bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 6357: Establishing a reverse translational platform to dissect mode of action and mechanisms of resistance to GUCY2C-CD3 T cell engager
Authors: Borlido Joana , Lolarga Jade , Whaley Rachael , Damore Michael A. , Guo Cen , Abayasiriwardana Keith , Xu Xiaojun , Liu Maggie , Nocula-Lugowska Gosia , Stoner Sam , Kraser Christopher , Cheronis Ioanna , Delioukina Maria , Clark Lee , Bhadra Raj , Gururajan Murali 
Published: March 2024

Abstract
PF-07062119 (GUCY2C x CD3), a bispecific T cell engager (TCE) targeting Guanylyl Cyclase C (GUCY2C), a GI tumor associated antigen, is currently being evaluated in a Phase 1 clinical trial in colorectal cancer (CRC) and other GI malignancies. Improved pre-clinical understanding of the correlates of PF-07062119 resistance mechanisms and PD in a human disease relevant context is critical to better inform drug combination and patient selection strategy. Due to limited translatability of mouse syngeneic tumor models, establishing a more human disease-relevant platform leveraging tumor patient material to better inform PF-07062119 clinical strategy is needed. Here, we will discuss our efforts to perform immune profiling of T cell and myeloid tumor infiltrates, and to evaluate tumor cell depletion and cytokine production of colorectal carcinoma (CRC) samples treated ex vivo with PF-07062119. This platform may be leveraged to 1) provide clinically relevant disease insights to the effect of TCEs across a range of tumor indications; 2) determine impact of different combinatorial partners on tumor cell killing to inform clinical decisions; 3) address questions related to the minimal efficacy of TCEs in the solid tumor space; and 4) provide potential solutions for future combination partners to overcome immunosuppression in the tumor microenvironment.
Citation Format: Joana Borlido, Jade Lolarga, Rachael Whaley, Michael A. Damore, Cen Guo, Keith Abayasiriwardana, Xiaojun Xu, Maggie Liu, Gosia Nocula-Lugowska, Sam Stoner, Christopher Kraser, Ioanna Cheronis, Maria Delioukina, Lee Clark, Raj Bhadra, Murali Gururajan. Establishing a reverse translational platform to dissect mode of action and mechanisms of resistance to GUCY2C-CD3 T cell engager [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 6357.
Abstract 6361: KY-HC-mouse: A low-cost and rapid nanobody discovery platform
Authors: Wu Guojin , Hao Feng , He Feng , Peng Hao , Gu Yi , Ning Jinying 
Published: March 2024

Abstract
Nanobodies, primarily derived from camelid animals, have gained prominence in antibody-drug development due to their small molecular weight and ease of modification. However, the high cost associated with camelid animals for nanobody discovery led us to develop a strain of heavy-chain mice known as KY-HC-mouse. This genetically modified mouse expresses IgG without the CH1 domain, resulting in the production of nanobodies in IgG format. Utilizing hybridoma techniques, we developed a variety of nanobodies against multiple targets, such as PSMA, CD38, PD-L1, CD28, and 4-1BB, from KY-HC-mouse. These nanobodies all demonstrate high affinity, with KD ranging from 0.01 nM to 10 nM. We also selected antagonist nanobodies that block the interaction of PD1 and PDL1, as well as agonist nanobodies that stimulate 4-1BB signaling in T cells. After humanization, most nanobodies have a half-life of more than five days in the blood of both mice and monkeys. Subjected to various treatments, such as high concentration, low pH, repeated freezing and thawing, and high temperature, most humanized nanobodies show neither aggregation nor degradation, suggesting good developability of these nanobodies. Finally, we have developed multiple bispecific antibodies (BsAbs) targeting both PDL1 and 4-1BB, PSMA and 4-1BB, or B7H3 and 4-1BB. These BsAbs exhibit good developability and efficacy. In conclusion, our KY-HC-mouse is a powerful nanobody discovery platform.
Citation Format: Guojin Wu, Feng Hao, Feng He, Hao Peng, Yi Gu, Jinying Ning. KY-HC-mouse: A low-cost and rapid nanobody discovery platform [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 6361.
Abstract 6364: The bispecific antibody KA-3006 against both EGFR and MET surpasses amivantamab in efficacy
Authors: Wu Guojin , Liang Jiabei , Peng Hao , Hao Feng , Liu Tongtong , Ning Jinying 
Published: March 2024

Abstract
A bispecific antibody (BsAb) like amivantamab, which targets both the epidermal growth factor receptor (EGFR) and mesenchymal-epithelial transition factor (MET) by blocking downstream pathways, has been proven to overcome resistance to targeted therapies, including EGFR inhibitors, in patients with various cancers. In this study, we developed a bispecific antibody, KA-3006, targeting both EGFR and MET using our common light chain antibody discovery platform. KA-3006 has a regular antibody structure with an identical light chain, developed through knob-into-hole technology. It exhibits high affinity for MET and relatively low affinity for EGFR. KA-3006 specifically blocks both the binding of EGF to EGFR and HGF to MET with higher efficiency than amivantamab, resulting in the blockade of downstream signaling from EGFR and MET. In comparison to amivantamab, KA-3006 demonstrates a faster internalization rate when binding to the surface of tumor cells expressing both EGFR and MET. KA-3006 showed superior antitumor activity over amivantamab in the HCC827-HGF in vivo model. Additionally, KA-3006 has a half-life of more than five days in the blood of Balb/c mice. Finally, we assessed the developability of this BsAb with different treatments such as high concentration, low pH, repeated freezing and thawing, and high temperature, and KA-3006 showed neither aggregation nor degradation. In conclusion, the BsAb KA-3006, developed with our common light chain antibody discovery platform, is a promising pre-clinical candidate drug for the treatment of various solid cancers with overactivated EGFR and MET signaling, and it holds potential for developing ADCs targeting both EGFR and MET.
Citation Format: Guojin Wu, Jiabei Liang, Hao Peng, Feng Hao, Tongtong Liu, Jinying Ning. The bispecific antibody KA-3006 against both EGFR and MET surpasses amivantamab in efficacy [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 6364.
Abstract 6480: In-hospital mortality risk factors for uveal melanoma patients in the emergency department
Authors: Beneke Alice A. , Taneja Kamil , Ladehoff Lauren , Root Kevin , Toloza Eric 
Published: March 2024

Abstract
Purpose: A considerable amount of uveal melanoma patients present to the emergency department (ED) for a complication related to their primary tumor. However, there is not much research into the primary reasons for these patients to present to the ED and their outcomes.
Methods: The Nationwide Emergency Department Sample was queried from the last quarter of 2015 to 2019 to identify patients with a diagnosis of uveal melanoma. Multivariable logistic regression, with patient- and hospital-level characteristics as covariates, was used to identify factors associated with increased risk of in-hospital death.
Results: From the last quarter of 2015 to 2019, there were 7,561 ED encounters with a secondary diagnosis of uveal melanoma. Most patients were at least 65 years of age (43.5%), male (52.5%), and a Medicare beneficiary (44.2%), or belong to a family in the 3rd income quartile (25.6%). The median age of these patients was 61 years (IQR: 32-74). Most patients presented to hospitals in the South (40.8%), with a Trauma Level I designation (47.2%), and to a metropolitan teaching hospital (72.6%). The most common diagnosis for presentation to the ED were the following general clinical categories: blood disorders (7.1%), genitourinary tract disorders (5.1%), infections (6.0%), respiratory diseases (9.0%), nervous system disorders (4.8%), endocrine/nutrition disorders (4.3%), and vascular disorders (8.3%). The rate of metastatic uveal melanoma was 5.8%. The rate of in-hospital mortality was 3.6%. In a multivariable logistic regression identified the following clinical categories as factors associated with a higher risk of in-hospital death: infections (odds ratio [OR]=10.22; p&lt;0.001), metastases (OR=10.22; p&lt;0.001), genitourinary tract disorders (OR=7.05; p&lt;0.001), respiratory diseases (OR=3.31; p=0.031), and vascular disorders (OR=3.14; p=0.044). Nervous system, blood, and endocrine/nutrition disorders were not associated with a higher rate of in-hospital mortality. The only demographic variable associated with a higher risk of in-hospital death was being part of the top income quartile (OR=3.10; p=0.14).
Conclusion: Physicians have to be mindful of different complications associated with uveal melanoma that can lead to presentation to the ED and possible in-hospital death. Specifically, physicians need to be mindful of infections, metastases, genitourinary tract disorders, respiratory diseases, and vascular disorders in these patients.
Citation Format: Alice A. Beneke, Kamil Taneja, Lauren Ladehoff, Kevin Root, Eric Toloza. In-hospital mortality risk factors for uveal melanoma patients in the emergency department [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 6480.
Abstract 6505: Targeting PINK1 reduces medulloblastoma progression in animal models
Authors: Alsubaiee Reema N. , Alghamdi Amani , Alrfaei Bahauddeen M. 
Published: March 2024

Abstract
Medulloblastoma is a brain cancer that mainly arises during infancy and childhood. Medulloblastoma is the most common pediatric malignant brain tumor worldwide. It comprises of approximately 20% of all childhood brain tumors and 63% of intracranial embryonic tumors. One of the major effects of proliferating cancer cells is altered mitochondrial metabolism, as well as aberrant metabolism. Medulloblastoma patients suffer severe complications due to intensive and long-term treatments. Thus, we aim to improve applications against medulloblastoma by targeting the PINK1 gene. We hypothesize that PINK1 inactivation slows down medulloblastoma progression. PINK1 is a mitochondrial serine/threonine protein kinase that protects cells by controlling mitochondria quality in response to cellular stress. PINK1 recruits parkin to target damaged mitochondria for degradation through autophagy. In this study, PINK1 has been knocked-out using gene editing technology (CRISPR/Cas9) in two commercial medulloblastoma cell lines (DAOY, and D283 cell lines). We validated PINK1 editing using RT-PCR and Western blot. Then, cell viability was studied in comparison to the control sample. The control sample contained scramble fragments with empty CRISPR/Cas9. We studied apoptosis and performed cell cycle analysis using flow cytometry. Next, orthotopic medulloblastoma mouse model was generated which showed differential survivals comparing the PINK1 knockout group and control. The results showed a low expression of PINK1 within the PINK1 knockout group. In addition, the Western blot showed reductions in PINK1 expression in the knockout group. The knockout group showed more apoptosis (cell death) 40% more than the control. The mouse model showed increased survival of the PINK1 knockout group compared to the control with a p-value of 0.0288 (log-rank). Our analysis shows that survival differences approximately extend human life by one year. We conclude that inhibiting the PINK1 gene in medulloblastoma decreases cell metabolic activities. PINK1 Knockout in medulloblastoma enhances the apoptosis pathways. Engrafted medulloblastoma mouse model treated with PINK1 inhibitor showed superior survival than the control. These results qualify PINK1 to be used as potential therapeutic target for medulloblastoma. The Future work needs additional preclinical studies to investigate the proper dose of PINK1 inhibitor and measurement of toxicity index.
Citation Format: Reema N. Alsubaiee, Amani Alghamdi, Bahauddeen M. Alrfaei. Targeting PINK1 reduces medulloblastoma progression in animal models [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 6505.
Abstract 6513: Discovery and characterization of a KRASG12C/D/V degrader with potent anti-tumor activity in KRASmut-driven preclinical models
Authors: Li Zhengqing , Xu Renqi , Yang Xiaofeng , Zou Zhengyao , Kong Xiaoqiang , Chen Haibo , Sun Yongqing , Zhao Ying , Guo Jing , Yang Cheng , Han Han , Liu Xiaoyun , Lan Hong , Ding Lieming , Zhou Quan , Wu Hao , Wang Jiabing 
Published: March 2024

Abstract
KRAS mutations are one of the most common oncogenic drivers for multiple cancers. KRASG12X mutations are identified in approximately 25% of lung cancer, 24% of colorectal (CRC), and 79% of pancreatic ductal adenocarcinoma (PDAC). Although the approval of Sotorasib in 2021 by the FDA partially addressed the needs of patients with KRASG12C mutant, other mutations, such as G12D and G12V, still lack effective target therapies. Here, we report RD0255359, a proteolysis targeting chimera (PROTAC) KRASG12C/D/V degrader with highly potent cell viability and KRASG12C/D/V degradation ability. In vitro, RD0255359 exhibited a remarkable KRAS degradation property in NCI-H358 (G12C), AGS (G12D), and SW620 (G12V) cell lines at concentrations below 10 nM. RD0255359 suppressed the proliferation of these cells with nanomolar IC50 without affecting the viability of KRASWT or KRAS-independent cell lines. Meanwhile, using protease inhibitor MG132 or corresponding ligand pretreatment and VHLKD-AGS cell experiment confirmed that RD0255359-induced KRAS degradation was VHL and UPS dependent. In vivo, weekly IV injection of 1-10 mg/kg RD0255359 led to tumor growth suppression or tumor regression in PK-59 PDAC xenograft model. The in vivo PK/PD demonstrated that durable KRAS degradation could be achieved with once- weekly IV injection. Notably, after injection, the drug can distribute into tumor tissue rapidly and abundantly, and maintaining a high concentration till the next administration. Taken together, RD0255359 is a highly potent and selective KRASG12C/D/V degrader with favorable PK properties. It exhibits a promising therapeutic index in preclinical studies.
Citation Format: Zhengqing Li, Renqi Xu, Xiaofeng Yang, Zhengyao Zou, Xiaoqiang Kong, Haibo Chen, Yongqing Sun, Ying Zhao, Jing Guo, Cheng Yang, Han Han, Xiaoyun Liu, Hong Lan, Lieming Ding, Quan Zhou, Hao Wu, Jiabing Wang. Discovery and characterization of a KRASG12C/D/V degrader with potent anti-tumor activity in KRASmut-driven preclinical models [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 6513.
Abstract 6530: TREM1 inhibition: A novel approach to suppress tumor growth and enhance immune checkpoint therapy
Authors: Ajith Ashwin , Moamouni Kenza , Horuzsko Daniel D , Horuzsko Anatolij 
Published: March 2024

Abstract
In the context of cancer, inflammation is a multifaceted contributor to tumorigenesis. The Triggering Receptor Expressed on Myeloid Cells 1 (TREM1) is recognized for its role in amplifying inflammatory responses, yet its specific pro-tumorigenic mechanisms have remained elusive. This study employs Trem1-deficient mice and a novel inhibitor, VJDT, to explore the therapeutic potential of targeting TREM1 in cancer. Both genetic silencing and pharmacological inhibiton of Trem1 led to remarkable reductions in tumor growth in mouse models of melanoma (B16F10) and fibrosarcoma (MCA205). In-depth analysis using single-cell RNA sequencing unveiled that TREM1 deficiency resulted in a decrease in the frequency and suppressive capabilities of myeloid-derived suppressor cells (MDSCs) within the tumor microenvironment, concomitant with an increase in cytotoxic CD8+ T cells and enhanced T cell activation. Furthermore, TREM1 inhibition not only curtailed tumor growth but also potentiated the effectiveness of anti-PD-1 therapy, primarily by mitigating MDSC frequency and reversing T cell exhaustion. Notably, in melanoma xenografts from patient samples, pharmacological TREM1 inhibition via VJDT treatment significantly downregulated critical oncogenic pathways linked to cell proliferation, migration, and survival. This research underscores the pivotal role of TREM1, expressed both within cancer cells and the tumor microenvironment, in driving cancer progression. Consequently, targeting TREM1 for therapeutic intervention holds promise for reshaping the immunosuppressive tumor milieu and augmenting the success of immune checkpoint therapy.
Citation Format: Ashwin Ajith, Kenza Moamouni, Daniel D Horuzsko, Anatolij Horuzsko. TREM1 inhibition: A novel approach to suppress tumor growth and enhance immune checkpoint therapy [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 6530.
Abstract 6531: Anti-tumor immune function of NR2F6, an orphan nuclear receptor, in stromal cells
Authors: Kim Hyungsoo , Feng Yongmei , Radaeva Marria , Sergienko Eduard , Cherkasov Artem , Ronai Ze'ev A. 
Published: March 2024

Abstract
Growing evidence points to the importance of the tumor microenvironment (TME) in tumor growth control, progression, and therapy response. Among those is the greater understanding of immune system components within the TME as mediators of tumor growth control. NR2F6 is an orphan nuclear receptor, which was shown to serve as an immune intrinsic checkpoint component and has been suggested to elicit tumor-intrinsic suppression of anti-tumor immunity. Correspondingly, genetic depletion of NR2F6 in CD8 T cells abrogates the immune-activating cytokines (e.g., IL-2, IFNg). In addition, genetic ablation of NR2F6 in melanoma cells activates CD8 T cell-mediated anti-tumor immunity partly by suppressing the expression of tumor-intrinsic immune repressors NACC1 and FKBP10. Notably, combined genetic ablation of tumor cells (NR2F6 KO melanoma) and stroma cells (NR2F6 KO mouse) resulted in a more pronounced inhibition of tumor growth compared with ablation of either tumor cells or TME. The latter provides the foundation for screening NR2F6 inhibitors, which are expected to have a strong systemic (tumor inhibition and immune cell activation) effect on tumor growth. Interestingly, single-cell transcriptomic data from human tumors identified high expression of NR2F6 in stroma cells, cancer-associated fibroblasts (CAFs), and tumor-associated endothelial cells (TAEs). Consistent with these, scRNAseq analysis of mouse melanoma revealed higher expression of NR2F6 in SMA+ immune suppressive myo-CAFs than in immune activating CAFs. Studies that directly reveal the role of stromal NR2F6 in anti-tumor immunity and tumor growth and the state of NR2F6 inhibitors will be discussed.
Citation Format: Hyungsoo Kim, Yongmei Feng, Marria Radaeva, Eduard Sergienko, Artem Cherkasov, Ze'ev A. Ronai. Anti-tumor immune function of NR2F6, an orphan nuclear receptor, in stromal cells [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 6531.
Abstract 6546: Spatial immunology landscapes that correlate with survival in triple negative breast cancer
Authors: Foroughi pour Ali , Martinek Jan , Wu Te-Chia , Sivajothi Santhosh , Liu Zichao , Zhou Jie , Rimm David , Robson Paul , Bates Katherine , Palucka Karolina , Chuang Jeffrey H. 
Published: March 2024

Abstract
Triple negative breast cancer (TNBC) is an aggressive subtype of breast cancer characterized by negative immunohistochemistry staining for estrogen receptor (ER), progesterone receptor (PR), and human epidermal growth factor receptor 2 (HER2). Treatment options for TNBCs are limited due to lack of tumor-specific targeted therapies, resulting in poor prognosis and patient survival. This is exacerbated by lack of prognostic markers of response. While current studies suggest tumor immune interactions are important, current immune activity quantifications, such as scores quantifying abundance of tumor-infiltrating lymphocytes (TILs), are not sufficient to define tumor immune status. We used imaging mass cytometry (IMC) to measure 33 markers on primary tumors of 100 patients undergone chemotherapy with long-term follow-up to explore the tumor immune microenvironment of TNBCs. Concordant with previous studies, a higher ratio of T-cells was associated with response to chemotherapy and longer overall survival (adjusted p-value&lt;0.05). Moreover, using Kmeans clustering we identified 13 distinct cellular neighborhoods, reflective of the heterogenous nature of TNBCs. Among others, we identified a neighborhood, characterized by low CD14+ expression, low cytokeratin, high vimentin expression and high CD45RO, that contributes highest impact on correlation with overall survival (adjusted p-value&lt;0.01). These results suggest an important role for memory T cells in the stroma. Thus, resolving spatial organization of the tissue is important to understanding patient response to therapy in TNBCs.
Citation Format: Ali Foroughi pour, Jan Martinek, Te-Chia Wu, Santhosh Sivajothi, Zichao Liu, Jie Zhou, David Rimm, Paul Robson, Katherine Bates, Karolina Palucka, Jeffrey H. Chuang. Spatial immunology landscapes that correlate with survival in triple negative breast cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 6546.