tbuckley/cabot-search huggingface dataset:
Abstract 6699: Development of a fully modified miR-34a (FM-miR-34a) cancer therapeutic: a translational research study
Authors: Shreyas Ganesan Iyer, Digambar Waiker, Ana C. Betustak, Sharjeel Anjum, Andrea L. Kasinski
Journal: Cancer Research (2025)

Abstract MicroRNAs (miRNAs) regulate gene expression by binding to sites within the 3′ untranslated region (UTR) of target mRNAs and exert negative control through mRNA cleavage or translational repression. In cancer, downregulation of tumor-suppressive miRNAs is common, prompting exploration of miRNA restoration strategies for inhibiting tumor growth and suppressing key oncogenic pathways. MicroRNA-34a (miR-34a), known for its tumor-suppressive properties, has advanced to clinical trials as an anti-cancer agent. However, clinical implementation faces challenges such as precise tumor-targeted delivery, susceptibility to degradation in circulation, rapid renal clearance and hindered cytosolic entry due to endosomal entrapment. We tackled a few obstacles by generating a first-in-class fully modified miR-34a (FM-miR-34a) supported by a ligand-mediated vehicle-free delivery platform which exhibited enhanced stability and sustained target gene repression in vitro and in vivo. Prior to the generation of FM-miR-34a, the molecule would have degraded in circulation quickly. However, with FM-miR-34a showing increased stability in serum, we can now aim to increase the circulation half-life of the molecule, which would allow more miR-34a to be biologically available. To achieve this, we incorporated an albumin-binding moiety within the delivery ligand, allowing the molecule to bind to human serum albumin, the most abundant protein in blood. This in turn increases the overall molecular weight of the cancer therapeutic, pushing it over the renal clearance limit and thus increasing its circulation half-life. We also observe a potent combinatorial anti-tumor response when FM-miR-34a is combined with paclitaxel, a standard chemotherapy for breast cancer. Paclitaxel induces mitotic arrest at G2/M and apoptosis at G0 and G1/S phases, making it an ideal partner for synergistic effects with miR-34a. This approach will potentially allow for reduced dosing of paclitaxel and contribute to better therapeutic efficacy, thus improving quality of life of triple negative breast cancer patients. The research, thus, aims to contribute to the development of a robust therapeutic agent utilizing the miR-34a restoration strategy, addressing delivery challenges, and exploring synergies with existing treatments for enhanced efficacy against cancer. Citation Format: Shreyas Ganesan Iyer, Digambar Waiker, Ana C. Betustak, Sharjeel Anjum, Andrea L. Kasinski. Development of a fully modified miR-34a (FM-miR-34a) cancer therapeutic: a translational research study [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 6699.
Abstract 4625: The optimal tumor mutational burden cutoff value for predicting the efficacy of the PD-1 checkpoint inhibitor combined with chemotherapy in advanced gastric cancer
Authors: Jaeyeon Jang, Youngkyung Jeon, Sun Young Jeong, Sung Hee Lim, Jeeyun Lee, Seung Tae Kim
Journal: Cancer Research (2025)

Abstract Purpose: Chemotherapy is associated with an increase in tumor mutational burden (TMB). When receiving the combination of programmed cell death-1 (PD-1) checkpoint inhibitor and chemotherapy, TMB can be a better option for predicting the response, especially for tumors with initially low TMB. We aimed to investigate the optimal TMB cutoff value that could predict the efficacy of PD-1 checkpoint inhibitors combined with chemotherapy in advanced gastric cancer. Materials and Methods: Patients with AGC who received nivolumab with capecitabine and oxaliplatin as the 1st line palliative treatment, between September 1, 2021, and July 15, 2023, at Samsung Medical Center in Korea were retrospectively analyzed. The TMB levels were measured using a next-generation sequencing assay. Based on receiver operating characteristic curve analysis, the TMB cutoff value was determined. Results: A total of 101 patients were analyzed. The TMB cutoff value for predicting the overall response rate (ORR) to nivolumab combined with capecitabine and oxaliplatin was defined as 10.2 mutations per megabase (mt/Mb) with 97.7% sensitivity and 22.4% specificity. Based on this definition, 14 (13.9%) patients were TMB-high (TMB-H). The ORR differed between the TMB-low (TMB-L) and TMB-H groups (51.7% vs. 92.9%, P=0.004). The progression-free survival (PFS) and overall survival (OS) for 101 patients were 11.8 (95% confidence interval [CI], 8.46-15.14) and 27.9 months (95% CI, 20.34-35.45), respectively. The median PFS tended to be longer in the TMB-H group (22.0 months; 95% CI, 11.86-32.14) than in the TMB-L group (11.1 months; 95% CI, 8.56-13.64; P=0.217). The median follow-up duration of the TMB-H group was 23.7 months, and the median OS was not reached. The median OS of the TMB-L group was 27.9 months (95% CI 20.50-35.23; P=0.241). Conclusions: The TMB cutoff value for predicting treatment response in AGC patients who received the PD-1 checkpoint inhibitor combined with capecitabine and oxaliplatin as the 1st line palliative treatment was 10.2 mt/Mb. When applying the programmed death ligand-1 status to TMB, patients who would benefit from PD-1 checkpoint inhibitors can be selected. Citation Format: Jaeyeon Jang, Youngkyung Jeon, Sun Young Jeong, Sung Hee Lim, Jeeyun Lee, Seung Tae Kim. The optimal tumor mutational burden cutoff value for predicting the efficacy of the PD-1 checkpoint inhibitor combined with chemotherapy in advanced gastric 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 4625.
Abstract 6707: Direct <i>in vivo</i> CRISPR screen identifies <i>BAP1</i> and <i>FAT1</i> as potent tumor suppressors in sarcomagenesis
Authors: Jianguo Huang, Xingliang Liu, Warren Floyd, William Haugh, Andrea R. Daniel, Zhaoyu Sun, Nerissa T. Williams, Melissa J. Kasiewicz, Yaping Wu, Diana M. Cardona, Brian Piening, John T. Welle, Wesley K. Rosales, Venkatesh Rajamanickam, So Young Kim, Eric Xu, Lixia Luo, Yan Ma, Kristianne M. Oristian, Omar Lopez, Nicholas E. Sibinga, Rutulkumar Patel, Ziqiang Zhang, Alexander J. Lazar, Corinne M. Linardic, Brady Bernard, William L. Redmond, Walter J. Urba, David G. Kirsch
Journal: Cancer Research (2025)

Abstract Undifferentiated pleomorphic sarcoma (UPS) is among the most common soft tissue sarcomas (STS) in adults. For decades, little therapeutic progress has been made for STSs, including UPSs. Targeted therapies for tumors driven by specific genetic mutations have proven to be more effective than standard chemotherapies. However, the molecular pathogenesis of UPSs remains unknown, hindering the development of targeted therapies for UPSs. Approximately 65% of UPSs harbor TP53 mutations, but somatic mutation of Trp53 alone is insufficient to induce sarcomas in vivo. The addition of Rb1 mutation alongside a Trp53 mutation induces sarcomas in vivo, though with low frequency of tumor onset and slow growth. The role of other genes in facilitating Trp53-driven sarcomas is largely unknown. Through a customized in vivo CRISPR/Cas9 screen of 35 genes commonly mutated in UPSs, followed by individual gene validation in vivo, we discovered that Bap1 knockout cooperates with Trp53 knockout to induce sarcomas in vivo. Furthermore, we demonstrated that Fat1 deletion increased the onset frequency and growth of Trp53 and Rb1-driven sarcomas in a genetically engineered mouse model. Through multiplex immunohistochemistry and flow cytometry, we found that mouse sarcomas induced by Trp53 and Rb1 mutations are significantly enriched with immune cells compared to other mouse sarcomas we generated in vivo. Finally, we show that PARP inhibition may be a potential targeted therapy for RB1-loss STSs and BRD4 inhibition may be a potential targeted therapy for FAT1-loss STSs. Citation Format: Jianguo Huang, Xingliang Liu, Warren Floyd, William Haugh, Andrea R. Daniel, Zhaoyu Sun, Nerissa T. Williams, Melissa J. Kasiewicz, Yaping Wu, Diana M. Cardona, Brian Piening, John T. Welle, Wesley K. Rosales, Venkatesh Rajamanickam, So Young Kim, Eric Xu, Lixia Luo, Yan Ma, Kristianne M. Oristian, Omar Lopez, Nicholas E. Sibinga, Rutulkumar Patel, Ziqiang Zhang, Alexander J. Lazar, Corinne M. Linardic, Brady Bernard, William L. Redmond, Walter J. Urba, David G. Kirsch. Direct in vivo CRISPR screen identifies BAP1 and FAT1 as potent tumor suppressors in sarcomagenesis [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 6707.
Abstract 6283: Performance evaluation of tumor microenvironment deconvolution and gene prediction methods in lung cancer
Authors: Fanying Tang, Dean Lee, Lexiang Ji, Jincheng Wu
Journal: Cancer Research (2025)

Abstract The tumor microenvironment (TME) is complex and plays a key role in cancer development, progression and metastasis. Two layers of information are critical for understanding tumor compositions (1) the proportion of each cell type (2) the level of gene expression in each cell type. Many single-cell profile-assisted algorithms have been developed to infer cell type proportions from bulk RNA-seq data, including CIBERSORTx, MuSic and Scaden, and there are several benchmark studies published to compare the methods. However, most of the deconvolution methods do not support prediction of gene expression in a heterogenous population of tumor cells, and there’s no published study systemically comparing the gene expression prediction performance of the methods. To overcome the limitations, we simulate large-scale of pseudobulk data using scRNA-seq profiling from lung tumors, representing various levels of tumor purities and cell lineages, to compare the cell fraction and gene expression prediction performance of recently published TME deconvolution methods. Our results indicate BayesPrism is the best at predicting gene expression in each of the cell types, and differential gene expression between two groups across cell types, especially in tumor epithelial cells, with higher balanced accuracy and correlation with ground truth. The inclusion of normal epithelial cells in the reference could increase additional risks for tumor deconvolution. Altogether we evaluate both cell type proportion and gene expression prediction performance of recently published methods and offer a guideline for future benchmarking work. Currently we're working on the downstream application of inferring cellular composition and gene expression in large cohorts of bulk RNA-seq data, allowing for more insights into tumor-intrinsic expression and tumor-microenvironment interactions. Citation Format: Fanying Tang, Dean Lee, Lexiang Ji, Jincheng Wu. Performance evaluation of tumor microenvironment deconvolution and gene prediction methods in 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 6283.
Abstract 6546: Iron accumulation correlates with tumor progression in mouse models of prostate cancer
Authors: Jennifer Rooks, Caleb Taylor, Asmaa El-Kenawi
Journal: Cancer Research (2025)

Abstract Tumor-associated macrophages (TAMs) are well-known as anti-inflammatory immune cells that contribute to various facets of prostate cancer development. An emerging aspect of TAMs is their “iron-rich” phenotype. This accumulation of iron can contribute to cancer cell initiation and tumor progression. In the current study, we aim to explore the key role of TAMs in regulating iron balance within the prostate tumor microenvironment (TME). We induced prostate tumorigenesis in the NP mice using Tamoxifen. The NP mice (Nkx3.1CreERT2/+ ; Ptenflox/flox ; Rosa26-CAG-LSL-EYFP/+ mice) develop prostate intraepithelial neoplasia and localized prostate adenocarcinoma by 12 months of age. We also utilized male TRAMP which spontaneously develops poorly differentiated prostate tumors reminiscent of the neuroendocrine subtype. We then stained prostate tissues using different immune cell markers and Perls''s method which stains “non-heme” iron to identify cells with high abundance of iron. Our results demonstrate that prostate tissues from two distinct transgenic prostate cancer models (adenocarcinoma and neuroendocrine), spanning different developmental stages (12 and 18 months) exhibited high level of non-heme iron in stromal regions compared with non-tumor bearing controls. The areas with high iron abundance exhibited high expression of F4/80 and the iron exporter Ferroportin-1, also known as solute carrier family 40 member 1 (SLC40A1). In summary, we found that the availability of non-heme iron correlates with the abundance of TAMs in prostate tumor microenvironment. Future studies will focus on understanding how TAMs are regulating iron availability in the dynamic tumor environment. Citation Format: Jennifer Rooks, Caleb Taylor, Asmaa El-Kenawi. Iron accumulation correlates with tumor progression in mouse models of prostate 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 6546.
Abstract 6549: Immune cell-derived lymphotoxin associated with survival of patients with endometrial cancer
Authors: Tat San Lau, Jie Wu, Kit Ying Chan, Joseph Kwong, Ho Sze Lee, Chi Chiu Wang
Journal: Cancer Research (2025)

Background: Endometrial cancer (EC) is a prevalent gynecological malignancy, often associated with poor prognosis in advanced stages. The tumor microenvironment (TME) plays a critical role in modulating immune responses and disease progression. This study aimed to investigate the prognostic significance of lymphotoxin (LT) in EC patients. Methods: Transcriptomic data from The Cancer Genome Atlas (TCGA) for EC were analyzed to access LT expression level, identified LT-associated gene signatures and evaluate the clinical outcomes. The cellular source of LT was determined by analyzing single-cell RNA sequencing (scRNA-seq) data from public databases. Additionally, these findings were validated in a cohort of 138 EC tissue samples from our center using quantitative PCR (qPCR) and multiplex immunofluorescence (mIF) staining. Results: Analysis of TCGA data demonstrated that EC patients with high LT expression exhibited significantly improved overall survival (OS) and disease-free survival (DFS) compared to those with low LT expression. Gene signature analysis indicated that high LT expression correlates with increased immune cell infiltration, suggesting a robust anti-tumor immune response. scRNA-seq analysis suggested that LT is predominantly expressed in T cells and B cells in EC samples when compared to normal samples. Validation in our cohort of 138 EC tissues revealed that patients with high LT expression had better OS. EC patients with high LT expression showed high expression of immune cell-related gene signatures, including Territory lymphoid structure signature, Tfh cell signature, Th1 and B cell signature and HEV signature, by qPCR. mIF staining further confirmed that increased infiltration of T cells and B cells in the TME of patients with high LT expression. Conclusion: Our findings indicate that immune cell-derived lymphotoxin serves as a potential prognostic biomarker in endometrial cancer, associated with enhanced immune cell infiltration and improved patient outcomes. These results highlight the importance of the immune microenvironment in tumor progression and support further exploration of lymphotoxin regulations in TME for identification of therapeutic target in EC. Citation Format: Tat San Lau, Jie Wu, Kit Ying Chan, Joseph Kwong, Ho Sze Lee, Chi Chiu Wang. Immune cell-derived lymphotoxin associated with survival of patients with endometrial 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 6549.
Abstract 6551: Exploring oncolytic viral therapy to target osteosarcoma
Authors: Sumbul Khan, Terri Higgins, Isabella Shimko Lofano, Payal Agarwal
Journal: Cancer Research (2025)

Abstract Osteosarcoma (OS) is a mesenchymal neoplasm. OS makes up approximately 3% of all malignancies in children. The mortality rate has not changed in the last few decades; therefore, the development of advanced cancer therapies is essential. We hypothesize that next-generation conditionally replicative oncolytic virus with an armed anti-PD1 HcAb will lyse the OS cells and initiate the immune response against tumor cells in the tumor microenvironment.The purpose of the study is to evaluate the oncolytic activity and production/ secretion of anti-PD1 Hcab by conditionally replicative Canine adenovirus armed with anti-PD1 Hcab (CAV 2 AU M3). We have infected canine OS cell lines viz D17-GLP, CF11-GLL, MCKOS and D22-GLP with CAV2 AU M3 and measured its cytotoxicity by performing cell viability assay (Luciferase assay) and cytotoxicity assay (LDH assay). To assess whether the virus can stimulate an immune response or not, we performed an immunogenicity assay (ATP assay). To evaluate the secretion and expression of anti-PD1 HcAb we have performed western blot. Flow cytometry was done to confirm the functionality of anti-PD1 Hcab i.e binding of anti-PD1 HcAb to PD1 receptors and inhibition of PD1 and PDL1 interaction. We have found that CAV2 AU M3 is lytic in OS cell lines (D17-GLP, CF-11-GLL, and MCKOS) in both 2D (Monolayers) and 3D (Tumor spheroids) cell cultures and it also produced and secreted anti-PD1 HcAb, which binds to PD1 receptor efficiently and inhibited the interaction between PD1 and PDL1. We concluded that CAV2 AU M3 is a potent armed oncolytic virus that can lyse and kill OS cells and produce functional anti-PD1 HcAb. Citation Format: Sumbul Khan, Terri Higgins, Isabella Shimko Lofano, Payal Agarwal. Exploring oncolytic viral therapy to target osteosarcoma [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 6551.
Abstract 6233: Human cytomegalovirus, tumor characteristics and patient survival in head and neck squamous cell carcinoma
Authors: Heather H. Nelson, DeVon Hunter-Schlichting, Rondi Butler, Karl Kelsey
Journal: Cancer Research (2025)

Abstract Human cytomegalovirus (CMV) is a beta-herpes virus that may play a role in head and neck squamous cell carcinoma (HNSCC). CMV is a highly prevalent latent infection among older US adults, and viral reactivation occurs in response to immune suppression and inflammation. Previously, in a study of 184 HNSCC we reported that elevated CMV IgG titers were associated with worse patient survival. Here, we have expanded our evaluation of CMV IgG and patient survival in 983 cases from the CoHANDS study. CMV positive patients had significantly worse HNSCC survival (p&amp;lt;0.003); this association remained after controlling for age, sex and stage (HR=1.30, 95% CI 1.02- 1.74). The association between CMV and outcome was independent of the known association between human papilloma virus infection (HPV) and patient survival. Next, we used nCounter gene expression data to evaluate immune infiltration and inflammation in 34 tumors from HNSCC patients with and without active CMV infection; active infection was defined as having DNAemia, the presence of cell-free CMV DNA in serum. Tumors from patients with active CMV infection were more likely to contain CMV transcript (p&amp;lt;0.06) and have increased T-cell infiltration (p&amp;lt;0.05), however there were no other differences in the immune infiltrate. The Tumor Inflammation Signature (TIS), a gene expression indicator that correlates with response to immune checkpoint inhibitors, was significantly higher in CMV positive patients (p=0.007). CMV positive patients were 12 times more likely to have an elevated TIS score (adjusted OR 12.4, 95% CI 1.2 - 124.2). In summary, HNSCC patients who are CMV IgG positive have poor survival and tumors from patients with active CMV infection have both increased T-cell infiltration and elevated tumor inflammation. These findings may have potential implications for immune therapy in HNSCC. Citation Format: Heather H. Nelson, DeVon Hunter-Schlichting, Rondi Butler, Karl Kelsey. Human cytomegalovirus, tumor characteristics and patient survival in head and neck squamous cell carcinoma [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 6233.
Abstract 6690: A novel B7H3-targeting macrocyclic peptide conjugate efficiently delivers siRNAs to cancer cells and tumor endothelium
Authors: Danyan Li, Lincy Edatt, Jillian Perry, Avery Huber, William David Green, Jarred Michael Green, Justin Milner, Albert Bowers, Chad Pecot
Journal: Cancer Research (2025)

Abstract Short-interfering RNAs (siRNAs) can treat a wide range of human diseases from viral outbreaks to cancer, however, targeted siRNA delivery remains a significant challenge. Recently, significant efforts have focused on developing novel delivery technologies for siRNAs, targeting tumors and other extrahepatic tissues. B7-H3 (CD276), a B7 family of immune checkpoint proteins, is highly expressed in cancer cells and tumor endothelial cells (TECs). We employed an mRNA display campaign against the hB7-H3 protein and discovered a macrocyclic binding peptide, JP5. Using surface plasmon resonance, we confirmed specific binding of JP5 to both human and murine B7-H3 with a KD of approximately 770nM and 600nM, respectively. Characterization of protease stability showed that greater than 80% of the peptide remains intact after incubation with 50% serum for 24h. Further, our team conjugated JP5 to chemically stabilized siRNAs labeled with a Cy5 fluorophore to observe biodistribution of siRNAs, including cancer cells and and TECs. Mice were implanted with A431 WT or B7H3 KO cells, and upon xenograft tumor formation, mice were given PBS (control) or JP5-siRNA-Cy5 (n=5 mice/group). Gross biodistribution by IVIS imaging was found in the tumors, skin, bowel, liver and kidney, with minimal accumulation in the heart and lungs. Flow cytometry and immunofluorescence revealed that JP5 conjugation directed siRNAs to ∼80% of TECs and to 40-60% of cancer cells, with a significant reduction in B7H3 KO cells. In conclusion, the JP5 macrocycle delivers siRNAs to B7H3-expressing cancer cells and TECs in the tumor microenvironment, paving a path forward for sophisticated cancer therapeutics. Citation Format: Danyan Li, Lincy Edatt, Jillian Perry, Avery Huber, William David Green, Jarred Michael Green, Justin Milner, Albert Bowers, Chad Pecot. A novel B7H3-targeting macrocyclic peptide conjugate efficiently delivers siRNAs to cancer cells and tumor endothelium [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 6690.