tbuckley/cabot-search huggingface dataset:
Abstract 2230: Persistent elimination of tumors via balanced regulation of immune signals
Authors: Xiaodong Xiao, Lei Han, Yuan Yuan, Hua Jiang, Yueqing Xie, Jianwei Zhu
Journal: Cancer Research (2025)

Abstract Despite its success, there are still numerous unmet clinical needs in cancer immunotherapy. Many patients failed to respond due to the lack of effective and properly regulated T cell stimulation. Molecules capable of inhibiting multiple immune checkpoints, enhancing the co-stimulatory signals on T cells to “revive” the tumor antigen-specific T cell response, as well as sustaining the responses to prevent the recurrence of the tumor are highly desirable. Here we report a Fc-based, tripartite, multifunctional fusion protein JLM019 that has been rationally designed to integrate the multiple mechanisms of PD-1/PD-Ligands checkpoint inhibition and T cell co-stimulations through CD80-mediated signaling. Fused at the C-terminus of the Fc fragment, structure-guided mutations A132L and Loop15 were introduced into the human PD-1 ectodomain to improve affinity with its ligands. Fused at the N-terminus, the wild-type CD80 provided a canonical co-stimulatory signal compared to hyperreactive anti-CD28 agonistic antibodies. Combined effect of PD-1 signaling blockade and balanced T cell activation through CD80 binding with CTLA4/CD28 by JLM019 led to persistent elimination of wide spectrum of tumors, including tumors with no PD-L1 expression, or those resistant to conventional PD-1 checkpoint inhibitors in CDX models. JLM019 acts not only on the tumor but also through activating tumor-specific T cells that depend on other APCs and/or through PD-L2 signaling. Significantly, JLM019 treatment induced effective immune memory, which was confirmed by experiments using transferred splenocytes from cured mice that not only prevented tumor initiation but also eliminated tumors in the established tumor-bearing mice. The sophisticated mechanism of the action by JLM019 is explored and discussed. In summary, we developed an immune signal regulator JLM019 that can modulate immune signaling against advanced tumors in a potent yet well-balanced manner. Pre-clinical toxicity and PK/PD studies in cynomolgus monkey have shown a promising safety and toxicity profile, with a dose up to 100mg/kg being tolerated. These encouraging results prompted us to advance JLM019 for clinical studies in humans. Citation Format: Xiaodong Xiao, Lei Han, Yuan Yuan, Hua Jiang, Yueqing Xie, Jianwei Zhu. Persistent elimination of tumors via balanced regulation of immune signals [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 2230.
Abstract 681: A novel approach of Claudin 18 immunohistochemistry testing demonstrated comparable performance and high concordance compared to Ventana 43-14A in gastric cancer
Authors: Zhenghua Tang, None peng cheng, Xin Liu, Huangbin Lu, Jingjing Xu, Yiling Cai, Changbin Zhu
Journal: Cancer Research (2025)

Abstract Background: Claudin(CLND)18 is a tight-junction molecule consisting two Isoforms:CLND18.1 and CLND18.2. Isofrom CLND18.2 is specificly expressed in gastric cancer. Zolbetuximab is the first CLDN18.2 therapeutic monoclonal antibody approved by FDA. VENTANA® CLND18(43-14A), a pan-CLND18 immunohistochemistry (IHC) testing, was approved as companion diagnostics simutanusly. Validation between different Claudin 18 IHC testing approaches could improve the convenience of diagnostics in clinical use. Methods: A total of 68 gastric cancer samples were enrolled in this study. Expressing status of Claudin 18 was evaluated independently by two IHC approaches. AmoyDx CLDN18 (43-14A) assay was used as testing reagent and VENTANA® CLDN18 (43-14A) RxDx acts as reference reagent. Claudin 18 positive was defined as: tumor with staining intensity of 2+ or 3+(total) in ≥75% of tumor cell. Results: Validtaion results was shown in Table 1. 21 positive cases and 47 negative cases were identified by two reagents. Standing for a 100%(84.54% - 100%) positive percent agreement (PPA), 100% (92.44% - 100%) negative percent agreement (NPA), and 100% (94.65% - 100%) overall percent agreement (OPA). Poisson distribution analysis of the proportion of cells with four staining intensities(3+, 2+, 1+ and 0) demostrated that the staining intensity of the two approaches was highly consistent (R = 0.99-1, p &amp;lt; 2.26e-16). When the positive threshold was exploratively adjusted ( 2+/3+ cells ≥50%), high concordance was still maintained (PPA 100%, NPA 93.55%, OPA 97.06%, Table 1.) except 2 conflict samples, which were close to the exploratively threshold. Conclusion: Two Claudin 18 testing approaches demonstrated high concordance. It has potential versatility in future clinical practice. Citation Format: Zhenghua Tang, peng cheng, Xin Liu, Huangbin Lu, Jingjing Xu, Yiling Cai, Changbin Zhu. A novel approach of Claudin 18 immunohistochemistry testing demonstrated comparable performance and high concordance compared to Ventana 43-14A in 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 681.
Abstract 1208: The neuroimmune impact of chronic stress on triple-negative breast cancer
Authors: Chao Zhang, Lizhong Wang, Runhua Liu
Journal: Cancer Research (2025)

Breast cancer is the most frequently diagnosed cancer among American women, with triple-negative breast cancer (TNBC) being particularly aggressive and disproportionately impacting young African American women. TNBC has a threefold higher mortality risk compared to other breast cancer subtypes. Although chronic stress has been recognized as a risk factor that promotes tumor progression, its specific impact on TNBC progression and metastasis remains unclear. To investigate the role of chronic stress in TNBC, 4T1 cells were implanted in the tibia or fourth mammary pad of BALB/c and NSG mice. Mice were subjected to chronic stress through restraint over four weeks. The tumor microenvironment (TME) change was analyzed using single-cell RNA sequencing (scRNA-seq) and flow cytometry. Chronic stress accelerated tumor progression and metastasis in both BALB/c and NSG mouse models of TNBC. scRNA-seq and flow cytometry analysis revealed that chronic stress significantly upregulated ADRβ2 expression in M2 macrophages and monocytes but downregulated it in CD8+ T cells relative to controls. Notably, selective inhibition of ADRβ2 with Butaxamine significantly decreased the tumor burden, reduced M2 macrophage and monocyte numbers, and increased TCD8+ cells in the TME of BALB/c mice compared to the control group. Moreover, chronic stress elevated nerve fiber density within the TME of BALB/c and NSG mice. Depletion of peripheral nerve fibers using 6-hydroxydopamine (6-OHDA) significantly reduced tumor burden and correspondingly decreased M2 macrophages and monocytes in the TME compared to the control group. These findings suggest that chronic stress promotes TNBC progression and metastasis by modulating the tumor-neuroimmune network within the TME. Targeting components of this network, such as ADRβ2 and nerve fibers, may offer new therapeutic avenues for managing TNBC, especially in patients under chronic stress. Citation Format: Chao Zhang, Lizhong Wang, Runhua Liu. The neuroimmune impact of chronic stress on 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 1208.
Abstract 686: Retrospective analysis of estrogen receptor expression in prostatic neoplasms: Implications across age and racial groups
Authors: Laura B. Pagan, Tingting Yang, Jinghe Mao, Xinchun Zhou
Journal: Cancer Research (2025)

Abstract Background: Prostate cancer (PCa) is the most common cancer in men in the United States, aside from non-melanoma skin cancer. The roles of estrogen receptor α (ERα) and estrogen Receptor β (ERβ) in PCa have not been fully elucidated yet. This study aims to evaluate the expression levels and localizations of ERα and ERβ in benign prostatic tissue (BPT) and PCa across different racial and age groups. Methods: Immunohistochemistry (IHC) for ERα and ERβ was performed on tissue microarrays (TMA) containing 240 samples of BPT and PCa from Black and White individuals and age groups ≤60 and &amp;gt;60 years. The localization of the IHC signal for ERα and ERβ was determined in glandular and stromal regions. Expression levels of ERα and ERβ were quantified using an IHC score, calculated by multiplying the area score (percentage of stained cells: 0 for no staining, 1 for &amp;lt;10% staining, 2 for 10-50% staining, and 3 for &amp;gt;50% staining) by the intensity score (0 for no signal, 1 for weak, 2 for moderate, and 3 for strong staining). Statistical analysis was performed using Student's t-test; a p-value ≤0.05 was considered significant. Results: In the entire population, the IHC scores for glandular ERα, stromal ERα, and glandular ERβ were lower in all PCa cases than in BPT, but a significant difference was only seen in glandular ERβ between PCa and BPT (3.43±2.3 vs. 4.86±2.8; p=0.0021). Interestingly, the IHC scores for all glandular ERα, stromal ERα, and glandular ERβ were significantly lower in metastatic PCa than in BPT (p=0.014, p=0.0001, and p=0.0035, respectively). While the entire population was stratified by race, there was no significant difference in IHC score for glandular ERα, stromal ERα, or glandular ERβ in both BPT and PCa between Black and white populations. While entire population was stratified by age, individuals with age &amp;gt;60 years had significantly lower IHC scores for glandular ERα (p=0.0023) and stromal ERα (p=0.03), but not for and glandular ERβ (p=0.1) in BPT; and significantly lower IHC score for stromal ERα (p=0.0036). Conclusions: These findings suggest that ERα and ERβ could be potentially diagnostic and prognostic biomarkers for PCa. Declined expression levels of glandular ERα, stromal ERα, and glandular ERβ may correlate to the oncogenesis, progression and disparities in race and age PCa. Citation Format: Laura B. Pagan, Tingting Yang, Jinghe Mao, Xinchun Zhou. Retrospective analysis of estrogen receptor expression in prostatic neoplasms: Implications across age and racial groups [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 686.
Abstract 683: NaDC3: a potential tumor suppressor and biomarker in renal cell carcinoma
Authors: Miswakumari Lad, Tianyu Yang, Karina Aguilar, Vinata Lokeshwar
Journal: Cancer Research (2025)

Introduction and Objective: The five-year survival rate for patients with metastatic renal cell carcinoma (mRCC) is less than 10%, with the highest incidence found among African American males. Addressing racial disparities in renal cell carcinoma (RCC) are essential for the development of biomarkers and targeted therapies. NaDC3, a succinate/citrate transporter expressed in kidney epithelial cells, has not yet been studied in relation to any diseases. In our research, we assessed NaDC3 expression in both normal and RCC tissues and examined its correlation with clinical outcomes and racial disparities. Additionally, we investigated the biological functions and molecular signaling pathways influenced by NaDC3 in RCC cells. Methods: Differences in gene expression in the matched normal and RCC tissues (n=6/category) was evaluated using microarray analysis; results were then validated by QPCR and immunoblotting in tissues from 83 patients (White=46; Hispanic=24; AA=13). VHL+ and VHL- RCC cells were stably transfected with a NaDC3 construct. Transfectants were assessed for cell proliferation, cell cycle, motility, succinate/citrate transport and reactive oxygen species (ROS) measurement assays under normoxic and hypoxic conditions. SDCT2 induction was evaluated following 5-azacytidine plus Trichostatin A treatment. Results: NaDC3 was 63- and 100-fold downregulated in low- and high-stage RCC tissues respectively. QPCR validation showed 40-fold downregulation of NaDC3 in RCC tissues when compared to normal kidney (P&amp;lt; 0.0001). Downregulation was 40-fold in White and Hispanic patients, but 198-fold in AA patients (P=0.0049) and correlated with tumor stage and metastasis (P=0.009). Under hypoxic conditions, NaDC3 expression caused 3-4-fold inhibition of proliferation, cell-cycle, and motility in both VHL+ and VHL- cells (P&amp;lt;0.01); only VHL+ cells were inhibited under normoxia. NaDC3 expression induced ROS levels and succinate transport by &amp;gt;3-fold (P&amp;lt;0.01) and activated the p16INK4a-RB pathway and apoptosis (caspase-3 and PARP activation). NaDC3 expression was silenced in patient-derived primary cell lines from AA patients. Conclusion: This is the first study on a functional biomarker in RCC, NaDC3, that is a possible novel tumor suppressor gene. NaDC3 loss promotes RCC growth and survival and inhibits cellular senescence, while its downregulation correlates with metastasis and racial disparity. Support: 1R01CA227277-05A1; 1R01CA283699-01 Citation Format: Miswakumari Lad, Tianyu Yang, Karina Aguilar, Vinata Lokeshwar. NaDC3: a potential tumor suppressor and biomarker in renal 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 683.
Abstract 223: Evaluating the therapeutic potential of MDM2 inhibitor RG-7388 and epigenetic modulator CM-272 in cisplatin-resistant ovarian cancer
Authors: Fatimah Alssamani, Umamaheswari Natarajan, Shyam Jaganathan, Appu Rathinavelu
Journal: Cancer Research (2025)

Abstract Ovarian cancer (OC) is the deadliest gynecological malignancy, often presenting late diagnosis and exhibiting treatment resistance, partly due to dysregulation of the crucial tumor suppressor p53. The oncoprotein MDM2 also negatively regulates p53, and therefore, MDM2 specific inhibitors may offer potential therapeutic avenues through reactivation of p53 and reversing adverse epigenetic modifications causing growth or resistance. In this study, we investigated the therapeutic potential of the MDM2 inhibitor RG-7388, chemotherapeutic agent cisplatin, and the epigenetic modulator CM-272 in cisplatin-resistant A2780cis ovarian cancer cells. We first characterized the growth kinetics of cisplatin sensitive and resistant A2780 cell lines, which confirmed significantly longer doubling times in the resistant cells (approximately 35 hours versus 20 hours in sensitive cells). Treatment efficacy was evaluated through cell viability and cell death assays, along with the expression levels of DNMT1 and EZH2, which are key epigenetic regulators. Treatment of A2780cis cells with RG-7388 demonstrated significant anti-cancer activity, by reducing live cell populations by 42-48% through increased cell death. Despite resistance, qRT-PCR analysis revealed that both cisplatin and CM-272 treatments significantly suppressed DNMT1 expression by 96%A2780cis cells. Western blot analysis also confirmed that both RG-7388 and cisplatin reduced DNMT1 protein levels in A2780cis cells along with the most pronounced reduction of DNMT1 after CM-272 treatment. Notably, CM-272 significantly decreased the levels of EZH2 also while RG-7388 did not impact the EZH2 protein levels. Interestingly, treatments with RG-7388 and CM-272 drug combinations showed varied effects, while maintaining strong inhibition of PARP. Overall, our findings suggest that the MDM2 inhibitor RG-7388 could be a promising therapeutic agent for cisplatin-resistant ovarian cancer, particularly because of its ability to modulateepigenetic regulators like DNMT1. However, the complex interplay between cell survival and epigenetic regulation in drug resistant cells warrant further investigation to optimize the outcomes of combination treatment strategies. Acknowledgement: This project was supported by the Royal Dames of Cancer Research Inc. Ft. Lauderdale, Florida Citation Format: Fatimah Alssamani, Umamaheswari Natarajan, Shyam Jaganathan, Appu Rathinavelu. Evaluating the therapeutic potential of MDM2 inhibitor RG-7388 and epigenetic modulator CM-272 in cisplatin-resistant 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 223.
Abstract 34: From fluid to function: Leveraging ascites to build orthotopic ovarian cancer models
Authors: Cheryl Davis, Melissa Tran, Helen Ketteringham, Corrine Silvio, Ben Hoerner, Marcus Josey, Victoria Caruso, Kathleen Hutchinson, Dawn Lusk, Chris Holding, Shorena Nadaraia-Hoke
Journal: Cancer Research (2025)

Often referred to as the “silent killer”, ovarian cancer poses significant challenges due to its asymptomatic nature and lack of reliable early detection methods, leading to late-stage diagnoses in over 70% of cases. As the eighth most common cancer among women worldwide, robust translational models for preclinical testing of ovarian cancer are essential. Unfortunately, the limited availability of orthotopic in vivo models presents a significant challenge in accurately replicating ovarian cancer for research purposes. By harnessing the ascitic nature of two well-established ovarian adenocarcinoma cell lines, we have successfully generated robust orthotopic ovarian in vivo models, which we can now offer as a valuable platform for preclinical research. Both our intra-peritoneal and intra-bursal models exhibit predictable growth patterns, thus contributing to the advancement of ovarian cancer treatments by enabling the exploration of tumor biology, drug resistance mechanisms, and therapeutic efficacy. The innovative models presented here are powerful tools for investigating tumor biology and advancing preclinical drug development, with the ultimate goal of improving therapeutic outcomes for patients with ovarian cancer. Citation Format: Cheryl Davis, Melissa Tran, Helen Ketteringham, Corrine Silvio, Ben Hoerner, Marcus Josey, Victoria Caruso, Kathleen Hutchinson, Dawn Lusk, Chris Holding, Shorena Nadaraia-Hoke. From fluid to function: Leveraging ascites to build orthotopic ovarian cancer models [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 34.
Abstract 891: Therapeutic role of NK cells in treatment of myeloid malignancies using hypomethylating agents
Authors: Junshik Hong, Suji Min, Jihyun Park, Carly Fielder, Qianni Hu, Seula Kim, Sung-Soo Yoon, Tae Kon Kim
Journal: Cancer Research (2025)

We previously analyzed serial bone marrow (BM) aspirates from a patient with high-risk myelodysplastic syndrome (HR-MDS) who responded to a hypomethylating agent (HMA), azacitidine using single-cell RNA sequencing. Our finding showed an increased proportion of NK cells in the BM, with elevated CXCR4 expression following azacitidine treatment (Hong J, et al. AACR 2023). Building on these observations, we tested our hypothesis that HMA can potentiate BM homing and cytotoxic effect of NK cells in myeloid leukemia. To test our hypothesis, we will carry out in vitro assays, animal experiments, and patients’ serial BM samples. First, we assessed NK cells changes in BM aspirates from AML or HR-MDS patients before and after HMA treatment. Flow cytometric analysis revealed that patients who achieved complete remission after HMA treatment exhibited a significant increase in NK cells proportion in the BM compared to non-responders (add statistics). Additionally, CXCR4 expression on NK cells was higher in patients with a favorable response, suggesting a link between NK cell dynamics and treatment outcomes (add statistics). To carry out mechanistics studies, C1498 mouse AML cells were transplanted into C57/BL6 mice, which were treated with decitabine or vehicle for 5 days. Decitabine not only inhibited in vivo AML proliferation but also increased the proportion of NK cells cells in the BM. Of interest, CXCR4, a chemokine receptor that has been known for BM homing, was also upregulated on the surface of NK cells. In addition, CXCR4 expression was first increased in NK cells, and then NK cell homing was followed. To investigate whether HMA treatment increases CXCR4 expression and induces NK cell migration, an in vitro Transwell migration assay was performed using NK92 cells (a human NK cell line) with AML cell lines (MV4-11 and OCI-AML3) and mesenchymal stromal cells (MSC) from AML patients. CMFDA-labeled NK92 cells showed higher migration and increased CXCR4 expression in decitabine-treated wells compared to vehicle controls, with the effect being more pronounced in the presence of MSCs. Taken together, these findings suggest that HMA-induced NK cell recruitment to the BM via CXCR4 upregulation may play a key role in the anti-leukemic effects of HMAs in AML and HR-MDS. Increased NK cell migration and CXCR4 expression are associated with better treatment responses, highlighting the potential of enhancing NK cell immunity as a therapeutic strategy. Citation Format: Junshik Hong, Suji Min, Jihyun Park, Carly Fielder, Qianni Hu, Seula Kim, Sung-Soo Yoon, Tae Kon Kim. Therapeutic role of NK cells in treatment of myeloid malignancies using hypomethylating agents [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 891.