tbuckley/cabot-search huggingface dataset:
Abstract B062: Transcriptomic analysis of whole blood samples from prostate cancer patients: A comparative study of patients from geographically diverse populations
Authors: Srinivas V Koduru, Mark Kidd, Ané Pieters, S E Nagel, Robert P Millar, Abdel B Halim
Journal: Clinical Cancer Research (2024)

Abstract Introduction: Prostate cancer is the most frequently diagnosed cancer across 112 countries. Among American men, an estimated 299, 010 new cases and 35,250 deaths are projected for 2024. In this study, the transcriptomic profile of prostate cancer patients from geographically and ethnically diverse cohorts (USA-Caucasian, RSA-Black) were compared to identify gene expression patterns associated with prostate cancer. Methods: Whole blood samples were collected from PCa and controls. Controls had the same age-range as PCa with no clinical indication of prostatic disease and serum PSA levels below 1.5 ng/ml. RNA was isolated, sequencing was carried out on Novaseq 6000, and data analyzed using PartekFlow to identify differential gene expression patterns (RSA-PCa: 6, RSA-Control: 6, USA-PCa: 7, USA-Control: 11). qRT-PCR was undertaken on a cohort of 27 biomarkers (PROSTest) related to PCa in whole blood. Results: Differential expression analysis identified distinct patterns in USA and RSA groups. In the USA PCa cohort, 2,193 genes were differentially expressed compared to the controls with fold change (FC) &amp;gt;1, p-value (p) &amp;lt;0.05, while in the RSA PCa cohort, 1,627 genes were differentially expressed compared to the controls. Pathway analyses identified enrichment for immune responsive genes in the RSA cohorts. We identified that 26 of 27 Wren’s PROSTest genes detectable in both groups. RNAseq and normalized PCR gene expression were well- correlated (r=0.44, p=0.0012, n=30 pairs). Conclusion: Based on this RNAseq study, there may be geographic differences related to ethnicity in overall blood RNA gene expression. We specifically identified alterations in immune function gene expression between the USA and RSA. Importantly, PROSTest genes were detected in both populations and exhibited a significant correlation. Development of gene signatures for biomarker discovery should, however, consider specific ethnicities and geographical regions. Citation Format: Srinivas V Koduru, Mark Kidd, Ané Pieters, S E Nagel, Robert P Millar, Abdel B Halim. Transcriptomic analysis of whole blood samples from prostate cancer patients: A comparative study of patients from geographically diverse populations [abstract]. In: Proceedings of the AACR Special Conference: Liquid Biopsy: From Discovery to Clinical Implementation; 2024 Nov 13-16; San Diego, CA. Philadelphia (PA): AACR; Clin Cancer Res 2024;30(21_Suppl):Abstract nr B062.
Abstract IA007: Modulating cfDNA biology to enhance liquid biopsies
Authors: Viktor Adalsteinsson
Journal: Clinical Cancer Research (2024)

Abstract Liquid biopsies could transform cancer care but require higher sensitivity to detect early-stage tumors and minimal residual disease (MRD) and to enable tumor molecular profiling and therapy response monitoring for most patients. In this talk, I will focus on the significant biological bottlenecks upstream of cell-free DNA (cfDNA) testing. I will posit that in many circumstances, insufficient circulating tumor DNA (ctDNA) drawn in a blood tube cannot be overcome by assay technology alone, and that in vivo modulation of cfDNA biology may also be required to enhance liquid biopsies. Inspired by widespread use of diagnostic drugs in other areas of medicine, we sought to create the first “priming agents” for liquid biopsies that could be administered before a blood draw to recover more ctDNA. I will describe two such approaches—a monoclonal antibody against double-stranded DNA and a liposome nanoparticle—that briefly attenuate cfDNA clearance by shielding it from nuclease digestion and cellular uptake. These enabled &amp;gt;10x more ctDNA to be collected when administered within 1-2 hours of a blood draw in mice. This improved the analytical limit of detection for ctDNA testing by &amp;gt;10-fold, provided more complete representation of the tumor genome in each blood sample, and increased the sensitivity for detection of small tumors from &amp;lt;10% to &amp;gt;75% in mice. Envisioning a future where liquid biopsies are optionally enhanced with priming, I will also explore a unique potential pairing with our tumor-informed, whole-genome, mutation enrichment sequencing MRD test called MAESTRO, and how it stands to enable routine ctDNA detection below 1 part per million. Citation Format: Viktor Adalsteinsson. Modulating cfDNA biology to enhance liquid biopsies [abstract]. In: Proceedings of the AACR Special Conference: Liquid Biopsy: From Discovery to Clinical Implementation; 2024 Nov 13-16; San Diego, CA. Philadelphia (PA): AACR; Clin Cancer Res 2024;30(21_Suppl):Abstract nr IA007.
Abstract B037: Disks large-associated protein 5 (DLGAP5) is a putative prognostic biomarker for intraductal papillary mucinous neoplasm (IPMN) of pancreas
Authors: Radoslav Janostiak, Peter Mačinga, Lucia Csergeová, Ondřej Fabián, Eva Sticová, Jiří Zahradník, Martin Květoň, Tomáš Hucl
Journal: Clinical Cancer Research (2024)

Abstract Pancreatic cancer is one of the deadliest malignant diseases, accounting for nearly 500,000 deaths worldwide each year. One of the pancreatic cancer precursors are mucinous pancreatic cystic lesions (PCL). Although only a minority of these PCLs undergo malignant transformation, the clinical significance is considerable, particularly given the prevalence of up to 45% in individuals over the age of 65. The most prevalent type of neoplastic PCL is intraductal papillary mucinous neoplasm (IPMN) and the management of different IPMN grades varies, with high- grade dysplasia and invasive carcinoma being indicated for surgery. However, the current guidelines for patient stratification are limited and often lead to either overtreatment or undertreatment, both of which are associated with high mortality and morbidity. Therefore, there is a pressing need to identify biomarkers associated with progression of IPMN from low to high grade that can be used for more accurate lesion assessment. Here we identified a novel biomarker highly correlated with IPMN progression – DLGAP5. Both mRNA as well as protein expression of DLGAP5 is positively associated with increased grade of IPMNs as determined by analysis of patient derived tumor samples. Additionally, in vitro experiments confirmed that knock down of DLGAP5 in pancreatic cancer cells leads to reduction of cell proliferation, and conversely, overexpression of DLGAP5 in IPMN precursor cells resulted in increased proliferation. Since one of the functions of DLGAP5 is microtubule stabilization, we hypothesized that the secretome of IPMN precursor cells will be altered by the expression of DLGAP5. Indeed, our mass spectrometry-based analysis of secreted proteins identified several hits (e.g. DKK1) that were correlated with DLGAP5 expression and were previously confirmed to be present in IPMN cyst fluid in patients. Subsequently, we aim to validate the correlation of the putative biomarkers in IPMN cyst fluid and serum with IPMN grade and patients’ clinical outcome in a prospective manner. To sum up, we validated DLGAP5 as an IPMN-progression biomarker and identified several secreted proteins that could serve as DLGAP5-surrogate biomarkers for stratification of the patients with IPMN and subsequent treatment optimalization. Citation Format: Radoslav Janostiak, Peter Mačinga, Lucia Csergeová, Ondřej Fabián, Eva Sticová, Jiří Zahradník, Martin Květoň, Tomáš Hucl. Disks large-associated protein 5 (DLGAP5) is a putative prognostic biomarker for intraductal papillary mucinous neoplasm (IPMN) of pancreas [abstract]. In: Proceedings of the AACR Special Conference: Liquid Biopsy: From Discovery to Clinical Implementation; 2024 Nov 13-16; San Diego, CA. Philadelphia (PA): AACR; Clin Cancer Res 2024;30(21_Suppl):Abstract nr B037.
Abstract B021: tRNA fragments extracted from patient plasma extra cellular vesicles display potential as biomarkers for high-grade glioma
Authors: Thomson R Phinney, Ali Alwadei, Gabriel Gabriel Wajnberg, Jae Han, Simi Chacko, Kathleen Attwood, Jeremy Roy, Adriennne Weeks
Journal: Clinical Cancer Research (2024)

Abstract Transfer RNA (tRNA) are non-coding RNAs that bring amino acids to ribosomes during translation. Recent studies have shown that cleaved fragments derived from tRNA (tRFs) serve regulatory roles in epigenetics, signaling, transcription, and translation. tRFs can be released from cells and can be found in extracellular vesicles to perform some aspects of paracrine signaling. Utilizing high throughput small RNA sequencing, we have identified over 750 uniquely or multi-mapped (6.9% of total sRNA mapped reads) tRFs in extracellular vesicles of high-grade glioma (IDH-WT) patient plasma. By performing differential expression analysis, we identified 6 upregulated tRFs and 36 downregulated tRFs between high-grade glioma plasma EVs and non-cancer controls (n = 14, FDR&amp;lt;0.05). Differentially expressed tRFs (all 42) were further analyzed using bioinformatic techniques (RNAhybrid and IntaRNA) to predict potential gene targets. By performing gene ontology analysis (ShinyGO) we found that 70 of 75 genes related to glioma formation were identified as potential gene targets, indicating a possible role of tRFs in the regulation and formation of gliomas. A number of differentially expressed tRFs were predicted to target cancer-related genes including Metastasis Associated Lung Adenocarcinoma Transcript 1 (MALAT-1). This analysis demonstrates that tRFs may serve as important biomarkers and regulators with therapeutic potential in the future Citation Format: Thomson R Phinney, Ali Alwadei, Gabriel Gabriel Wajnberg, Jae Han, Simi Chacko, Kathleen Attwood, Jeremy Roy, Adriennne Weeks. tRNA fragments extracted from patient plasma extra cellular vesicles display potential as biomarkers for high-grade glioma [abstract]. In: Proceedings of the AACR Special Conference: Liquid Biopsy: From Discovery to Clinical Implementation; 2024 Nov 13-16; San Diego, CA. Philadelphia (PA): AACR; Clin Cancer Res 2024;30(21_Suppl):Abstract nr B021.
Abstract A063: Highly accurate detection of early-stage colorectal cancer using tumor and immune extracellular vesicles biomarkers
Authors: Poorva Mudgal, Cheryl Bandoski, Zachary Opheim, Martin Mehnert, Valesca Anschau, Issa Isaac, Alan Ezrin, Todd Hembrough
Journal: Clinical Cancer Research (2024)

Abstract This abstract is being presented as a short talk in the scientific program. A full abstract is printed in the Proffered Abstracts section (PR013) of the Conference Program/Proceedings. Citation Format: Poorva Mudgal, Cheryl Bandoski, Zachary Opheim, Martin Mehnert, Valesca Anschau, Issa Isaac, Alan Ezrin, Todd Hembrough. Highly accurate detection of early-stage colorectal cancer using tumor and immune extracellular vesicles biomarkers [abstract]. In: Proceedings of the AACR Special Conference: Liquid Biopsy: From Discovery to Clinical Implementation; 2024 Nov 13-16; San Diego, CA. Philadelphia (PA): AACR; Clin Cancer Res 2024;30(21_Suppl):Abstract nr A063.
Abstract B001: ctDNA release kinetics and fragmentation to monitor treatment response and resistance in esophageal adenocarcinoma
Authors: Alexandra Bartolomucci, Laura Kienzle, Sarah Tadhg Ferrier, Lisa-Monique Edward, Jeffrey Bruce, Kwang-Bo Joung, Stephenie Prokopec, Wotan Zeng, Abirami Sharma, Kyle Dickinson, Nicholas Bertos, Jonathan Cools-Lartigue, Lorenzo Ferri, Trevor J. Pugh, Julia V. Burnier
Journal: Clinical Cancer Research (2024)

Abstract This abstract is being presented as a short talk in the scientific program. A full abstract is printed in the Proffered Abstracts section (PR003) of the Conference Program/Proceedings. Citation Format: Alexandra Bartolomucci, Laura Kienzle, Sarah Tadhg Ferrier, Lisa-Monique Edward, Jeffrey Bruce, Kwang-Bo Joung, Stephenie Prokopec, Wotan Zeng, Abirami Sharma, Kyle Dickinson, Nicholas Bertos, Jonathan Cools-Lartigue, Lorenzo Ferri, Trevor J. Pugh, Julia V. Burnier. ctDNA release kinetics and fragmentation to monitor treatment response and resistance in esophageal adenocarcinoma [abstract]. In: Proceedings of the AACR Special Conference: Liquid Biopsy: From Discovery to Clinical Implementation; 2024 Nov 13-16; San Diego, CA. Philadelphia (PA): AACR; Clin Cancer Res 2024;30(21_Suppl):Abstract nr B001.
Abstract B038: Application of Liquid Biopsy-RECIST (LB-RECIST) criteria to track metastatic colorectal cancer (mCRC) molecular response in first-line (1L) setting: Findings from the PLATFORM-B study
Authors: Valentino Martelli, Joana Vidal, Maria Concepción Fernández-Rodríguez, Pilar García-Alfonso, David Páez, Joan Gibert, Jennifer Linares, Annarita Sibilio, Vicente Alonso, Maria Teresa Cano, Cristina Santos, Gema Duran, Elena Élez, José Luis Manzano, Rocio Garcia-Carbonero, Reyes Ferreiro, Ferran Losa, Estela Pineda, Javier Sastre, Auxiliadora Gomez-España, Rodrigo Toledo, Fernando Rivera, Beatriz Bellosillo, Josep Tabernero, Ramon Ramon Salazar, Enrique Aranda, Clara Montagut
Journal: Clinical Cancer Research (2024)

Abstract This abstract is being presented as a short talk in the scientific program. A full abstract is printed in the Proffered Abstracts section (PR009) of the Conference Program/Proceedings. Citation Format: Valentino Martelli, Joana Vidal, Maria Concepción Fernández-Rodríguez, Pilar García-Alfonso, David Páez, Joan Gibert, Jennifer Linares, Annarita Sibilio, Vicente Alonso, Maria Teresa Cano, Cristina Santos, Gema Duran, Elena Élez, José Luis Manzano, Rocio Garcia-Carbonero, Reyes Ferreiro, Ferran Losa, Estela Pineda, Javier Sastre, Auxiliadora Gomez-España, Rodrigo Toledo, Fernando Rivera, Beatriz Bellosillo, Josep Tabernero, Ramon Ramon Salazar, Enrique Aranda, Clara Montagut. Application of Liquid Biopsy-RECIST (LB-RECIST) criteria to track metastatic colorectal cancer (mCRC) molecular response in first-line (1L) setting: Findings from the PLATFORM-B study [abstract]. In: Proceedings of the AACR Special Conference: Liquid Biopsy: From Discovery to Clinical Implementation; 2024 Nov 13-16; San Diego, CA. Philadelphia (PA): AACR; Clin Cancer Res 2024;30(21_Suppl):Abstract nr B038.
Abstract B046: Methylation based circulating tumor DNA serial monitoring correlates with immunotherapy response in non-small cell lung cancer
Authors: Angela Hsiao, Brian Woodward, Patrick Ye, Matthew Varga, Kevin Lu, Ghaith Altaie, Naomi Searle, Robb Veins, Sydne Langpap, Zeqian Li, Gary Palmer, Hatim Husain
Journal: Clinical Cancer Research (2024)

Abstract Purpose: Circulating tumor DNA (ctDNA) can reflect the genetic and epigenetic composition of malignancies and can serve as a non-invasive biomarker for cancer diagnostics and monitoring. This study aimed to evaluate the utility of a methylation based ctDNA assay as a predictive tool in non-small cell lung cancer (NSCLC) anti-PD1 based immunotherapy monitoring. Methods: We evaluated a cohort of patients with NSCLC treated with anti-PD1 based immunotherapy, from which 108 blood specimens were collected at baseline and during treatment follow-up. Tumor Methylation Scores (TMS) were measured with an amplicon-based, multiplexed cfDNA assay that utilizes quantitative counting templates (QCTs) in conjunction with next-generation sequencing to count the number of methylated molecules at more than 500 genomic locations that are hypermethylated in cancer tissue. The association between TMS and real-world progression-free survival (rwPFS) on therapy was conducted using Cox proportional hazards model and plotted using the Kaplan-Meier method. Results: The change in TMS measured 4-10 weeks post-treatment initiation strongly correlated with immunotherapy response, as measured by rwPFS (p&amp;lt;0.0001), compared to a weaker correlation of imaging RECIST v1.1 measurements with rwPFS (p=0.55). Furthermore, TMS tracked with tumor burden on therapy in real-world cases. Conclusions: In this real-world dataset of NSCLC patients treated with anti- PD1 immunotherapy regimens, TMS scores measured within a 4-10 week window after treatment initiation can be predictive of response to therapy. Beyond this window, the TMS score can be associated with rwPFS and tumor dynamics. Early evidence suggests that changes in the methylation profile may be informative for monitoring occurrence of new somatic mutations. The cases presented demonstrate the applicability of using TMS for serial therapeutic response monitoring. Citation Format: Angela Hsiao, Brian Woodward, Patrick Ye, Matthew Varga, Kevin Lu, Ghaith Altaie, Naomi Searle, Robb Veins, Sydne Langpap, Zeqian Li, Gary Palmer, Hatim Husain. Methylation based circulating tumor DNA serial monitoring correlates with immunotherapy response in non-small cell lung cancer [abstract]. In: Proceedings of the AACR Special Conference: Liquid Biopsy: From Discovery to Clinical Implementation; 2024 Nov 13-16; San Diego, CA. Philadelphia (PA): AACR; Clin Cancer Res 2024;30(21_Suppl):Abstract nr B046.
Abstract A057: Cancer-induced epigenomic changes in circulating immune cells enable breast, colorectal and lung cancer detection
Authors: Gulfem D Guler, Giuliana P Mognol, Yuhong Ning, Carolina Fraire, David Haan, Michael Kesling, Roger Malta, Melissa Peters, Anna Bergamaschi, Tierney Phillips, Shimul Chowdhury, Wayne Volkmuth, Samuel Levy
Journal: Clinical Cancer Research (2024)

Abstract Background: Epigenomic changes via the measurement of 5-hydroxymethylation cytosine (5hmC) in DNA have been shown to enable detection in a variety of cancers including pancreatic and ovarian cancer in plasma-derived cell-free DNA (cfDNA). Here, we investigated whether blood-based 5hmC profiling of genomic DNA (gDNA) derived from cells of the buffy coat (BC) possess signals that enable the detection of breast, colorectal and lung cancers. Method: Blood samples collected in Streck tubes from cancer patients or non-cancer controls were processed to obtain buffy coat and plasma samples. gDNA and cfDNA was isolated from buffy coat and plasma, respectively. gDNA or cfDNA was then subjected to 5hmC enrichment by click chemistry followed by preparation of sequencing libraries. Sequencing was performed to obtain genome-wide 5hmC profiles of buffy coat gDNA and cfDNA samples. Results: Differential hydroxymethylation analysis of BC gDNA revealed increased 5hmC over genes associated with myeloid lineage in breast, colorectal and lung cancers relative to non-cancer controls. Flow cytometry analysis confirmed increases in myeloid cells in cancer samples relative to non-cancer controls. 5hmC patterns in BC gDNA showed a larger number of cancer-associated changes compared to cfDNA, in particular this was found in early-stage disease. 5hmC features from BC gDNA or plasma-derived cfDNA were used to build prediction models that yielded cancer classification with overall sensitivity of 51.3% and 52.6% at 98% specificity, for BC or cfDNA, respectively. For early-stage cancer, the sensitivity at 98% specificity was 46.5% for the BC and 28.2% for cfDNA model. A final prediction model incorporating features from both tissue sources achieved superior classification (65.8% sensitivity) at 98% specificity, compared with using features from either tissue source alone, particularly for early-stage cancer which achieved 53.5% sensitivity of cancer detection. Conclusion: Our results demonstrate that cancer impacts the 5hmC profiles of buffy coat cells which can be leveraged for cancer detection using blood. Citation Format: Gulfem D Guler, Giuliana P Mognol, Yuhong Ning, Carolina Fraire, David Haan, Michael Kesling, Roger Malta, Melissa Peters, Anna Bergamaschi, Tierney Phillips, Shimul Chowdhury, Wayne Volkmuth, Samuel Levy. Cancer-induced epigenomic changes in circulating immune cells enable breast, colorectal and lung cancer detection [abstract]. In: Proceedings of the AACR Special Conference: Liquid Biopsy: From Discovery to Clinical Implementation; 2024 Nov 13-16; San Diego, CA. Philadelphia (PA): AACR; Clin Cancer Res 2024;30(21_Suppl):Abstract nr A057.
Abstract IA024: Validation of liquid biopsy approaches for the care of children with cancer
Authors: Brian Crompton
Journal: Clinical Cancer Research (2024)

Abstract Pediatric cancers are driven by a unique set of mutations, destinct from the variants that typically drive adult cancers. Therefore, widely available liquid biopsy assays are often not relevant for detection, quantificaiton, or profiling of circulating tumor DNA in childhood cancer. Custom liquid biopsy approaches have been developed by the Crompton lab and others and these assays demonstrate that ctDNA levels provide valuable prognostic information and can guide some therapeutic choices in pediatrics. Implementation of liquid biopsies into national phase 3 trials for children with cancer will require translation of these approaches into a clinical molecular laboratory environment. Citation Format: Brian Crompton. Validation of liquid biopsy approaches for the care of children with cancer [abstract]. In: Proceedings of the AACR Special Conference: Liquid Biopsy: From Discovery to Clinical Implementation; 2024 Nov 13-16; San Diego, CA. Philadelphia (PA): AACR; Clin Cancer Res 2024;30(21_Suppl):Abstract nr IA024.
Abstract IA011: Heterogeneity of cancer-derived extracellular vesicles
Authors: Dolores Di Vizio
Journal: Clinical Cancer Research (2024)

Abstract Extracellular vesicles (EVs) are heterogenous in size, biogenesis, cargo and function. Beside small EVs, aggressive tumor cells release a population of particularly large EVs, namely large oncosomes (LO). This study provides the first resource of label-free quantitative proteomics of LO and small EVs obtained from distinct cancer cell types (prostate, breast, and glioma). This dataset was integrated with a SWATH Proteomic assay on LO, rigorously isolated from the plasma of patients with metastatic prostate cancer (PC). Proteins enriched in LO, which were identified also at the RNA level, and found in plasma LO significantly correlated with PC progression. Single EV RNA-Seq of the PC cell-derived LO confirmed some of the main findings from the bulk RNA-Seq, providing first evidence that single cell technologies can be successfully applied to EVs. This multiomics resource of cancer EVs can be leveraged for developing a multi-analyte approach for liquid biopsy. Citation Format: Dolores Di Vizio. Heterogeneity of cancer-derived extracellular vesicles [abstract]. In: Proceedings of the AACR Special Conference: Liquid Biopsy: From Discovery to Clinical Implementation; 2024 Nov 13-16; San Diego, CA. Philadelphia (PA): AACR; Clin Cancer Res 2024;30(21_Suppl):Abstract nr IA011.