bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 739: AMT-253, a first-in-class MUC18-targeting antibody-drug conjugate, for the treatment of MUC18-positive solid tumors
Authors: Shi Jing , Yan Jiaqing , Huang Yaling , Guo Jun , Kong Yan , Meng Xun , Liu Shu-Hui 
Published: March 2024

Abstract
MUC18, also known as MCAM (melanoma cell adhesion molecule) or CD146, is a type I transmembrane glycoprotein originally identified as a cell adhesion molecule of melanoma that plays important roles in tumor growth and progression including tumor angiogenesis, epithelial-mesenchymal transition (EMT), and metastasis. MUC18 is overexpressed in a variety of solid tumors including (but not limited to) melanoma, osteosarcoma, head and neck, lung, esophagus, breast, ovarian, and cervical cancer and hepatocellular carcinoma, with restricted presence on normal healthy tissues, mainly on blood vessels and a minor subset of T helper cells. Limited expression in normal tissues and high expression in tumors makes MUC18 a promising target for the development of antibody drug conjugate (ADC). AMT-253 is a novel ADC targeting MUC18. It is composed of a humanized MUC18-targeting IgG1 antibody conjugated with Exatecan, a topoisomerase I inhibitor, attached to a proprietary self immolative T moiety linker through reduced interchain disulfide bonds with a drug-to-antibody ratio (DAR) of 8. AMT-253 was stable in vitro with less than 0.5% of payload releasing when incubated with human, monkey, mouse or rat plasma for 21 days at 37°C. AMT-253 selectively bound to cell surface MUC18 and was efficiently internalized into MUC18-positive cancer cells. AMT-253 exhibited antiproliferative activity against several MUC18-positive cancer cell lines and demonstrated potent bystander killing effect in vitro. Treatment with AMT-253 resulted in tumor growth inhibition or regression in a panel of MUC18 positive cell line derived xenograft (CDX) or patient derived xenograft (PDX) models. In addition, AMT-253 was well tolerated in a GLP compliant toxicity study in cynomolgus monkeys at dose levels ≤45 mg/kg. Taken together, our preclinical in vivo efficacy and toxicity studies demonstrated that AMT-253 has a wide therapeutic window and could potentially provide benefits for cancer patients with highly unmet medical needs. AMT-253 is currently being evaluated in a Phase I first-in-human clinical trial (NCT05906862).
Citation Format: Jing Shi, Jiaqing Yan, Yaling Huang, Jun Guo, Yan Kong, Xun Meng, Shu-Hui Liu. AMT-253, a first-in-class MUC18-targeting antibody-drug conjugate, for the treatment of MUC18-positive solid tumors [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 739.
Abstract 740: CNTN4 as a novel target for solid cancer with antibody-drug conjugate
Authors: Cha Mi Young , Kim Hyunuk , Byun Seungmin , Ha Youngeun , Park Kitae , Yu Hyunkyung , Jeon Bu-Nam , Kim Mira , Moon Soojung , Park Kyung Mi , Park Hansoo 
Published: March 2024

Abstract
As a novel immune checkpoint, we previously confirmed that contactin 4 (CNTN4) regulates T cell activity negatively by binding to amyloid precursor protein (APP) on T cells. CNTN4 is highly expressed in various types of tumors, including gallbladder, pancreas, stomach, endometrium, liver, prostate, bladder cancer, melanoma, and other tumors, with positive rates over 70% through immunohistochemistry analysis in contrast to low-level expression in normal tissues. Based on the tumor-specific expression profile of CNTN4, we evaluated the potential of CNTN4 as a novel target for antibody-drug conjugate (ADC). First, the internalization of the anti-CNTN4 antibody in the IND submission stage, GENA-104A16, into CNTN4-positive cancer cells was confirmed. For investigation of the potential of targeting CNTN4 using ADC, clinically validated various linker-payloads (MMAE, MMAF, SN-38, and exatecan derivate) were conjugated to GENA-104A16 using thiol maleimide conjugation with average drug-to-antibody ratio (DAR) in the range of 4.0 to 4.8. After preparing ADCs, we confirmed the binding affinity for CNTN4 was maintained as high even after the payload conjugation through an ELISA. In vitro studies have demonstrated the highly cytotoxic effect of MMAF conjugate among the conjugates of GENA-104A16 on CNTN4-positive cancer cells compared to negative cancer cells. And there was no cytotoxic effect on normal cells. Furthermore, treating MMAF conjugate of GENA-104A16 showed promising efficacy in the Pan02 pancreatic orthotopic mouse model and the patient-derived xenograft model. These results suggest that CNTN4 could be a highly potential ADC target that could expand the options for cancer treatment strategies.
Citation Format: Mi Young Cha, Hyunuk Kim, Seungmin Byun, Youngeun Ha, Kitae Park, Hyunkyung Yu, Bu-Nam Jeon, Mira Kim, Soojung Moon, Kyung Mi Park, Hansoo Park. CNTN4 as a novel target for solid cancer with antibody-drug conjugate [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 740.
Abstract 7411: CAMStool: Cancer-associated somatic mutation selection tool for cancer risk prediction in whole-genome data
Authors: Kim Jae-Yoon , Park Seung-Jin , Park Seong-Hwan , Kim Seon-Kyu 
Published: March 2024

Abstract
Predicting cancer risk plays a useful role in presenting guidelines to prevent and manage cancers of individuals. Genomic variants have recently been widely used as a genetic factor, and the utilization of the genetic factor consisting of somatic mutations has shown remarkable predictive performance in many cancer prediction studies. Typically, the accuracy of such prediction studies is significantly affected by the composition of somatic mutations used as the genetic factor; however, in practice, choosing the optimal set of mutations with high prediction accuracy is a challenging task in cancer prediction research. From this perspective, we present a new analysis tool for selecting an optimal set of somatic mutations associated with cancers of interest, named CAMStool. The CAMStool is based on the statistical values, which are the effect size and its p-value of each somatic mutation for the cancers of interest. It heuristically searches for the only somatic mutations that directly increase the prediction accuracy of cancer, through statistical and machine-learning models. Then, our tool presents the finally selected somatic mutations as the final optimal mutation set, and additionally presents an optimal cancer risk prediction model through various machine/deep learning modeling using the optimal set as a genetic factor. For the evaluation, the CAMStool was applied to our real whole-genome dataset which are sequenced from normal-tumor tissues of 459 individuals with thyroid cancer. The CAMStool selected 36 and 55 optimal somatic mutations associated with the benign thyroid and non-invasive follicular thyroid cancer, and presented risk prediction models with sensitivity of 88.04% and 90.32%, respectively. Although the CAMStools has some limitations, it is expected to contribute to various cancer prediction studies that require selecting optimal mutation sets in the future. The CAMStools is written in R and will be released soon on our github (https://github.com/JaeYoonKim72).
Citation Format: Jae-Yoon Kim, Seung-Jin Park, Seong-Hwan Park, Seon-Kyu Kim. CAMStool: Cancer-associated somatic mutation selection tool for cancer risk prediction in whole-genome data [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 7411.
Abstract 7460: Characterizing the role of PCBP1 in the activation of the cGAS-STING/type I Interferon axis to promote anti-tumor immunity
Authors: Fréreux Cécile , Chakraborty Paramita , Dalton Annamarie C. , Howley Breege V. , Granger Bryan , Karam Joseph A. , Vaena Silvia G. , Romeo Martin J. , Howe Philip H. 
Published: March 2024

Abstract
The emergence of immunotherapies has encouraged the need to better understand the molecular mechanisms that modulate the tumor immune microenvironment to kill cancer cells as well as the strategies used by cancer cells to evade the immune system. In several cancer types, the Poly(rC) Binding Protein 1 (PCBP1) has shown to have tumor suppressive effects, however its function in regulating the tumor immune environment remains unclear. To investigate this in the context of breast cancer, we established a CRISPR-Cas9-medited knock-out of PCBP1 in a Py8119 murine breast cancer cell line. PCBP1−/− cells revealed a decrease in the activation of the cGAS-STING pathway and is associated with lower levels of type I interferons (IFNs) and Interferon Stimulated Genes’ (ISGs) expression. The cGAS-STING pathway plays an important role in innate immunity as it fights pathogenic infections and tumorigenesis through the production of type I IFN and ISGs. It also promotes the priming and infiltration of T cells at the tumor site to fight cancer cells. Our results suggested that PCBP1 is acting on the activation of the cGAS-STING pathway and could further modulate the tumor immune microenvironment. We then confirmed our results in vivo by establishing a tumorigenic C57BL/6 PyMT transgenic mouse model with conditional knockout for PCBP1 in mammary cells. Our data demonstrate that PCBP1−/− PyMT mice have higher tumor burdens compared to PCBP1+/+ PyMT mice and also show a decreased ISGs’ signature by RNA-sequencing, qPCR and western blot, as previously observed in vitro in the Py8119 PCBP1−/− cell line. Additional single nuclei RNA-sequencing analyses confirmed that this downregulation of ISGs is observed in mammary cancer cells where PCBP1 is knocked-out. Strikingly, IHC and flow cytometry analyses of PCBP1−/− tumors isolated from these mice also revealed a decrease in CD8+ T-cells. Therefore, PCBP1 silencing may promote tumor growth by impairing the activation of the cGAS-STING/IFN-I/ISGs axis, which may contribute to the decrease in CD8+ T-cells’ infiltration at the tumor site. Additionally, we are further investigating the molecular mechanisms mediated by PCBP1 that trigger this activation of the cGAS-STING pathway.
Citation Format: Cécile Fréreux, Paramita Chakraborty, Annamarie C. Dalton, Breege V. Howley, Bryan Granger, Joseph A. Karam, Silvia G. Vaena, Martin J. Romeo, Philip H. Howe. Characterizing the role of PCBP1 in the activation of the cGAS-STING/type I Interferon axis to promote anti-tumor immunity [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 7460.
Abstract 7468: Development of a high complexity flow cytometry panel to assess minimum residual disease in acute myeloid leukemia
Authors: Pearl Jessica , Bruni Elena , Hsu Haoting , Walling Brandon , Abarca-Heidemann Karin 
Published: March 2024

Abstract
Acute Myeloid Leukemia (AML) is a highly heterogeneous disease with a diverse range of abnormal myeloid subpopulations resulting in challenges in clinical diagnosis and treatment. Many methods such as flow cytometry are used to provide precise information for risk stratification and treatment methods. Flow cytometry utilizes the expression patterns of cellular markers to characterize the high diversity in AML subpopulations with high sensitivity and specificity. This coupled with rapid analysis timelines allows for flow cytometry to be an excellent tool for the identification of AML lineage and progression through both phenotypic analysis and difference from normal. As AML lineage and disease progression are predictors of residual disease and relapse; the need for effective and accurate characterization of AML populations is critical. Here, Champions Oncology has developed a high-complexity 18-color flow cytometry panel to identify AML subpopulations at high resolution. We have characterized AML samples to evaluate the expression of phenotypic markers and their heterogeneity. Utilizing primary AML samples, we have evaluated the stability of AML subpopulations to understand how delayed analysis, such as what is seen in clinical trials, may impact marker expression and observed key populations were stable for up to 72 hours after collection. In addition to stability, understanding the lower limits of detection is critical for AML patients, particularly for minimum residual disease and relapse screening. The use of a flow cytometric panel again provides an excellent tool for these tests due to the single cell nature that allows for the interrogation of individual populations with primary AML subpopulations detected at a range of 10−3 to 10−4. Finally, with hundreds of never-passaged AML models characterized and cryopreserved by both flow cytometry and sequencing at Champions Oncology, we investigated how the cryopreservation processes impacted the expression of AML subpopulations. We have observed similar expression and detection of AML populations following cryopreservation indicating that these models can be utilized as an excellent tool for further studies. Collectively, our data indicates that the panel developed at Champions Oncology provides robust data analysis of AML subpopulations and can be an excellent tool for the tracking of AML disease progression in the clinic.
Citation Format: Jessica Pearl, Elena Bruni, Haoting Hsu, Brandon Walling, Karin Abarca-Heidemann. Development of a high complexity flow cytometry panel to assess minimum residual disease in acute myeloid leukemia [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 7468.
Abstract 7486: Development and analytic validation of an ARv7/PSMA dual biomarker circulating tumor cell assay
Authors: Ladd Jon , Bayer Erin , Bartels Brock , Kaldjian Eric , Ramirez Arturo 
Published: March 2024

Abstract
Background Prostate cancer drug targets and biomarkers may be investigated non-invasively on circulating tumor cells (CTCs) obtained via liquid biopsies. PSMA is an important drug target in prostate cancer, and ARv7 is a splice variant that confers resistance to second-generation androgen receptor inhibitors. In this study, we describe the development and analytic validation of a novel assay to quantify ARv7 and PSMA protein expression on CTCs. The assay was validated with blood samples from patients with Stage IV prostate cancer to demonstrate clinical feasibility. To our knowledge, a PSMA/ARv7 dual protein assay for CTCs has not previously been reported.
Methods LNCaP (PSMA positive), PC3 (PSMA negative), 22Rv1 (ARv7 positive), and BT474 (ARv7 negative) cells were spiked into healthy donor blood to generate model CTCs. Nucleated cells were collected from these spike-in samples using the AccuCyte® sample preparation kit and spread onto microscope slides. Slides were fixed and stained with antibodies to cytokeratin, EpCAM, and CD45 to detect CTCs and exclude white blood cells (WBCs), and with PSMA and ARv7 to evaluate protein expression on identified CTCs. The slides were imaged with the CyteFinder® automated immunofluorescence scanning microscope that identifies CTCs for confirmation by trained reviewers based on machine learning algorithms and quantitatively measures biomarker signal mean fluorescence intensity (MFI).
Results For ARv7/PSMA expression classification of the model CTCs, the dual biomarker assay showed analytic sensitivity of 83%/97% and specificity 98%/99%, yielding accuracy of 90.2%/97.9%, respectively. The dynamic range of MFI for both biomarkers was approximately three orders of magnitude. Inter-run reproducibility CV was 13.6% (ARv7) and 6.9% (PSMA). Slide repeatability mean CV was 11.1% (ARv7) and 12.0% (PSMA). Clinical feasibility of the assay was investigated in 9 progressing Stage IV prostate cancer patient blood samples. CTCs were identified in all clinical samples (median 4, range 1 - 384). Thresholds for biomarker positivity were established based on MFI measurements of positive and negative control cell lines. ARv7 positivity in clinical samples ranged from 33% to 100%, and PSMA positivity ranged from 0% to 75%.
Conclusions We have developed a dual ARv7/PSMA assay that simultaneously measures protein expression of both biomarkers on individual CTCs. The assay is accurate and reproducible for the assessment of ARv7 and PSMA expression by liquid biopsy in clinical studies.
Citation Format: Jon Ladd, Erin Bayer, Brock Bartels, Eric Kaldjian, Arturo Ramirez. Development and analytic validation of an ARv7/PSMA dual biomarker circulating tumor cell assay [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 7486.
Abstract 7574: Exploring the therapeutic potential of proteasome inhibitors in targeting SOX2-driven LUSC and SCLC
Authors: Mohanty Atish , Guo Linlin , Ramisetty Sravani , Singhal Sharad , Massarelli Erminia , Kulkarni Prakash , Salgia Ravi 
Published: March 2024

Abstract
This study addresses the current lack of small molecules targeting SOX2, a pivotal protein in cancer, through an examination of the effectiveness of FDA-approved drugs and proteasome inhibitors. Building on prior research demonstrating the proteasome inhibitor CFZ's capacity to diminish the expression of ITGB4 and PXN in LUAD effectively, our investigation highlights CFZ and IXA as potent inhibitors at nanomolar concentrations. Notably, CFZ treatment enhances sensitivity to cisplatin by suppressing the expression of ITGB4 and the stemness-associated gene SOX2.At a mechanistic level, CFZ hinders histone acetylation at the SOX2 promoter site, leading to rapid and specific downregulation. RNA-seq analysis of COH2 cells treated with CFZ unveils substantial downregulation of genes related to transcription and DNA binding. Z score analysis further reveals a noteworthy inhibition of key transcription factors (TFs), including SOX2, NANOG, POU5F1, SALL4, and KLF4. This TF inhibition extends to neuroendocrine cell lines, identifying 16 overlapping targets of SOX2 associated with stemness. These findings suggest a potential therapeutic approach for targeting cisplatin-resistant cancer stem cells across various cancer types. Moreover, the study proposes a synergistic effect of cisplatin and CFZ in mitigating the growth of neuroendocrine phenotype, SCLC. Given the limited medical options currently available for this phenotype, this insight holds particular significance. In conclusion, our study unveils CFZ as a potent transcriptional suppressor of SOX2, providing a novel strategy to sensitize cisplatin-resistant cancer stem cells. The results underscore the interplay of genetic and non-genetic mechanisms in drug resistance, emphasizing the significance of repurposing drugs for other indications.
Citation Format: Atish Mohanty, Linlin Guo, Sravani Ramisetty, Sharad Singhal, Erminia Massarelli, Prakash Kulkarni, Ravi Salgia. Exploring the therapeutic potential of proteasome inhibitors in targeting SOX2-driven LUSC and SCLC [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 7574.
Abstract 7575: BPI-460372, a covalent, irreversible TEAD inhibitor in Phase I clinical development
Authors: Han Xiaohong , Guo Jing , Jin Xiangyu , Zhu Lingyin , Shen Hongling , Xu Xiaofeng , Zhang Mengjie , Liu Xiaoyun , Liu Yanju , Cheng Hongke , Guo Shunna , Ding Lieming , Wang Jiabing , Lan Hong , Wang Mengzhao 
Published: March 2024

Abstract
The Hippo signaling pathway is critical for the regulation of organ development, tissue homeostasis, and tumorigenesis by controlling the activation status of yes-associated protein (YAP) or its homolog PDZ-binding motif (TAZ). As a major downstream effector, the transcription factor TEAD is activated by forming a complex with YAP/TAZ. Hippo pathway aberrations leading to TEAD activation have been reported in many cancers. Inhibiting TEAD function by directly blocking the palmitoylation pocket of TEAD is a potential therapeutic approach for cancer treatment. Betta Pharma has discovered a selective, covalent and irreversible TEAD inhibitor known as BPI-460372. The discovery of BPI-460372 was first reported in AACR 2023. Here we present additional preclinical and clinical data characterizing BPI-460372 as a promising candidate drug. In the dose-escalating part of the Phase Ι study, the exposure of BPI-460372 increased proportionally over 10 to 80 mg dose range after oral administration and exhibited linear pharmacokinetics, with a clearance rate suitable for once-daily dosing. The compound is generally well tolerated, with no drug-related Grade ≥3 adverse event observed. Remarkably, we have not seen renal toxicities that was perceived as a potential risk associated with certain TEAD inhibitors. Preliminary efficacy was observed in a few subjects. In preclinical studies, we found that intermittent dosing schedule of 3 days on/4 days off, compared with continuous dosing at equivalent weekly exposure, can ameliorate kidney damage and improve early renal injury biomarkers while maintaining anti-
tumor activity. Thus, alternative dosing schedule could further improve the therapeutic window and enable combination studies in clinical development. Collectively, these results support further development of BPI-460372 for the treatment of cancers harboring Hippo pathway alterations.
Citation Format: Xiaohong Han, Jing Guo, Xiangyu Jin, Lingyin Zhu, Hongling Shen, Xiaofeng Xu, Mengjie Zhang, Xiaoyun Liu, Yanju Liu, Hongke Cheng, Shunna Guo, Lieming Ding, Jiabing Wang, Hong Lan, Mengzhao Wang. BPI-460372, a covalent, irreversible TEAD inhibitor in Phase I clinical development [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 7575.