tbuckley/cabot-search huggingface dataset:
Abstract 2607: Dual payload immunochemotherapy to treat CD276 positive cancers
Authors: Zhuoxin Zora Zhou, Jiashuai Zhang, Lufang Zhou, Xiaoguang Margaret Liu
Journal: Cancer Research (2024)

Abstract The Cancer Genome Atlas (TCGA) dataset showed higher level of CD276 (B7-H3) transcript in multiple cancers, including triple-negative breast cancers (TNBCs), non-small cell lung cancers (NSCLCs) and other cancers, than normal tissues. Our immunohistochemistry staining of hundreds of patient tissue microarrays confirmed the high expression of CD276 surface receptor in &amp;gt;60% of TNBC and &amp;gt;70% of NSCLC while minimal or low expression in 33 normal organs or tissues. This study aims to develop and evaluate a novel treatment strategy, i.e. anti-CD276 mAb-dual payloads conjugate (DualADC), as immune-chemotherapy to treat CD276-positive TNBCs and NSCLCs. First, a new CD276-targeting monoclonal antibody (mAb) capable of delivering payloads and upregulating tumoral immunity was developed and engineered. Then, a new platform to concurrently conjugate both traditional cytotoxic payload and immunoregulating regent with one CD276 mAb (DualADC) was established. Our evaluations showed that this targeted therapy effectively killed multiple subtypes of TNBC and NSCLC, significantly upregulated immune functions in tumor microenvironment, and reduced tumor burden by up to 90-100% in seven animal models (including patient-derived xenograft). The post-treatment analysis using single-cell RNA sequencing, Luminex multiplex cytokine assay, whole blood, histology and histopathology analysis demonstrated an integrated anti-cancer mechanisms and minimal systematic toxicity. Altogether, our study suggested that the 276-DualADC could provide a promising targeted chemo-immunotherapy for CD276-postive cancer patients. In future, translational investigations will be performed to determine the toxicology, optimal dose, and treatment strategy, and the combination with other therapy will also be evaluated. Citation Format: Zhuoxin Zora Zhou, Jiashuai Zhang, Lufang Zhou, Xiaoguang Margaret Liu. Dual payload immunochemotherapy to treat CD276 positive cancers [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 2607.
Abstract 5752: Enhanced cancer therapy strategies utilizing gelatin-lipidoid hybrid nanoparticles for RNA delivery
Authors: Abilash Gangula, Dhananjay Suresh, Agasthya Suresh Babu, Zhaohui Li, Anandhi Upendran, Raghuraman Kannan
Journal: Cancer Research (2024)

Abstract Nanoparticle delivery platforms have provided impetus for the emergence of novel RNA-based cancer therapeutics due to their ability to circumvent the physiological and cellular barriers in the delivery. The clinical success of these strategies hinges primarily on the safety and efficacy of the delivery vehicle. Here, we have developed a gelatin-lipidoid hybrid nanoparticle (GLNP) that utilizes gelatin's biocompatibility, biodegradability, and lipidoids' high transfection efficiency. With GLNP, we have demonstrated the efficacy of delivering siRNA and silencing AXL, a receptor tyrosine kinase commonly associated with cancer progression, metastasis, and drug resistance. siRNA is attached to the surface of GLNP through covalent conjugation with gelatin, while the lipidoid on the system's interior electrostatically complexes with the siRNA. siRNAs are well protected by the GLNP when exposed to serum for at least 48 hours. The GLNP's bivalency significantly enhanced the downregulation of target genes in vitro and in vivo. Furthermore, the bivalent GLNP can simultaneously target and downregulate two oncogenes. Apart from siRNA, GLNP was also able to encapsulate and deliver mRNA, thereby suggesting the potential to simultaneously deliver RNA therapeutics to effect knockdown and expression of target proteins and maximize therapeutic effect. The length of the carbon chain of the lipidoid can be manipulated to influence the physico-chemical properties of the GLNP and its efficiency in encapsulating and delivering RNA drugs. Importantly, gelatin was found to effectively shield the cationic lipidoid and negate its toxicity. Toxicity studies indicate that high doses of GLNPs (up to 48 mg/kg BW) are well-tolerated with no significant changes in body weight, hematology, or serum chemistry. The co-administration of GLNP-siAXL and TKI in PDX models has shown notable control of tumor growth. It is important to note that immune checkpoint blockade (ICB) therapy has shown significant survival benefits in NSCLC patients. However, the therapeutic effect is limited to only 20% of patients due to several resistance mechanisms, such as increased expression of oncogenic proteins. Therefore, our future study will explore GLNP's ability to sensitize NSCLC tumors to immune therapy. Citation Format: Abilash Gangula, Dhananjay Suresh, Agasthya Suresh Babu, Zhaohui Li, Anandhi Upendran, Raghuraman Kannan. Enhanced cancer therapy strategies utilizing gelatin-lipidoid hybrid nanoparticles for RNA 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 5752.
Abstract 471: Attenuation of circulating miR-17-5p, miR-20b-5p, and miR-106a-5p in low-risk prostate cancer patients following proton therapy
Authors: Johnny Velasquez, Curtis Bryant, Nancy Mendenhall, Luisel Ricks-Santi
Journal: Cancer Research (2024)

Abstract Introduction: Liquid biopsies offer a novel approach to diagnose, predict cancer outcomes, and monitor treatment response by analyzing tumor-derived substances. Circulating cell-free microRNAs (miRNAs) show clinical promise as biomarkers within prostate cancer (PCa) and have been implicated with PCa prognosis and outcomes. However, their potential for monitoring and assessing radiotherapy (RT) treatment response remains understudied. Understanding miRNA expression changes during RT is crucial, as they impact RT efficacy by directly affecting genes and proteins within RT-response pathways. Aim: This study aimed to profile the expression of three oncogenes, miR-17-5p, miR-20b-5p, and miR-106a-5p and to determine their association with PCa risk groups in patients receiving proton therapy (PT). Patients and Methods: Plasma was obtained from the University of Florida Health Proton Therapy Institute Outcomes Tracking Protocol biobank. Plasma was collected from men diagnosed with localized PCa without metastatic disease at three time points: prior to PT (PRE-PT), at 4 weeks following the start of PT (4WKSPD1), and at 8 weeks following the start of PT (8WKSPD1). The pilot study consisted of 38 patients, with 23 categorized as low-risk and 15 categorized as high-risk for PCa. MiRNA expression levels were evaluated using reverse transcription-polymerase chain reaction and quantified using the Livak method. Results: The study revealed a downregulation of miR-17-5p in response to PT, with median gene expression levels decreasing from 0.73 at PRE-PT to 0.587 at 8WKSPD1. Low-risk PCa patients also showed distinct miRNA expression changes with all three miRNAs (miR-17-5p, miR-20b-5p, and miR-106a-5p) downregulated from 0.953, 1.037, and 1.010 at PRE-PT to 0.398, 0.216, and 0.298 at 8WKSPD1, respectively. Statistical analysis using a Kruskal-Wallis test followed by a Dunn's post-hoc test identified significant differences (p=0.035) specifically between PRE-PT and 8WKSPD1 for miR-17-5p. Conclusion: The study revealed that PT led to a time-dependent reduction in miRNA levels, indicating a higher responsiveness in low-risk compared to high-risk PCa patients. This differential response highlights miR-17-5p, miR-20b-5p, and miR-106a-5p as potential PT response biomarkers, with clinical implications for personalizing PCa treatment. These results underscore the necessity for further validation of these miRNAs to maximize their clinical utility. Citation Format: Johnny Velasquez, Curtis Bryant, Nancy Mendenhall, Luisel Ricks-Santi. Attenuation of circulating miR-17-5p, miR-20b-5p, and miR-106a-5p in low-risk prostate cancer patients following proton 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 471.
Abstract 2178: Metagenomic analysis unveils the microbial landscape of pancreatic tumors
Authors: Sheema Khan, Goutam Banerjee, Saini Setua, Anupam Dhasmana, Pratik Banerjee, Murali Mohan Yallapu, Stephen W. Behrman, Subhash Chauhan, Daleniece Higgins Jones, Bhavin Chauhan
Journal: Cancer Research (2024)

Abstract The composition of resident microbes in the human body is linked to various diseases and their treatment outcomes. Although studies have identified pancreatic ductal adenocarcinoma (PDAC) associated bacterial communities in the oral and gut samples, herein we hypothesize the prevalence of microbiota in pancreatic tumor tissues is different as compared to their matched adjacent, histologically normal appearing tissues and these microbial molecular signatures can be highly useful for PDAC diagnosis/prognosis. In this study, we performed comparative profiling of bacterial populations in pancreatic tumors and their respective adjacent normal tissues using 16S rRNA-based metagenomics analysis. This study revealed a higher abundance of Proteobacteria and Actinomycetota in tumor tissues compared to adjacent normal tissues. Interestingly, the Linear Discriminant Analysis (LDA) scores unambiguously revealed an enrichment of Delftia in tumor tissues, whereas Sphingomonas, Streptococcus, and Citrobacter exhibited depletion in tumor tissues. Furthermore, we analyzed the microbial composition between different groups of patients with different tumor differentiation stages. The bacterial genera, Delftia and Staphylococcus were very high in G1 stages (well differentiated) compared to G2 (well to moderate/moderately differentiated) and G3/G4 (poorly differentiated). However, the abundance of Actinobacter and Cloacibacterium was found to be very high in G2 and G3, respectively. Additionally, we evaluated the correlation of PD-L1 expression with the abundance of bacterial genera in tumor lesions. Our results indicated that three genus such as Streptomyces, Cutibacterium, and Delftia have a positive correlation with PD-L1 expression. Collectively, these findings demonstrate that PDAC lesions harbor relatively different microbiota compared to their normal tumor-adjacent tissues, and this information might be helpful for the diagnosis and prognosis of PADC patients. Citation Format: Sheema Khan, Goutam Banerjee, Saini Setua, Anupam Dhasmana, Pratik Banerjee, Murali Mohan Yallapu, Stephen W. Behrman, Subhash Chauhan, Daleniece Higgins Jones, Bhavin Chauhan. Metagenomic analysis unveils the microbial landscape of pancreatic 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 2178.
Abstract 2590: Automating 6-plex chromogenic multiplexing with BOND RX
Authors: Dean Talia, Stacey Lindsay, Sarah Ketting, Rebecca Williamson, Damian Cockfield
Journal: Cancer Research (2024)

Abstract Multiplex staining using a sequential approach provides a means of visualizing multiple targets in a single biopsy section, further evaluation paired with digital imaging provides a deeper analysis into the spatial relationship at a cellular level. Leica Biosystems enables researchers to complete proof of concept for sequential multiplex staining methods, on board the BOND RX system. Thus, paired with a compatible reagent workflow and a digital slide imaging offering (Aperio GT 450/Aperio AT2) enhances the possibilities for analysis. As with any assay there is a requirement for user optimization, in particular, marker/chromogen layer selection and the pertinent use of an elution step. Such elution step is specifically important within a sequential stain utilizing the same detection reagents on subsequent layers. The results from the multiple staining rounds show a successful 6-plex fully automated stain, possible without the removal and reapplication of the slide onto the BOND system between staining layers. The marker combinations chosen demonstrate compatibility of different host species (Rabbit &amp; Mouse), cellular compartments and isotypes which are provided by Leica Biosystems as BOND Ready to Use reagents. Overall, chromogenic multiplexing provides a stained image which enables color separation, due to the assignment of each chromogen to a marker with an individual cell type and cellular compartment. Finally, the process outlined avoids the risk of signal quenching commonly associated with fluorescent offerings and negates the requirement for specialized equipment due to the enablement of brightfield primary analysis. Citation Format: Dean Talia, Stacey Lindsay, Sarah Ketting, Rebecca Williamson, Damian Cockfield. Automating 6-plex chromogenic multiplexing with BOND RX [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 2590.
Abstract 341: Co-detection of BCR::ABL1 common and atypical fusion and mutation using a novel NGS assay, Dup-Seq BCR-ABL1
Authors: Jin Li, Zhenyu Yan, Lin Shi, Wei Li, Weihua Liu, Cynthia Spittle, Chad Galderisi
Journal: Cancer Research (2024)

Abstract The clinical management of CML and Ph+ ALL patients requires the identification of BCR::ABL1 transcript variants and drug resistance mutations. Currently these assessments need to be performed using separate assays resulting in higher sample requirements, longer turnaround times and higher costs. In this study a custom NGS assay (Dup-Seq BCR-ABL1) was developed and validated that enables co-detection and identification of transcript variants (common and atypical) and resistance mutations. The assay design covers BCR exon 1 to ABL1 exon 10 and employs duplicate PCR amplification of BCR-ABL1 from a single source of the 1st strand cDNA initiated by ABL1 specific priming. The custom data analysis pipeline enables overlapped mutation calling from duplicates as well as transcript determination. The assay minimizes the low-level artifacts that can be seen with other NGS-based BCR::ABL1 assays. This study demonstrates that the Dup-Seq BCR-ABL1 assay achieves high accuracy (PPA for fusion: 0.985; PPA and NPA for mutation at 0.978 and 0.9999, respectively) and sensitivity (LoD for mutation detection at 3% from 10,000 copies of BCR-ABL1 input). The use of the Dup-Seq BCR-ABL1 assay for both transcript variant identification and mutation detection provides comprehensive and accurate results for the clinical management of CML and Ph+ ALL patients while reducing sample requirements, testing costs and turnaround time. Citation Format: Jin Li, Zhenyu Yan, Lin Shi, Wei Li, Weihua Liu, Cynthia Spittle, Chad Galderisi. Co-detection of BCR::ABL1 common and atypical fusion and mutation using a novel NGS assay, Dup-Seq BCR-ABL1 [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 341.
Abstract 6257: Genome wide, high-throughput, high-resolution structural variation detection at low variant allele fraction for oncology samples
Authors: Alex R. Hastie, Pat Lynch
Journal: Cancer Research (2024)

Abstract Structural variation detection remains an elusive undertaking. For decades, G-banded karyotyping has remained the standard practice for nearly all hematological malignancy samples. Cancers are diseases of the genome and structural variants (SVs) are a hallmark of nearly all cancers, are often drivers of oncogenicity, and can sometimes be targeted for treatment, as highlighted by the discovery of the Philadelphia chromosome and later the development of targeted kinase inhibitors. One of the most important limitations of karyotyping, its requirement for cells to divide in culture, has prevented its application for most solid tumors and therefore, there is considerably less understanding of the impact of SVs in solid tumors. Optical genome mapping is a technique that is revolutionizing cytogenomics and unlocking the understanding of SVs in the genome at a level never seen before. It not only can detect nearly all variants that a karyotype can, but it can provide 10,000x higher resolution and does not require cell culture. Because of this, it is being adopted for oncology studies across hematological malignancies and solid tumors. This study demonstrates the performance of a new high throughput Stratys instrument for generation of optical genome map data at extraordinarily high coverage depth. With this instrument, 12 samples can be loaded at once, each loaded onto its own cartridge and the instrument can collect 400x genome coverage for each of these samples in 24 hours. The instrument has random access to the cartridges so that completed samples can be swapped out to facilitate optimal instrument run efficiency. To date, this system has been demonstrated to run 60 samples in a week, each at 400x coverage. Data from the instrument can be processed by Bionano Access™ and VIA™ software to call SVs, copy number variants (CNVs), regions of loss of heterozygosity (LOH), on a genome wide basis, and to classify those variants automatically according to guidelines such as the National Comprehensive Cancer Network (NCCN), World Health Organization (WHO), and National Health Services (NHS, United Kingdom). This new high throughput system with advanced bioinformatic data analysis has the potential to further transform structural variation analysis in cancer research. Citation Format: Alex R. Hastie, Pat Lynch. Genome wide, high-throughput, high-resolution structural variation detection at low variant allele fraction for oncology samples [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 6257.
Abstract 6346: IgG engineered to target PIGR-mediated transcytosis specifically targets intracellular oncoproteins and abrogated tumor growth
Authors: Carmen Maria Anadon Galindo, Luis U. Lopez-Bailon, Ricardo A. Chaurio, Jessica A. Mine, Noah E. Plappert, Jose R. Conejo-Garcia
Journal: Cancer Research (2024)

Abstract Despite their long half-life, therapeutic antibodies are considered ineffective against intracellular antigens due to their perceived inability to penetrate epithelial cells. Using recombinant antibodies targeting common mutations in oncogenes, we have demonstrated that dimeric IgA, but not the same antibody on an IgG backbone, penetrates human epithelial cancer cells through PIGR-dependent directional transcytosis, specifically neutralizing mutated oncodrivers and expelling antigens outside the cell, bound to secretory IgA. Accordingly, targeting of KRASG12D abrogated tumor cell proliferation in cell culture assays. In vivo, KRASG12D-specific dIgA1 limited the growth of RASG12D-mutated ovarian and lung carcinomas, including in syngeneic tumor-bearing immunocompetent mice. Moreover, dIgA targeting of KRASG12D restricted tumor growth more effectively than small-molecule KRASG12D inhibitors, supporting the potential of this approach for the treatment of human cancers. Since producing dimeric IgA is more challenging than producing monomeric IgG, and because the half-life of IgA is shorter (4-7 days) than IgG (21 days), we have developed a new approach combining KRASG12D specific IgG with a peptide that could join PIGR and penetrates tumor cells through transcytosis, that showed the same effect than IgA controlling tumor growth. Our results provide a rationale for developing modified IgG cell-penetrating antibodies to effectively target common mutations in intracellular oncogenes that drive many aggressive and frequent human cancers. In addition, further experiments suggest that these antibodies could be effectively used to target tumors that have become resistant to existing KRAS inhibitors. Citation Format: Carmen Maria Anadon Galindo, Luis U. Lopez-Bailon, Ricardo A. Chaurio, Jessica A. Mine, Noah E. Plappert, Jose R. Conejo-Garcia. IgG engineered to target PIGR-mediated transcytosis specifically targets intracellular oncoproteins and abrogated tumor growth [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 6346.
Abstract 3976: Single-cell TCRɑ/β and TCRγ/δ immune receptor profiling and immunophenotyping using a 96-well plate sorted-cell approach
Authors: Alex Chenchik, Tianbing Liu, Mikhail Makhanov, Dongfang Hu, Lester Kobzik, Khadija Ghias, Paul Diehl
Journal: Cancer Research (2024)

Abstract Single-cell immune receptor profiling is a revolutionary approach that allows investigators to combine clonotype repertoire identification with paired-chain information and the phenotype of cells (e.g., cell subtype). Single-cell immune receptor profiling can be performed using a medium-throughput approach (1,000-5,000 cells) using microwell arrays or droplet microfluidics technologies. However, these assays are more complicated to run and require expensive reagents and limited sequencing throughput when compared to bulk immune receptor profiling methods. Here, we describe a low-throughput, single-cell immune profiling strategy using sorted cells in 96-well plates. The plate is pre-aliquoted with either T-cell receptor (TCR) ɑ/β or TCR γ/δ primers along with 30 crucial T-cell markers. We perform multiplex RT-PCR amplification and sequencing of the CDR3 regions. The resulting data provides the abundant clonotype counts along with the chain pairing information for these ɑ/β and γ/δ chains, together with the T-cell subtype information using gene-expression profiles. By analyzing the TCR gene rearrangement at the single-cell level, researchers can better understand T cell development, proliferation, and clonality, which are crucial for studying diseases such as cancer, immunodeficiency, and autoimmunity. Furthermore, single-cell TCR sequencing when combined with RNA sequencing datasets, facilitates the identification of γδ T cells. This method provides a standardized tool for identifying potential γδ T cell-based cancer immunotherapies. The technology's cost-effectiveness and ability to analyze clonotypes and immunophenotypes of cells in a single assay make it a valuable tool for unraveling the immune dynamics in various diseases. Citation Format: Alex Chenchik, Tianbing Liu, Mikhail Makhanov, Dongfang Hu, Lester Kobzik, Khadija Ghias, Paul Diehl. Single-cell TCRɑ/β and TCRγ/δ immune receptor profiling and immunophenotyping using a 96-well plate sorted-cell approach [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 3976.