tbuckley/cabot-search huggingface dataset:
Abstract 7161: HMGA2 predicts treatment outcome in pancreatic cancer
Authors: Naomi Yamamoto, Stephanie Dobersch, Ian Loveless, Annie Samraj, Gun Ho Jang, Miki Haraguchi, Ryan Fields, David DeNardo, Faiyaz Notta, Howard Crawford, Nina Steele, Sita Kugel
Journal: Cancer Research (2025)

Abstract The recognition of distinct transcriptional subtypes in pancreatic ductal adenocarcinoma (PDAC) has defined a group of poorly differentiated tumors with worse prognosis, but these findings have yet to reach clinical application. These tumors, termed “basal, ” are unique for their loss of epithelial identity and relative chemoresistance compared to “classical” tumors. To develop a prognostic biomarker for the basal subtype, we have identified that the chromatin architectural protein HMGA2 is highly expressed in this subset of cancers. Using a tumor microarray of 580 primary biopsies from a diverse set of PDAC patients undergoing surgical resection, we performed multiplex immunohistochemistry for HMGA2, previously published markers of basal and classical disease, and immune subsets. We then associated patient outcome and known clinical data from 491 of these samples to staining patterns. We found that expression of HMGA2, but not published basal markers CK5 or CK17, predicted overall survival in our cohort. Combination of HMGA2 status with GATA6 status allowed for identification of two key study groups: an HMGA2+/GATA6- cohort with worse survival, decreased CD8+ T cells, and poorer response to gemcitabine-based chemotherapies (n=94, median survival = 11.2 months post-surgery); and an HMGA2-/GATA6+ cohort with improved survival, increased CD8+ T cell infiltrate, and improved survival with gemcitabine-based chemotherapy (n=198, median survival = 21.7 months post-surgery). Importantly, these findings were also true for Black patients, who have been underrepresented in previous subtyping studies. HMGA2 was also predictive of overall survival in RNA sequencing from metastatic tumors in an independent cohort. As a positive nuclear marker for basal disease, HMGA2 complements GATA6 as a dual-indicator test for disease subtype in PDAC. We aim to introduce this novel biomarker in a prospective multi-center clinical trial to further validate its use in selecting chemotherapy regimens and across other under-represented racial groups. Citation Format: Naomi Yamamoto, Stephanie Dobersch, Ian Loveless, Annie Samraj, Gun Ho Jang, Miki Haraguchi, Ryan Fields, David DeNardo, Faiyaz Notta, Howard Crawford, Nina Steele, Sita Kugel. HMGA2 predicts treatment outcome in pancreatic 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 7161.
Abstract 3517: A bispecific pan-γδT cell engager with IL-15 fusion that activates both δ1 and δ2 types of γδT cells for the treatment of acute myeloid leukemia
Authors: Mingcan Yu, Peng Chen, Ying Jin, Fulai Zhou, Honglei Bi, Mark Chiu, Di Zhang
Journal: Cancer Research (2025)

Abstract Background: Bispecific T cell engagers redirecting pan CD3+ T cells for tumor immunotherapy have demonstrated clinical promise in treating mainly hematologic cancers but are often accompanied with severe toxicity due to cytokine storms. An alternative approach involves engaging innate-like γδ T cells instead which possess inherent antitumor activity but are less prone to toxicity. Unfortunately, most γδ T cell-based therapeutics reported so far exhibit suboptimal clinical efficacy due to subtype-specific engagement, limited quantity, and poor durability of γδ T cells in cancer therapy. Methods and Results: We characterized a pan γδ T cell receptor antibody capable of binding and activating γδ T cell receptors from both δ1 γδ T cells (mainly resident in mucosal tissues and tumors) and δ2 γδ T cells (predominantly found in blood circulation). When paired with an antibody targeting the acute myeloid leukemia (AML) associated target CD123, this bispecific pan γδ T cell engager, TAVO317A, mediated tumor cell dependent activation and degranulation of both δ1 and δ2 γδ T cells and redirected them to potently kill antigen-specific hematologic cancer cells. To enhance the durability of bispecific pan γδ T cell engagers in tumor therapy, we engineered an attenuated IL-15 along with the IL-15 receptor α sushi domain as a fusion component on the CD123 bispecific pan γδ T cell engager. The addition of the IL-15 domain further boosted the ability of the engager to promote the activation and proliferation of γδ T cells. In humanized AML cell xenograft models, the CD123 bispecific pan γδ T cell engager effectively recruited γδ T cells to control AML tumor growth. Moreover, the CD123 engager with IL-15 fusion exhibited even better efficacies in tumor cell elimination and sustained γδ T cell activity without requiring IL-2 supplementation. Conclusions: By recruiting both δ1 and δ2 γδ T cells, our bispecific pan γδ T cell engager can mobilize more γδ T cells that may otherwise be of limited quantity for tumor therapy. In addition, the engineered IL-15 domain for immune modulation can facilitate enhanced durability of γδ T cells in tumor cytotoxicity. Our novel proprietary bispecific pan γδ T cell engager platform has the potential to serve as a potent and efficacious alternative to CD3-based therapy by offering enhanced liquid and solid tumor immunotherapy with a better safety profile. Citation Format: Mingcan Yu, Peng Chen, Ying Jin, Fulai Zhou, Honglei Bi, Mark Chiu, Di Zhang. A bispecific pan-γδT cell engager with IL-15 fusion that activates both δ1 and δ2 types of γδT cells for the treatment of acute myeloid 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 3517.
Abstract 1902: Novel monoclonal antibodies specific for cancer-associated proliferating cellular nuclear antigen for tumor monitoring and diagnosis
Authors: Malaney C. Young, Caroline M. Li, Robert G. Lingeman, Chun Li, Aimin Li, Linda H. Malkas, Robert J. Hickey
Journal: Cancer Research (2025)

Abstract Proliferating cellular nuclear antigen (PCNA) is a biomarker associated with cancer progression and is expressed in all cancer types. Its expression is increased before DNA synthesis with the transition of cells from G1 to S phase, making it a useful diagnostic marker for tumor cell proliferation. Our lab has identified an acidic and basic isoform of PCNA that can be resolved using 2-dimensional gel electrophoresis (2DE). Cancer cells express the acidic, cancer-associated isoform of PCNA (caPCNA), whereas healthy cells only express the basic, non-malignant isoform of PCNA (nmPCNA). Thus, caPCNA is an important biomarker that can be used for identifying early-stage cancer and monitoring tumor growth, metastasis, and response to treatment. Immunohistochemical staining (IHC) of tissue biopsies is an essential method for tumor detection and monitoring of cancer progression. Antibodies are used either individually or in panels and typically require markers that are specific to each tumor’s origin. Because caPCNA is not specific to a single cancer type, it is a universal biomarker which can be used to monitor cancer of any origin. Commercially available antibodies for PCNA do not distinguish between the cancer isoform and the non-cancer associated normal isoform. We have developed a series of monoclonal antibodies that are capable of distinguishing caPCNA from nmPCNA and have characterized these antibodies using 2DE and IHC. These novel monoclonal antibodies targeting the caPCNA isoform could enable pathologists to distinguish the presence of cancer cells in difficult to diagnose biopsy specimens, more efficiently monitor surgical margins, and potentially identify the presence of circulating tumor cells in blood samples. Citation Format: Malaney C. Young, Caroline M. Li, Robert G. Lingeman, Chun Li, Aimin Li, Linda H. Malkas, Robert J. Hickey. Novel monoclonal antibodies specific for cancer-associated proliferating cellular nuclear antigen for tumor monitoring and diagnosis [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 1902.
Abstract 6501: The SRG RAT supports in vivo human cell xenotransplantation through enhanced tumor microenvironment interactions
Authors: Caitlin M. O'Connnor, Diane Begemann, Kaitlin P. Zawacki, Kelsey Barrie, Fallon K. Noto, Grace Walton, Gabrielle H. Onishi, Jessica Durant, Taylor Branyan, Mike Schlosser, Goutham Narla
Journal: Cancer Research (2025)

Abstract The use of immunodeficient mice for human tumor engraftment has proven to be an essential model of human cancer, with uses ranging from basic science to translational research. However, low engraftment rates, slow growth, and smaller tumor volumes can be limitations. Previously, we reported a highly immunodeficient rat strain developed by Hera BioLabs, with the functional deletion of both the Rag2 and Il2rg genes on the Sprague-Dawley background (SRG RAT®), which lacks B, T, and NK cells. We have shown that the SRG rat supports the growth of multiple PDX and CDX models, however, the mechanisms underlying the supportive growth are not fully understood. Additionally, direct comparison of tumor growth and the rates of engraftment between the SRG rat and NSG mice has remained limited. Here, we subcutaneously engrafted two CDX and five PDX models into SRG or NSG animals and tracked tumor growth. These models included prostate, lung, ovarian, and uterine cancer models. In all cases, the engraftment and tumor growth rates were better supported in the SRG rat compared to the NSG mouse. Interestingly, the SRG rat is not more immunocompromised than the NSG mouse, suggesting alternative mechanisms leading to the supportive growth in the SRG rat. To understand this, we explored potential differences in the tumor microenvironment (TME) between models grown in the two host animals. We analyzed tumors from the H660 CDX model of castrate-resistant prostate cancer grown in either SRG rats or NSG mice using markers of the TME via immunohistochemistry. This analysis showed differences in the vasculature and macrophages between the two host species. We complemented this analysis using Xenium in situ by 10X genomics to allow for single-cell spatial imaging of engrafted tumors. This analysis showed upregulation of the human CXCL2, LAMP3, and other genes in H660 tumors grown in the SRG rat vs the NSG mouse. Interestingly, high expression of these two genes has been linked to poor prognosis in cancer. Combined, our data demonstrate that the SRG rat supports the growth of multiple human cancer types and displays enhanced tumor microenvironment interactions compared to NSG mice. Citation Format: Caitlin M. O'Connnor, Diane Begemann, Kaitlin P. Zawacki, Kelsey Barrie, Fallon K. Noto, Grace Walton, Gabrielle H. Onishi, Jessica Durant, Taylor Branyan, Mike Schlosser, Goutham Narla. The SRG RAT supports in vivo human cell xenotransplantation through enhanced tumor microenvironment interactions [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 6501.
Abstract 6735: E-cM-Topi, a potent EGFR-cMET bispecific antibody drug conjugate, with superior anti-tumor effect in non-small-cell lung cancer (NSCLC)
Authors: Huihui Chen, Le Sun, Bing Hu, Zhiping Zhao, Ziheng Liu, Guangbao Qiu, Dongmei Bai, Ying Li, Ziwei Ren, Ting Zhang, Xin Ye, Lingfeng You, Zhendong Xue, Yuchang Mao, Huaixin Dang, Shuyu Cai, Jun Feng, Min Hu, Feng He
Journal: Cancer Research (2025)

Abstract EGFR-tyrosine kinase inhibitors (EGFR-TKIs) are standard clinical treatment for NSCLC patients with activating EGFR mutations. However, both intrinsic and acquired resistance to EGFR-TKIs limited their long-term efficacy, posing a significant unmet medical need. The protein overexpression of c-MET has been observed in 5-22% of EGFR-TKIs resistant NSCLC patients. Therefore, a bispecific ADC targeting EGFR and c-MET will shed a light on the management for EGFR-TKI resistance. E-cM-Topi is an EGFR and cMET bispecific ADC, consisting of a Fc-silenced EGFR-cMET bispecific antibody, a cleavable linker and a topoisomerase I inhibitor payload (Topi) with superior bystander effect. The binding affinities to EGFR and c-MET were optimized to enhance tumor-cell-selectivity, increase endocytosis, and improve pharmacokinetics (PK). Considering the wide expression of EGFR in normal tissue, the binding affinity to EGFR was adjusted to be weaker than that to c-MET, thereby enhancing the selectivity for EGFR-cMET-co-expressing tumors while minimizing the toxicity on normal tissues. E-cM-Topi demonstrated strong EGFR/cMET-dependent growth inhibition in various NSCLC cell lines. In HCC827 and EBC-1 xenograft models, E-cM-Topi inhibited tumor growth in a dose-dependent manner. Tumor regression was observed at a single dose of 4.5 mg/kg and sustained till day 35 in HCC827 model and day 20 in EBC-1 model. In addition, E-cM-Topi showed good human plasma stability and favorable cyno PK profile. Less than 0.5% of payload was released in human plasma after a 14-day incubation. Half-life of E-cM-Topi was more than 3 days in cyno monkey. In summary, by fine-tuning the EGFR-cMET bispecific antibody affinity and incorporating a superior bystander effect of payload, E-cM-Topi represents a best-in-class potential. It holds promise as an effective treatment option for EGFR-TKI resistant NSCLC patients. Citation Format: Huihui Chen, Le Sun, Bing Hu, Zhiping Zhao, Ziheng Liu, Guangbao Qiu, Dongmei Bai, Ying Li, Ziwei Ren, Ting Zhang, Xin Ye, Lingfeng You, Zhendong Xue, Yuchang Mao, Huaixin Dang, Shuyu Cai, Jun Feng, Min Hu, Feng He. E-cM-Topi, a potent EGFR-cMET bispecific antibody drug conjugate, with superior anti-tumor effect in non-small-cell lung cancer (NSCLC) [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 6735.
Abstract 6748: Comparison of activities and identification of predictive genomic biomarkers of response to trastuzumab and the trastuzumab deruxtecan ADC using the OncoPanel® platform
Authors: Luciano Galdieri, Steven Garner, Brogan Epkins, Emily Schultz, Daria Clucas, Kaitlyne Powers, Justin Lipner, Elsa Liu, ChunYao Lee, Alastair J. King
Journal: Cancer Research (2025)

Abstract Antibody-drug conjugates (ADCs) represent a novel class of therapeutic agents that allow the targeted delivery of cytotoxic payloads to tumor cells via the selectivity afforded by monoclonal antibodies (mAbs) directed against tumors expressing particular antigens. When the mAb component of the ADC binds to its cell surface antigen, the ADC-antigen complex is internalized by the cancer cell. Once inside the cell, the drug payload is released from the mAb either through a chemical reaction or enzymatic digestion within lysosomes, ultimately allowing the exertion of its cytotoxic effects. In 2013, the first ADC approved for treating solid tumors was the Her2-targeted ado-trastuzumab emtansine, which was developed for metastatic breast cancer. As of June 2024, the US Food and Drug Administration has approved thirteen ADCs, with many more currently undergoing preclinical development and clinical trials. The anti-Her2-targeted ADC trastuzumab deruxtecan (TDxd) features a cleavable enzymatic linker, unlike trastuzumab emtansine, which utilizes a non-cleavable thioether linker. This cleavable linker enables deruxtecan, a topoisomerase I inhibitor, to diffuse out of cells following cleavage, thereby inducing cytotoxic effects even in tumors with low Her2 expression levels. Solid tumors overexpressing Her2—including breast, colorectal, and gastric cancers, as well as Her2-mutated lung cancers—have shown significant responses to TDxd. We evaluated the activity and selectivity of TDxd, along with the unmodified antibody and free payload when administered separately, against a panel of 300 human tumor cell lines. Potencies were assessed from ten-point dose response curves using a four-parameter log-logistic model with custom curve-fitting software to determine IC50 and EC50 values. In this study, we compare and contrast the potency and efficacy of each tested agent and explore the genomic biomarkers associated with sensitivity and resistance to each of these treatments. Additionally, we have also evaluated the effect of these agents from a broader tissue biology perspective, including use of the BioMAP® cellular phenotypic platform. Citation Format: Luciano Galdieri, Steven Garner, Brogan Epkins, Emily Schultz, Daria Clucas, Kaitlyne Powers, Justin Lipner, Elsa Liu, ChunYao Lee, Alastair J. King. Comparison of activities and identification of predictive genomic biomarkers of response to trastuzumab and the trastuzumab deruxtecan ADC using the OncoPanel® platform [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 6748.
Abstract 6755: Discovery of the synergistic dual-payload antibody-drug conjugate (CTPH-02) by combination of MMAE and novel payloads
Authors: Chang-Sun Lee, Myeong Joo Kim, Da hyun Kim, Soyeon Lim, Jiwoo Lee, Eunseok Choi, Wonbin Ha, Han ah Kim, Jaebeom Park, Seung Chan Kim
Journal: Cancer Research (2025)

Abstract Many ADC drugs in clinical trials are showing poor performance without providing sufficient dose due to dose-limiting toxicity, which is rooted from on-target toxicity related to payload itself. There are many efforts to increase the therapeutic index (TI) of ADC, but research on discovering novel payloads based on unique anticancer mechanisms of action is relatively limited. We have developed unique ADC platform technology by adopting multi-drug payloads concept, where we aim to achieve three different goals, (1) increasing MTD and lowering MED (2) showing cytotoxic activity in antigen low-expressed cell lines (3) overcoming resistance cell lines with better cytotoxic effects. This study began with the search for a drug combination that could maintain or increase efficacy of MMAE even with lower dose of MMAE. Drugs with various mechanisms of action were tested to select a combination that showed a high synergy effect with MMAE, and a cell cycle regulating drug was found to offer the most synergistic combination efficacy with MMAE. By conjugating a dual-payload with two-different mechanisms of action to HER2 antibody(trastuzumab), the resulting ADC(CTPH-02) was confirmed to show synergistic effect in terms of cytotoxicity. Very excitingly, CTPH-02 shows significantly high synergistic efficacy in the case of cell lines with low HER2 antigen expression. These findings based on the right combination of two-different payloads open a new paradigm for ADC drug design strategies in cancer therapy in order to provide treatment options to wider range of cancer patients such as low TPS % with low IHC score. Citation Format: Chang-Sun Lee, Myeong Joo Kim, Da hyun Kim, Soyeon Lim, Jiwoo Lee, Eunseok Choi, Wonbin Ha, Han ah Kim, Jaebeom Park, Seung Chan Kim. Discovery of the synergistic dual-payload antibody-drug conjugate (CTPH-02) by combination of MMAE and novel payloads [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 6755.
Abstract 2171: Amezalpat, a peroxisome proliferator-activated receptor alpha (PPARα) antagonist, inhibits suppressive macrophage development, activation and function
Authors: Mandy I. Cheng, Ademola Esomojumi, Dara Burdette, Valerie Chen, Jorg H. Fritz, Sam Whiting, Nathan Standifer
Journal: Cancer Research (2025)

Amezalpat (TPST-1120) is a first-in-class, small molecule competitive antagonist of peroxisome proliferator-activated receptor alpha (PPARα), the master transcriptional regulator of fatty acid oxidation (FAO). Analysis of biomarker data from a previous Phase I study demonstrated amezalpat dose-dependent changes in immune genes associated with myeloid populations. Suppressive M2 macrophages are a prominent myeloid population associated with poor prognosis in many cancers. As M2 macrophages are reliant on FAO, we sought to assess the effects of amezalpat on development, activation and function of these cells. Flow cytometry analysis of M2 macrophages polarized in the presence of amezalpat displayed concentration-dependent reductions in canonical M2 macrophage markers CD163, CD206, and Arg-1 (p&amp;lt;0.05 by Wilcoxon’s test). ELISA measurement of cytokine production by amezalpat-treated M2 macrophages demonstrated a statistically significant reduction in the suppressive cytokines IL-10 (n=8; p&amp;lt;0.05 by Wilcoxon’s test) and TGF-β (n=3 by One-way ANOVA), suggesting amezalpat-induced functional impairment of this population. Additionally, amezalpat treatment of M2 macrophages caused significant reductions in mitochondrial mass, measured with a mitochondria-specific dye by flow cytometry (p&amp;lt;0.01 by two-sample T test). Finally, in co-cultures of M2 macrophages with autologous activated CD8+ T cells and HCC tumor cells (SNU-449), amezalpat induced tumor cell cytotoxicity and M2 cell death commensurate with cell-type specific expression levels of its target PPARα. Together, these data suggest amezalpat modulates suppressive macrophage development and function and supports the contribution of an immune-mediated mechanism to anti-tumor activity reported in clinical studies. Citation Format: Mandy I. Cheng, Ademola Esomojumi, Dara Burdette, Valerie Chen, Jorg H. Fritz, Sam Whiting, Nathan Standifer. Amezalpat, a peroxisome proliferator-activated receptor alpha (PPARα) antagonist, inhibits suppressive macrophage development, activation and function [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 2171.