tbuckley/cabot-search huggingface dataset:
Abstract 846: Circular RNA based cancer vaccine encoding NY-ESO-1 is effective for the treatment of lung cancer
Authors: Shaoyi Chen, Mantang Qiu
Journal: Cancer Research (2025)

Abstract Nucleic acid vaccines have undergone rapid development in recent years and are playing an increasingly prominent role in cancer therapy. Circular RNA (circRNA), with its unique closed-loop structure, extended protein expression half-life, enhanced stability, and simplified production process, represents a next-generation RNA carrier that offers significant advantages over traditional mRNA. In this study, we utilized our proprietary circRNA platform (NeoAna) to synthesize circRNA encoding NY-ESO-1, a highly immunogenic cancer-testis antigen expressed in various types of cancer, including lung cancer. This circRNA was delivered via lipid nanoparticles to develop a cancer vaccine. Our in vitro experiments demonstrated that circRNA encoding EGFP which was synthesized by NeoAna platform, achieved higher protein expression levels and prolonged expression duration in various cell lines compared to its mRNA counterpart. Moreover, NY-ESO-1 circRNA was found to effectively promote dendritic cell maturation, as well as T cell proliferation and activation in vitro. To assess the vaccine-induced anti-tumor immune responses, we collected spleens and lymph nodes from C57BL/6 mice following intramuscular vaccination. ELISpot assays and flow cytometry assays revealed that circRNA vaccine significantly increased the CD8/CD4 T cell ratio in these tissues, along with enhanced IFN-γ and TNF-α secretion by CD8+ and CD4+ T cells. Elevated NY-ESO-1-specific IgG antibody and IL-12 were confirmed by ELISA. In a murine lung cancer model established by subcutaneous injection of Lewis lung carcinoma cells overexpressing NY-ESO-1 into C57BL/6 mice, the circRNA vaccine demonstrated superior tumor suppression compared to an mRNA vaccine, with a higher proportion of antigen-specific T cells detected in peripheral blood. Additionally, histological examination of (H&amp;E staining) and blood tests confirmed the safety of the circRNA vaccine for biological applications. In conclusion, our novel circRNA vaccine effectively activates anti-tumor immune responses and inhibits lung cancer progression, thereby providing a promising strategy for the clinical treatment of lung cancer. Citation Format: Shaoyi Chen, Mantang Qiu. Circular RNA based cancer vaccine encoding NY-ESO-1 is effective for the treatment of 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 846.
Abstract 592: Theranostic 68Ga/131I compounds for PSMA targeted radioligand therapy
Authors: Lars Hvass, Marcel Martin, Anne Clausen, Panagiota Iakovidou, Marius Müller, Umberto Battisti, Vladimir Shalgunov, Agustin Lenero, Nadia Pedersen, Sophie Stotz, Matthias Herth, Andreas Kjaer
Journal: Cancer Research (2025)

Abstract Introduction: Prostate cancer is the most common cancer in men and continues to be a common cause of cancer related death. With progression to castration resistant metastatic prostate cancer, treatment options are scarce. Radioligand therapy has emerged as a successful treatment for these patients, significantly prolonging survival when other treatments fail. Thus far, approved PSMA targeting radiopharmaceuticals mainly use DOTA-based precursors to chelate gallium-68 for diagnosis and lutetium-177 for therapy. Here we suggest a gallium-68/iodine-131 theranostic pair as an alternative radiohalogenated treatment option. Method: Four compounds based on a common urea PSMA binding motif with additional peptidic linkers were synthesized. These compounds are suitable for both radiohalogenation as well as radiometal labeling via DOTA-chelator(s). For comparative screening, all compounds were labelled with 68Ga in &amp;gt;95% radiochemical purity. Subsequently, BALB/c nude mice carrying LNCaP xenografts were intravenously injected with 8-13 MBq of compound [1]-[4]. Mice were PET/CT scanned one and two hours after injection. After final scan, mice were euthanized and organs harvested for ex vivo biodistribution. Based on tumor and off-target accumulation, a lead compound is selected for iodine-131 labelling by dematallation to assess distribution and dosimetry. Results: All compounds screened demonstrated favorable tumor uptake and fast clearance. Ex vivo Tumor, blood and kidney accumulation is presented in Table 1 Table 1: %ID/g and T/B and T/K in tumor, blood and kidney of compound 1-4 as well as PSMA-617. 68Ga[1] 68Ga[2] 68Ga[3] 68Ga[4] [68Ga]Ga-PSMA617 Tumor %ID/g 6.7 4.9 7.7 6.1 7.4 Blood %ID/g 0.2 2.8 0.2 1.1 0.4 Kidney %ID/g 19.9 22.7 3.8 22.6 2.0 T/B ratio 43.0 1.7 30.8 5.6 16.9 T/K ratio 0.3 0.2 2.0 0.3 3.6 , alongside tumor- (T/B) and tumor-to-kidney (T/K) ratios. Notably, compound 3 demonstrated high tumor uptake similar to PSMA-617, as well as low renal retention and faster blood clearance. Conclusion: Here we tested four different compounds in a mouse model of prostate cancer and identified compound 3 as lead candidate for further translational investigation using iodine-131. Citation Format: Lars Hvass, Marcel Martin, Anne Clausen, Panagiota Iakovidou, Marius Müller, Umberto Battisti, Vladimir Shalgunov, Agustin Lenero, Nadia Pedersen, Sophie Stotz, Matthias Herth, Andreas Kjaer. Theranostic 68Ga/131I compounds for PSMA targeted radioligand therapy [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 592.
Abstract 3158: CARP: a high-throughput platform for rapid VHH discovery of potent CAR-T therapy
Authors: Weihong Wang, Huiyuan Tang, John Lee, Xinhao Wang, Leo Ng, Yong Wang, Toya N. Baral, Jia Yu, Jiaguo Li, Wenfeng Xu
Journal: Cancer Research (2025)

Abstract Background: The conversion of suitable antibodies into functional CAR-T therapy presents challenges. Traditional methods for antibody discovery and screening face significant bottlenecks, including the difficulty of high-throughput identification of high-quality antibodies with diverse epitope and affinity coverage, also carry a high risk of missing functionally relevant candidates or falsely identify unsuitable candidates. Methods: Here, we introduce CARP (CAR-T AI-powered Rapid high-throughput screening Platform), a novel solution designed to rapidly identify VHHs with clinical potential in CAR structures. Our screening platform was applied for the development of CAR T-cell therapy targeting Cadherin 17 (CDH17). Following immunization of alpacas and llamas, hundreds of CDH17 VHH hits were analyzed using an AI-powered platform for lineage determination (epitope coverage), humanization, and immunogenicity profiling. A library of &amp;gt;400 CDH17 VHHs was screened in serial proliferation tumor cell line co-culture assays simulating long-term tumor-CAR-T interactions to evaluate their target-specific expansion capacity in CAR-T format. Results: After screening and validation of individual VHH candidates, CDH17 CAR hits consistently outperformed VHHs via traditional methods in functional assays, demonstrating superior activity and robustness. Moreover, CARP successfully identified multiple VHHs with identical target binding domain that demonstrated superior target-dependent expansion compared to clinical CDH17 CAR benchmarks and traditionally selected VHHs. Conclusion: Our CAR VHH platform not only accelerates the discovery process by enabling high-throughput screening to identify highly target-dependent and proliferative VHH leads, but also eliminates the need for additional rounds of immunization and immunogenicity assessments once lead VHHs are identified. CARP offers a powerful, efficient approach for uncovering VHHs that enhance CAR-T cell functionality, providing significant promise for advancing CAR-T therapy development. Citation Format: Weihong Wang, Huiyuan Tang, John Lee, Xinhao Wang, Leo Ng, Yong Wang, Toya N. Baral, Jia Yu, Jiaguo Li, Wenfeng Xu. CARP: a high-throughput platform for rapid VHH discovery of potent CAR-T therapy [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 3158.
Abstract 1396: Additional flexibility and choice with Annexin V StarBrightTM Dyes
Authors: Michael Blundell, Ryan Mendoza, Sharon Sanderson
Journal: Cancer Research (2025)

Abstract Annexin V staining combined with a viability dye is the gold standard to detect apoptotic cells and necrotic cells by flow cytometry due to its quick and reliable detection of externalized phosphatidylserine on cell membranes. Annexin V staining can be readily combined with immunophenotyping using fluorescently labeled antibodies to obtain cell specific apoptosis information. Unfortunately, when it comes to choice of fluorescent label on Annexin V there are limited options, with traditional fluorophores such as FITC, PE and APC being prevalent. This can cause issues with spillover and spreading when multiplexing, with bright fluorescent proteins such as GFP and with viability dyes that have excitation by multiple lasers, leading to suboptimal data and an inability to expand panel size. Here we present data using StarBright Dye Annexin V conjugates. Not only are the dyes bright so you get excellent separation of positive and negative populations, but they are available in a range of eight excitation and emission wavelengths. StarBright Dyes have been selected to have spectral properties that avoid excitation and emission of common viability dyes, such as 7-AAD and propidium iodide, fluorescent proteins like GFP, and are proven to be compatible in large immunophenotyping panels. When combining with immunophenotyping panels you still have the flexibility and choice to apply best practice, even with larger panels, improving the data obtained. Simplify compensation and avoid resolution issues caused by excessive spreading by using Annexin V conjugated to StarBright Dyes in your flow cytometry panels. Citation Format: Michael Blundell, Ryan Mendoza, Sharon Sanderson. Additional flexibility and choice with Annexin V StarBrightTM Dyes [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 1396.
Abstract 1568: Humanized PD1 mouse with MC38-hCLDN18.2 cell line provide powerful syngeneic model platform for evaluating Claudin18.2-targeted therapies
Authors: Jane Hong, Shuang Li, Xiaolei Qiu, Hechun Ma, Yi Li, Ruilin Sun
Journal: Cancer Research (2025)

Abstract Claudin18.2 is a highly specific tight junction protein that is minimally expressed in normal tissues but aberrantly activated and overexpressed in various malignancies, particularly digestive system tumors such as gastric cancer (approximately 70%) and pancreatic cancer (around 50%). In these tumors, the loss of cell polarity exposes Claudin18.2 on the cell surface, making it accessible to biologics and effector cells. Innovative therapeutic strategies, including monoclonal antibodies, bispecific antibodies, ADCs, and CAR-T cells, leverage this accessibility to enhance tumor-targeting precision and immune activation. Combining Claudin18.2-targeted therapies with immune checkpoint inhibitors, such as PD-1 blockade, holds promising therapeutic potential.To evaluate the efficacy of antibody drugs and ADCs, tumor cell lines overexpressing tumor-associated antigens are critical. We generated MC38-CLDN18.2 murine colon cancer cell lines by overexpressing human CLDN18.2 in MC38 cells. Human CLDN18.2 protein expression was confirmed by flow cytometry. The tumorigenic potential of MC38-CLDN18.2 cells was further validated in vivo.To investigate novel combination therapies or bispecific antibodies targeting CLDN18.2 and PD-1 in an immunocompetent model, we developed a humanized PD-1 (hPD1) mouse model on a C57BL/6 (C57) background. Using CRISPR/Cas9-based gene engineering, the murine Pdcd1 gene was replaced with the human PDCD1 gene, ensuring full-length human PD-1 protein expression in the knock-in model. Human PD-1 protein expression was validated by FACS analysis after in vivo anti-CD3 stimulation.The tumor growth inhibition of two CLDN18.2 monoclonal antibodies (IMAB362 and ASKB589) was evaluated in hPD1 mice engrafted with MC38-CLDN18.2 syngeneic tumors. The therapeutic effects of these antibodies were also investigated in combination with anti-PD-1 treatment. Both anti-CLDN18.2 monotherapies demonstrated moderate antitumor efficacy, while their combination with PD-1/PD-L1 immune checkpoint blockade produced significant synergistic effects, resulting in enhanced tumor suppression and increased antitumor immunity with robust T-cell infiltration.In summary, the humanized PD-1 mouse model and MC38-CLDN18.2 cell line provide robust in vivo platforms to evaluate novel therapeutic candidates targeting CLDN18.2. Citation Format: Jane Hong, Shuang Li, Xiaolei Qiu, Hechun Ma, Yi Li, Ruilin Sun. Humanized PD1 mouse with MC38-hCLDN18.2 cell line provide powerful syngeneic model platform for evaluating Claudin18.2-targeted therapies [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 1568.
Abstract 1321: Glycosylation dependent metastatic seeding of circulating tumor cells in breast cancer
Authors: Nurmaa Khund Dashzeveg
Journal: Cancer Research (2025)

Abstract Chemotherapy has been standard of care for triple negative breast cancer for decades; however, how chemotherapy evasion enables metastasis remains elusive and is one of the biggest challenges impacting patient survival in cancer clinics. Circulating tumor cells (CTC) are pivotal component of longitudinal liquid biopsies. Most of the CTCs are detected as a single cell, whereas small proportion of CTCs are found in multicellular clusters which possess 20-100 times higher metastatic potential than single CTCs and corelates with unfavorable survival in breast cancer patients. Here we observed that chemotherapy evasion is linked to the aggregation of CTCs in breast cancer. Chemo-evasive linked aggregated CTCs show specific loss of ST6GAL1-catalyzed alpha2,6-sialylation. Deficiency of ST6GAL1 promotes CTC cluster formation for metastatic seeding and enables cellular quiescence to evade paclitaxel treatment in metastatic breast cancer. Glycoproteomic analysis identified protein substrates of ST6GAL1, such as adhesion and stemness markers PODXL, ICAM1, ECE1, ALCAM1, CD97, and CD44, contributing to CTC clustering (aggregation) and metastatic seeding. As proof-of-concept, neutralizing antibody against one of the most significant contributors, PODXL, inhibits CTC cluster formation and lung metastasis exacerbated by paclitaxel treatment for breast cancer. This study sheds light in the evaluation of chemotherapy response and developed potential therapy approach against chemotherapy resistance. Citation Format: Nurmaa Khund Dashzeveg. Glycosylation dependent metastatic seeding of circulating tumor cells 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 1321.
Abstract 621: Changes in the senescence biomarker p16INK4a among older adults with early breast cancer treated with and without chemotherapy and non-cancer controls
Authors: Chaiyaporn C. Vatanatham, Jingran Ji, Canlan Sun, Marla D. Lipsyc-Sharf, Nikita V. Baclig, Yuliya A. Zektser, Ali Al Saleem, Joseph D. Olivera, Kelly S. Synold, Lauren R. Zelman, Hyman B. Muss, Mina S. Sedrak
Journal: Cancer Research (2025)

Abstract Background: Our group previously showed that p16INK4a (p16) expression, a biomarker of senescence (a fundamental process of aging), increases after adjuvant breast cancer chemo. However, no study has examined whether this increase in p16 is driven by cancer, chemo, or both. Here, we compare the change in p16 between older adults with early breast cancer who receive chemo, those who do not, and those without cancer. Methods: We prospectively recruited 701 adults age ≥65 with stage I-III breast cancer (composed of three age-matched cohorts: 501 treated with chemo [BC chemo], 100 treated without chemo [BC control]), and 100 without cancer (NC control). Sociodemographic, functional, and clinical characteristics were collected at baseline. The p16 level in peripheral blood CD3+ T lymphocytes was obtained at two time points: ≤14 days pre-chemo (T1) and ≤30 days post-chemo (or at matched time points in the BC and NC control groups, T2). The primary endpoint was the mean ∆p16 level from T1 to T2. Data was analyzed using descriptive statistics, t-tests, and analysis of variance (ANOVA). Results: There were no differences in T1 age, race/ethnicity, education, comorbidities, or functional status across the three groups. At T1, there was no difference in mean p16 levels across the three groups (p=0.06) (Table). At T2, the BC chemo group had a significantly higher mean p16 level compared to the BC and NC control groups (p&amp;lt;0.01). The mean ∆p16 levels from T1 to T2 were significantly different among the three groups (p=0.04). The BC chemo group had a 15% increase in mean ∆p16 from T1 to T2 (p&amp;lt;0.01), while the BC and NC control groups had no significant change. Conclusions: In a cohort of older adults with early breast cancer, the combination of breast cancer and chemo led to increases in p16 levels. Further independent validation of these findings is needed to understand the role of senescence in older adults with early breast cancer treated with chemo. Citation Format: Chaiyaporn C. Vatanatham, Jingran Ji, Canlan Sun, Marla D. Lipsyc-Sharf, Nikita V. Baclig, Yuliya A. Zektser, Ali Al Saleem, Joseph D. Olivera, Kelly S. Synold, Lauren R. Zelman, Hyman B. Muss, Mina S. Sedrak. Changes in the senescence biomarker p16INK4a among older adults with early breast cancer treated with and without chemotherapy and non-cancer controls [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 621.
Abstract 610: Manzamine and mitragynine: investigation of beta carboline compounds from marine sponges and kratom leaves as ovarian cancer therapeutics
Authors: Ashley Gabriel, Haifa Sahouri, Helen Fischer, Kimberly A. Gonzalez, Jihad Aburas, Cai M. Roberts
Journal: Cancer Research (2025)

Epithelial ovarian cancer (EOC) is the leading cause of death among gynecologic cancers. Five-year survival rates hover around 35%, largely due to widely metastatic and drug-resistant recurrent disease. Prior studies in our laboratory and others have shown that tumor progression, as evidenced by epithelial to mesenchymal transition (EMT) and metastasis, can have a significant impact on the response of cancer cells to treatment. Tumor heterogeneity is a substantial barrier to effective therapy. For instance, stem-like cells can withstand treatment that eliminates faster-growing cells and have the potential to give rise to recurrence. Thus, novel therapies or drug combinations that can eliminate all subpopulations within a tumor are needed. Natural products have a long history in cancer treatment. Prior studies in the natural products space on anti-EMT drugs focused on the beta carboline molecule harmine and its derivatives. While these compounds have shown efficacy, translation of these compounds to the clinic is complicated by their hallucinogenic properties. Therefore, we sought alternatives with similar beta carboline moieties. In the present study, we investigated alkaloids from marine sponges (Halicloa spp.) and the kratom plant (Mitragyna speciosa) as potential therapeutics for EOC. We tested the kratom compound mitragynine, the marine compound manzamine A, and several of their derivatives and analogues, in multiple EOC cell lines. We found that mitragynine killed EOC cells with an IC50 of ∼20 µM. The marine alkaloid manzamine A killed EOC cells with IC50 values in the low micromolar range. Each of these outperformed their respective analogues in cell survival assays. Importantly, both pre- and post-EMT cells, and models of primary and recurrent disease, all responded to manzamine treatment. Our findings also suggest an additive effect when manzamine therapy is combined with conventional chemotherapy. Additional work will be needed to fully elucidate the full mechanism of action of these compounds and whether inclusion of these alkaloids in treatment regimens will be effective in combating drug resistance. However, our results suggest that there is a place for these compounds in our arsenal for the deadliest gynecologic cancers. Citation Format: Ashley Gabriel, Haifa Sahouri, Helen Fischer, Kimberly A. Gonzalez, Jihad Aburas, Cai M. Roberts. Manzamine and mitragynine: investigation of beta carboline compounds from marine sponges and kratom leaves as ovarian cancer therapeutics [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 610.