tbuckley/cabot-search huggingface dataset:
Abstract 5798: Preclinical safety assessment for specificity of biotherapeutics using the membrane proteome array
Authors: Kristopher S. Raghavan, Jonathan T. Sullivan, Carmen Navia, Rachel H. Fong, Benjamin J. Doranz
Journal: Cancer Research (2024)

Abstract Rigorous specificity analysis is critical for the development of antibody-based therapies, as even minimal off-target binding can lead to toxicity and clinical failures. Long believed to be exquisitely specific, recent preclinical data and our own work indicate that monoclonal antibodies (MAbs) frequently (~25%) display cross-reactivity. In many cases, off-target interactions occur with unrelated proteins that cannot be predicted by protein sequence homology. Cross-reactivity can lead to serious or even life-threatening consequences especially when MAbs are configured as bispecifics, antibody-drug conjugates (ADC) or CAR-T cell therapies, and IND applications for biotherapeutics require cross-reactivity assessment to prevent adverse events. Tissue cross-reactivity (TCR) studies have traditionally been used to screen for off-target binding, however, with poor predictive value for in vivo safety and toxicity. We developed the Membrane Proteome Array (MPA) platform to de-risk MAb-based therapeutics by testing for specificity across 6,000 human membrane proteins expressed in unfixed cells. The MPA assesses binding interactions by high-throughput flow cytometry allowing for high sensitivity detection and rapid analysis. All targets identified on the MPA screen are validated by secondary titration analysis. In contrast to TCR studies, proteins in the MPA exist in their native conformations and are not altered by fixation. Recently, we used the MPA to select a lead antibody candidate targeting the oncotherapeutic target Claudin 6 (CLDN6). Through MPA screening, we successfully identified a lead candidate devoid of cross-reactivity against other CLDN family members or any other membrane protein across the human genome. The MPA has also been used to rapidly evaluate the specificity of novel CAR-T cell therapies for cancer and autoimmunity. The MPA has been used for lead selection and data from the MPA has been accepted by the FDA as a part of IND applications for antibody-based therapies. The MPA is currently under consideration for being developed as an FDA-qualified Drug Development Tool. Citation Format: Kristopher S. Raghavan, Jonathan T. Sullivan, Carmen Navia, Rachel H. Fong, Benjamin J. Doranz. Preclinical safety assessment for specificity of biotherapeutics using the membrane proteome array [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 5798.
Abstract 6161: Investigating the relationships between race and socioeconomic status on the biology of ER+ breast cancer
Authors: Jerry Tyler DeWitt, Elena Oropeza, Svasti Haricharan
Journal: Cancer Research (2024)

Abstract Black women in the US have worse health care options, poorer educational opportunities, and decreased income quality which collectively contribute to an overall lower socioeconomic status (SES) compared to white women. Furthermore, although the incidence of estrogen receptor positive (ER+) breast cancer is similar for Black and white women in the US, Black patients have significantly worse outcomes. The field has traditionally focused on systemic factors such as SES to explain outcome disparities. Consequently, differences in the molecular biology between tumors from Black and White women remains a gap in knowledge in the field. Recent studies have found that Black cancer patients have a unique gene expression profile that may modulate treatment response. However, how SES contributes to these differences in molecular biology and whether these differences in SES alter treatment response remain unknown. One challenge to addressing these questions is that existing datasets significantly underrepresent Black women and are not sufficiently annotated to understand the complex interplay between molecular biology and SES. Here, we present analysis of RNA expression datasets from 60 ER+ patient tumors (38 Black, 22 White), with corresponding SES and patient outcome annotations which suggest that the ECM and TIME of ER+ breast cancer are influenced by race and factors of SES including BMI and community poverty burden. We further provide evidence that these alterations in the TME may also associate with worse patient outcomes. Citation Format: Jerry Tyler DeWitt, Elena Oropeza, Svasti Haricharan. Investigating the relationships between race and socioeconomic status on the biology of ER+ 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 6161.
Abstract 739: AMT-253, a first-in-class MUC18-targeting antibody-drug conjugate, for the treatment of MUC18-positive solid tumors
Authors: Jing Shi, Jiaqing Yan, Yaling Huang, Jun Guo, Yan Kong, Xun Meng, Shu-Hui Liu
Journal: Cancer Research (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 7476: Obtusifolin attenuates LPS-induced inflammation and NLRP3 inflammasome activation by suppressing the MAPK/NF-κB signaling pathway and ROS production in BV2 cells
Authors: Hsin Yi Lin, Che-Hsin Lee, Chia-Yang Li
Journal: Cancer Research (2024)

Abstract Neuroinflammation, along with activation of microglia and oxidative stress, plays an important role in the development and progression of neurodegenerative diseases. During the inflammation process, immune cells release inflammatory mediators such as cytokines and chemicals that may promote the formation and growth of cancer cells. Obtusifolin, an anthraquinone extracted from the seeds of Senna obtusifolin, has anti-inflammatory properties. However, the effect of obtusifolin on neuroinflammation and its regulatory mechanism have not been yet investigated. In the present study, BV2 microglial cells were used to investigate the effects of obtusifolin on LPS-induced inflammatory responses, NLRP3 inflammasome activation, and reactive oxygen species (ROS) production. The secretion of nitric oxide (NO) was analyzed by Griess reagent assay, and the cell viability was detected by the CCK-8 assay. The expressions of iNOS, COX-2, STAT3, ERK, JNK, and p38 were examined using Western blotting, and the production of IL-6 and TNF-α was measured by ELISA. To examine whether obtusifolin affected NLRP3 inflammasome activation, BV2 cells were pretreated with LPS and then stimulated with ATP or nigericin. The secretion of IL-1β was measured by ELISA, whereas the expression of NLRP3 inflammasome-related proteins was detected using Western blotting. The production of ROS was analyzed by flow cytometry. Our experimental results showed that obtusifolin suppressed the production of NO and the secretion of proinflammatory cytokines by LPS-induced BV2 cells under noncytotoxic concentrations. In addition, obtusifolin decreased the expression of iNOS, COX-2, phospho-STAT3, phospho-ERK, phosphor-JNK and phospho-p38, and also attenuated the expression of NLRP3 and ASC, cleaved caspase-1 and cleaved IL-1β by LPS- induced BV2 cells. Moreover, obtusifolin reduced the production of both intracellular and mitochondrial ROS by LPS-induced BV2 cells. Overall, these results demonstrated that obtusifolin attenuated LPS-induced inflammation by suppressing the activation of MAPK and NF-κB signaling pathways, inhibiting NLRP3 inflammasome activation, and reducing the production of ROS in microglia, suggesting that obtusifolin might have benefits in the treatment of neurodegenerative diseases. Citation Format: Hsin Yi Lin, Che-Hsin Lee, Chia-Yang Li. Obtusifolin attenuates LPS-induced inflammation and NLRP3 inflammasome activation by suppressing the MAPK/NF-κB signaling pathway and ROS production in BV2 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 7476.
Abstract 2755: Characterizing breast cancer cells following immune pruning in mice
Authors: Sarina McElduff, Daniel Bronder, Mercedes Duran, Samuel Bakhoum
Journal: Cancer Research (2024)

Abstract In cancer patients, metastasis is the leading cause of death. Indeed, primary tumors which are diagnosed early and treated in a timely manner have the highest rate of success. In contrast, metastatic disease and late diagnosis of tumors portend poor outcomes. Thus, understanding the underlying biology and developing novel therapeutic approaches for metastatic cancers is pivotal. Most cancer-based mutational characteristics are tissue-dependent, and cancers with higher mutational load are generally more susceptible to immunotherapy. We observed that poorly metastatic, murine breast cancer cells established a clear phenotypic difference in lung metastasis formation assays. Upon injection of these cells into immune-proficient mice, few, large metastases developed, whereas in immuno-deficient mice, many small metastases grew instead. To determine the molecular features which enable escape under immune editing, we designed the following workflow. We intravenously injected immune-proficient and immune-deficient mice with our poorly metastatic, murine breast cancer cells. As expected, cells readily engrafted in the lungs, causing a significant reduction in survival of immune-deficient mice. Furthermore, liver metastases were observed only in immune-deficient mice. Upon euthanasia, we resected and dissociated both organs. To isolate the tumor cells from these samples, we flow-sorted and subjected them to next-generation sequencing. To elucidate the epigenomic, genomic, and transcriptomic differences between metastases of each background, we performed ATAC, WGS, and RNAseq, respectively. By dissecting the evolutionary mechanisms which allow cancer cells to evade immune detection in metastasis, we can develop targeted immunotherapy strategies to diminish the spread (and lethality) of metastatic cancers. In the future, we plan to examine the descriptive discrepancies between the tissues reared with and without immune pruning in order to put forward innovative therapeutic strategies. Citation Format: Sarina McElduff, Daniel Bronder, Mercedes Duran, Samuel Bakhoum. Characterizing breast cancer cells following immune pruning in mice [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 2755.
Abstract 5804: Preclinical evaluation of LCB84, a novel next-generation TROP2 directed ADC utilizing a cancer selective linker and an MMAE payload
Authors: Stephen Slocum, Hyejung Kim, Chul-Woong Chung, Changsik Park
Journal: Cancer Research (2024)

Abstract LCB84 is an antibody-drug conjugate (ADC) that consists of an antibody targeting human trophoblast cell-surface antigen-2 (TROP2) linked to monomethyl auristatin E (MMAE) via a beta-glucuronidase cleavable linker with a drug-to-antibody ratio (DAR) of 4. LCB84 demonstrates tumor selective killing by multiple mechanisms, increasing both safety and efficacy in parallel. Firstly, the over-expression of TROP2 in many solid tumors allows for targeted delivery of MMAE by LCB84 to Trop2-positive tumor tissues. Secondly, the overexpression of beta-glucuronidase in the lysosome of most tumors facilitates the selective release of active payload within tumor cells compared to normal healthy tissues. Thirdly, the intrinsic selectivity of tubulin inhibitor payloads, such as MMAE, for proliferating cells provides additional protection for non-proliferating normal cells. MMAE is also cell-permeable in its free drug form and can lead to increased efficacy of LCB84 via a bystander effect, enabling activity in heterogenous tumors. LCB84 demonstrates superior efficacy in mouse tumor xenograft studies when compared to benchmark TROP2-targeting ADCs, including sacituzumab govitecan and datopotamab deruxtecan. LCB84 also shows an improved safety profile compared to these clinical benchmarks, as well as compared to traditional MMAE-bearing ADCs, in both in vitro and in vivo toxicity assessments. Additionally, LCB84 shows a stable preclinical pharmacokinetic profile with minimal loss of payload over time. The utilization of an ADC for target-mediated delivery, in combination with a stable beta-glucuronide trigger for selective payload release in tumors, allows for a superior preclinical therapeutic index which is expected to translate to a best-in-class ADC in the clinic. Citation Format: Stephen Slocum, Hyejung Kim, Chul-Woong Chung, Changsik Park. Preclinical evaluation of LCB84, a novel next-generation TROP2 directed ADC utilizing a cancer selective linker and an MMAE payload [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 5804.
Abstract 7384: Regulation of phosphorylated VGLL1 by the positively charged binding pocket on the surface of TEAD4
Authors: Jae Mun Choi, Huong Van Le, Young Bin Park, Yu Kyung Yun, Jun Hong Kim, Jonathan Wilianto, Nuzup Shadiev, Chul Sung, Bonsu Ku, Kwan-Young Chang, Misun Won
Journal: Cancer Research (2024)

Abstract Vestigial-like 1 (VGLL1) is a transcriptional co-activator that binds to TEA domain-containing transcription factors (TEADs), regulating hippo pathway. High expression of VGLL1 is associated with gastric cancer, breast cancer, and pancreatic cancers. VGLL1 is transcriptionally regulated by PI3K/β-catenin signaling and is phosphorylated by ribosomal S6 kinase 2 (RSK2) in the presence of TGF-β. It is clear that phosphorylation at S84 of the VGLL1 protein is critical for its interaction with TEAD4 to express their target genes involved in the proliferation and metastasis of cancer cells. In the isothermal titration calorimetry study, we observed S84-phosphorylated VGLL1 peptide bound to TEAD4. However, it is difficult to understand structure-based molecular mechanism of the phosphorylated VGLL1 at S84 due to lack of the detailed human VGLL1-TEAD4 complex structure for rational drug design. In this study, we modeled full-length human VGLL1-TEAD4 or YAP1-TEAD4 complexes and performed MMPBSA calculations or Kd/Ki predictions followed by MD simulations using Pharmaco-Net's CNN-based artificial intelligence model. Our study suggests that a positively charged binding pocket on the surface of TEAD4 can regulate interaction between Trp243 from YAP1 and phosphorylated-Ser84 from VGLL1. The newly identified binding pocket is composed of Lys297, Val414, and Tyr429, which can interact with phosphorylated Ser84 residue and maintain Omega loop-like structure shown in YAP1-TEAD4 complex. The computed binding energy for phosphorylated-VGLL1-TEAD was -134.80 +/- 8.20 Kcal/mol which was a similar binding energy to YAP1-TEAD4 complex. In addition, global peptide docking using S84-containing-VGLL1 peptide (SCVP) indicated that SCVP can bind to the same binding pocket with average 1.39 μM. This suggested that there could be a novel therapeutic approach targeting this interaction with SCVP, an agent that seems to mimic phosphor-VGLL1 interaction and thus demonstrates promise as a potential therapeutic intervention. Nevertheless, further experimental verification and clinical investigations are needed to validate these innovative findings. Citation Format: Jae Mun Choi, Huong Van Le, Young Bin Park, Yu Kyung Yun, Jun Hong Kim, Jonathan Wilianto, Nuzup Shadiev, Chul Sung, Bonsu Ku, Kwan-Young Chang, Misun Won. Regulation of phosphorylated VGLL1 by the positively charged binding pocket on the surface of TEAD4 [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 7384.
Abstract 2802: <i>Enterococcus faecalis</i>-derived X facilitates pancreatic tumor by regulating immune microenvironment
Authors: Bin Wang, Chao Yang, Yongjie Xie, Tianxing Zhou, Jun Yu, Jihui Hao
Journal: Cancer Research (2024)

Abstract Previous research in human samples has found a link between the intratumoral microbiome and the development and progression of pancreatic cancer. Nevertheless, the bacterial strains that may have an effect, and the underlying mechanisms, are largely unknown. To identify potential bacterial species, microbiome sequencing was performed on fecal and tumor samples obtained from KPC mice and patients with pancreatic tumors in this study. To identify metabolites associated with bacteria, untargeted metabolomics were analyzed on serum and tumor samples. Furthermore, advanced and high-throughput techniques, such as single-cell RNA sequencing, tumor organoids, engineered bacteria and germ-free mouse models, were used to elucidate the specific influence on the immune microenvironment of pancreatic tumors. Our findings reveal an increased abundance of Enterococcus faecalis (E. faecalis) in the gut during the development of pancreatic cancer, accompanied by its accumulation in the tumor. Patient-derived E. faecalis strain and its metabolite X, facilitated pancreatic tumor growth, reduced the recruitment of CD8+T cells, and caused their dysfunction in the tumor, relying heavily on E. faecalis intratumoral colonization. We found that X inhibits the production of anti-tumor chemokines like CCL21 and CCL8 in tumor cells, reducing peripheral CD8+ T cell infiltration into the tumor. Furthermore, X was found to inhibit glycolysis and compromise the function of tumor-infiltrating CD8+ T cells by decreasing the activity of lactate dehydrogenase (LDH) in CD8+ T cells. Additionally, oral doxycycline, an antibiotic that targets intratumoral E. faecalis, effectively enhanced the therapeutic effect of gemcitabine in pancreatic cancer. Finally, we present evidence that X may predicts efficacy and survival in pancreatic cancer patients. Together, our findings provide new insights into the role of E. faecalis in mediating the immune environment of pancreatic tumors, highlighting E. faecalis and X as potential therapeutic targets for pancreatic cancer patients. Citation Format: Bin Wang, Chao Yang, Yongjie Xie, Tianxing Zhou, Jun Yu, Jihui Hao. Enterococcus faecalis-derived X facilitates pancreatic tumor by regulating immune microenvironment [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 2802.