tbuckley/cabot-search huggingface dataset:
Abstract 6750: QLS5132, a highly selective anti-CLDN6 ADC with broader therapeutic window
Authors: Ying Huang, Zhongcui Sun, Shuyong Zhao, Xinmei Wang, Ling Zhang, Yang Yang, Hua Ying, Weikang Tao
Journal: Cancer Research (2025)

Abstract Background: Claudin-6 (CLDN6), a member of the claudin family, is localized in the tight junctions of epithelial cells to regulate permeability, barrier function and polarity of epithelial layers. CLDN6 is notably upregulated in multiple solid tumor types, including ovarian cancer, testicular cancer, endometrial cancer and non-small cell lung cancer, while exhibiting minimal or no expression in healthy adult tissues. Therapeutic potential of CLDN6 as a target for ADC was unraveled by TORL-1-23, a clinical stage ADC drug with MMAE as the payload from TORL BioTherapeutics, LLC, while QLS5132, a novel CLDN6-targeting ADC in IND-enabling stage, demonstrates superior efficacy and tolerability to TORL-1-23. Method: QLS5132 is composed of a humanized anti-CLDN6 hIgG1 antibody with no cross-reactivity to CLDN9 conjugated to Qilu’s proprietary topoisomerase-1 inhibitor, QLS6916, via a hydrophilic cleavable linker. The payload QLS6916 showed nanomolar activity across a wide range of cancer cell lines in vitro and rapid systematic clearance in rodent models. Result: QLS5132 showed sub-nanomolar activity in CLDN6-positive cancer cell lines, with faster internalization efficacy and stronger bystander killing activity than TORL-1-23. In in vivo pharmacology studies, QLS5132 demonstrated superior antitumor efficacy to TORL-1-23 across a panel of ovarian cancer cell line-derived xenograft (CDX) models with varying levels of CLDN6 expression. Furthermore, QLS5132 displayed synergistic activity when combined with PARP inhibitors in CLDN6-expressing ovarian CDX models, indicating its potential for possible combination with PAPR inhibitors in ovarian cancers. QLS5132 was well tolerated in cyno monkeys, with HNSTD up to 60 mpk Q3W x 4 in non-GLP toxicity study, which is 5 folds higher to TORL-1-23. Conclusion: QLS5132 showed an expanded therapeutic window with superior efficacy and tolerability to TORL-1-23 in preclinical models. QLS5132 also demonstrated great potential to combine with PARPi in CLDN6 positive ovarian cancers. QLS5132 is expected to offer a novel and promising treatment option either as a single agent or combo with PARPi or other SoCs for patients with CLDN6 expressing tumors. QLS5132 will enter clinical trials. Citation Format: Ying Huang, Zhongcui Sun, Shuyong Zhao, Xinmei Wang, Ling Zhang, Yang Yang, Hua Ying, Weikang Tao. QLS5132, a highly selective anti-CLDN6 ADC with broader therapeutic window [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 6750.
Abstract 6498: Development of a rat model to study <i>ESR1</i> mutations in estrogen receptor-positive breast cancer
Authors: Lillian He, Wen Bu, Ruixin Xu, Yi Li
Journal: Cancer Research (2025)

Abstract Estrogen receptor α (ER)-positive breast cancers constitute approximately 70% of all breast cancers and are commonly treated with surgery and endocrine adjuvant therapies. While these treatments significantly reduce mortality, resistance to endocrine therapies often emerges, leading to metastatic disease. One notable mechanism of resistance is ESR1 gene mutations, which usually alter the ligand-binding domain of ERα. To advance the understanding of ESR1 mutation-driven tumorigenesis and metastasis, an immunocompetent animal model is essential. Existing models, such as patient-derived xenografts, lack an intact immune system. However, rat mammary tumors are predominantly ER-positive, offering a unique advantage over mouse models, which typically form ER-negative tumors. Despite this, no rat models harboring ESR1 mutations currently exist. Here, we report the development of a novel ER-positive breast cancer model in rats carrying the Esr1 D538G somatic mutation, created using a CRISPR-Cas9-mediated homology-directed repair (HDR) precision genome-editing approach. The Esr1 D538G mutation is paired with a tumor-initiating Neurofibromin 1 (Nf1) loss-of-function mutation which was previously shown to establish ER-positive and estrogen-dependent rat mammary tumors. Detailed characterizations of this tumor model will be presented at the conference. This innovative platform provides an essential tool for investigating mechanisms of endocrine resistance in ER-positive breast cancer and for exploring novel therapeutic strategies to treat endocrine-resistant breast cancer. Citation Format: Lillian He, Wen Bu, Ruixin Xu, Yi Li. Development of a rat model to study ESR1 mutations in estrogen receptor-positive 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 6498.
Abstract 3520: EM1031, a novel KLK2 x CD3 bispecific T-cell engager with highly effective efficacy in preclinical models
Authors: Zelong Ma, Beilei Shi, Zheng Wei, Weiqing Guo, Li Hu, Yixuan Li, Xuan Wu, Shiyong Gong, Danqing Wu, Chengbin Wu
Journal: Cancer Research (2025)

Therapeutic options for metastatic castration-resistant prostate cancer (mCRPC) are limited within hormonal therapies, taxane-based chemotherapies and palliative radiotherapy. Currently available targeted therapies or immunotherapies have limited efficacy and can only benefit a small population of mCRPC patients. Human kallikrein 2 (KLK2) is a membrane-bound trypsin-like serine protease that shares 78% homology with prostate specific antigen (PSA). Directly regulated by androgen receptor (AR), KLK2 is specifically expressed in epithelial cells of prostate and prostate cancer cells and was considered as a promising tumor associated target. In this case, we have developed EM1031, a novel KLK2 x CD3 bispecific T-cell engager (TCE) based on EpimAb’s proprietary CD3 antibody and bispecific antibody platform, adopting optimized CD3 affinity and binding arm valency to achieve potent redirected tumor cell lysis while maintaining minimal cytokine release. In vitro T-cell activation and cytokine release assay showed that EM1031 activates T cells only in the presence of KLK2 positive target cells. A clinical stage reference KLK2 TCE was also generated with published sequences for comparison. In preclinical studies, EM1031 showed less cytokine release against KLK2 positive prostate cancer cell lines than the reference KLK2 TCE, while it maintained comparable in vitro tumor cell killing activity. In xenograft models derived from KLK2 positive prostate cancer cell lines, EM1031 completely eradicated tumors with lower cytokine release compared to the reference TCE. Taken together, these data suggest that EM1031 has the potential in the treatment of prostate cancer. Citation Format: Zelong Ma, Beilei Shi, Zheng Wei, Weiqing Guo, Li Hu, Yixuan Li, Xuan Wu, Shiyong Gong, Danqing Wu, Chengbin Wu. EM1031, a novel KLK2 x CD3 bispecific T-cell engager with highly effective efficacy in preclinical 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 3520.
Abstract 1935: New emerging patients-derived circulating tumor cells (CTCs) as promising tools for cancer research
Authors: Paul Lovell, Karlie Wysong, Fang Tian
Journal: Cancer Research (2025)

Abstract Circulating tumor cells (CTCs) play a significant role in understanding the mechanisms of cancer biology and, more specifically, metastatic tumors. CTCs are cells from a primary tumor that break away to circulate through the bloodstream and metastasize in other areas of the body. CTCs have been proposed as valuable tools for the early diagnosis, monitoring, and identification of tumor progression as they provide possible new therapeutic targets. However, CTCs have relatively low numbers in the bloodstream as compared to other cell types, which makes isolating and establishing a CTC line difficult. Further, while researchers are able to identify and isolate these cells with new techniques, there is a lack of established CTC lines that are widely available to the research community for basic mechanism studies and translational research. Collaborating with leading research institutions, ATCC® is putting effort into developing methods and protocols for the expansion and characterization of human CTC lines isolated from clinical patient samples. In this study, we demonstrated the propagation and characterization of a melanoma CTC line MEL 167 (ATCC® CRL-3651™), which originated from a metastatic melanoma patient sample. Here, we evaluated the MEL 167 cell line at the genetic and protein levels and assessed its bio-functional aspects. Genetic profiling of MEL 167 by sequencing analysis revealed various oncogenes that may enable the progression of metastasis. Immunofluorescence staining was performed to assess the presence of a distinct melanoma molecular marker panel. Additionally, the drug response to BRAF-inhibitors of MEL 167 was evaluated. We also compared the drug profile of this new CTC model to the established melanoma cell line model A375 and two other drug-resistant melanoma cell lines that were created through CRISPR gene editing. We found that melanoma metastases are highly malignant with a low response rate to immunotherapies and high potential for relapse from drug-resistance stemming from tumor heterogeneity. As a newly emerging CTC model, MEL 167 (ATCC® CRL-3651™) offers a promising tool for pre-clinical studies and for evaluating CTCs in the early diagnosis and monitoring of metastatic melanoma. Citation Format: Paul Lovell, Karlie Wysong, Fang Tian. New emerging patients-derived circulating tumor cells (CTCs) as promising tools for cancer research [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 1935.
Abstract 6739: Antibody-drug conjugates with novel payloads are enabled by an ultra-high DAR platform
Authors: Emmalyn Lecky, Adam Voelker, Isabella Ranieri, Andrew Kassick, Cassandra Crihfield, Christopher Fried, Destiny Carpenter, David Wilson, Robert Fryberger, Jingyi Li, Amanda Mincey, Matthew Cummings, Alex Toker, Krzysztof Matyjaszewski, Antonina Simakova, Laura E. Benjamin
Journal: Cancer Research (2025)

Abstract Antibody-drug conjugates (ADCs) have emerged as a powerful modality to increase the therapeutic index of potent chemotherapy drugs by selectively increasing drug delivery to tumor cells while minimizing exposure to non-tumor tissue. Recent advances have improved efficacy by increasing the drug-antibody ratio (DAR) and optimizing linkers to reduce payload release in plasma and increase release within tumor tissue. Despite this significant progress and the clinical success of recent ADCs, particularly in breast cancer, challenges persist, including managing toxicity and diversifying payload classes to broaden the clinical applications of ADCs. This study demonstrates the engineering and biological potency of ADCs comprised of 50-200 single or mixed kinase inhibitors, enabling the utilization of previously unusable payloads. Small molecules are linked to a specialized polymer scaffold using cathepsin-cleavable linkers and internalized by tumor cells in an antibody target-dependent manner, where they inhibit signaling pathways essential for survival. These HER2-targeted biomolecules combined with payloads inhibiting PI3K/mTOR (apitolisib) or MEK (cobimetinib) demonstrate the use of ADCs as precision medicine to selectively target cancer cells via antibody and payload. For example, many HER2-positive tumors also carry oncogenic mutations in the PI3K pathway rendering those tumors exquisitely sensitive to these ADCs, especially when HER2 expression is low. As shown in Table 1, PI3K pathway mutations can increase the sensitivity to ADCs with apitolisib as a payload, in some cases surpassing the potency of the exatecan derivative DXd in trastuzumab-DXd (DAR8). We will also present data supporting the in vivo safety and efficacy of these ADCs which may provide a novel solution to expand the therapeutic landscape, particularly for HER2-positive cancers. Citation Format: Emmalyn Lecky, Adam Voelker, Isabella Ranieri, Andrew Kassick, Cassandra Crihfield, Christopher Fried, Destiny Carpenter, David Wilson, Robert Fryberger, Jingyi Li, Amanda Mincey, Matthew Cummings, Alex Toker, Krzysztof Matyjaszewski, Antonina Simakova, Laura E. Benjamin. Antibody-drug conjugates with novel payloads are enabled by an ultra-high DAR 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 6739.
Abstract 3965: Targeting mTORC2 in lung squamous cell carcinoma improves anti-tumor immunity through the PSGL-1-VISTA axis
Authors: Verra Ngwa, Yoonha Hwang, Wenqiang Song, Deanna Edwards, Jin Chen
Journal: Cancer Research (2025)

Abstract Lung squamous cell carcinoma (LUSC) represents 30% of non-small cell lung cancer (NSCLC) cases and has a high mortality rate with limited targeted therapies. Unlike lung adenocarcinoma (LUAD), which has seen advancements in targeted therapies, LUSC has not benefited from similar breakthroughs despite having similar genetic abnormalities. While immune checkpoint inhibitor therapies have shown promise in some LUSC patients, a significant portion does not respond effectively, leaving limited treatment options. The metabolic landscape of tumors plays a crucial role in shaping the efficacy of immunotherapies, especially adoptive T cell therapies. However, identifying actionable metabolic vulnerabilities involved in T cell therapy is poorly understood. In this study, we investigated vulnerabilities in NSCLC and found that a substantial number of LUSC patients have genetic alterations in the PI3K-mTORC2-AKT signaling pathway. By using CRISPR/Cas9, we showed that disrupting mTORC2 function in LUSC cells reduced glycolysis and lactate secretion, which in turn reduced tumor growth in vivo. Remarkably, the loss of mTORC2 also enhanced the activity of cytotoxic T cells within the tumors. To further understand the metabolic and immune changes associated with mTORC2 loss of function, we performed RNA sequencing comparing wild-type (WT) and mTORC2-deficient cells. Our results confirmed a link between mTORC2 and HIF-2α, while regulating PSGL-1, a ligand of the VISTA/PD-1H checkpoint receptor. Furthermore, introducing a stable, non-degradable form of HIF-2α in mTORC2-deficient tumor cells restored PSGL-1 expression in vitro and in vivo. These results suggest that the interaction between PSGL-1 and VISTA plays a role in suppressing the anti-tumor immune response in LUSC tumors. Indeed, anti-VISTA treatment inhibited the growth of LUSC WT tumors in vivo, suggesting that mTORC2 plays a role in regulating PSGL-1 expression in the tumor microenvironment. Together, these data demonstrate that targeting mTORC2 or inhibiting VISTA checkpoint receptor may serve as a potential therapeutic strategy for improving immunotherapy in LUSC. Experiments are underway to perform an in vivo CRISPR screening to uncover metabolic genes that can modulate the immune response in lung squamous cell carcinoma (LUSC) while sensitizing this tumor subtype to T cell therapy. Citation Format: Verra Ngwa, Yoonha Hwang, Wenqiang Song, Deanna Edwards, Jin Chen. Targeting mTORC2 in lung squamous cell carcinoma improves anti-tumor immunity through the PSGL-1-VISTA axis [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 3965.
Abstract 3988: Patient-specific 3D engineered microphysiological systems to model triple-negative breast cancer chemotherapy using patient-derived xenograft (PDX) tissue
Authors: Edgar A. Borrego, Linjie Luo, Janine Hagar-Montoya, Jose L. Perez, Paula Delgado, Khandan Keyomarsi, Sylvia L. Natividad-Diaz
Journal: Cancer Research (2025)

Abstract Chemotherapy efficacy and pharmacokinetics are influenced by a patient’s unique characteristics, including gender, ethnicity, age, gene expression, and disease state. Three-dimensional (3D) tissue models integrated into microfluidic devices offer a controlled and reproducible platform to study cellular responses to drugs, leveraging fluid circulation for precise quantification. These models can be tailored to individual patients through the incorporation of patient-derived xenograft (PDX) tissues, which are purified and encapsulated within biomimetic hydrogels that replicate the tumor extracellular matrix (ECM). The objective of this study was to develop a patient-specific 3D model of triple-negative breast cancer (TNBC) cultured in a self-driven, closed-capillary microfluidic device to assess chemotherapy efficacy, toxicity, and tumor microenvironment interactions in vitro. We hypothesized that integrating human TNBC PDX tissue into customized microfluidic devices would create physiologically relevant systems to study disease pathology and treatment responses in vitro. TNBC-PDX tissues were isolated to establish a cell line expressing human EpCAM with a population doubling time of 48 hours. A CC50 value of ∼10 µM was determined via flow cytometry viability assays following treatment with a 10-fold dilution series of Doxorubicin (DOX). The cells were encapsulated in 3D collagen hydrogels (0.2 wt%) and cultured in transwell (TW) dishes or microfluidic devices (DwP). These 3D TNBC-PDX models demonstrated viability, elongated morphology, and tumor-like clustering within DwP, reorganizing according to device microfeatures. When treated with 10 µM DOX, the 3D cultures in both TW and DwP conditions exhibited limited cell death, reflecting the original tumor’s drug-resistant phenotype. These findings highlight the feasibility of integrating PDX tissues into microfluidic systems to create patient-specific 3D models, offering a physiologically relevant platform for evaluating chemotherapy responses. This approach may advance personalized cancer treatment strategies by enabling in vitro assessment of drug efficacy and resistance mechanisms. Citation Format: Edgar A. Borrego, Linjie Luo, Janine Hagar-Montoya, Jose L. Perez, Paula Delgado, Khandan Keyomarsi, Sylvia L. Natividad-Diaz. Patient-specific 3D engineered microphysiological systems to model triple-negative breast cancer chemotherapy using patient-derived xenograft (PDX) tissue [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 3988.
Abstract 6070: A novel epitope specific TIM-3 antibody significantly enhanced anti-tumor activities with bispecific format, not with combination strategy
Authors: Xin Dong, Bu Tining, Bishnu Nayak, Jinyu Dong, Meiguang Xiong, Binbin Wang, Dong Wang, Haojie Wang, Yu Zhang
Journal: Cancer Research (2025)

Abstract Introduction: T-cell immunoglobulin and mucin domain containing-3 (TIM-3) is expressed on T cells, NK cells and some myeloid cells, like macrophage and dendritic cells. Moreover, TIM-3 plays as a negative regulatory receptor and increased expression upon resistance to checkpoint inhibitor therapy. Particularly, recent studies strongly suggest that TIM-3 on myeloid cells, like dendritic cells, play a critical role for anti-tumor activity. Therefore, the dual blockade of PD-1 and TIM-3 holds hopes for enhanced clinical benefits. Results: we have designed a bispecific anti-PD-1/TIM-3 antibody to optimize the immune response and anti-tumor activities by utilizing a novel epitope-specific anti-human TIM-3 antibody which displays enhancing NK cell activity and improving antigen processing ability of antigen presenting cells (APC), like DCs. This PD-1/TIM-3 bispecific antibody has demonstrated high affinity binding to human TIM-3 and PD-1 in the low nanomolar range. Moreover, it simultaneously binds to TIM-3 and PD-1 receptors through a trans manner, suggesting its potent capacity to enhance the interaction between T-cells and dendritic cells (DCs). In both MLR (mixed lymphocyte reaction) and T cell stimulation assays, the PD-1/TIM-3 exhibits synergistic activity compared to combination of PD-1 mAb and TIM-3 monoclonal antibodies or mAb alone. In addition, we have demonstrated superior anti- tumor activities in PBMC humanized xenograft mouse model as well as syngeneic human PD-(L)1 and human TIM-3 knock-in mice. Conclusion: A bispecific humanized PD-1/TIM-3 antibody binds to both human PD-1 and TIM-3 strongly and effectively blocks the interaction with its ligand. This bispecific antibody enhances immune responses and anti-tumor activities in vitro and in vivo as measured by MLR assay, various animal models, etc., supporting the synergistic effects by targeting both acquired and innate immunity with this bispecific antibody. Citation Format: Xin Dong, Bu Tining, Bishnu Nayak, Jinyu Dong, Meiguang Xiong, Binbin Wang, Dong Wang, Haojie Wang, Yu Zhang. A novel epitope specific TIM-3 antibody significantly enhanced anti-tumor activities with bispecific format, not with combination strategy [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 6070.