tbuckley/cabot-search huggingface dataset:
Abstract 7060: Semi-quantitative lateral flow immunoassay for HPV serology for detection of HPV+ oropharyngeal cancer
Authors: Akshansh Kaushik, Tej Patel, Joshua Eger, Ching Wen Hou, Jennifer Blain Christen, Karen S. Anderson
Journal: Cancer Research (2025)

Abstract Background: HPV (human papilloma virus) is a leading cause of 60-70% of oropharyngeal cancer in the US. Antibodies to HPV early antigens are detectable in serum samples up to two decades prior to diagnosis, so that HPV serology are potential biomarkers for screening. We have developed a rapid colorimetric lateral flow assay (LFA) for the semi-quantitative detection of antibodies for HPV16 CE2 and HPV16 E7 antigens. Methods: Recombinant his-tagged proteins (HPV16 CE2 184-365aa and HPV16 E7) were printed separately on nitrocellulose membranes, with human IgG as a control line. Plasma samples from newly diagnosed HPV+ or p16+ oropharyngeal cases (n=38) and controls (n=46) were selected for assay development and image analysis based on known serostatus. The plasma was applied to the membranes, washed and blocked with casein, and antibodies were detected using a gold-conjugated protein G secondary antibody. A Python program was developed using the OpenCV library for image processing and the scipy.signal library was used to detect bands on the strip as peaks. The area under the curve for these peaks was calculated, with a threshold &amp;gt;700 unit squares. The seropositivity of the LFA was compared with laboratory-based RAPID ELISA HPV serology. Results: By RAPID ELISA, the sensitivity of CE2 serology was 84% and E7 was 78.9% at &amp;gt;97% specificity for the plasma samples specifically selected for the assay development (not a random or matched cohort). On the LFA, the sensitivity of CE2 serology was 52.6% and E7 was 76.3% at &amp;gt;97% specificity. By LFA, 89.5% of cases were positive for either CE2 or E7 serology at 95.6% specificity, with strong concordance with RAPID ELISA (κ=0.853). Conclusion: The LFA test demonstrated high concordance for detecting antibodies in plasma samples compared to RAPID ELISA, providing a promising point-of-care tool for large-scale screening of oropharyngeal cancer. Citation Format: Akshansh Kaushik, Tej Patel, Joshua Eger, Ching Wen Hou, Jennifer Blain Christen, Karen S. Anderson. Semi-quantitative lateral flow immunoassay for HPV serology for detection of HPV+ oropharyngeal 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 7060.
Abstract 7004: CT7439 an oral first-in class selective CDK12 and 13 inhibitor and cyclin K degrader: Profiling activity and combination efficacy in an ovarian cancer model
Authors: Ashwani K. Bahl, Matthew Carr, Stuart Thompson, Adrian Campbell, Andrew Leishman, Edward Ainscow
Journal: Cancer Research (2025)

Abstract CT7439 is a small molecule kinase inhibitor of cyclin-dependent kinases CDK12/CDK13 that received FDA IND approval in 2023. In addition to inhibiting CDK12/13, CT7439 acts as a monovalent glue degrader of cyclin K (CCNK), the cyclin required for CDK12/13 function. Proteomics quantification by DIA LCS/LCSMS mass spectrometry was conducted after exposure to 30 nM CT7439 at 4 &amp; 24 hr. OV-90 cells were cultured in media and exposed to CT7439 at various concentrations and time points. Combination studies were conducted with the PARP inhibitors and Carboplatin. The following parameters were assessed: proliferation/cell survival, confluency formation, CCNK protein levels and DNA damage and repair (DDR) genes. CT7439 inhibited OV-90 cell growth with an IC50 of 4.4nM and this impact on cell growth was significantly attenuated by co-treatment of the cells with proteasome inhibitor. Proteomics analysis revealed that 99 proteins were found to be differentially abundant between samples from CT7439 (30 nM) treated and vehicle at 4 hrs. At 24 hrs 1, 666 proteins were found to be differentially abundant. CCNK was the only cyclin impacted by CT7439. Pathway and ontology analysis showed reduced abundance for proteins involved in DDR. DDR genes (BRCA1, ERCC4, RAD51C and POLQ) are inhibited by treatment with CT7439, at concentrations consistent with inhibition of CDK12/13-Cyclin K in the cells. CT7439 activity in OV-90 in cellular assays: Data is mean ± SD (**Western blot, *qPCR) In addition to single agent activity of CT7439 a strong combination activity between CT7439 and the PARP inhibitors Olaparib, Niraparib and AZD10530 as well as the carboplatin was observed in an OV-90 cellular confluency assay. CT7439 is an orally bioavailable selective CDK12/13 inhibitor and degrader of CCNK. Pre-clinical studies demonstrates clinical potential for monotherapy use in solid tumors and as a combination therapy with agents known to cause a DNA damage response. Citation Format: Ashwani K. Bahl, Matthew Carr, Stuart Thompson, Adrian Campbell, Andrew Leishman, Edward Ainscow. CT7439 an oral first-in class selective CDK12 and 13 inhibitor and cyclin K degrader: Profiling activity and combination efficacy in an ovarian cancer model [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 7004.
Abstract 4482: Development of a stable and efficient therapeutic mRNA cancer vaccine utilizing RNA-plex technology
Authors: Yongbin Liu, Dongfang Yu, Lingyi Huang, Junhua Mai
Journal: Cancer Research (2025)

Abstract Background: Therapeutic mRNA vaccine is a promising approach for cancer immunotherapy. However, one of its major challenges is the inherent instability of mRNAs, as it is highly sensitive to ambient environments. Consequently, current mRNA vaccines require production, shipping, and storage at ultra-low temperatures, limiting their global application and increasing costs. Thus, enhancing mRNA stability is essential to develop stable mRNA-based therapeutic vaccines. Methods: In this study, we developed a novel mRNA stabilization technology termed "RNA-plex", which prevents mRNA from hydrolytic degradation using polymeric macromolecules known as “carrier-base”, composed of a poly-glutamic/aspartic acid backbone conjugated with nucleobases. Results: We demonstrated that unprotected (naked) mRNA was completely degraded after incubation at 95°C in only 5 minutes, while mRNA complexed with carrier-base remained intact, showing resistance to hydrolytic degradation at high temperatures. Additionally, RNA-plex stabilized mRNA in water at room temperature (RT) for over two weeks and at 4°C for more than two months, whereas naked mRNA degraded within 3 days at RT and within one month at 4°C. Moreover, the protective effect of carrier-base is independent of RNA sequence and structure, effectively safeguarding various linear mRNAs, circular RNAs, and single guide RNAs, and being compatible to commonly used RNA delivery systems. In addition to mRNA protection, RNA-plex effectively boosts mRNA translation in 293T cells and antigen presentation in dendritic cells, making it a potent tool for enhancing cellular responses. We prepared mRNA vaccines by encapsulating either naked OVA mRNA or OVA RNA-plex within in vivo-jetRNA (jetRNA), a liposomal in vivo mRNA transfection reagent, and tested its effectiveness in cancer immunotherapy in an ovalbumin (OVA) engineered B16 melanoma model (B16-OVA). The jetRNA-RNA-plex formulation demonstrated robust efficacy in inhibiting melanoma growth compared to the formulation containing naked mRNA only (p&amp;lt;0.01). Conclusion: Our findings demonstrate that the RNA-plex technology effectively stabilizes mRNA, offering impressive potential for long-term storage in ambient environment. Moreover, RNA-plex enhances mRNA translation and significantly improves anti-cancer efficacy in cancer vaccines by eliciting a robust anti-tumor immune response. These promising results suggest that RNA-plex holds substantial potential for advancing mRNA-based therapeutics for cancers. Citation Format: Yongbin Liu, Dongfang Yu, Lingyi Huang, Junhua Mai. Development of a stable and efficient therapeutic mRNA cancer vaccine utilizing RNA-plex technology [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 4482.
Abstract 6995: Novel 4,6-disubstituted-7<i>H</i>-pyrrolo[2,3-<i>d</i>]pyrimidines as dual mEGFR/AURK inhibitors for non-small cell lung cancer
Authors: Sonali Kurup, QiQi Hu, Kexin Zheng, Samantha Satawa, Felix Amissah, Erika Lisabeth
Journal: Cancer Research (2025)

Abstract The epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs) constitute the recommended therapy for non-small cell lung cancer (NSCLC) expressing mutant epidermal growth factor receptor (mEGFR). Resistance to first-generation EGFR-TKIs was addressed by osimertinib, an irreversible EGFR-TKI. However, newer mutations and redundant signaling pathways continue to drive resistance to osimertinib in mEGFR+ NSCLC. There are currently no viable EGFR-mediated treatments for osimertinib-resistant NSCLC. The aurora kinases (AURKA, AURKB) are mitotic kinases involved in centrosome maturation and separation during mitosis and can contribute to tumorigenesis. The AURK inhibitors have resensitized osimertinib-resistant mEGFR+ NSCLC cells when combined with osimertinib. Thus, dual mEGFR/AURK inhibition provides a unique approach for mEGFR+NSCLC. Kurup et al. previously investigated 4-substituted-7H-pyrrolo[2,3-d]pyrimidines as dual mEGFR/AURK inhibitors. Compounds 1-8 were developed as 4,6-disubstituted-7H-pyrrolo[2,3-d]pyrimidines to determine their effects as dual mEGFR/AURK inhibitors. The design, synthesis, and evaluation of compounds 1-8 will be presented and discussed. The anticancer effects of dual mEGFR and AURK inhibition in osimertinib-resistant mEGFR+ NSCLC cells will also be presented. Citation Format: Sonali Kurup, QiQi Hu, Kexin Zheng, Samantha Satawa, Felix Amissah, Erika Lisabeth. Novel 4,6-disubstituted-7H-pyrrolo[2,3-d]pyrimidines as dual mEGFR/AURK inhibitors for 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 6995.
Abstract 4484: Targeting DNA repair mechanism that leverages current standard of care interventions with a novel agent in glioma
Authors: Meser M. Ali, Hamid Suhail, Mahesh Yadab, Ataur Rahman, James Snyder
Journal: Cancer Research (2025)

Abstract Glioblastoma (GBM) is a malignant glioma characterized by molecular heterogeneity and poor prognosis. GBM remains a uniformly lethal malignancy, with patient survival rarely exceeding two years despite the best available treatments. In clinical practice, about 60% of GBM patients have shown overexpression of O6-methylguanine-methyl-transferase (MGMT), an enzyme responsible for DNA repair, were found to receive little benefit from TMZ and represent a group of great unmet need with no chemotherapeutic agents that significantly improve survival. A key factor contributing to treatment resistance and disease relapse is the overexpression of MGMT. MGMT overexpression reduces the efficacy of standard therapies like temozolomide (TMZ) and radiotherapy (RT), leaving patients with active MGMT expressions in urgent need of new treatment strategies. The depletion of MGMT in tumors has been investigated as a strategy to increase TMZ and RT efficacies in resistant, MGMT-positive GBMs. Chemical depletion using O6-benzylguanine derivatives as MGMT inhibitors have been actively tested, but these compounds are associated with high hematologic toxicity. Recent studies have shown that disulfiram (DSF), an alcohol aversion drug, combined with copper (Cu), can inhibit MGMT and improve the response to TMZ in GBM. However, phase II clinical trials using oral Cu/DSF demonstrated no survival benefit, primarily due to the instability of DSF in vivo. To address this limitation, we developed a novel delivery system using 2-hydroxypropyl beta cyclodextrin (HPßCD) encapsulating the Cu complex of DSF's active metabolite, diethyldithiocarbamic acid (DDC). This HPßCD-Cu(DDC)2formulation stabilizes the complex, preventing degradation and reducing non-specific interactions in the bloodstream. In vitro studies revealed that HPßCD-Cu(DDC)2 inhibited MGMT through the ubiquitin-proteasome pathway. Inhibition of MGMT activity in cell cultures vastly increased the alkylation-induced DNA double-strand breaks (gama-H2AX), that are hallmark of TMZ effectiveness as supported by cytotoxicity and the increased levels of apoptotic markers, like JNK-P and cleavage of PARP-1. Systemic delivery of HPßCD-Cu(DDC)2 in MGMT overexpressed patient derived orthotropic xenograft resulted in depletion of MGMT with tumor size regression. Tumor burden has been evaluated within patient derived orthotropic rat models that represent high expression of MGMT followed by oral vs intravenous treatments. Citation Format: Meser M. Ali, Hamid Suhail, Mahesh Yadab, Ataur Rahman, James Snyder. Targeting DNA repair mechanism that leverages current standard of care interventions with a novel agent in glioma [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 4484.
Abstract 6996: Integrating high-throughput screening with ligand-based pharmacophore modeling and virtual screening strategies to optimize exonuclease 1 inhibitor design
Authors: Jessica Hess, Li Zheng, Binghui Shen
Journal: Cancer Research (2025)

Abstract Pharmacophores are the specific steric and electronic features of a small molecule that are necessary to ensure interaction with a specific biological target and to trigger or block its biological response. Three-dimensional quantitative structure-activity relationship (3D-QSAR) pharmacophore modeling is a computational approach that utilizes data collected from in vitro experiments and molecular docking to map the shared features of known actives, producing a template that can be used to optimize the physical and chemical properties of lead compounds. Our goal is to generate a 3D-QSAR model for exonuclease 1 (EXO1) inhibition to support the pre-clinical development of a potent, EXO1-specific, small molecule inhibitor and define the molecular interactions that drive inhibitor specificity toward EXO1 instead of related nucleases. Construction of this model will facilitate the development of a potent EXO1 inhibitor that is selective, cancer-specific, and synthetic lethal with BRCAness. Additionally, it will establish a structural foundation for enhancing the selectivity of inhibitors targeting highly similar 5’ nuclease family members, such as FEN1. Here, we describe our approach to integrating the high-throughput and virtual screening data we have collected for ∼365, 000 small molecule compounds to map a preliminary 3D-QSAR hypothesis for EXO1 inhibition. Citation Format: Jessica Hess, Li Zheng, Binghui Shen. Integrating high-throughput screening with ligand-based pharmacophore modeling and virtual screening strategies to optimize exonuclease 1 inhibitor design [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 6996.
Abstract 5025: Applying deep learning transformers and expression quantitative trait loci to interrogate immunogenetic determinants of cancer risk
Authors: Sophie Herszterg, Gustavo Arango-Argoty, Etai Jacob
Journal: Cancer Research (2025)

Abstract The immune system plays a pivotal role in suppressing cancer development through a process known as cancer immunosurveillance. However, substantial immune variation among healthy individuals suggests that the effectiveness of the immune system in eliminating cancer is very likely to vary. This study aims to identify genetic immune characteristics that either protect against or increase cancer risk and to understand how these immune factors interact with known environmental and lifestyle-related risk factors. &amp;#x2028; To achieve this, we have employed a deep learning approach, leveraging transformer models. Transformers can capture complex, non-linear interactions between features, accommodate multimodal input data and incorporate prior knowledge through self-supervised pre-training, which are all relevant properties for our application. As a discovery dataset, we have utilized the UK Biobank, a comprehensive longitudinal cohort consisting of half a million individuals with over 15 years of follow-up. Immune characteristics were derived from plasma proteomics as well as whole genomic sequencing data, in the form of immune cell-specific expression quantitative trait loci (eQTLs). Immune-cell specific eQTLs have been associated with multiple diseases and can provide mechanistic insight into the genetic basis of cancer risk. Here, we share our analysis in exploring immunogenetic factors modulating cancer risk by integrating advanced deep learning techniques with extensive genomic and environmental data. We hope this work will contribute to enhancing our understanding of individual susceptibility to cancer and thereby inform risk stratification strategies and personalized approaches to cancer prevention and intervention, leading to better health outcomes. Citation Format: Sophie Herszterg, Gustavo Arango-Argoty, Etai Jacob. Applying deep learning transformers and expression quantitative trait loci to interrogate immunogenetic determinants of cancer risk [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 5025.
Abstract 7005: Discovery and characterization of DAC-1522, a novel Trop2-targeting degrader-antibody conjugate for precision oncology
Authors: Chuanjie Chen, Qianqian Shen, Xinhui Cai, Yaqi Ding, Xiaoyu Yang, Yanfen Fang, Jiangnan Luo, Jian Ding, Yi Chen, Xuan Zhang
Journal: Cancer Research (2025)

Abstract Antibody-drug conjugates (ADCs) have revolutionized cancer therapies by enabling the targeted delivery of cytotoxic payloads to tumor cells. However, their efficacy and safety heavily rely on the toxins as their payloads, and the rare availability of toxin types often limits their efficacy and broader expansion of indications. Combining the precision targeting feature of ADCs and diverse options of protein degraders, degrader-antibody conjugates (DACs) have emerged as a next-generation therapeutic modality and offer a promising strategy to overcome these challenges. The human trophoblast cell surface antigen 2 (Trop-2) is a transmembrane glycoprotein widely expressed in various types of tumors. It has been clinically proven as a well-suited antigen for ADCs with its widespread overexpression in cancer cells and much lower expression in normal cells. Despite the clinical success of Trop2-targeting ADCs like IMMU-132 (sacituzumab govitecan-hziy), their dependence on topoisomerase inhibitors as payloads has exposed significant limitations, particularly in addressing both intrinsic and acquired drug resistance. This has created an urgent need for innovative therapeutic solutions. Here we introduce DAC-1522, a novel Trop2-directed DAC, that can potentially overcome the limitations of ADCs. In vitro studies have shown that DAC-1522 efficiently degrades the target protein in a dose-dependent manner and exhibits potent antiproliferative activity against multiple human cancer cell lines. Its efficacy is strongly correlated with the level of Trop2, ensuring selective cytotoxicity in Trop2-positive cells and sparing Trop2-negative cells, resulting in a favorable therapeutic window. Notably, DAC-1522 retains uncompromised antiproliferative activity in an ADC-induced acquired drug resistance model, underscoring its potential to overcome the drug resistance after ADC treatments. In vivo, DAC-1522 achieves complete tumor regression with a single intravenous injection in mice (human pancreatic cancer BXPC-3 xenograft model), significantly outperforming IMMU-132 in terms of efficacy. No obvious safety concerns were observed. These findings support further preclinical and clinical development of DAC-1522 as a highly promising therapeutic candidate for the Trop2-expressing cancers. Citation Format: Chuanjie Chen, Qianqian Shen, Xinhui Cai, Yaqi Ding, Xiaoyu Yang, Yanfen Fang, Jiangnan Luo, Jian Ding, Yi Chen, Xuan Zhang. Discovery and characterization of DAC-1522, a novel Trop2-targeting degrader-antibody conjugate for precision oncology [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 7005.
Abstract 4788: Discovery of HX035, an OX40-bi-epitope bi-specific antibody (BsAb), for the treatment of inflammatory/autoimmune diseases
Authors: Hang Ke, Tao Yang, Feiyu Peng, Jialing Li, Cen Chen, Peixuan Song, Lei Zhang, Faming Zhang, Henry Qixiang Li
Journal: Cancer Research (2025)

Abstract With hyperactive OX40+CD4+ T-cells implicated as the pathogenic cells in various inflammatory/autoimmune disorders, we hypothesized that OX40-antagonistic and/or depleting antibody are both important candidate therapeutics for these diseases. To test this hypothesis, we designed and tested a novel bi-specific antibody (BsAb), HX035 and a 1+1 asymmetric IgG1 mAb, against two different OX40 epitopes. Epitope-1 is featured with non-ligand blocking but strong ADCC (depleting antibody), while epitope-2 is characterized by ligand blocking and antagonistic activity. We found that HX035 binds to recombinant OX40 proteins with the similar binding affinity as the respective parental mAbs, with EC50 0.056 nM (avidity) as opposed to 0.027 nM (epitope 1-mAb) and 0.036 nM (epitope 2-mAb), respectively. Although the binding avidity of HX035 to OX40+ cells is similar to its parental mAbs, HX035 showed more binding to OX40lo and even more to OX40hi cells, as anticipated. HX035 is also an OX40 ligand blocker slightly less potency than the epitope 2-mAb (IC50 5.0 nM vs. 2.6 nM). HX035 also showed similar extent of antagonistic activity to epitope2-mAb in an in vitro reporter bioassay. Remarkably, HX035 induced significantly enhanced ADCC over both parental mAbs, making it a stronger depleting antibody than both parental mAbs. We have also further engineered an ADCC-enhanced (5 times stronger) HX035 molecule, so making it an even stronger depleting-antibody. A human PBMC acute graft-versus-host disease (aGVHD) mouse model indeed confirmed the superior anti-aGVHD activities of HX035, over both parental mAbs in the preclinical setting, accompanied with significant depletion of CD4+ T-cells in vivo. All these suggested that HX035 may be a potential “best-in-class” (FIC) candidate for the treatment of autoimmune diseases. Citation Format: Hang Ke, Tao Yang, Feiyu Peng, Jialing Li, Cen Chen, Peixuan Song, Lei Zhang, Faming Zhang, Henry Qixiang Li. Discovery of HX035, an OX40-bi-epitope bi-specific antibody (BsAb), for the treatment of inflammatory/autoimmune diseases [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 4788.