tbuckley/cabot-search huggingface dataset:
Abstract 5821: DXC008, a novel STEAP1 antibody-tubulysin analog conjugate with a function linker, demonstrates a potential to broaden therapeutic opportunities for prostate tumors
Authors: Qingliang Yang, Yuanyuan Huang, Junxiang Jia, Huihui Guo, Lingli Zhang, You Zhou, Zhicang Ye, Hangbo Ye, Yifang Xu, WenJun Li, Zhiyu Zhao, Lingyao Zhao, Lu Bai, Jun Zheng, Robert Y. Zhao
Journal: Cancer Research (2024)

Abstract Six-transmembrane epithelial antigen of the prostate 1 (STEAP1), is a cell surface protein frequently expressed in prostate cancer, with limited expression in non-prostate tissues. A Steap1 antibody called Vandortuzumab conjugated with MMAE (DSTP3086S) was in the clinical phase I trial for treating STEAP1-expressing metastatic castration-resistant prostate cancer and showed acceptable safety at 2.4 mg/kg once every 3 weeks. However, many patients are nonresponsive to DSTP3086S due to low target expression levels and common treatment-related AEs which were caused by MMAE payloads. DXC008 was generated through screening the therapeutical index in vitro of conjugates of an anti-Steap1 antibody with varieties of payloads of tubulysin B analogs through function peptide spacer linkers. The generated DXC008 exhibited not only good affinity for Steap1 but also moderate affinity for Prostate-specific membrane antigen (PSMA) which is as well specifically overexpressed in most prostate cancer with limited expression in normal tissue. DXC008 demonstrated couple tens to a hundred of picomolar concentration (pM) of potency against several prostate tumor cells and over 60% internalization rate within 90 min in vitro. And in vivo it showed very good durable antitumor response as low dose as 1 mg/kg one injection in both high and moderate of both Steap1 and PSMA expression xenograft models. Pharmacokinetic profiles of DXC008 were favorable and the safety of Maximal Tolerable Dose (MTD) was over 120 mg/kg in single injection in mice. DXC008 has been forward to NHP toxicity study and it has potential to be a good STEAP1/PSMA-targeting ADC with a wide therapeutic window for prostate cancers. Citation Format: Qingliang Yang, Yuanyuan Huang, Junxiang Jia, Huihui Guo, Lingli Zhang, You Zhou, Zhicang Ye, Hangbo Ye, Yifang Xu, WenJun Li, Zhiyu Zhao, Lingyao Zhao, Lu Bai, Jun Zheng, Robert Y. Zhao. DXC008, a novel STEAP1 antibody-tubulysin analog conjugate with a function linker, demonstrates a potential to broaden therapeutic opportunities for prostate 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 5821.
Abstract 5800: Ultrasound-mediated nano-drug delivery system to enhance cancer treatment efficacy: An <i>in vitro</i> study
Authors: Farshad Moradi Kashkooli, Anshuman Jakhmola, Tyler K. Hornsby, Graham A. Ferrier, Jahangir (Jahan) Tavakkoli, Michael C. Kolios
Journal: Cancer Research (2024)

Abstract Conventional non-targeted nano-sized drug delivery systems face limitations such as restricted drug penetration depth and treatment efficacy in solid tumors. External stimulus such as ultrasound waves can trigger targeted, on-demand drug release from the nanocarriers. We demonstrate a first-of-its-kind use of low-intensity pulsed ultrasound (LIPUS) to induce Doxorubicin release from the surface of gold nanoparticle drug carriers. Our 1-MHz LIPUS beam is capable of penetrating tissue to sufficient depths with the required power/intensity for drug release applications with a nominal intensity of around 3 W/cm2 in the region of interest (ROI). This level of intensity is necessary to elevate the tissue temperature to the mild hyperthermia range of 41 to 45 °C. Our in vitro experiments demonstrate a remarkable 22% enhancement in drug release with the addition of LIPUS. Measurements of drug release kinetics, with and without LIPUS, suggest that LIPUS shifts the drug release mechanisms from static (Fickian) to dynamic (non-Fickian) release in vitro. Thus, revealing the intricate interactions between ultrasound and drug release from gold nanoparticle drug carriers. To assess the efficacy of the delivery system, we developed an in vitro cell culture model with a customized ultrasound exposure setup. The LIPUS device was situated at the bottom base of a water tank, directing ultrasound beam upward toward a region of interest where the MDA-MB-231 breast cancer cells were located 35 mm away from the LIPUS element. We found that the LIPUS device operating at an acoustic power of around 4 W increased cell killing efficacy by approximately 15% ± 2% when compared to conventional nano-drug delivery, highlighting a significant improvement attributed to ultrasound-induced mechanical effects. At the cellular level, these results underscore the potential advantages of ultrasound-mediated nano-drug delivery over conventional chemotherapy and non-targeted nano-drug delivery. Citation Format: Farshad Moradi Kashkooli, Anshuman Jakhmola, Tyler K. Hornsby, Graham A. Ferrier, Jahangir (Jahan) Tavakkoli, Michael C. Kolios. Ultrasound-mediated nano-drug delivery system to enhance cancer treatment efficacy: An in vitro study [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 5800.
Abstract 4415: Utilization of MBD-seq to elucidate differentially methylated regions in cfDNA across healthy and cancer patients
Authors: Camille Michelon, Brian Egan, Benjamin Delatte
Journal: Cancer Research (2024)

Abstract 5-Methylcytosine (5-mC) is the most abundant epigenetic DNA modification in eukaryotes. The presence of 5-mC alters gene expression and genome metabolism, and its deregulation is associated with many human diseases. Cell-free DNA (cfDNA) released from apoptotic cells has recently gained attention, as mutations or epimutations (e.g. 5-mC variations) detected in cfDNA were shown to have high diagnostic potential to assess the presence, stage and outcome of several cancers. However, 5-mC detection in cfDNA remains a challenge as input material is often very scarce. MBD-Seq is a method that leverages the ability of Methyl-CpG-binding domain protein 2 (MBD2) to capture and detect highly methylated regions of DNA genome-wide. We evaluated MBD-Seq for the detection of aberrant methylation patterns in cfDNA from healthy and diseased patients. We found MBD-seq on cfDNA to be specific (over 100-fold mC:C detection ratio) and sensitive (5 ng of input cfDNA). Applying MBD-seq to samples from healthy vs colorectal and breast cancer patients showed striking differences in methylation of key tumor-associated genes. Hence, MBD-Seq can elucidate aberrant methylation patterns from cfDNA, highlighting its potential as a diagnostics tool for the detection of cancer. Citation Format: Camille Michelon, Brian Egan, Benjamin Delatte. Utilization of MBD-seq to elucidate differentially methylated regions in cfDNA across healthy and cancer patients [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 4415.
Abstract 1533: Characterizing tumor-immune surveillance in Li-Fraumeni syndrome
Authors: Camilla Giovino, Nicholas Fischer, Noel Ong, Ashby Kissoondoyal, Ran Kafri, David Malkin
Journal: Cancer Research (2024)

Abstract Li-Fraumeni Syndrome (LFS) is a cancer predisposition syndrome associated with germline TP53 mutations and increased lifetime risk of developing multiple cancers. p53, the protein encoded by TP53, plays a role in regulating various aspects of immune cell biology. Accordingly, inactivation of p53 in tumor cells shapes interactions with the immune system and influences the anti-tumor immune response. Mutation or deletion of p53 in immune cells also favors tumor development and progression. However, to date, a comprehensive study of immune cell populations and the anti-tumor immune response has not been undertaken in the context of LFS. We hypothesized that germline TP53 mutation carriers possess dysfunctional immune cells and/or immune responses, supporting LFS-associated tumor progression. Our preliminary data indicate a profound defect in tumor-immune surveillance in an LFS murine model. We observed that MC38 cancer cells develop significantly faster into tumors when injected into LFS mice (harboring a gain-of-function mutation Trp53R172H/WT) compared to wildtype (WT) control mice. Importantly, we identified significant alterations in immune cell compositions and phenotypes within the tumor microenvironment as well as immune organs using flow cytometry. We are currently using ex vivo proliferation assays and cytotoxicity assays to investigate the impact of mutant p53 on the tumor-killing ability of immune effector cells. Altogether, an improved understanding of anti-tumor immune dysfunction in the context of germline TP53 mutation may reveal the potential for innovative therapies to target different facets of the immune system to intercept cancer progression in LFS patients. Citation Format: Camilla Giovino, Nicholas Fischer, Noel Ong, Ashby Kissoondoyal, Ran Kafri, David Malkin. Characterizing tumor-immune surveillance in Li-Fraumeni syndrome [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 1533.
Abstract 1537: CD63 acts as a key modulator of tumor progression and innate immune evasion in non-small cell lung cancer
Authors: Tristan Lerbs, Lu Cui, Cristabelle De Souza, Reinhard Buettner, Gerlinde Wernig
Journal: Cancer Research (2024)

Abstract Introduction: Lung cancer is a major reason for cancer-related mortality worldwide, causing more than two million cancer deaths per year. Over the last decade, new therapies have allowed long-term survival for patients even in advanced stages. However, only a minority of patients benefits from these therapies and patients often grow resistant over time. An important mechanism that contributes to cancer growth and the development of therapy resistances is the cross-talk between cancer cells and their tissue microenvironment, in particular fibroblasts and macrophages. In this context, we explored whether the tetraspanin CD63 - which is commonly found on intra- and extracellular membranes - stimulates cancer growth and mediates pro-tumorigenic functions of the tissue microenvironment in NSCLC. Methods: We analyzed patient tissue via immunohistochemistry and in-situ-hybridization. We deleted CD63 in cancer cell lines (A549, H810, LC19) and primary fibroblasts via CRISPR-Cas9. To assess phagocytosis, we used in vitro EdU assays and adaptive transfer models in vivo, and identified changes in cell signaling via mass spectrometry. We used an in vitro phagocytosis assay to determine the effect of CD63 on cancer cell phagocytosis through macrophages and analyzed the expression of M1 and M2-associated surface markers through flow cytometry upon co-culturing PBMC with cancer cells over one week. Results: In patient sections, cancer tissue did not only express more CD63 on the gene expression and protein level but a stronger CD63 expression also correlated with a denser macrophage infiltrate. Looking for pro-tumorigenic functions, deleting CD63 in three cancer cell lines reduced cancer cell growth both in vitro and in an adaptive transfer model in vivo. Additionally, deleting CD63 impaired the pro-tumorigenic focal adhesion signaling in primary fibroblasts. Concerning the interaction between cancer cells and macrophages, deleting CD63 reduced the macrophage-mediated phagocytosis of cancer cells and co-culturing primary monocytes with CD63-deficient lung cancer cells induced the expression of M1-associated surface markers on the PBMC. Conclusion: In conclusion, these results demonstrate that the tetraspanin CD63 drives NSCLC growth by stimulating cancer cell proliferation - in part by interfering with focal adhesion signaling - and facilitating immune evasion by preventing cancer cell phagocytosis through macrophages and inducing an immunosuppressive phenotype in macrophages. Citation Format: Tristan Lerbs, Lu Cui, Cristabelle De Souza, Reinhard Buettner, Gerlinde Wernig. CD63 acts as a key modulator of tumor progression and innate immune evasion in non-small cell lung 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 1537.
Abstract 3877: Multi-modal analysis of paracrine signaling in group 3/4 medulloblastoma
Authors: Bohyeon Yu, Jangham Jung, Aaron Diaz
Journal: Cancer Research (2024)

Abstract Medulloblastoma (MB) is the most common primary brain malignancy in kids, with the group 3 and 4 subtypes (G3/4) being the most aggressive. Recent single-cell genomics studies have identified the G3/4 MB cell of origin and point to disrupted stem-cell differentiation as a key factor in MB pathogenesis. However, surprisingly little is known about the contribution of tumor-supportive paracrine signaling to the ontogeny of this disease. The spatial organization of MB cellular hierarchies is not completely understood. We profiled N=24 G3/4 MBs from UCSF patients via single-nucleus RNA sequencing (snRNA-seq). Of these cases, N=10 were profiled via single-cell assay for transposase-accessible chromatin by sequencing (scATAC-seq). To capture the spatial context, we profiled an additional 20 samples via spatial transcriptomics using the Visium and Xenium platforms. We found that the standard Xenium brain capture set was inadequate, and we developed a highly specific capture set for G3/4 MBs. In particular, our panel resolves cell-type differences in the stage of MB lineage commitment, from rhombic-lip progenitors to more differentiated unipolar brush-like cells. Altogether, over 110,000 nuclear-sequencing libraries and over 1,898,000 spatially-resolved single-cell libraries were generated. We inferred cell-cell communication signals from our snRNA-seq data by identifying co-expressed receptors and their cognate ligands. We then performed an integrated analysis of our snRNA-seq and scATAC-seq data to infer the cis-regulatory enhancers of those signaling genes, as well as the transcription factors that bind them. We employed our spatial transcriptomics data to confirm paracrine signaling networks inferred from nuclear-sequencing data. We found that distinct MB cell types corresponding to different stages of differentiation occupied specific spatial domains. The results of our ongoing analysis of this spatially-resolved single-cell atlas will be presented. This study paves the way for innovative therapeutic strategies targeting paracrine signaling in G3/4 MB. Citation Format: Bohyeon Yu, Jangham Jung, Aaron Diaz. Multi-modal analysis of paracrine signaling in group 3/4 medulloblastoma [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 3877.
Abstract 3872: Multi-ancestral origins of colorectal lesionsMulti-ancestral origins of colorectal lesions
Authors: Ryan O. Schenck, Aziz Khan, Aaron Horning, Edward D. Esplin, Debra Van Egeren, William Greenleaf, James M. Ford, Michael P. Snyder, Christina Curtis
Journal: Cancer Research (2024)

Abstract The widely accepted paradigm that cancer initiation is a monoclonal event has not been definitively resolved. In sporadic cancers this is due to the requirement for longitudinal sampling to study this occult process, which occurs over years to decades. Individuals with familial adenomatous polyposis (FAP) possess a germline APC mutation, leading to hundreds of colonic polyps in adolescence and a 100% lifetime risk of colorectal cancer. Resected colons from FAP patients contain normal mucosa, benign and dysplastic polyps that embed the natural history of colorectal tumorigenesis at different points of malignant progression. Through genome sequencing of 127 independent polyps or mucosa samples from six FAP patients, we characterized the genomic landscape, relative timing of somatic alterations, and clonal dynamics in normal, dysplastic, and invasive colon tissue. Comparison with multi-region sequencing data from FAP patients and sporadic colorectal adenomas and carcinomas indicates similar molecular profiles, with canonical cancer driver genes present across benign and dysplastic premalignant lesions and shared mutational orders. Pairwise sample comparisons and phylogenetic reconstructions revealed extensive heterogeneity and subclonal sharing within a patient’s benign and dysplastic lesions, irrespective of location in the colon. These data imply that polyps were initiated from multiple cells from distinct lineages whose most recent common ancestor arose during development. We corroborate these findings using a mechanistic mathematical model, which infers polyclonality in 100% of benign and 83% of dysplastic samples. Based on these findings, we propose a conceptual model of the multi-ancestral origin of intestinal malignancies. Citation Format: Ryan O. Schenck, Aziz Khan, Aaron Horning, Edward D. Esplin, Debra Van Egeren, HTAN–FAP Consortium, William Greenleaf, James M. Ford, Michael P. Snyder, Christina Curtis. Multi-ancestral origins of colorectal lesionsMulti-ancestral origins of colorectal lesions [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 3872.
Abstract 3848: Comprehensive protein analysis to identify the proteins responsible for sarcopenia and their impact on antitumor immunotherapy in non-small cell lung cancer
Authors: Takaaki Masuda, Satoshi Watanabe, Tomoya Wakabayashi, Susumu Tanaka, Kunihiro Shono, Ryo Suzuki, Tomoki Sekiya, Naohiro Yanagimura, Masashi Arita, Aya Ohtsubo, Tomohiro Tanaka, Koichiro Nozaki, Yu Saida, Satoshi Hokari, Rie Kondo, Kenjiro Shima, Yosuke Kimura, Nobumasa Aoki, Yasuyoshi Ohshima, Toshiyuki Koya, Kazuko Sakai, Kazuto Nishio, Motohiko Yamazaki, Hiroyuki Ishikawa, Toshiaki Kikuchi
Journal: Cancer Research (2024)

Abstract Background: Previous retrospective studies have shown that sarcopenia (Sar) is associated with poor outcome in cancer patients (pts) receiving immune checkpoint inhibitors (ICIs). We conducted a prospective study to determine whether Sar-related proteins induce Sar and reduce the efficacy of ICI. Method: Non-small cell lung cancer (NSCLC) pts receiving ICI as first-line treatment at Niigata University Medical and Dental Hospital were eligible. Sar was diagnosed with physical performance and skeletal muscle mass. Comprehensive protein analysis of pre-treatment blood samples was performed to identify factors that correlate with muscle loss and ICI effects. Result: 41 patients were enrolled from October 2019 through August 2022. PFS for Sar was 4.6 months, 6.7 months for Pre-Sar, and 16.7 months for Non-Sar (P=0.0028). OS for Sar was not reached, 15.7 months for Pre-Sar, and not reached for Non-Sar (P=0.0014). Leptin, IL-1β, IL-12, and Pentraxin 3 were significantly correlated with loss of muscle mass. In contrast, leptin, insulin, IGF-1, GDF-8, Activin A, IL-2Ra, IL-8, MMP-3, osteopontin, and Pentraxin-3 were significantly associated with poor OS. Pentraxin 3 and leptin were associated with both the effectiveness of immunotherapy and sarcopenia. A multivariate analysis that considered factors commonly associated with the effectiveness of immunotherapy, including age, PD-L1 expression rate, and neutrophil-lymphocyte ratio, Pentraxin 3 was determined to be an independent prognostic factor. Conclusion: This study indicated that Sar-related proteins and inflammatory cytokines are involved in the development of Sar and ICI efficacy. Citation Format: Takaaki Masuda, Satoshi Watanabe, Tomoya Wakabayashi, Susumu Tanaka, Kunihiro Shono, Ryo Suzuki, Tomoki Sekiya, Naohiro Yanagimura, Masashi Arita, Aya Ohtsubo, Tomohiro Tanaka, Koichiro Nozaki, Yu Saida, Satoshi Hokari, Rie Kondo, Kenjiro Shima, Yosuke Kimura, Nobumasa Aoki, Yasuyoshi Ohshima, Toshiyuki Koya, Kazuko Sakai, Kazuto Nishio, Motohiko Yamazaki, Hiroyuki Ishikawa, Toshiaki Kikuchi. Comprehensive protein analysis to identify the proteins responsible for sarcopenia and their impact on antitumor immunotherapy in non-small cell lung 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 3848.
Abstract 2798: Oral fungal infection tweaks the innate immune tumor microenvironment promoting
Authors: Xin Li, Na-Young Song, Amit Kumar Singh, Jonathan Badger, Chengfei Jiang, Feng Zhu, Debra Tross, Yongmei Zhao, Bao Tran, Yinling Hu
Journal: Cancer Research (2024)

Abstract It is yet unknown how a fungus and tumor interplay impairs innate immunity, modulating tumorigenesis. Here, we found that oral infection with Cladosporium cladosporioides of mice with Ikka deficiency in epithelial stem cells enhanced STAT3-dependent oral squamous cell carcinoma (SCC) development and fungal colonization. In wild-type mice infection was cleared up, suggesting a synergic tumor-fungus loop involved in the accelerated carcinogenesis. C. cladosporioides-mediated EGFR activation stimulated intratumor STAT3-led pathways to generate an acidic oral milieu, which disrupted bacterial compositions and suppressed neutrophil’s ROS but increased Il1b expression, dampening neutrophil’s fungitoxicity and allowing oral fungal and bacterial overgrowth. In addition, fungus-induced IL-1β/IL-17A augmented STAT3 activity in SCC cells, contributing to local and distal carcinogenesis. Significantly, fungal signals were greater in human head and neck SCCs (HNSCCs) and SCC-adjacent tissues than in healthy controls and were co-localized with IL1B-expressing neutrophils in HNSCCs. These similar traits of oncogenic pathways, microbiota dysbiosis, and defective neutrophils in HNSCC patients with poor survival highlight the importance of increased fungal infection for human malignant development and therapy. Citation Format: Xin Li, Na-Young Song, Amit Kumar Singh, Jonathan Badger, Chengfei Jiang, Feng Zhu, Debra Tross, Yongmei Zhao, Bao Tran, Yinling Hu. Oral fungal infection tweaks the innate immune tumor microenvironment promoting [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 2798.