tbuckley/cabot-search huggingface dataset:
Abstract 6317: Developing a fully human heavy chain only Claudin-18.2-specific CAR-T cell therapy
Authors: Jason Noon, Yao Lu, Itishree Kaushik, Oyku Ay, Adam Luk, Bradley Delaney, David DeMeritt, Musheng Bao
Journal: Cancer Research (2024)

Abstract Camelid VHH/nanobodies have been widely applied as the antigen binding domain of CAR-T cell therapies due to a smaller size and simpler structure compared to the traditionally used single chain variable fragment (scFv). Additionally, camelid VHH/nanobodies provide greater flexibility for dual-targeting CAR-T cell therapies. However, camelid VHH/nanobodies require laborious and costly humanization and still have a significant risk of inducing anti-drug antibodies when administered to patients. Transgenic mice exclusively harboring the most stable human VH genes (HCAb Harbour Mice®) provide one of the best solutions to get fully human heavy chain only antibodies (HCAbs). To efficiently identify lead HCAb VHs for Claudin-18.2-targeting CAR-T cells, we developed an innovative direct CAR-function based HCAb library screening platform. From Claudin-18.2-immunized HCAb Harbour Mice®, we constructed a total VH library in a CAR lentiviral vector that we developed in-house. After producing the lentiviral particle library, we transduced a Jurkat-NFAT-GFP reporter cell line and stimulated with Claudin-18.2 overexpression cell line. Subsequently, GFP positive reporter cells, representing Claudin-18.2-specific CARs, were isolated through FACS sorting, expanded, and further stimulated with Claudin-18.2-positive NUGC-4 tumor cells. Then, Next Generation Sequencing and abundance ranking was performed on VHs recovered from sorted CAR-reporter cells. Lead VH candidates were cloned into the CAR-P2A-RFP lentiviral vector, and many of these VH clones exhibited superior Claudin-18.2-specific functionality compared to a clinically-validated reference scFv in both reporter and primary CAR-T cells. Many lead VH clones also exhibited excellent developability as soluble HCAbs. These data suggest that this innovative method of combining our fully human HCAb and CAR-based library screening platform will provide new avenues for CAR-T cell therapies. Citation Format: Jason Noon, Yao Lu, Itishree Kaushik, Oyku Ay, Adam Luk, Bradley Delaney, David DeMeritt, Musheng Bao. Developing a fully human heavy chain only Claudin-18.2-specific CAR-T cell 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 6317.
Abstract 6285: Defining androgen receptor function and the effects of PARP inhibition in BRCA1/2-deficient vs. proficient prostate cancer
Authors: Nicole A. Traphagen, Esme Wheeler, Rong Li, Xintao Qiu, Myles Brown
Journal: Cancer Research (2024)

Abstract Mutation or loss of the tumor suppressor genes BRCA1 and BRCA2 promotes the development of aggressive prostate cancer with poor outcomes and a high risk of metastatic relapse. Approximately 15% of metastatic prostate tumors are BRCA1/2-deficient. These tumors are frequently resistant to standard-of-care treatments that block androgen receptor (AR) function, although the mechanisms underlying this effect remain unclear. PARP inhibitors are synthetically lethal with BRCA1/2-deficiency and are commonly used as a late-line treatment in metastatic prostate cancer; however, both preclinical and clinical data have provided conflicting results on whether PARP inhibitors can be effective in BRCA1/2-proficient prostate tumors. BRCA1, BRCA2, PARP-1, and PARP-2 all have proposed roles in regulating transcription and the chromatin landscape. We therefore hypothesized that loss of BRCA1, BRCA2, and/or inhibition of PARP modulates AR function through changes in global chromatin structure and transcriptional pathways. We used patient-derived xenograft models and next-generation sequencing techniques to profile AR function in BRCA1/2-deficient vs. proficient prostate tumors. We found that loss of BRCA1 and BRCA2 is associated with chromatin accessibility changes, and differentially accessible regions correlate with DNA binding motifs for AR and AR cofactors. ChIP-seq for AR in these tumors demonstrated that BRCA1/2-deficiency is associated with an altered AR cistrome and a global decrease in AR genomic binding. Corresponding RNA-seq data confirmed a downregulated androgen response in BRCA1/2-deficient tumors. In cell line models, inhibition of PARP1 and PARP1/2 inhibited AR-driven transcription. Combining PARP inhibition with either androgen deprivation or the AR antagonist enzalutamide dampened the growth-inhibitory effects of PARP inhibitor treatment. Together, these results indicate that BRCA1/2-deficiency and PARP inhibition modulate AR function in prostate cancer. Citation Format: Nicole A. Traphagen, Esme Wheeler, Rong Li, Xintao Qiu, Myles Brown. Defining androgen receptor function and the effects of PARP inhibition in BRCA1/2-deficient vs. proficient prostate 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 6285.
Abstract 6303: Innovative strategies for managing chemotherapy-induced alopecia: Scalp cooling
Authors: Simonetta I. Gaumond, Rama Abdin, Rory O. McPhillips, Lina M. Ferrari, Sammya Mufarrej, Joaquin J. Jimenez
Journal: Cancer Research (2024)

Abstract Chemotherapy-Induced Alopecia (CIA) is a visibly distressing consequence of chemotherapy. Although it does not pose a life-threatening risk, CIA can significantly affect patient’s self-esteem. Regarding the mechanism of action, stress induced by chemotherapy treatment can lead to the shedding of hair follicles, generating varying degrees of hair loss. In recent years, scalp cooling has emerged as a beneficial preventative agent for CIA due to its ability to induce vasoconstriction in the scalp and reduce follicular metabolic rate. To assess the efficacy of scalp cooling in preventing CIA, we conducted a review of randomized control trials published on PubMed in the last 10 years. Five studies met our inclusion criteria, in which three examined hair preservation and two evaluated treatment duration efficacy. All studies investigating hair preservation with scalp cooling reported highly significant results from the cooling device when compared to a placebo (56.3% vs. 0%, 39.3% vs. 0%, and 50.5% vs. 0%, respectively). Additionally, one of these studies also assessed hair regrowth, revealing higher rates in the scalp cooling group compared to the control at 6 weeks (89% vs. 12%) and at 12 weeks (100% vs. 59%). Both studies evaluating the effectiveness of scalp cooling based on treatment duration concluded that 20 minutes of cooling was as effective as 45 and 90 minutes in preventing CIA. Collectively, these findings add to the mounting evidence endorsing scalp cooling as a powerful management strategy in averting CIA. Citation Format: Simonetta I. Gaumond, Rama Abdin, Rory O. McPhillips, Lina M. Ferrari, Sammya Mufarrej, Joaquin J. Jimenez. Innovative strategies for managing chemotherapy-induced alopecia: Scalp cooling [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 6303.
Abstract 7435: PATTY: A bias estimation and correction model for bulk and single-cell CUT&amp;Tag data
Authors: Sheng'en Shawn Hu, Qingying Chen, Megan Grieco, Chongzhi Zang
Journal: Cancer Research (2024)

Abstract The accurate detection of transcription factor (TF) binding sites and histone modifications (HM) on the genome-wide scale is essential for studying functional epigenetics and gene regulation. Cleavage Under Targets &amp; Tagmentation (CUT&amp;Tag) is a low-cost and easy-to-implement epigenomic profiling method that can be performed on a low number of cells and on the single-cell level. CUT&amp;Tag experiments use the hyperactive transposase Tn5 for tagmentation. We find that Tn5 is subject to intrinsic sequence insertion bias (intrinsic bias). Additionally, the preference of Tn5 insertion toward accessible chromatin also affects the distribution of CUT&amp;Tag reads (open chromatin bias). Both types of biases can significantly confound bulk and single-cell CUT&amp;Tag data analysis, which requires careful assessment and new analytical methods. To address this challenge, we present PATTY (Propensity Analyzer for Tn5 Transposase Yielded bias), a computational method for systematic characterization and correction of biases in CUT&amp;Tag data. We demonstrate that histone modification signals (H3K27me3 and H3K27ac) detected from CUT&amp;Tag data after bias correction using PATTY are better associated with orthogonal biological features such as gene expression. PATTY-corrected single-cell CUT&amp;Tag signals for histone modification can better cluster cells into their true cell types. This new computational method can improve both bulk and single-cell CUT&amp;Tag data analysis. Citation Format: Sheng'en Shawn Hu, Qingying Chen, Megan Grieco, Chongzhi Zang. PATTY: A bias estimation and correction model for bulk and single-cell CUT&amp;Tag 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 7435.
Abstract 5193: Molecular evolution of chemoresistance acquisition and predictive insights into the progression of bladder cancer
Authors: Gi-Eun Yang, Jae-Jun Kim, Tae Hwan Shin, Sun-Hee Leem
Journal: Cancer Research (2024)

Abstract Cancer heterogeneity arises from cellular features, suggesting that distinct molecular drivers may be latent within cancers diagnosed at different clinicopathological stages. We thoroughly assessed phenotypic traits and molecular alterations linked to chemoresistance and constructed chemoresistant bladder cancer cell lines representing the stepwise transformation. Model cell lines (5637GRCs, gemcitabine-resistant cells) with stepwise gemcitabine resistance representing early, intermediate, and late resistance phases were developed from non-muscle-invasive bladder cancer (NMIBC) cells. Notably, an increase in cell motility was observed at a relatively early phase. The results from the time-course analysis of molecular evolution showed changes in focal adhesion kinase signaling, PI3K-Akt signaling, and TGF-β signaling pathways during the phase of increasing cell motility. As chemoresistance increased, the levels of genes related to differentiation and MAPK signaling gradually increased. A 63-gene chemoresistance-motility (CrM) signature was constructed and weighted according to cell motility, and a strong correlation was observed between cancer metastasis and drug resistance; the signature also showed prognostic relevance in patients with NMIBC. This study affords a significant understanding of the molecular evolution of chemoresistance acquisition and enables prediction of cancer progression during chemotherapy treatment. Moreover, it provides insights into the progression of cells through all chemoresistance stages from NMIBC to MIBC. Therefore, this study proposes the feasibility of utilizing biomarkers correlated with cancer motility to predict cancer progression in the early phase of chemotherapeutic intervention in patients with non-muscle-invasive bladder cancer. Citation Format: Gi-Eun Yang, Jae-Jun Kim, Tae Hwan Shin, Sun-Hee Leem. Molecular evolution of chemoresistance acquisition and predictive insights into the progression of bladder 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 5193.
Abstract 5194: Pre-operative markers extracted from extracellular vesicles related with lung cancer relapse
Authors: Hayato Koba, Shigeki Nanjo, Seiji Yano
Journal: Cancer Research (2024)

Abstract Background: Pre- and post-operative immunotherapy have been a new standard of care for lung cancer patients. On the other hand, post-operative Osimertinib; EGFR-TKI therapy had obtained new evidence to the EGFR mutant lung cancer patients. Both treatments revealed to make patient survival prolonged. However, there are quite a lot patients who had experienced disease relapse, despite of multimodal therapy. Extracellular vesicles (EVs) have reported to have potent for searching a new target to cancers. Purpose: Exploration of novel risk factors related with post-operative recurrence of lung cancer. Methods: We retrospectively examined patient background, disease-free survival, overall survival, and preoperative liquid biopsy analysis in lung cancer patients who underwent surgery at Kanazawa University Hospital between January 2017 and May 2020, in whom preoperative chemotherapy was not administered. EVs were extracted from 500 μl serum within 7 days before surgery using MagCapture Exosome isolation Kit PS Ver.2 (FUJIFILM). First, we focused the six cases that had the 3 phase samples: preoperative, disease free and relapse phase. According to the EV concentrations calculated by BCA method, comprehensive protein assessment of these subjects was performed using shotgun mass spectrometry. Secondly, all cases’ prognosis were analyzed in connection with the detected marker using Dot blotting. Results: All EV samples from primary 6 cases were able to be detected and median concentration of those was 27 μg/ml (9-82). We focused on three factors (LCEV1-3) among the 6 cases analysis, when we disease fluctuation. Among LCEV1-3 examination to all preoperative samples, LCEV2 had been related with disease recurrence. Discussions: EVs contain amount of information such as cancer biomarker. Not only that, these factors may have a potency for therapeutic target. Further investigations are needed. Citation Format: Hayato Koba, Shigeki Nanjo, Seiji Yano. Pre-operative markers extracted from extracellular vesicles related with lung cancer relapse [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 5194.
Abstract 2046: Targeting cellular models of glioblastoma versus non-target and off-target cell populations using U87-MG membrane lipid-modified nanoliposomes
Authors: Kaylee Janton, Duha Baamir, Aesha Patel, Sheren Boco, Robert Campbell
Journal: Cancer Research (2024)

Abstract Background: Glioblastoma Multiform (GBM) is an aggressive and malignant form of brain cancer known for its invasiveness and significant heterogenicity. The majority of GBM cases are linked to genetic mutations (ie. TP53, EGFR, and PTEN), which disrupt the normal regulation of cell growth and division, resulting in uncontrolled cell proliferation. The utilization of nanoparticles presents a promising approach for addressing the complexities associated with selective drug delivery to GMB and treatment. The purpose of this study was to investigate the effect of including U87-MG membrane lipid extracts in nanoliposomes using target, non-target, and normal healthy cellular populations in vitro. Methods: The nanoliposomes employed for the experiments included various ratios of U87-MG lipid extracts (lipids derived from U87-MG cells), DOPC, Cholesterol, and DPPE-Rhodamine for fluorescence studies. The particle size and zeta potential values were measured and monitored throughout for consistency. Fluorescence intensity values (arbitrary units) were used to assess extent of cell binding, and uptake at the various time points. In vitro studies were employed to evaluate the cellular uptake activity of U87-MG-modified nanoliposome preparations using mixed ratios and compositions of lipid materials. Cell lines employed were, LN-18 (human glioma), T98G (human glioma), U87-MG (human glioma), 4TI (murine breast), and HBEC-5i (normal healthy) cells. Results: The average size for the nanoliposomes (with and without lipid extract) fell within the range of 110 to 220 nm, while the zeta potential for the CLENs was negatively-charged. In vitro studies revealed that the inclusion of U87MG lipid extract in nanoliposomes increased cellular uptake in glioma cells when compared to control. Current investigations focus on different microenvironments, including non-target and off target cell populations. The findings from the cellular uptake analyses to date suggest that the in vitro cellular uptake of the CLENs varied in accordance with the total lipid extract content for all cell lines. Citation Format: Kaylee Janton, Duha Baamir, Aesha Patel, Sheren Boco, Robert Campbell. Targeting cellular models of glioblastoma versus non-target and off-target cell populations using U87-MG membrane lipid-modified nanoliposomes [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 2046.
Abstract 2038: Combination therapy leads to decreased viability in cardiomyblasts cells
Authors: Ashley N. Greenlee, Ethan J. Schwendeman, Sakima A. Smith
Journal: Cancer Research (2024)

Abstract Anti-cancer therapies (ACT) have been extremely effective in improving survival in cancer patients; however, they have also been known to cause cardiovascular diseases (CVD) in the same patients. Published research shows that ACTs are toxic to cardiomyocytes through decreased viability. However, they have mainly focused on drugs that are phasing out of clinical practice while newly generated tyrosine kinase inhibitors (TKIs) and immune checkpoint inhibitors (ICIs) have rarely been studied, despite their increase in popularity for treating multiple cancers as monotherapies and combination therapies. Additionally, most of the concentrations tested tend to be higher than the concentration that directly interacts with cardiomyocytes, therefore overestimating its effects. The goal of this project is to elucidate whether newly generated TKIs and ICIs, both by itself and in combination, lead to decreased viability in cells. We tested three TKIs (Axitinib, Cabozantinib, and Lenvatinib) and two ICIs (Nivolumab and Pembrolizumab), both solely and together, on rat ventricular myoblasts (H9c2) cells using clinically relevant concentrations by calculating the unbound serum drug concentrations found in cancer patients. After 24 hours, we tested cell viability using the cell counting kit-8 (CCK-8) assay. After 24 hours, neither TKIs nor ICIs by themselves caused decreased viability compared to the control group. However, there were significant decreases in viability when treated with combination of the two, with more than 50% depletion in the Lenvatinib/Pembrolizumab group. Our study indicates although TKIs and ICIs by themselves do not effect viability, they have significant effects after 24 hours when the drugs are combined, even at clinically relevant concentrations. We plan to further characterize whether these drug combinations lead to cardiomyocyte death and through which pathway. Additionally, our lab has successfully differentiated and validated human-induced pluripotent ventricular myocytes (hiPSC-CMs) and testing whether these monotherapies and combination therapies effect viability and functionality on human-induced pluripotent ventricular myocytes (hiPSC-CMs) is currently in progress. Citation Format: Ashley N. Greenlee, Ethan J. Schwendeman, Sakima A. Smith. Combination therapy leads to decreased viability in cardiomyblasts 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 2038.
Abstract 2039: Cellular characterization of small molecule PD-L1 inhibitors reveal their novel mechanisms of action
Authors: Weiling Pan, Yongxian Zhang, Fangfei Qi, Wenqun Xin, Zhigang Feng, Zhui Chen, Haiyan Ying
Journal: Cancer Research (2024)

Abstract Introductions: Immune checkpoint inhibitors, including PD-1/L1, are key regulators of immune response and promising targets in cancer immunotherapy. Like anti-PD-1/L1 antibodies, small molecule PD-L1 inhibitors that have been discovered by us and others could also efficiently block PD-1 and PD-L1 interaction and exhibit anti-tumor efficacy in preclinical and clinically settings. In this study, we explore the cellular mechanism of small molecule PD-L1 inhibitors, unveiling their novel mechanisms of action in the regulation of PD-L1 and its functions. Materials and Methods: The cellular effects of the small molecule PD-L1 inhibitor on PD-L1 protein and RNA levels were assessed through Western blot and real-time qPCR experiments. HTRF assay and cellular luciferase reporter assay were used to evaluate the blockade of PD-1 and PD-L1 interaction in vitro and in cells. Flow cytometry and confocal microscopy were used to investigate the internalization of PD-L1 upon treatment with inhibitors. MSD assay was used to evaluate the alteration of soluble PD-L1 proteins. Results: Small molecule PD-L1 inhibitors discovered by Abbisko Therapeutics potently blocked PD-1/PD-L1 interaction in vitro and in cellular system. It could also rapidly and strongly induce PD-L1 internalization in cells. Further profiling suggested that small molecule PD-L1 inhibitors specifically disrupt PD-L1 N-glycosylation, resulting in aberrant PD-L1 glycosylation. This, in turn, may hinder the proper translocation of newly synthesized PD-L1 to the cell surface, thereby abolishing its interaction with PD-1 and functions in immune regulation. Conclusion: Taken together, these results for the first time revealed the distinctive mechanisms of our small molecule PD-L1 inhibitors. With their multi-layer inhibitory effects stemming from various mechanisms, small molecule PD-L1 inhibitors may offer potentially improved activities and an alternative therapeutic treatment for the cancer patients. Citation Format: Weiling Pan, Yongxian Zhang, Fangfei Qi, Wenqun Xin, Zhigang Feng, Zhui Chen, Haiyan Ying. Cellular characterization of small molecule PD-L1 inhibitors reveal their novel mechanisms of action [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 2039.