tbuckley/cabot-search huggingface dataset:
Abstract 5361: Aberrant glycosylation in mPDAC is associated with increased epithelial-mesenchymal transition and recruitment of immunosuppressive cells
Authors: Shawna Brookens, David Degaramo, Kiesha Wilson, Wilder Condori Obregon, Prakash Nagarkatti, Mitzi Nagarkatti, Avery Posey Jr.
Journal: Cancer Research (2024)

Abstract The tumor-associated glycan Tn antigen (GalNAc-α-O-Ser/Thr) is associated with poor prognosis in various solid tumors. However, the mechanisms that Tn antigen promotes tumorigenesis are incompletely understood. Here, we generated Tn antigen-expressing murine pancreatic ductal adenocarcinoma (mPDAC) tumor cell lines through CRISPR/Cas9-mediated knockout of the C1galt1c1 gene. Tn antigen expressing mPDAC cell lines exhibited increased in vitro proliferation and migration compared to parental controls. RNA sequencing revealed that loss of C1galt1c1 in mPDAC cells correlated with increased expression of genes associated with epithelial-mesenchymal transition, myeloid recruitment, and extracellular matrix deposition. Consequently, knock-down of elevated genes using CRISPR interference dampened in vitro cell proliferation of C1galt1c1 knockout mPDAC cells to the growth rate of parental controls. Additionally, C1galt1c1 knockout mPDAC cells implanted into mice led to accelerated tumor growth and increased tumor infiltration of myeloid-derived suppressor cells and neutrophils as determined by flow cytometry and scRNAseq. Interestingly, surface expression of a binding partner of Tn antigen, macrophage galactose-type lectin 2 (Mgl2), was altered in the immune infiltrate of C1galt1c1 knockout tumors suggesting a role for the Mgl2-Tn interaction in tumor progression. Mgl2-deficient mice exhibit increased T effector cells in the draining lymph nodes of tumors highlighting a potential mechanism for promoting the influx of immune cells in ordinarily cold tumors. Together, our data indicate that truncated O-glycans expressed commonly on tumor cells promotes tumorigenesis through creating an immunosuppressive microenvironment in mPDAC. Citation Format: Shawna Brookens, David Degaramo, Kiesha Wilson, Wilder Condori Obregon, Prakash Nagarkatti, Mitzi Nagarkatti, Avery Posey Jr.. Aberrant glycosylation in mPDAC is associated with increased epithelial-mesenchymal transition and recruitment of immunosuppressive 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 5361.
Abstract 5385: Synthetic disulfide derivative of vitamin B1, fursultiamine, prevents VEGF-induced angiogenesis
Authors: Sabrina Tran, Zachary Frost, Kota Ramana
Journal: Cancer Research (2024)

Abstract Angiogenesis is a process in which new blood vessels are formed from the existing blood vessels required to supply nutrients and oxygen to various tissues. Angiogenesis plays a significant role in the growth and spread of many cancers, and several anti-angiogenic agents act as chemotherapeutic agents. Recent studies have shown that fursultiamine (thiamine tetrahydrofurfuryl disulfide), a lipid-soluble synthetic disulfide derivative of thiamine, possesses viable antineoplastic and antiviral effects. However, its role in preventing angiogenesis is not known. We hypothesize that fursultiamine, with its potent antioxidative actions, prevents VEGF-induced angiogenesis in vitro and in vivo. Human umbilical vein endothelial cells (HUVECs) were treated with VEGF in the absence and presence of fursultiamine (0-100 uM) in a time and dose-dependent manner. Cell viability was determined by MTT assay and in vitro angiogenesis by tube formation assays. The expression of various pro-angiogenic, anti-angiogenic and inflammatory markers will be determined by specific antibody arrays. Our results indicate that fursultiamine prevents VEGF-induced endothelial cell growth in a dose-dependent manner. Further, fursultiamine prevents the in vitro tube formation as determined tube formation assays. Further, fursultiamine also regulated the VEGF-induced expression of various angiogenic markers such as VEGF, PDGF, EGF, Ang1, Ang2, angiogenin, and FGF, inflammatory markers such IL-1b, GM-CSF, TGF-b, MMPs, and others such as TIMPs, PTX3 and CF-III. Based on our in vitro data, we suggest that fursultiamine could prevent VEGF-induced angiogenesis, and this compound as a potent anti-angiogenic agent that could prevent cancer growth and metastasis. Citation Format: Sabrina Tran, Zachary Frost, Kota Ramana. Synthetic disulfide derivative of vitamin B1, fursultiamine, prevents VEGF-induced angiogenesis [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 5385.
Abstract 336: Genome integrity assessment by optical genome mapping for cell manufacturing/bioprocessing applications
Authors: Alex Hastie, Andy W. Pang, Alka Chaubey
Journal: Cancer Research (2024)

Abstract Cells and cell lines are used for multiple applications such as bioprocessing, therapy, and research. To ensure quality of cells and downstream applications, appropriate quality control (QC) methods are critical. Historically, karyotyping has been employed, but it is limited by its very low resolution and tedious laboratory workflow. Other methods such as PCR and targeted sequencing can characterize only small genomic variants at specific loci. Whole genome sequencing can detect small variants genome-wide but has limited sensitivity in detecting structural variants (SVs). Optical genome mapping (OGM) is a novel genome analysis technique that can fill many of the gaps in current capabilities for assessing genome integrity. To find clonal variants, 400 Gbp of data is collected from the parental/control and test samples. For both samples, a de novo assembly is constructed, and homozygous or heterozygous SVs are assessed. Subsequently, the dual variant annotation pipeline identifies unique SVs in the test sample compared to the parental sample. To discover subclonal SVs down to 5% variant allele fraction (VAF), the workflow leverages the generation of 1.5 Tbp of data, requiring a simple adjustment to longer data collection time. Comparison of test sample to parental sample enables easy determination of acquired variants. Finally, generation of ~5 Tbp of data, requiring 2-3 flowcells to be run, enables the detection of SVs at ultra-low VAF down to ~1%. In this study, several dilutions and simulations were performed to examine OGM’s limit of detection. Targeting a coverage of 5 Tbp and analysis using the somatic SV-analysis workflow revealed that OGM has the sensitivity to detect deletions &amp;gt;50kbp, insertions &amp;gt;20kbp, duplications &amp;gt;100 kbp, and translocations at ~1% VAF. We have applied the clonal and somatic workflows to verify genomes’ integrity after cell immortalization, induced pluripotency, transgene-integration, and gene-editing. The data using the robust and sensitive workflows demonstrate that the OGM platform is a cost-effective solution for cell manufacturing/bioprocessing QC applications. Citation Format: Alex Hastie, Andy W. Pang, Alka Chaubey. Genome integrity assessment by optical genome mapping for cell manufacturing/bioprocessing applications [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 336.
Abstract 5489: The spatial landscape of early-stage lung adenocarcinoma
Authors: Junbum Kim, Hiranmayi Ravichandran, Liron Yoffe, Bhavneet Binder, Timothy McGraw, Nasser K. Altorki, Vivek Mittel, Olivier Elemento
Journal: Cancer Research (2024)

Abstract Cellular and molecular basis of ground-glass opacities (GGO), which has been used as a screening indicator for lung cancer, remains a gray area. Our aim was to investigate the tumor-immune microenvironment (TIME) in a cohort of early-stage lung adenocarcinomas (LUAD) through imaging mass cytometry, enabling us to examine the TME spatial composition of nodules at single-cell resolution. We collected 354 imaging mass cytometry (IMC) regions of interest (ROI) from 135 early-stage lung adenocarcinoma patients to investigate the spatial and molecular profiles of early stage LUAD. Specifically, we gathered 27 solid (S), 39 part-solid (PS), 74 pure non-solid (PNS) patients and 89 matched adjacent-normal cases to profile the phenotype of 2.24 million cells across the two IMC panels to characterize the cellular and molecular composition of GGO nodules. Comparing progression from adjacent normal, pure non-solid, part-solid, to solid, we observed consistent reduction in RAGE+ AT1 cells (p*&amp;lt;1.6E-7) and a reciprocal increase in SFTPC+ AT2 cells (p*&amp;lt;1.3E-8) and PanCK+Ki67+ proliferative epithelial cells (p*&amp;lt;2.8E-7). We also report fibrogenesis and an increase in immune cell populations such as regulatory (p*&amp;lt;1.4E-5), CD4 (p*&amp;lt;0.0024), CD8 T (p*&amp;lt;0.017) cells, B (p*&amp;lt;5.5E-9) cells, and macrophages. Spatially, we quantify an upregulation of tumor-tumor and tumor-fibroblast interaction, and a downregulation of tumor-immune interaction. We believe this evidence suggests the role of fibroblasts as liner for tumors, barricading immune infiltration and harvesting uninterrupted tumorigenesis. In summary, we performed a highly multiplexed IMC data to analyze the TIME spatial profiles of GGO nodules in early-stage LUAD at a single-cell level. Spatial analysis of this integrated multidimensional omics dataset provides insight into the pivotal role of fibroblasts in early-stage LUAD in immune suppression, evasion, tumorigenesis, and potentially metastasis. Citation Format: Junbum Kim, Hiranmayi Ravichandran, Liron Yoffe, Bhavneet Binder, Timothy McGraw, Nasser K. Altorki, Vivek Mittel, Olivier Elemento. The spatial landscape of early-stage lung adenocarcinoma [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 5489.
Abstract 4826: Cancer mortality attributable to area-level socioeconomic inequalities in Japan from 2015 to 2020
Authors: Yuri Ito, Tomoki Nakaya, Manami Inoue, Tomotaka Sobue, Hitoshi Nakagama
Journal: Cancer Research (2024)

Abstract Background: In the 3rd Healthy Japan 21 and the 4th National Cancer Plan, the government focused on reducing health inequalities. However, current monitoring of socioeconomic inequalities in cancer is still insufficient to set the targets for the plan. To prioritize strategy aimed at reducing socioeconomic inequalities in cancer mortality, we estimated the population attributable risk fraction (PAF) and excess death due to socioeconomic inequalities, by sex, age group and cancer site. Method: We used the areal deprivation index (ADI) to establish area-based socioeconomic status. We categorized municipalities to ADI quintile weighted by the size of population, Q1 is the least deprived and Q5 the most deprived group. Excess death due to socioeconomic inequalities was calculated by the difference between observed number of deaths and expected death of Q2 to Q5 group with Q1 as standard population. We used cancer mortality data obtained from vital statistics in 2015-2020. Results: In total, about 12000 male and 2800 female excess deaths per year due to socioeconomic inequalities were estimated; that is 5.5% and 1.8% as PAF. PAF due to socioeconomic inequalities limited to premature death, less than 75 years old, was estimated as 7.6% in men and 3.3% in women. By age group, the 0-39 years group showed the largest PAF at 15.7% in men and 16.6% in women. In men of all age groups, except 0-39 years, lung cancer was the highest excess death due to socioeconomic inequalities. For women, some cancer sites (breast, ovary, esophagus) showed an opposite association, Q1 was the highest mortality group. Therefore, total excess death was lower than in men. In women of all ages, the highest rate of excess death due to socioeconomic inequalities was gallbladder cancer. For the 0-39 years group, a high rate of excess death in stomach, leukemia, and cervical cancer was observed. Discussion: Excess death and PAF due to socioeconomic inequalities differed by sex and age group. A greater impact of socioeconomic inequality on cancer mortality was observed in men than in women. Among women, further attention should be paid to areal variation of cancer death related to socioeconomic inequalities, based on the different area-based indices. Citation Format: Yuri Ito, Tomoki Nakaya, Manami Inoue, Tomotaka Sobue, Hitoshi Nakagama. Cancer mortality attributable to area-level socioeconomic inequalities in Japan from 2015 to 2020 [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 4826.
Abstract 6714: AI-guided tailor-made anti-TROP2 T-cell engagers for T-cell mediated cancer immunotherapy with enhanced therapeutic index
Authors: Chuan Chen, Liang Tian, Chenpeng Su, Dandan Liu, Xiaoqian Chen, Yifei Zhou, Suze Jiang, Guifang Wang, Jiyuan Tian, Yuan Yuan, Bing Yang, Jian Peng
Journal: Cancer Research (2024)

Abstract Bispecific T-cell engagers (TCEs) have shown significant therapeutic advances in the treatment of hematologic cancers. However, the clinical efficacy of TCEs in treating solid tumors remains to be demonstrated. Accumulating evidence suggests novel TCE modalities that simultaneously engage both CD3 (signal 1) and CD28 (signal 2) co-stimulatory signals may offer potential advantage to enhance clinical efficacy of TCEs with improved therapeutic index. To explore the full potential of TCEs as a powerful approach of immunotherapy for solid tumors, we developed an integrated AI-guided TCE platform to streamline the discovery, optimization and high-throughput function screening and characterization of TCE molecules. Here we report the construction and characterization of a novel panel of TROP2-targeting TCEs by leveraging our AI-guided optimization technology, plus a high-throughput in vitro screening platform. These tailor-made TCE molecules exhibit favorable developability and functional properties. Our data show that a novel TROP2 × CD3 x CD28 trispecific TCE that contains a CD3-targeting arm in concomitant with a CD28-targeting arm can induce potent T-cell co-stimulation and promising synergistic T cell-mediated tumor cell killing in vitro, compared to its counterparts with a single CD3-targeting arm. We further generate a trivalent TROP2 x CD3 bispecific TCE constructed as an asymmetric ‘2+1’ format with bivalent binding to TROP2 but a monovalent CD3-targeting arm. This molecule stimulates very low levels of cytokine release, but drives robust antigen-specific killing in in vitro assessment. Anti-tumor activity of the various TROP2 x CD3 TCEs is currently being investigated in multiple tumor xenograft mouse models. Citation Format: Chuan Chen, Liang Tian, Chenpeng Su, Dandan Liu, Xiaoqian Chen, Yifei Zhou, Suze Jiang, Guifang Wang, Jiyuan Tian, Yuan Yuan, Bing Yang, Jian Peng. AI-guided tailor-made anti-TROP2 T-cell engagers for T-cell mediated cancer immunotherapy with enhanced therapeutic index [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 6714.
Abstract 4853: Impact of different therapeutic strategies on survival in laryngeal squamous cell carcinoma (LSCC)
Authors: Sakhr Alshwayyat, Ayah Erjan, Miassar Rawashdeh, Tala Abdulsalam, Mustafa Alshwayyat
Journal: Cancer Research (2024)

Abstract Background: LSCC has seen a rise in cases and deaths over the past 30 years. Considering advancements in the treatment landscape, therapeutic options for patients with LSCC were evaluated to assess their efficacy in improving survival rates. Methods: Data were retrieved from the Surveillance, Epidemiology, and End Results (SEER) (2000-2020) for localized/regional-stage cancer only, including the glottis (GC), supraglottic (SuGC), and subglottic (SC). Patients with a histologically confirmed diagnosis, no other malignancies, and complete data were included. Eight therapeutic groups were identified: surgery (Sx), chemotherapy (CTX), radiotherapy (RT), Sx + adjuvant radiotherapy (ART), Sx + CTX, Sx + RT, Sx + CTX + RT, and CTX + RT. T-tests and chi-square tests were used to compare variables, while Kaplan-Meier, log-rank tests, and Cox regression were used to identify prognostic factors for overall survival (OS) and cancer-specific survival (CSS). Results: 68,282 patients were included (43,434 GC, 24,010 SuGC, and 838 SGC). 12.8% underwent Sx, 0.8% CTX, 0.3% Sx + CTX, 17.1% Sx + ART, 35.3% RT, 1.5% Sx + RT, 5.1% Sx + CTX + RT and 21.5% CTX + RT. 80.8% were males and 63.5% were over 60 years old and white (n=56,171). The median age was 64 years, and median tumor size was 3.2 cm. 36.5% underwent surgery with local tumor excision in 23.9 % and total laryngectomy in 5.7%. White race, regional stage, large tumor size, and CTX were poor prognostic factors for GC. Asian, white race, and total laryngectomy were good prognostic factors for SuGC, whereas male sex and older age were poor prognostic factors. In terms of SCG, Sx + ART was associated with a better prognosis, while regional and white race were associated with a poor prognosis. Conclusion: This study shows survival differences among treatment groups and identifies factors for personalized treatment. It is the first study on all types of laryngeal tumors with a large sample size. Further research is necessary to validate and expand these results. The 5-year survival rates (as a percentage of OS/CSS) for each therapeutic group Cancer Type Sx CTX Sx + CTX RT Sx + RT CTX + RT Sx + CTX + RT Sx + ART GC 91.9/75.5 79.8/77.3 89.2/81.8 89.8/78.1 89.5/85.3 87.8/83 79.1/90.1 90/78.1 SuGC 54.7/56.5 12.9/46.7 25.6/56.2 43.1/51.9 33.5/56.4 45.7/49.7 50.5/59.4 49.3/59.3 SGC 42.2/42.2 75/75 17.7/17.7 53/53 44.4/44.4 47.2/47.2 44.1/41.1 58.7/58.7 Citation Format: Sakhr Alshwayyat, Ayah Erjan, Miassar Rawashdeh, Tala Abdulsalam, Mustafa Alshwayyat. Impact of different therapeutic strategies on survival in laryngeal squamous cell carcinoma (LSCC) [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 4853.
Abstract 487: Peptide amphiphiles hitchhike on endogenous biomolecules for enhanced drug delivery
Authors: Jared M. Fischer, Morgan Stewart, Mingchong Dai, Samuel Drennan, Sinan Sabuncu, Benjamin Kingston, Isabel Dengos, Li Xiang, Karla Bonic, Xin Yi, Srivathsan Ranganathan, Bruce Branchaud, Adem Yildirim
Journal: Cancer Research (2024)

Abstract Peptide amphiphiles (PAs) have been applied as building blocks for self-assembled nanostructures with various morphologies. These self-assembled nanostructures are promising drug delivery platforms as they are naturally biodegradable and biocompatible with low immunogenicity. One primary focus in drug delivery using the PA nanostructures has been to develop strongly assembled structures to avoid disassembly in the blood and allow them to carry payloads to their intended targets. In this work, rather than developing stable self-assembled PA structures, we focused on weakly assembled PA nanostructures to investigate their interactions with blood components and to understand how these interactions affect their biodistribution. We found that weakly assembled PA nanostructures (SA-E) quickly disassembled in plasma and reassembled with lipoproteins (LPs), which significantly prolonged the blood circulation of SA-E in mice. We showed that SA-E crossed the endothelial barriers through transcytosis only when they were assembled with LPs. Cellular uptake studies showed that SA-E accumulated in cancer cells through lipid-raft-mediated uptake. Interestingly, their cellular internalization was independent of LP receptors, suggesting that SA-E assembles with different endogenous biomolecules in vivo. By exploiting these endogenous interactions, SA-E demonstrated high tumor accumulation in a myriad of small animal tumor models of breast, colon, pancreatic, brain, skin, prostate, or lung cancers. SA-E demonstrated large tumor-to-background signal ratios in live animals (&amp;gt;5), extended retention (&amp;gt;2 weeks), and excellent tissue distribution (tumor to liver signal &amp;gt;3) in these tumor models. Encouraged by the excellent tumor accumulation of SA-E, we prepared SA-E drug conjugate using a highly potent and toxic chemotherapeutic agent, Monomethyl auristatin E (MMAE). SA-E-MMAE conjugate demonstrated strong antitumor efficacy in aggressive breast and glioma models in mice with reduced side effects. With its simple and modular design and universal tumor accumulation mechanism, SA-E represents a promising platform for broad applications in cancer therapy. Citation Format: Jared M. Fischer, Morgan Stewart, Mingchong Dai, Samuel Drennan, Sinan Sabuncu, Benjamin Kingston, Isabel Dengos, Li Xiang, Karla Bonic, Xin Yi, Srivathsan Ranganathan, Bruce Branchaud, Adem Yildirim. Peptide amphiphiles hitchhike on endogenous biomolecules for enhanced drug delivery [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 487.