tbuckley/cabot-search huggingface dataset:
Abstract 4045: Dependence of human immune cell type, and impact of IL-7R or TLR1/2 agonism, upon trastuzumab-mediated ADCC
Authors: Mark Bryant, Gokhan Tut, Neale Harrison, Emma Welsh, Ines Morano, Arshpreet Kaur, Ashley Pegg, Hujo Chan, Zhi Li, Jamie Cowley, Catherine Brady, John Gordon, Nicholas Barnes, Omar Qureshi
Journal: Cancer Research (2024)

Abstract Targeting of tumors over-expressing HER2 using trastuzumab provides clinical benefit for patients by inhibiting HER2 signalling and enhancing immune responses against the tumor by antibody-dependent cell-mediated cytotoxicity (ADCC). Cytokines such as IL-7 augment cytotoxic anti-viral responses through up-regulation of FasL, whereas TLR1/2 agonists enhance T cell cytotoxic responses but may also promote tumor cell survival. We therefore investigated the ability of IL-7R or TLR1/2 agonism to enhance trastuzumab-mediated ADCC. We first determined the contribution of various human immune cell subsets (e.g. monocytes, T cells, NK cells) to deliver ADCC of human tumor cells using a live high-content imaging assay in both 2D and 3D formats. Our results demonstrate that trastuzumab evoked immune cell dependent, concentration-dependent killing of tumor cells that exhibited some differential sensitivity dependent upon the cell culture format. We then tested trastuzumab-mediated killing in the absence or presence of IL-7R or TLR1/2 agonism, and noted evident donor and immune cell dependent modulation of the cytotoxic response. Modulation of this cytotoxic response was associated with differential immune cell marker expression when analysed by flow cytometry. Our findings provide mechanistic insight into trastuzumab-mediated ADCC and highlight how cytokine receptor and TLR pathways may modulate this response. Citation Format: Mark Bryant, Gokhan Tut, Neale Harrison, Emma Welsh, Ines Morano, Arshpreet Kaur, Ashley Pegg, Hujo Chan, Zhi Li, Jamie Cowley, Catherine Brady, John Gordon, Nicholas Barnes, Omar Qureshi. Dependence of human immune cell type, and impact of IL-7R or TLR1/2 agonism, upon trastuzumab-mediated ADCC [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 4045.
Abstract 5708: Silence exportin 7 sensitizes esophageal squamous cell cancer to CDK4/6 inhibition through block the cell cycle coresectory
Authors: Zhong Wu, Lin Xu, Chuang Jiang, Adam Bass, Jin Zhou
Journal: Cancer Research (2024)

Abstract Introduction: There is a lack of effective target therapies for esophageal squamous cell cancer. Our previous studies have demonstrated that CDK4/6 is a potency target for ESCC and combination with ERBB inhibitors is sufficient to achieve durable response. The aim of the current study is to prospectively map the landscape of sensitivity and resistance to CDK4/6 inhibition and develop novel combination therapies in ESCC. Experimental Procedures: We performed a genome-wide functional genetic screening and mini-pool designed CRISPR screen approaches to identify the modulators whose depletion sensitize CDK4/6 inhibition or confer resistance to the CDK4/6 inhibitor Palbociclib and elucidate new therapeutic strategies. Results: Our screen identified RB as the most enriched sgRNA, while guides targeting CCNE1 and CDK2 as the most depletion sgRNAs after CDK4/6 inhibition. These results validates our experimental approach as RB loss and CCNE1/CDK2 reactivation is the main mechanisms of CDK4/6 resistance. After gathering potential candidates from both screens, we found that genetically ablation of Exportin 7, a nuclear export factor, strongly sensitize CDK4/6 inhibition both in vitro and in vivo. RNAseq revealed a further repression of transcriptional activity of E2F and G2M by addition of XPO7depletion under CDK4/6 inhibitor treatment. To increase our insight in the molecular mechanism that could explain the synergy between XPO7 and CDK4/6, we further performed proteomics of nuclear and cytoplasm in ESCC lines with or without CDK4/6 inhibition. We found that silence XPO7 result in nuclear accumulation of mitosis-regulated genes such as CENPM, KIF4A and WEE1. Combined CDK4/6 inhibition with XPO7 depletion results in further downregulate of CENPM and KIF4A expression in nucleus, abrogating compensatory activation of cell cycle regulation and promote the cytostatic effect in ESCC. We further validated that CENPM and KIF4A depletion also sensitize CDK4/6 inhibition, and consequentially use WEE1 inhibitor after CDK4/6 inhibitor also effectively block the growth of ESCC lines. Conclusion: Overall, our comprehensive functional genetic screening approach revealed modulation of sensitive and resistance to the inhibition of CDK4/6 in ESCC. XPO7 was identified as a driver to change cell cycle landscape and merits as a therapeutic target combined with CDK4/6 inhibition in ESCC, which is beneficial to provide a novel treatment strategy. Citation Format: Zhong Wu, Lin Xu, Chuang Jiang, Adam Bass, Jin Zhou. Silence exportin 7 sensitizes esophageal squamous cell cancer to CDK4/6 inhibition through block the cell cycle coresectory [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 5708.
Abstract 871: Unveiling the potential of bispecific antibodies: A comprehensive analysis of efficiency, toxicity, and repurposing in cancer treatment
Authors: Binbin Wang, Sanna Madan, Alejandro Schaffer, Eytan Ruppin
Journal: Cancer Research (2024)

Abstract Bispecific antibodies have emerged as promising candidates for cancer treatment, prompting the necessity for a comprehensive understanding of their potential efficacy and toxicity across various cancer types. Leveraging single cell sequencing data, we systematically evaluated the efficacy and toxicity of all cell surface gene pairs across multiple cancers. First, we found that gene pairs involved in successful bispecific antibodies phase I/II clinical trials exhibited significantly higher efficacy scores and lower toxicity scores than gene pairs in those that failed, underscoring the utility of our method in selecting high-quality bispecific pairs. Second, to facilitate the identification of new pairs, we established baseline efficacy and toxicity scores based on successful phase I/II clinical trials, employing these scores to assess the potential of novel combinations. We systematically identified both cancer type-specific and pan-cancer candidate new bispecific antibody pairs. This extensive analysis not only provides valuable insights into the potential of bispecific antibodies to broaden the spectrum of cancer treatments, but also yields a highly confident list of candidate gene pairs capable of constructing effective bispecific antibodies. Citation Format: Binbin Wang, Sanna Madan, Alejandro Schaffer, Eytan Ruppin. Unveiling the potential of bispecific antibodies: A comprehensive analysis of efficiency, toxicity, and repurposing in cancer treatment [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 871.
Abstract 402: Aneuploidy-associated <i>SQLE</i> gain promotes prostate cancer aggressiveness by altering lipid metabolism
Authors: Thomas Walter Janas, Xiaofeng A. Su, Konrad H. Stopsack, Daniel R. Schmidt, Duanduan Ma, Zhe Li, Kathryn L. Penny, Tamara L. Lotan, Lorelei A. Mucci, Matthew G. Vander Heiden, Elise DeArment, Angelika Amon, Paul A. Scheet
Journal: Cancer Research (2024)

Abstract Prostate cancer (PCa) is the second leading cause of cancer-related death in men in the US. Epidemiology studies on primary PCa cohorts in Physicians' Health Study and Health Professionals Follow-up Study (PHS and HPFS) have shown that high levels of whole-genome aneuploidy, featured by imbalanced chromosome numbers, correlate with lethal progression in PCa. However, details of the mechanisms of how aneuploidy drives PCa aggressiveness are still unclear. Here, we used the case of chromosome 8q (chr 8q, the long arm of chr 8) gain to study aneuploidy-associated prostatic malignancies. Chr 8q gains are the most frequent gain events that occur in approximately 23% of PCa cases. By using the PHS and HPFS cohorts, we modeled the increased expression of each gene located on chr 8q, for predicting the risks for lethal progression, and obtained each corresponding gene’s odds ratio (OR). By ranking the ORs, we revealed that a cholesterol biosynthesis gene, squalene monooxygenase (SQLE), is one of the top associators with lethal progression, amongst all chr 8q genes. SQLE plays a pivotal role in cholesterol synthesis. Previous lymphoma studies have shown that loss of SQLE contributes to cholesterol auxotrophy, and squalene build-up protects against oxidative cell death. In our experimental study, we have used normal and cancerous TMPRSS2-ERG-driven organoid models and found that over-expression of SQLE promotes formation of invasive structures and proliferation in cancer organoids. Interestingly, overexpression of SQLE decreased the protein levels of TMPRSS2-ERG, which appeared to be independent of androgen receptor levels. We also utilized the TMPRSS2-ERG positive VCaP cell line, which harbors gains of SQLE gene copies. We found that knocking down SQLE expression significantly upregulated ERG protein levels. Our recent study has shown that ERG (or other ETS) positive prostate cancers have a strong correlation with downregulation of fatty acid metabolism signature. We speculate that gain of SQLE can drive aggressiveness of prostate cancer by modulating lipid metabolism for growth and migration. Inhibition of SQLE could translate to better clinical outcomes regarding prostate cancer lethality. Citation Format: Thomas Walter Janas, Xiaofeng A. Su, Konrad H. Stopsack, Daniel R. Schmidt, Duanduan Ma, Zhe Li, Kathryn L. Penny, Tamara L. Lotan, Lorelei A. Mucci, Matthew G. Vander Heiden, Elise DeArment, Angelika Amon, Paul A. Scheet. Aneuploidy-associated SQLE gain promotes prostate cancer aggressiveness by altering lipid metabolism [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 402.
Abstract 3494: KINOMO: A non-negative matrix factorization framework for recovering intra- and inter-tumoral heterogeneity from single-cell RNA-seq data
Authors: Somnath Tagore, Yiping Wang, Jana Biermann, Edridge K. D'Souza, Karan D. Luthria, Raul Rabadan, Elham Azizi, Benjamin Izar
Journal: Cancer Research (2024)

Abstract Single-cell RNA-sequencing (scRNA-seq) is a powerful technology to uncover cellular heterogeneity in tumor ecosystems. Due to differences in underlying gene load, direct comparison between patient samples is challenging, and this is further complicated by the sparsity of data matrices in scRNA-seq. Here, we present a factorization method called KINOMO (Kernel dIfferentiability correlation-based NOn- negative Matrix factorization algorithm using Kullback-Leibler divergence loss Optimization). This tool uses quadratic approximation approach for error correction and an iterative multiplicative approach, which improves the quality assessment of NMF-identified factorization, while mitigating biases introduced by inter-patient genomic variability. We benchmarked this new approach against nine different methods across 150 scRNA-seq experiments and find that KINOMO outperforms prior methods when evaluated with an adjusted Rand index (ARI), ranging 0.82-0.91 compared to 0.68-0.77. Thus, KINOMO provides an improved approach for determining coherent transcriptional programs (and meta-programs) from scRNA- seq data of cancer tissues, enabling comparison of patients with variable genomic backgrounds. Citation Format: Somnath Tagore, Yiping Wang, Jana Biermann, Edridge K. D'Souza, Karan D. Luthria, Raul Rabadan, Elham Azizi, Benjamin Izar. KINOMO: A non-negative matrix factorization framework for recovering intra- and inter-tumoral heterogeneity from single-cell RNA-seq 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 3494.
Abstract 4521: Investigating bAP15, a new inhibitor of UCHL5/USP14 deubiquitinating enzymes, as a potential treatment for chondrosarcoma: A comprehensive <i>in vivo</i> and <i>in vitro</i> study
Authors: Kuan-Lin Kuo, Fu-Shun Hsu, Shang-Jen Chang, Shih-Ming Liao, Wei-Chou Lin, Tzt-Yao Ke, Tzu-Ting Liu, Kuo-Yuan Huang
Journal: Cancer Research (2024)

Abstract Chondrosarcoma, a highly resilient cancer characterized by limited effective treatment options, represents a significant therapeutic challenge. bAP15, a novel inhibitor of deubiquitylating enzymes (DUBs), has emerged as a promising therapeutic agent, exhibiting anti-tumor activity in various cancer models. This study investigated the efficacy of bAP15 against chondrosarcoma in vitro and in vivo. To evaluate bAP15's effects on chondrosarcoma cells, the SW1353 and JJ012 cell lines were employed. Cell viability, apoptosis, and cell cycle progression were assessed using MTT assay and flow cytometry. Western blotting was utilized to analyze apoptosis, cell stress, and endoplasmic reticulum (ER) stress. Additionally, a xenograft mouse model was established to examine the in vivo anti-tumor potential of bAP15. Compared to normal cartilage tissue, chondrosarcoma cells exhibited significantly higher expression of the DUB UCHL5, suggesting its potential involvement in chondrosarcoma development. Treatment with bAP15 effectively induced apoptosis in chondrosarcoma cells by activating caspases and cleaving PARP. Furthermore, bAP15 enhanced ER stress by activating caspase-4 and CHOP. In the xenograft mouse model, bAP15 demonstrated remarkable anti-tumor efficacy with minimal toxicity. These findings highlight the potential of bAP15 as a therapeutic strategy for chondrosarcoma. Its ability to induce ER stress and cell cycle arrest, coupled with its in vivo anti-tumor activity, provides compelling evidence for its further development as a novel treatment option for this challenging cancer. Citation Format: Kuan-Lin Kuo, Fu-Shun Hsu, Shang-Jen Chang, Shih-Ming Liao, Wei-Chou Lin, Tzt-Yao Ke, Tzu-Ting Liu, Kuo-Yuan Huang. Investigating bAP15, a new inhibitor of UCHL5/USP14 deubiquitinating enzymes, as a potential treatment for chondrosarcoma: A comprehensive in vivo and 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 4521.
Abstract 6366: The triple-specific antibody KA-3009 against EGFR, B7H3, and 4-1BB specifically enhances T cell activity within the tumor
Authors: Guojin Wu, Tongtong Liu, Jiabei Liang, Hao Peng, Feng Hao, Jinying Ning
Journal: Cancer Research (2024)

Abstract Cancer immunotherapy with 4-1BB agonists faces limited further clinical development due to dose-limiting toxicity. Moreover, EGFR and B7H3 are highly expressed in various solid tumors, as well as in different normal tissues. In this study, we developed a trispecific antibody, KA-3009, targeting EGFR, B7-H3, and human 4-1BB, with the aim of restricting 4-1BB stimulation within tumors. KA-3009 was developed based on our common light chain bispecific antibody discovery platform and nanobody antibody discovery platform using knob-into-hole technology. It is in IgG1 format with mutations in the Fc domain to eliminate ADCC, ADCP, and CDC activity. Featuring two identical nanobodies at the C-terminal against 4-1BB, KA-3009 binds to EGFR and B7H3 respectively with two Fabs at the N-terminal, sharing an identical light chain. KA-3009 exhibits low avidity binding to tumor cells expressing only EGFR or B7H3, while binding to tumor cells co-overexpressing EGFR and B7H3 with increased avidity by more than ten times. Additionally, KA-3009 binds to 4-1BB expressed on 293T cells and activated human T cells. In the presence of a low concentration of CD3 antibody to stimulate T cell activation, co-culture of tumor cells co-expressing EGFR and B7H3 with primary T cells isolated from human PBMC enhances T cell activation and proliferation. In PBMC humanized immunodeficient mouse tumor models, KA-3009 effectively suppresses the growth of NCI-H1568 tumors expressing both EGFR and B7H3 but does not affect the growth of MS751 and NCI-H661 tumors, which only express EGFR or B7H3, respectively. Moreover, KA-3009 has a half-life of more than five days in the blood of Balb/c mice. Finally, we assessed the developability of this antibody with different treatments such as high concentration, low pH, repeated freezing and thawing, and high temperature, and KA-3009 shows neither aggregation nor degradation. In conclusion, the triple-specific antibody KA-3009, developed with our common light chain antibody discovery platform and nanobody antibody discovery platform, is a promising pre-clinical candidate drug for the treatment of different solid cancers that co-overexpress EGFR and B7H3. Citation Format: Guojin Wu, Tongtong Liu, Jiabei Liang, Hao Peng, Feng Hao, Jinying Ning. The triple-specific antibody KA-3009 against EGFR, B7H3, and 4-1BB specifically enhances T cell activity within the tumor [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 6366.
Abstract 4879: Delineating lymphocyte aggregates from tertiary lymphoid structures using spatial transcriptomics
Authors: Jordan Krull, Anjali Byappanahalli, Yi Jiang, Andrew Gunderson, Qin Ma
Journal: Cancer Research (2024)

Abstract Tertiary Lymphoid Structures (TLSs) are ectopic lymphoid structures that form in chronically inflamed non-lymphoid tissue. The presence of TLSs in tumors is largely associated with favorable outcomes among patients and also exhibit positive associations with response to immune checkpoint blockade. Although mainly comprised of lymphocytes (B cells and T cells), they are considered a separate entity from lymphocyte aggregates within tissue. Lymphocyte aggregates are fairly routine to identify in H&amp;E stained tissue sections, but delineating TLSs from simple lymphocyte aggregates is subjective and not clearly defined. Additionally, the definition of TLSs is only recently being elucidated, so a clear molecular definition of both TLSs and lymphocyte aggregates is needed. To address this problem, we leveraged open-source spatial transcriptomics (ST) data from 17 samples across 7 cancer types. High resolution H&amp;E images were manually evaluated for lymphocyte aggregates by identifying dense pockets of lymphocytic-appearing nuclei. Suspected aggregates were detected in 10 of 17 samples. We then applied a visium spot-level signature scoring method for 4 well published TLS signatures. Of the spots identified, 62% had enhanced signature expression for at least 2 of the signatures, although most of the incorrect annotations came from the lone gastric cancer sample. Differential expression between a TLS-sig- suspected lymphoid aggregate and a TLS-sig+ region not identified by H&amp;E enriched primarily for B cell identity genes, suggesting B-cell-rich TLSs may not always appear as lymphoid aggregates in histology. [AG1] Strikingly, ST revealed strongly positive enhancements in the TLS signatures, where no annotations were made, and no obvious lymphoid aggregation was present, suggesting manual annotation from H&amp;E is inadequate for identifying TLSs. Together, these results demonstrate that literature derived TLS signatures can correctly identify lymphoid aggregates as TLSs and that cellular and molecular differences between standard lymphoid aggregates and TLSs may be smaller than is currently accepted. Citation Format: Jordan Krull, Anjali Byappanahalli, Yi Jiang, Andrew Gunderson, Qin Ma. Delineating lymphocyte aggregates from tertiary lymphoid structures using spatial transcriptomics [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 4879.
Abstract 4887: Unveiling the functional impact of glioma non-coding germline variants using large language models
Authors: Maria del Mar Alvarez-Torres, Xi Fu, Romella K Sagatelian, Alejandro L Buendia, Raul Rabadan
Journal: Cancer Research (2024)

Abstract Efforts to identify the risk for developing gliomas through Genome-Wide Association Studies (GWAS) face relevant challenges, such as accurately pinpointing the genomic positions of germline variants, primarily found in non-coding regions, with unclear functional implications in glioma development. In this context, the GET method, a large language model designed to unveil regulatory grammars across 213 human cell types, emerges as a valuable tool for elucidating the mechanisms of non-coding mutations. Our aims include: I) Validate the efficacy of the GET method using a well-documented case and prioritize relevant variants for analysis; II) Refine the genomic positions of these variants and exploring their linkage disequilibrium (LD); III) Identify potential motifs and genes that might be influenced by these high-impact variants. After examining published GWAS, 39 non-coding SNPs in gliomas were found. Adding 316 variants in high LD (R2 &amp;gt; 0.8) expanded the dataset to 355 variants for analysis. Using the GET method, we calculated impact scores (ISs) for each variant, considering changes in motif binding score (ΔBM) and motif gradient (GM) across human astrocytes. We focused on rare variants (risk allele frequency &amp;lt;0.25) with the higher odds ratios (OR). The table presents GET results for a well-known case-control, showing its role in increasing glioma risk through OCT4 motif disruption and enhanced MYC expression, as previously was confirmed experimentally. Moreover, it details results concerning the 5 rare germline variants exhibiting the highest ISs, including precise genomic positions and the most affected motifs and genes that could potentially be impacted by each variant. Using a large language model, this study overcomes the challenge of mere variant identification, aiming to establish a framework for uncovering the underlying mechanism of risk variants. While further validation is essential, this is a promising approach to explore the impact of germline mutations. Variant ID Genomic Position Altered Motif Affected Gene Ref allele Alt allele Case-control rs55705857 Chr8:129633445 OCT4+SOX2:POU MYC A G H-I variant #1 rs78378222 Chr17:7668433 HD/18 PER1 T G H-I variant #2 rs518394 Chr9:22019673 KLF/SP/2 CDKN2A G C H-I variant #3 rs79495512 Chr15:76199995 KLF/SP/2 LINGO1 T C H-I variant #4 rs78185702 Chr15:76317893 SMAD LINGO1 C T H-I variant #5 rs2538067 Chr7:54907724 CTCF EGFR G A Citation Format: Maria del Mar Alvarez-Torres, Xi Fu, Romella K Sagatelian, Alejandro L Buendia, Raul Rabadan. Unveiling the functional impact of glioma non-coding germline variants using large language models [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 4887.