutational profiling; 4) a collateral sensitivity screening against 20 FDA approved drugs; and 5) a radiation sensitivity assay against 6 doses. The initial pretreatment dose response curve (DRC) against osimertinib showed a double plateau, suggesting the pre-existence of tolerant or even resistant subpopulation. In our control arms, we see consistent persistence of our double plateau throughout all 10 cycles, indicating this population is maintained in the absence of treatment but cannot expand. Conversely, across all 8 treated replicates we see a large shift in IC50 within the 1st treatment cycle, consistent with rapid selection and outgrowth of this population. More detailed analysis using time-lapse microscopy shows while these cells have a higher IC50, they also have a reduced growth rate, even if treatment is completely removed again (a “resistance cost”). This suggests potential evolutionary vulnerabilities which could be leveraged through strategic treatment breaks or drug sequences. Citation Format: Mina N. Dinh, Jinling Wu, Masahiro Hitomi, Maximilian Strobl, Jacob G. Scott. Characterizing the evolution of osimertinib resistance in EGFR mutated non-small cell lung cancer [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 1247.
Abstract 1438: HMGA2 and protein leucine methylation drive pancreatic cancer lineage plasticity
Authors: Sita Kugel, Stephanie Dobersch, Naomi Yamamoto, Aidan Schutter, Sarah M. Cavender, Tess M. Robertson, Gun Ho Jang, Annie N. Samraj, Ben Doron, Lisa A. Poole, Martine Roudier, Cindy L. Wladyka, Isabel English, Guillermo Barreto, Rosalie Sears, Srivatsan Raghavan, Faiyaz Notta, Robert N. Eisenman, Andrew C. Hsieh
Journal: Cancer Research (2025)

Abstract Pancreatic ductal adenocarcinoma (PDAC) is classified into two distinct subtypes, classical and basal. Basal PDACs (∼25% of PDACs) have the worst overall survival and are the only class to act as an independent poor prognostic factor. Therefore, there is an urgent need to understand basal PDAC development, identify biomarkers and find its unique vulnerabilities. We found high expression of the chromatin architectural protein, HMGA2 in the basal subtype of pancreatic cancer. This was across patient-derived cell lines, organoids and in RNA-seq and scRNA-seq patient datasets representing hundreds of patients. We also validated by multiplex immunohistochemistry (mIHC) in &amp;gt;500 diverse patient tissue microarray. We introduce a novel genetically engineered mouse model (GEMM) of basal pancreatic cancer. We find that in this model and in human orthotopic xenografts, HMGA2 is required for cancer growth and sufficient to drive a basal subtype. While HMGA2 is a chromatin factor, we have unexpectedly discovered that it plays an essential role in mRNA translation. Our data demonstrate that HMGA2 controls protein synthesis dynamics through reduced methylation of the protein phosphatase PP2A and subsequent activation of S6 Kinase, a key node of translation regulation. HMGA2 accomplishes this through inhibiting the expression of leucine carboxyl methyltransferase 1 (LCMT1). Importantly, loss of LCMT1 in the classical subtype is sufficient to increase mRNA translation and cause the acquisition of basal features. Thus, we describe a new mechanism by which lineage plasticity is regulated in pancreatic cancer. Most importantly, we demonstrate that high levels of HMGA2 in the basal subtype, and high levels of mRNA translation, render basal pancreatic cancer uniquely susceptible to inhibitors of protein synthesis. As such, we describe a new biomarker and subtype-specific treatment for basal pancreatic cancer. Citation Format: Sita Kugel, Stephanie Dobersch, Naomi Yamamoto, Aidan Schutter, Sarah M. Cavender, Tess M. Robertson, Gun Ho Jang, Annie N. Samraj, Ben Doron, Lisa A. Poole, Martine Roudier, Cindy L. Wladyka, Isabel English, Guillermo Barreto, Rosalie Sears, Srivatsan Raghavan, Faiyaz Notta, Robert N. Eisenman, Andrew C. Hsieh. HMGA2 and protein leucine methylation drive pancreatic cancer lineage plasticity [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 1438.
Abstract 3543: Combinatorial mRNA-LNP vaccines for triple-negative breast cancer
Authors: Sara L. Woessner, Xiaolei Cai, Caroline Kellogg, Jun Huang
Journal: Cancer Research (2025)

Abstract Breast cancer is the most commonly-diagnosed tumor in women, and there remains a need for effective treatment options for metastatic disease. mRNA-lipid nanoparticle (LNP) vaccines targeting tumor neoantigens are a potential avenue for treating triple-negative and basal-like breast cancers. Using established whole-exome and RNA-sequencing data, we identified a combination of neoantigens that induce CD4 and CD8 T cell responses. Administration of mRNA-LNPs encoding 4 neoantigens significantly delayed growth of 4T1 murine syngeneic tumors. When the vaccine is combined with IV injection of engineered IL7 and IL12, the median overall survival is increased by 14 days. Taken together, these improvements to current breast cancer vaccination approaches may represent a way to induce tumor regression and clearance in treatment-refractory disease. Citation Format: Sara L. Woessner, Xiaolei Cai, Caroline Kellogg, Jun Huang. Combinatorial mRNA-LNP vaccines for triple-negative breast cancer [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 3543.