tbuckley/cabot-search huggingface dataset:
Abstract 3475: Prediction of nausea or vomiting, and fatigue or malaise in cancer care
Authors: Raphael Vienne, Quentin Filori, Vincent Susplugas, Hugo Crochet, Loic Verlingue
Journal: Cancer Research (2024)

Abstract Introduction: Natural language processing has recently achieved unprecedented performances for several medical tasks, but requires additional improvements in oncology. Moreover, very few projects have assessed the potential of language models to help prevent the most frequent serious or severe medical events in medical oncology. We aim at predicting nausea or vomiting (ICD10 code R11), and fatigue or malaise (ICD10 code R53) from patients' medical reports. Material and methods: The study included all the patients of Centre Léon Bérard between 2000 and 2023 that have not refused to share their data for this analysis. We have retrieved all the clinical notes and manual coding of hospitalization stays in ICD10, in French. We have pretrained a BERT language model with a masking strategy on this data and then fine-tuned it and compared it to several medical pretrained open source models (DrBert and K-memBERT). The labels were medical events leading to or associated with a hospitalization in the 90 days after every patients’ notes. For OncoBERT, we included sequential reports from the patients’ history, along with a time-encoding layer, and integrated it in a final transformer layer. Results: We analyzed 140,523 patients, representing 2,515,957 pseudo-anonymized text reports and 6.6M hospitalizations codes in total. The medical texts were consultations reports (56%), end-of-stay reports (17%) and hospitalization summaries (9%). The most frequent types of oncology treatments received by the patients at each time point were 18.8% for chemotherapy, 10.8% for targeted therapies and 1.3% for immunotherapies. The most frequent medical events were nausea or vomiting (20% of patients with 1 or more events), and fatigue or malaise (18% of patients with 1 or more events). In the final dataset, nausea and vomiting (R11) accounted for 16% of the labels while malaise and fatigue (R53) accounted for 24.7% of the labels. We performed random undersampling of reports without any event to balance the label dataset. The fine-tuning on R11 and R53 achieved the performances of 0.58 macro-aucpr (OncoBERT) and 0.50 macro-aucpr (best open-source model) on the validation set. Conclusion: The language models achieved high performance on the prediction of the most frequent serious medical events in our hospital dedicated to cancer care. We plan to validate the external performances of these models on collaborating hospitals and prospectively and improve the interpretations that we will present at the congress. Citation Format: Raphael Vienne, Quentin Filori, Vincent Susplugas, Hugo Crochet, Loic Verlingue. Prediction of nausea or vomiting, and fatigue or malaise in cancer care [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 3475.
Abstract 2732: NB203: A Novel therapeutic bispecific antibody targeting CEACAM1/VEGF for tumor immunity and angiogenesis modulation in the tumor microenvironment
Authors: Jinyu Dong, Binbin Wang, Dong Wang, Jie Ni, Tingting Bu, Haojie Wang, Bishnu Nayak, Baiyang Wang, Xin Dong, Yu Zhang
Journal: Cancer Research (2024)

Abstract The carcinoembryonic antigen cell adhesion molecule 1 (CEACAM1) is detected on leukocytes, epithelia and endothelia, and involved in cell adhesion through homophilic or heterophilic binding. In various gastrointestinal cancers, NSCLC (non-small cell lung cancer), and melanoma, CEACAM1 is highly expressed on tumor cells and tumor stroma, with its levels increasing as the disease progresses. Notably, CEACAM1 has been found to dampen T and NK cell functions while promoting tumor angiogenesis and metastasis. In this study, we present NB203, a novel CEACAM1/VEGF bispecific antibody developed using Neologics CEACAM-plus, a bifunctional molecule engineering platform designed to target and modulate the tumor microenvironment (TME). NB203 effectively accumulated in the TME and hindered the homophilic or heterophilic interactions of CEACAM1. It demonstrated a significant enhancement in T cell activities and NK cell-mediated killing of CEACAM1-expressing tumor cells, and the inhibition of tumor cell migration and polyploidy through macrophages. More importantly, NB203 was specifically designed to impede tumor angiogenesis. It exhibited an increased binding capacity to both CEACAM1 and VEGF in pro-angiogenic TME, and undermined intratumoral vessel maturation by blocking VEGF and negatively regulating myeloid cell-dependent tumor angiogenesis. In summary, our preclinical data indicate that NB203 exhibits effective anti-tumor activity by mediating NK and cytotoxic T cell activities, improving the immune-suppressive TME, and suppressing tumor angiogenesis. The use of NB203 holds promise in overcoming resistance to anti-VEGF therapy and substantially improving the safety of therapeutic targeting of angiogenesis in cancer treatment. Citation Format: Jinyu Dong, Binbin Wang, Dong Wang, Jie Ni, Tingting Bu, Haojie Wang, Bishnu Nayak, Baiyang Wang, Xin Dong, Yu Zhang. NB203: A Novel therapeutic bispecific antibody targeting CEACAM1/VEGF for tumor immunity and angiogenesis modulation in the tumor 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 2732.
Abstract 2901: The apoptotic peptide TB511 targets activated CD18 and suppresses solid tumor progression
Authors: Ilsoeb Choi, Ik-Hwan Han, Soyoung Kim, Juwon Yang, Hye Yeon Kim, Daehwan Park, Hongseo Choi, Jeongyoon Choi, Heekyung Lee, Jin Sun Shin, Jinho Kim, Jihwan Moon, Hyunsu Bae
Journal: Cancer Research (2024)

Abstract Tumor-associated macrophages (TAMs) primarily exist in the M2-like phenotype in the tumor microenvironment (TME). M2-TAMs contribute to tumor progression by establishing an immunosuppressive environment. However, TAM targeting is hindered, mainly owing to a lack of specific biomarkers for M2-TAMs. Herein, we verified that TB511, a fusion peptide comprising a TAM-targeting peptide and the pro-apoptotic peptide dKLA, could preferentially bind to active CD18 in M2-TAMs, inducing apoptosis; it was less toxic to other tissue-resident macrophage lineages. TB511 suppressed tumor progression in various cancer models and humanized mouse models. Removal of M2-TAMs by TB511 significantly increased the infiltration of tumor-killing cells, such as granzyme B-positive CD8+ T cells and natural killer cells, in the TME. Collectively, our findings suggest that targeting CD18 in M2-TAMs using peptide drugs is a potential strategy for immunotherapy in various tumors, including non-small cell lung cancer, colorectal cancer, hepatocellular carcinoma, renal cell carcinoma, and prostate cancer. Citation Format: Ilsoeb Choi, Ik-Hwan Han, Soyoung Kim, Juwon Yang, Hye Yeon Kim, Daehwan Park, Hongseo Choi, Jeongyoon Choi, Heekyung Lee, Jin Sun Shin, Jinho Kim, Jihwan Moon, Hyunsu Bae. The apoptotic peptide TB511 targets activated CD18 and suppresses solid tumor progression [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 2901.
Abstract 2724: BCG020, a novel bispecific antibody targeting EGFR and CD70, is effective against EGFR and CD70 high expressed tumors
Authors: Yongfei Yang, Xiaoxia Sun, Ziyan Li, Yue Yan, Linpeng Xu, Xiaoxue Wu, Luheng Du, Ying Zhu, Chaoshe Guo, W. Frank An
Journal: Cancer Research (2024)

Abstract The epidermal growth factor receptor (EGFR) is highly expressed across a wide range of different cancers, and is a known driver of cancer growth; EGFR upregulation is frequently associated with adverse prognosis. Many patients undergoing EGFR-TKI (tyrosine kinase inhibitors) treatment will acquire resistance, which can be accompanied by increased expression of CD70 in some cancers. Simultaneous engagement of both EGFR and CD70 with a bispecific antibody (bsAb) is a potential strategy to overcome such resistance and achieve greater efficacy. To explore this strategy, we developed a novel IgG1 bsAb, BCG020, targeting EGFR and CD70. The parental EGFR antibody and CD70 antibody were developed from fully human common light chain antibody mice (RenLite®). When compared to EGFR benchmarks, the parental EGFR antibody exhibits similar affinity to both human and cynomolgus monkey EGFR, similar internalization activity in EGFR+ tumor cell lines, and superior blocking activity of EGF to EGFR in vitro. Furthermore, the EGFR parental antibody demonstrates good stability. The parental CD70 antibody exhibits high affinity to both human and monkey CD70, with superior internalization activity to benchmark antibody in CD70+ tumor cell lines, as well as superior blockade of CD70-induced signaling of CD27-Luc when compared to benchmark antibodies. When assembled into a bsAb, BCG020 exhitibs the same high affinity as both parental antibodies, with higher internalization activity than parental antibodies and benchmark antibodies. To evaluate the efficacy of BCG020 in vivo, we established cell line-derived xenograft (CDX) models in immunodeficient (B-NDG) mice. We observed that BCG020 treatment (10 mg/kg) potently inhibited growth of EGFR+CD70+ tumors. Taken together, these data indicate that BCG020 is a first-in-class bispecific antibody with potential to treat solid tumors with high expression of EGFR and CD70. Citation Format: Yongfei Yang, Xiaoxia Sun, Ziyan Li, Yue Yan, Linpeng Xu, Xiaoxue Wu, Luheng Du, Ying Zhu, Chaoshe Guo, W. Frank An. BCG020, a novel bispecific antibody targeting EGFR and CD70, is effective against EGFR and CD70 high expressed 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 2724.
Abstract 7132: Preclinical characterization of LAE119, a novel PARP1 selective inhibitor and trapper
Authors: Ming Li, Yan Chen, Junyan Chen, Ling Jiang, Xiaofen Lin, Justin Gu
Journal: Cancer Research (2024)

Abstract Current PARP inhibitors primarily target PARP1/2 and demonstrate high efficacy against tumors with deficiencies in homologous recombination repair, such as those with BRCA mutations. However, these inhibitors are also associated with significant hematological toxicities. Studies have indicated that the synthetic lethality observed with BRCA mutations is mainly driven by PARP1, while PARP2 is not essential in this context. PARP2 has been shown to be crucial for the survival of hematopoietic stem/progenitor cells in animal models. Therefore, selective inhibition of PARP1 could potentially reduce toxicity and improve therapeutic outcomes. Here we introduce LAE119, a potent and selective PARP1 inhibitor and PARP1-DNA trapper. It demonstrates more than a 1000-fold selectivity for PARP1 DNA trapping compared to PARP2. In comparison to most PARP inhibitors including AZD5305, LAE119 exhibits extremely long residence time on PARP1 in both biochemical and cellular assays. It demonstrates robust anti-proliferation activity against BRCA2−/− DLD-1 cells and MDA-MB-436 cells, with IC50 value of 0.6 nM in both cell lines. In CAL51 cells, which has a BRCA2 mutation but with low PARP1 expression level and are much less sensitive to AZD5305, LAE119 demonstrates much better activity than AZD5305, particularly when PARP1 level is increased with transgene expression. LAE119 demonstrated substantial tumor inhibition in MDA-MB-436 and Capan-1 xenograft models. LAE119 also displays favorable ADME properties and PK profiles. It has high tumor/plasma ratio which is beneficial for sustainable anti-tumor effect and reduction of off-target effects. In rat hematologic toxicity study, LAE119 at 10 mpk QD dose was well tolerated and had minimal effects on hematologic parameters. Both in vitro and in vivo data strongly support the further clinical investigation of LAE119. Citation Format: Ming Li, Yan Chen, Junyan Chen, Ling Jiang, Xiaofen Lin, Justin Gu. Preclinical characterization of LAE119, a novel PARP1 selective inhibitor and trapper [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 7132.
Abstract 3081: Targeting lipid kinases to enhance autophagy inhibition for the treatment of pancreatic cancer
Authors: Elyse G. Schechter, Jonathan M. DeLiberty, Clint A. Stalnecker, Kirsten L. Bryant
Journal: Cancer Research (2024)

Abstract Pancreatic ductal adenocarcinoma (PDAC) is characterized as the most KRAS-addicted cancer type, with KRAS mutations found in &amp;gt;95% of cases. Mutant KRAS relies on dysregulated metabolism to support growth. One dysregulated pathway upregulated in PDAC is autophagy, a lysosome-mediated process that degrades proteins and organelles to supply macromolecules for growth. Our lab and others have shown that inhibition of KRAS or the mitogen activated protein kinase (MAPK) components, MEK or ERK, further increases PDAC dependency on autophagy as a resistance mechanism. Cotreatment with ERK MAPK inhibitors and the autophagy inhibitor chloroquine (CQ) decreased autophagic flux, inhibited proliferation, and induced apoptosis in PDAC cells. CQ is the only FDA-approved autophagy inhibitor, and it demonstrates low potency in vivo, motivating our studies to identify strategies to improve autophagy inhibition in PDAC. We utilized a CRISPR-Cas9 loss-of-function screen to identify sensitizers to CQ in PDAC and identified 25 autophagy-related targets. We hypothesize that targeting the autophagy pathway at multiple nodes will increase the efficacy of CQ treatment in PDAC. To validate hits identified in the CRISPR-Cas9 screen, I designed an siRNA array that contained three distinct oligos for each target. I quantified changes in proliferation in a panel of four PDAC cell lines after siRNA-mediated suppression of the target genes following 3- or 6-day time points. I hypothesized that targets identified to be non-essential on their own would allow for potential synthetic lethality with CQ. To test this, I performed a 3-day knockdown followed by 3-day exposure to a dose response of CQ. I found that suppression of lipid kinases PIP4K2A, PIP4K2C, or PIK3C3 shift the dose response to CQ in a panel of PDAC lines. This indicates that loss of those targets sensitizes PDAC cells to CQ treatment. Furthermore, we found that pharmacological inhibition of VPS34, the lipid kinase encoded by PIK3C3 by the ATP-competitive inhibitor SAR-405 synergizes with CQ. My future studies will be focused on validating other targets identified in the loss-of-function CRISPR-Cas9 screen. I will measure changes in autophagic flux and apoptosis due to the loss of validated targets. The long-term goal of this project is to enhance the translatability of autophagy inhibition for patient care through identifying combinational approaches to improve CQ response in PDAC. Citation Format: Elyse G. Schechter, Jonathan M. DeLiberty, Clint A. Stalnecker, Kirsten L. Bryant. Targeting lipid kinases to enhance autophagy inhibition for the treatment of pancreatic 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 3081.
Abstract 2735: High affinity and potent anti-tumor efficacy of Nivo813, an anti-PD-1/ALK-1 bispecific antibody, in pre-clinical studies for solid tumors
Authors: Qingqing Zhou, Rong Tang, Lanfang Zhuang, Jianyu Huang, Jiang Qian, Zhihua Ren, Youzhi Tong
Journal: Cancer Research (2024)

Abstract Background: The activin-like kinase receptor 1 (ALK-1, encoded by ACVRL1) is a member of the transforming growth factor β (TGF-β) superfamily. Combination treatment using anti-PD-1/PD-L1 agents with anti-angiogenetic reagents might bring additional benefits, such as establishing a favorable TME leading to better responses towards immunotherapy. In the phase II clinical trial (NCT03893695) of combination therapy of ALK-1 (GT90001) and Nivolumab for the second line therapy in patients with metastatic hepatocellular carcinoma (“HCC”) in Taiwan, among the 20 evaluable patients, the overall response rate is 40%, and the side effects were well tolerated and manageable. Nowadays, the combination of GT90001 and nivolumab shows a remarkable long-tail effect, since 7 patients are still alive as of March 30, 2023, 6 of them had received no further systematic anti-tumor therapy after trial completion. Among them, 4 patients are still on progression free status. Our pre-clinical data demonstrated that Nivo813 has improved cell-binding potency and potent anti-tumor effects, lighting up its potential capacity as a therapeutic drug in the treatment of human cancers. Methods: The antigen binding activity of Nivo813 with PD-1 and ALK-1 were assessed by ELISA, Fortebio and flow cytometry. Endothelial cell tube formation assay was performed to identify the anti-angiogenesis function of Nivo813. The anti-tumor activity of Nivo813 was investigated in PBMC implanted with MDA-MB-231 breast cancer cells. Results:Nivo813 could specifically bind to human PD-1 and ALK-1 with high affinity. Intriguingly, Nivo813 was found to have much higher affinity (40-fold, nM) to cell surface PD-1 than that of nivolumab. Meanwhile, Nivo813 exhibited dose-dependent anti-angiogenesis activity in vitro. Nivo813 demonstrated greater anti-tumor efficacy compared to nivolumab in mice model. Conclusions: Nivo813, a dual-blocking anti-PD-1/ALK-1 bispecific antibody, shows improved binding potency to cell surface PD-1 and ALK-1 simultaneously, and displays dose-dependent anti-angiogenesis in vitro and great anti-tumor efficacy in vivo, supporting its clinical potentials for the treatment of human cancers. Citation Format: Qingqing Zhou, Rong Tang, Lanfang Zhuang, Jianyu Huang, Jiang Qian, Zhihua Ren, Youzhi Tong. High affinity and potent anti-tumor efficacy of Nivo813, an anti-PD-1/ALK-1 bispecific antibody, in pre-clinical studies for 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 2735.
Abstract 7144: BR0L075 (SCB01A), a microtubule inhibitor targeting the colchicine binding site, induces immunogenic cell death
Authors: Ayesha Bano, Xinli Liu
Journal: Cancer Research (2024)

Abstract BPR0L075 (also known as SCB01A in phase II clinical trial) is a novel anti-microtubule drug with potent anti-tumor and anti-angiogenic activity in vitro and in vivo. BPR0L075 inhibits tubulin polymerization (microtubule de-stabilizer) by binding to the colchicine-binding site of tubulin. We previously reported that BPR0L075 overcomes paclitaxel (microtubule stabilizer) resistance and induces vascular-disruption in vitro and in vivo. We observed that breast and ovarian cancer cells treated with BPR0L075 in vitro induced key hallmarks of immunogenic cell death (ICD). In both human and murine, ovarian (OVCAR3, ID8) and breast cancer (MDA-MB-231, 4T1) cell lines, treatment with low nanomolar concentration of BPR0L075 significantly decreased the viability of cells evidenced by SRB assay. Using a known ICD inducer mitoxantrone as a positive control, both flow cytometric analysis and immunofluorescence staining assays demonstrated that BPR0L075 treatment led to a time- and dose-dependent translocation of calreticulin, an endoplasmic reticulum chaperone protein, on the plasma membrane of dying cells which sends an “eat me” signal. The BPR0L75 treatment also led to secretion of High Mobility Group Box 1 (HMGB1), a non-histone chromatin-binding nuclear protein, as well as adenosine triphosphate (ATP) from the cell into the extracellular space using ELISA assay. These damage-associated molecular patterns (DAMPs) are known to lead to antigen-presenting cell recruitment, phagocytosis, maturation of dendritic cells, and chemotaxis. The appearance of the ICD biomarkers (calreticulin exposure, HMGB1 and ATP release) supports BPR0L075 as an ICD-inducing antimitotic agent. Further in vivo studies are warranted to delineate the effect of BPR0L075 on immune activation and recruitment of immune cells to the tumor microenvironment. Citation Format: Ayesha Bano, Xinli Liu. BR0L075 (SCB01A), a microtubule inhibitor targeting the colchicine binding site, induces immunogenic cell death [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 7144.
Abstract 113: Generation and validation of a novel humanized IL-31/IL-31RA/OSM/OSMR mouse model
Authors: Linlin Wang, Lei Zhao, Meiqi Zhang, Zhi Zhang, Zhen Chen, Mari Kuraguchi, Jingjing Lian, Jiansu Zhang
Journal: Cancer Research (2024)

Abstract Oncostatin M (OSM) and interleukin-31 (IL-31) are two pleiotropic cytokines that share a common signaling receptor subunit, the OSM receptor beta (OSMR). Both cytokines are released by monocytes, macrophages, dendritic cells and T lymphocytes in inflammatory situations, and upon binding to their respective receptors, induce the production of inflammatory cytokines (such as IL-6), chemokines, and other cellular growth factors during tissue repair, mainly via the JAK/STAT signal pathway. As OSM and IL-31 are reported to be involved in a variety of physiological and pathological processes, targeting IL-31 or OSM signaling is of therapeutic interest. To provide a novel preclinical platform for testing novel modulators of these signaling axes, a humanized IL-31/IL-31RA/OSM/OSMR mouse model was generated. First, single gene knock-in mice were constructed by gene editing technology; multigenic knock-in mice were then obtained by breeding, yielding a quadruple humanized model in which the murine cytokine sequences were replaced by full-length human cytokine sequences in situ, while the murine receptor sequences were replaced by chimeric sequences comprised of the human extracellular region and murine intracellular regions in situ. mRNA expression confirmed expression of IL-31, IL-31RA, and OSMR in this model, while ELISA confirmed expression of human OSM protein in the model without evidence of murine OSM expression. Next, the signaling capacity of the humanized OSMR receptor was confirmed: mouse embryonic fibroblasts (MEFs) isolated from humanized B-hOSM/hOSMR mice were capable of responding to human OSM to release IL-6, while wild-type MEFs could only respond to murine OSM. Subsequently, the ability of IL-31RA antibodies to alleviate scratching was tested in a chemically induced model of atopic dermatitis. Compared to mice receiving control antibodies, scratching frequency in humanized B-hIL31/hIL31RA/hOSMR mice treated with nemolizumab was attenuated (analog antibody was generated in-house). Finally, blood counts and flow cytometric profiling indicates that the humanized mice have a normal frequency of leukocytes and lymphocytes. Taken together, this quadruple humanized IL-31/IL-31RA/OSM/OSMR mouse model is a promising preclinical tool that can be used to evaluate novel modulators of this signaling pathway prior to clinical development. Citation Format: Linlin Wang, Lei Zhao, Meiqi Zhang, Zhi Zhang, Zhen Chen, Mari Kuraguchi, Jingjing Lian, Jiansu Zhang. Generation and validation of a novel humanized IL-31/IL-31RA/OSM/OSMR mouse model [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 113.