tbuckley/cabot-search huggingface dataset:
Abstract 6901: Paired colorectal and pancreatic cancer patient-derived tumor and organoids biobank
Authors: Juiling Wang, Wen-Hui Ma, Yun-Chi Lo, Hsiao-Chun Hsieh, Li-Ju Hsiao, Yu-Pin Bau, Nai-Chieh Yang, Shaw-Jenq Tsai, Yan-Shen Shan, Tzu-Yu Chen, Yu-Ling Chen, Pei-Ju Chiang, Tzu-Ling Chen, Hsiu-Ping Chang, Hsian-Jean Chin
Journal: Cancer Research (2024)

Abstract Patient-derived xenograft (PDX) models constitute a crucial tool in precision cancer medicine owing to their high accuracy in predicting the response to therapeutic drugs among patients in clinical settings. Our center has established a biobank that collects more than 80 colorectal cancer and 25 pancreatic cancer PDX tissues, along with essential information about patients’ tumors and PDX models. However, cost-intensive and time-consuming limit the usage of PDX model in high throughput screening during drug development. To overcome this hurdle, we are generating a PDX-match paired organoid (PDXO) biobank by using emerging three-dimensional culture techniques. Before large-scaled expansion, the concordance between PDX tissues and PDXOs of partial specimens was evaluated firstly using short-tandem repeat (STR) analysis, immunohistochemistry (IHC) and H&amp;E staining. Data of STR analysis performed by using AmpFLSTR Identifiler PLUS PCR Amplification Kit demonstrated that PDX tissues and PDXOs have identical DNA fingerprinting. IHC and H&amp;E staining revealed PDX tissues and PDXOs have highly similar organ-specific markers expression (e.g., Cytokeratin 20, Caudal Type Homeobox 2, and Pan Cytokeratin) and histological morphology. Even after passing to at least five generations, passed PDXOs maintained high fidelity to their original state, as confirmed by whole-exome sequencing (WES) and STR analysis across passages. The WES analysis for passage 0 (P0) and passage 5 (P5) of PDXOs from different PDX tissues revealed there is more than 95% intersection between P0 and P5 PDXOs with the same missense mutation gene. The results of STR analysis showed that P0 and P5 PDXOs have identical STR profile. To evaluate the capability of PDXOs in clinical response prediction, several effective and ineffective drugs (e.g., oxapliplatin, 5-FU, gemcitabine) were tested. The results of drug testing indicated that PDXOs can be used to accurately predict the response to therapeutic drugs as PDX model but more efficient than PDX model. Therefore, PDXO biobank can serve as a valuable resource for high throughput in vitro drug screening prior in vivo efficacy confirmation using PDX models. Citation Format: Juiling Wang, Wen-Hui Ma, Yun-Chi Lo, Hsiao-Chun Hsieh, Li-Ju Hsiao, Yu-Pin Bau, Nai-Chieh Yang, Shaw-Jenq Tsai, Yan-Shen Shan, Tzu-Yu Chen, Yu-Ling Chen, Pei-Ju Chiang, Tzu-Ling Chen, Hsiu-Ping Chang, Hsian-Jean Chin. Paired colorectal and pancreatic cancer patient-derived tumor and organoids biobank [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 6901.
Abstract 1765: The genetic landscape of head and neck cancer using brush biopsy
Authors: Evit John, Tom Lesluyes, Toby Baker, Maxime Tarabichi, Peter Van Loo, Xiao Zhao
Journal: Cancer Research (2024)

Abstract Oral premalignant lesions (OPLs) with genomic alterations have a heightened risk of evolving into oral squamous cell carcinoma (OSCC). Currently, genomic data are obtained through invasive tissue biopsy. Brush biopsy has been utilized for diagnosing dysplasia but its effectiveness in reflecting the complete genomic landscape of OPLs remains uncertain. This study investigates the potential of brush biopsy samples in accurately reconstructing the genomic profile of OPLs. The evolution and heterogeneity were assessed by assessing SNVs, copy number analysis, and subclonal architecture reconstruction of paired tissue-brush biopsy samples of oral epithelium, dysplastic lesion, and OSCC lesion. We found that brush biopsy accurately reflects the genomic landscape of oral lesions, mirroring about 90% of SNVs and comparable CNA profiles found in tissue biopsies. Genomic profiling with brush biopsy was tissue-specific, as SNVs identified in OPL or OSCC lesions were not found in adjacent normal mucosa. Shared SNVs and CNAs were observed between OPL and OSCC samples. This suggested a common ancestor giving rise to these lesions. Subclonal architecture reconstruction confirmed that both lesion types shared a common ancestor clone and then diverged evolutionarily. These findings underscore the potential of brush biopsies in accurately reconstructing the genomic profile of OPL and OSCC, highlighting their usefulness in understanding the biological processes involved in tumor evolution. Citation Format: Evit John, Tom Lesluyes, Toby Baker, Maxime Tarabichi, Peter Van Loo, Xiao Zhao. The genetic landscape of head and neck cancer using brush biopsy [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 1765.
Abstract 5039: Preanalytical workflow enabling cfDNA analysis from urine samples
Authors: Daniela Mancarella, Julia Rutsch, Lisa Erkelenz, Moritz Meyer, Laura Sofie Witthaus, Moritz Rath, Thorsten Voss
Journal: Cancer Research (2024)

Abstract Introduction: Urine has become an important source of information in the liquid biopsy field. In contrast to blood, specifications for the collection, storage, transport and processing of urine intended for molecular examination are not widely established. Preanalytical specifications were published for urine cell-free DNA (cfDNA) only recently (CEN/TS 17811:2022). In this study, we investigated post-collection changes to cfDNA profiles in urine samples and present the performance of an optimized preanalytical workflow for cfDNA analysis. Methods: Urine from apparently healthy, consented female individuals was spiked with processed cell-free male urine or with a cfDNA standard containing PIK3CA mutations (SensID). The urine was stabilized with a urine collection/stabilization solution under development at PreAnalytiX or was left unstabilized. Urine samples were stored for varying durations at different temperatures in a time course experiment to simulate different urine storage conditions. After storage, urine samples were centrifuged to remove cells and cfDNA was isolated from the supernatant via the QIAsymphony® platform (QIAGEN). Autosomal and male-specific targets were quantified using the Rotor-Gene® Q instrument and the therascreen® PIK3CA qPCR Kit (both QIAGEN) or the QIAcuity® Digital PCR System and a dPCR LNA PIK3CA Mutation Assay (both QIAGEN). Fragment size distribution was determined by TapeStation® Cell-free DNA ScreenTape® (Agilent Technologies). Results: Analysis of cfDNA profiles in unstabilized urine stored for varying durations and temperatures highlighted changes which create artificial cfDNA profiles. The yield of cfDNA drastically decreased over time. Furthermore, the size distribution of cfDNA isolated from unstabilized urine was impacted by release of gDNA as well as DNA degradation. Urine stabilization minimized cfDNA degradation and gDNA release and allowed isolation of cfDNA that was analyzed with qPCR and dPCR even after urine storage. Analysis of isolated cfDNA revealed positive detection of PIK3CA mutations in spiked urine samples. Conclusions: Changes in post-collection cfDNA profile can hinder downstream analysis, resulting in artificial or failed outcomes. Urine stabilization with a collection/stabilization solution under development at PreAnalytiX minimized DNA degradation and gDNA release. It enabled urine storage, allowed analysis of urine cfDNA and target detection by qPCR and dPCR. Citation Format: Daniela Mancarella, Julia Rutsch, Lisa Erkelenz, Moritz Meyer, Laura Sofie Witthaus, Moritz Rath, Thorsten Voss. Preanalytical workflow enabling cfDNA analysis from urine 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 5039.
Abstract 4662: High-throughput screening identifies potential combinatorial therapies to overcome lenvatinib resistance in liver cancer
Authors: Kevin Chau, Martina S. McDermott, KeWei Gong, Dennis J. Slamon
Journal: Cancer Research (2024)

Abstract Liver cancer has seen an increase in mortality rate over recent decades due to limited targeted therapies and growth in specific etiologies. Lenvatinib, a multi-TKI inhibitor, is used as a first-line therapy for liver cancer patients who cannot receive immunotherapy, which is a component of the current standard of care. Unfortunately, lenvatinib efficacy is short. Understanding why liver cancers become resistant and identifying interventions to restore sensitivity can help prolong the clinical efficacy of lenvatinib. A panel of 20 liver cancer lines was screened to identify four lenvatinib-sensitive lines. These lines were subsequently conditioned to grow under increasing lenvatinib concentrations to generate lenvatinib-resistant (LR) models. One such model, Hep3B LR, exhibited a stable resistance to lenvatinib for up to 12 weeks in culture. Hep3B LR showed cross-resistance to selective inhibitors of FGFR4 and FGFR1 but not of MAPK14 and PDGFR, suggesting that the resistance phenotype may result from FGFR dysfunction. Unlike parental Hep3B, Hep3B LR exhibited a 3.4X increase in migration. Western blot detected an increase in pAKT, a survival marker. Additionally, proteins associated with cancer drug resistance were higher in Hep3B LR cells: Notch receptors and ligands, pStat3, and Axl. To identify means of overcoming lenvatinib resistance in Hep3B LR, a Cell-Titer Glo high-throughput assay was developed to measure the growth inhibition of candidate drugs in the presence and absence of lenvatinib. Preliminary results from the first 24 drugs screened reproduced known drug sensitivities associated with lenvatinib resistance (i.e., MEK/ERK, EGFR, GPX4 inhibition) but also identified novel sensitivities to inhibition of PKMYT1 or γ-secretase, the latter a cleavage enzyme involved in Notch signaling activation. Validation of these candidate hits using a grid-based titration of both drugs showed additive growth inhibition of lenvatinib in combination with ERK, EGFR, or GPX4 inhibitors but not with PKMYT1 or γ-secretase inhibitors in resistant cells. Interestingly, EGFRi and lenvatinib were substantially synergistic in parental cells, suggesting that an upfront combination of these inhibitors could potentially be used before the emergence of lenvatinib resistance in liver cancer. We have established a lenvatinib-resistant liver cancer cell model and validated a drug screening assay to identify potential combinatorial therapies to overcome lenvatinib resistance in liver cancer. Citation Format: Kevin Chau, Martina S. McDermott, KeWei Gong, Dennis J. Slamon. High-throughput screening identifies potential combinatorial therapies to overcome lenvatinib resistance in liver cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 4662.
Abstract 6959: Acetylcholine potentiates invasion and migration of human pancreatic cancer cells under hypoxia through α7 nAChR-mediated increases in HIF-1α expression
Authors: Yunmi Cho, Eun-Taex Oh, Ha Gyeong Kim, Heon Joo Park
Journal: Cancer Research (2024)

Abstract The most significant nerve-related problem in clinical pancreatic cancer management is perineural invasion (PNI), characterized as the neoplastic invasion of cancer cells into or surrounding the nerves. It is a characteristic feature of pancreatic ductal adenocarcinoma (PDAC) associated with a poor prognosis, tumor recurrence, and emergent pain. However, why PDAC is associated with a higher incidence of PNI remains unclear. HIF-1 (hypoxia-inducible factor-1) regulates the expression of ~1000 genes involved in angiogenesis, metastasis, tumor growth, chemoresistance and radioresistance, underscoring the growing interest in targeting HIF-1 for cancer control. In the present study, we investigated the molecular mechanisms underlying neurotransmitter acetylcholine (Ach)-potentiated HIF-1α expression and subsequent increase in invasion and migration of human pancreatic cancer cells in hypoxia (2% O2). The expression of various acetylcholine receptors in six types of pancreatic cancer cell lines (MIA-PaCa-2, PANC-1, HPAF-II, Capan-1, AsPC-1, and BxPC-3 cells) was observed using qPCR, and α7 nAChRs was observed to be expressed in all pancreatic cancer cells. Therefore, we chose MIA-PaCa-2 cells, expressing high levels of α7 nAChRs, and HPAF-II cells, expressing low levels of α7 nAChRs, for loss- and gain-of-function studies, respectively. In vitro assays showed that, under hypoxic conditions, Ach caused a concentration-dependent increase in α7 nAChRs-mediated HIF-1α expression, enhancing expression of HIF-1α target genes, and promoting invasion and migration of human pancreatic cancer cells. We further found that Ach increased HIF-1α protein stability in pancreatic cancer cells under hypoxic conditions. This effect was mediated by YAP signaling, as evidenced by the fact that Ach-induced increases in HIF-1α protein stability were blocked by siRNA-mediated knockdown of YAP. Consistent with these findings, an investigation of the relationship between α7 nAChRs and clinicopathological features in pancreatic cancer patients using publicly available datasets showed that high levels of α7 nAChRs are correlated with a poorer prognosis in pancreatic cancer patients. Collectively, these findings identify novel mechanisms by which Ach potentiates invasion and migration of pancreatic cancer cells and provide further evidence that HIF-1α is a potential anticancer target in Ach-associated pancreatic cancer. Citation Format: Yunmi Cho, Eun-Taex Oh, Ha Gyeong Kim, Heon Joo Park. Acetylcholine potentiates invasion and migration of human pancreatic cancer cells under hypoxia through α7 nAChR-mediated increases in HIF-1α expression [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 6959.
Abstract 6670: Could immunotherapy offer potential in managing bacterial dysbiosis in prostate cancer
Authors: Tim Oliver, Belinda Nedjai, Emily Lane, Frank Chinegwundoh, Prabhakar Rajan, Jack Cuzick
Journal: Cancer Research (2024)

Abstract Background: Since 2006 three studies, involving 289,089 adolescents, demonstrated a significant association (1.67(0.79-3.55),1.7(1.03-2.70),2.37(1.19-4.73)) between pubertal acne and poor outcome prostate cancer(PC) 30+ years later. This suggested Cutibacterium acnes, amicroaerophylic bacterium, might be contributing to PC bacterial dysbiosis analogous to the role of H. pylori in stomach cancer and explain why circumcision reduces PC risk. Six years ago, using MALDI-TOF, we demonstrated that the presence of seven obligate anaerobe species in addition to C. acnes were increased in PC and linked to increased PSA. This presentation studies stored samples from the PROVENT chemoprevention randomised PC active surveillance phase 2 trial analysed using 16S rDNA sequencing, and comparing obligate anaerobe frequency with those detected by culture and MALDI-TOF identification and their influence on PSA expression. Methods: 89 urines of PROVENT trial patients were studied using 16S rDNA sequencing and followed for 24 months. In addition, 39 previously reported MALDI-TOF screened cohort patients (21 PCs and 18 BPHs) followed for 43 months. The frequency of 7 obligate bacterial genera (Actinobaculum, Finegoldia, Prevotella, Peptoniphilus, Peptostreptococcus &amp; Viellonella) was studied. Results: Twenty six of 89 (29%) PROVENT urine samples had a majority of bacteria detected as obligate anaerobes (mean=68%), while it was 12 of the 39 (31%) in PC tested in MALDI-TOF. In the combined series, those patients (n=38) with obligate anaerobes had mean PSA of 9.59 ug/L, while those without obligate anaerobes had a mean PSA of 6.29 ug/L (n=90), (t=-2.925, p = 0.0058). In the MALDI-TOF series, statistically increased urological intervention rate was associated with the presence of anaerobes (p=0.045, Fisher’s exact test). Discussion: These findings suggest that obligate anaerobe bacterial dysbiosis could be contributing to raised PSA through prostate cell damage, and possibly participating in the chronic inflammation and hypervascular changes that are seen in precancerous lesions. Checkpoint inhibitors have shown little benefit in prostate cancer. Recent reports from animal model studies of BCG resistance have suggested a short course combination of anti PDLI and anti NKG2a could break immune tolerance associated with expression of HLA-E and this approach could be of use to break tolerance to bacterial dysbiosis in the future. Citation Format: Tim Oliver, Belinda Nedjai, Emily Lane, Frank Chinegwundoh, Prabhakar Rajan, Jack Cuzick. Could immunotherapy offer potential in managing bacterial dysbiosis in prostate cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 6670.
Abstract 147: Identification of cell sub-populations in Neuroblastoma cell lines with single-cell-sequencing analysis
Authors: Michele Tomanelli, Davide Ceresa, Adriana Bajetto, Paola Modesto, Paolo Malatesta, Tullio Florio, Aldo Pagano
Journal: Cancer Research (2024)

Abstract Neuroblastoma is the most frequent extracranial tumor in neonatal patients. Engineering SKNBE2 Myc-N amplified Neuroblastoma cell lines we generated individual clones expressing NDM29 non-coding-RNA at different levels. Using these cell models we documented a specific role of NDM29 in tumor cell differentiation leading to the identification of novel genes to be pharmacologically targeted for an efficient control of tumor malignancy (CA9 and MCM2 genes). Further studies taking advantage of the same models suggested the possible co-existence of different cell sub-populations in the apparently homogeneous cell culture with possible different roles in tumor maintenance and growth. Here we test this hypothesis by performing single-cell sequencing analysis and identified different sub-populations on the base of their gene expression patterns. The characterization of their specific profiles of membrane markers allowed an efficient separation of the individual populations by FACS analysis. Our preliminary results show the co-existance of cells with a marked neural phenotype with other two populations one VEGF secreting and the other VEGF recipient/responder. These preliminary findings suggest further detailed investigations of possible paracrine loops that might be at the base of tumor cell nodule growth and maintenance. Citation Format: Michele Tomanelli, Davide Ceresa, Adriana Bajetto, Paola Modesto, Paolo Malatesta, Tullio Florio, Aldo Pagano. Identification of cell sub-populations in Neuroblastoma cell lines with single-cell-sequencing analysis [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 147.
Abstract 7217: Orthogonal targeting of NAD metabolism and ErbB2/ErbB3 signaling in pancreatic adenocarcinoma
Authors: Kranthi Kumar Chougoni, Nari Kim, Martin M. Dcona, Diana T. Dcona, Gautam K. Malhotra, Steven R. Grossman
Journal: Cancer Research (2024)

Abstract Background: Pancreatic ductal adenocarcinoma (PDAC) is now the third leading cause for cancer related deaths in the US with a five-year survival of ~10% that has improved little over the past 20 years. Thus, there is a critical need to fully understand mechanisms of PDAC tumorigenesis in order to develop novel and effective therapies. Nicotinamide Adenine Dinucleotide (NAD), a critical co-factor and energy source required for cellular processes such as DNA repair and epigenetic regulation is frequently upregulated in PDAC. We recently reported a novel oncogenic axis connecting the NAD-dependent epigenetic regulator and oncogene C-terminal Binding Protein (CtBP) with the EGFR family growth factor receptors ErbB2/ErbB3 (ErbB2/3) in PDAC cells and tumors. Indeed, previous reports have shown ~30% of human PDAC tumors overexpress ErbB3, and our work has shown that PDAC tumor cell growth relies on maintenance of ErbB3 expression. Moreover, we show that the majority of PDAC cells with high levels of ErbB3 expression are uniquely sensitive to the ErbB2-targeted tyrosine kinase inhibitor lapatinib. In addition, we have recently shown that co-targeting NAD and CtBP with small molecule inhibitors is an effective and synergistic therapeutic strategy in PDAC model systems. Methods and Results: In the current study, we demonstrate NAD-dependent regulation of ErbB2/3 signaling in PDAC cells in vitro. Upon depletion of NAD using the NAD salvage pathway inhibitor GMX1778 in human PDAC cells, we observed a striking coordinate decrease in the levels of both ErbB2 and ErbB3. Furthermore, stable knockdown of the limiting enzyme of the complementing Preiss-Handler NAD synthetic pathway, Nicotinamide Adenine Phosphoribosyl Transferase, also resulted in robust downregulation of ErbB2/3 protein levels, suggesting a direct linkage in PDAC cells between the status of NAD metabolism and synthesis and activity of the key growth factor receptors ErbB2/3. Conclusions: Our findings highlight the novel connection between NAD and ErbB2/3 in PDAC. Furthermore, our data suggests combining chemical or biologic inhibitors of ErbB2/3 with an inhibitor of NAD synthesis may result in highly synergistic cytotoxic effects in PDAC cells and PDAC preclinical models. Such data could support the future development of a human PDAC clinical trial repurposing agents targeting NAD synthesis and ErbB2/3 that are already FDA-approved or currently in clinical testing. Citation Format: Kranthi Kumar Chougoni, Nari Kim, Martin M. Dcona, Diana T. Dcona, Gautam K. Malhotra, Steven R. Grossman. Orthogonal targeting of NAD metabolism and ErbB2/ErbB3 signaling in pancreatic 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 7217.