tbuckley/cabot-search huggingface dataset:
Abstract 2356: Novel and recurrent germline mutations in Colombian families with colorectal cancer syndromes
Authors: Ana Lucía Rivera-Herrera, Ana Milena Gómez-Camargo, Martha Lucía Serrano-López, Luis G. Carvajal-Carmona, María Carolina Sanabria-Salas
Journal: Cancer Research (2020)

Abstract Hereditary colorectal cancer (CRC) syndromes accounts for approximately 5-10% of total CRC cases. Among those, Lynch syndrome (LS) is the most frequent, but the penetrance depends on the mismatch repair gene (MMR) affected. On the other hand, the Familial Adenomatous Polyposis (FAP) syndrome is less frequent, but with penetrance near to 100%. In Colombia we don't know the prevalence of these syndromes. In the National Cancer Institute from Colombia, the largest reference cancer center in the country, we aim to performed germline genetic analyses in Colombian CRC patients with a suspected hereditary cancer syndrome, as part of the Hereditary Cancer Program that seeks to identified high risk families to offer preventive measures and screening recommendations. A total of 66 patients with CRC fulfilling criteria have been so far analyzed with Next Generation Sequencing using a multigene panel. From those, the 32% have negative results, 41% have VUSs and 27% have positive results (meaning a pathogenic or potentially pathogenic genetic variant). The most prevalent CRC syndrome is Lynch (11/18, 61% with MMR mutated genes), followed by polyposis syndromes such as FAP (11% APC) and MAP (1.5% biallelic MUTYH). Most of our Lynch syndrome families fulfilled Bethesda or Amsterdam criteria. Two recurrent mutations in MLH1 were found in Lynch syndrome families (6/11, 54.5%), which are MLH1: c.1918C&amp;gt;T (p.Pro640Ser) and MLH1: c.790+1G&amp;gt;A. Further haplotype analysis will help us to determine if mutation carriers shared a common ancestry. Citation Format: Ana Lucía Rivera-Herrera, Ana Milena Gómez-Camargo, Martha Lucía Serrano-López, Luis G. Carvajal-Carmona, María Carolina Sanabria-Salas. Novel and recurrent germline mutations in Colombian families with colorectal cancer syndromes [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 2356.
Abstract 657: Inhibition of mTORC1 by dihydroartemisinin
Authors: Wang Liu, Jun Luo, Yoshinobu Odaka, Shile Huang
Journal: Cancer Research (2020)

Abstract mTOR functions as two complexes, mTORC1 and mTORC2, and is a central controller for cell growth and metabolism. Both mTORC1 and mTORC2 are activated in numerous cancers, and have become the focus of anticancer drug development. Rapalogs and mTOR kinase inhibitors (TORKIs) have been developed. However, the anticancer efficacy of rapalogs is clinically weak or mild to most cancers, and the adverse effects of rapalogs and TORKIs are greatly concerned. So, it is imperative to discover and develop new generation of mTOR inhibitors. Dihydroartemisinin (DHA) is an anti-malarial agent showing good safety in both children and adults. Recently, we have shown that DHA, at pharmacological concentrations, inhibits proliferation and induces apoptosis in cells derived from various cancer types but not in normal or immortalized cell lines, implying that DHA is potentially a selective anticancer agent and may be repurposed for cancer therapy. Of interest, DHA potently suppresses mTORC1-mediated phosphorylation of S6K1 and 4E-BP1, but does not obviously affect mTORC2-mediated phosphorylation of Akt, which is often activated by classic mTOR inhibitors (rapalogs) via a feedback mechanism. The results suggest that DHA is a novel mTORC1 inhibitor. This study was set to determine how DHA inhibits mTORC1. Here we found that DHA did not bind to any mTORC1 components (mTOR, mLST8 or raptor) directly, as determined by in vivo [3H]-DHA radiolabeling. Besides, our molecular docking revealed that DHA did not have the ability to bind FKBP12 or mTOR kinase domain, in contrast to the positive controls rapamycin (binding FKBP12) and INK128 (binding mTOR kinase domain). These data suggest that DHA inhibits mTORC1 via indirect mechanism(s). Further research revealed that DHA altered neither the phosphorylation of IGF-1R/PI3K/PTEN and ERK, nor the expression of REDD1, but induced phosphorylation of AMPKα (T172). Interestingly, DHA-induced mTORC1 inhibition was profoundly attenuated by inhibition with Compound C (AMPK inhibitor) or ectopic expression of dominant negative AMPKα2 (AMPKα2-DN), indicating that activation of AMPK links to inhibition of mTORC1. Collectively, the results support that DHA inhibits mTORC1 by activating AMPK. (Supported by the Feist-Weiller Cancer Center, LSU Health Sciences Center, Shreveport, LA, USA.) Citation Format: Wang Liu, Jun Luo, Yoshinobu Odaka, Shile Huang. Inhibition of mTORC1 by dihydroartemisinin [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 657.
Abstract 6539: Bioinformatics algorithm of mRNA-4157 identifies neoantigens with pre-existing TIL reactivities in colorectal tumors
Authors: Shan Zhong, Ben Breton, Wei Zheng, Iain McFadyen, Kristen Hopson, Joshua Frederick, Robert S. Meehan, Tal Zaks
Journal: Cancer Research (2020)

Abstract Background: Personalized cancer vaccines (PCVs) encode mutation-derived epitopes (neoantigens) predicted from each tumor's unique set of somatic mutations, and can trigger the activation of neoantigen-specific CD4+ and/or CD8+ T cells to target cancer cells. The accurate prediction of immunogenic neoantigens from a tumor's mutanome, which may contain hundreds of somatic mutations, is crucial for designing an effective PCV. In this study, we evaluated the performance of the bioinformatics algorithm for mRNA-4157, an mRNA-based therapeutic PCV, in identifying neoantigens that are recognized by pre-existing tumor infiltrating lymphocytes (TILs) in a cohort of colorectal cancers shared by the National Cancer Institute (NCI) [1]. Methods: Whole exome and transcriptome sequencing data from 29 patients with microsatellite stable, mismatch repair (MMR)-proficient metastatic colorectal cancer were shared by NCI. All patients had received at least one previous systemic therapy, and neoantigen-reactive TIL populations had been identified from these patients by high-throughput immunologic screening [1]. The same bioinformatics algorithm as used for mRNA-4157 was run on the sequencing data, to generate a vaccine design for each patient that included up to 34 neoantigens. Results: Overall, 41% (26/64) of the neoantigens recognized by CD8+ or CD4+ TILs according to the NCI assay were included in the vaccines designed by the mRNA-4157 bioinformatics algorithm. For 61% (18/29) of the patients, at least one neoantigen with demonstrated CD8+ or CD4+ TIL reactivity was included in the vaccines designed. For 28% (8/29) of the patients, all neoantigens associated with demonstrated CD8+ or CD4+ TIL reactivities were included in the vaccines designed. Conclusion: The bioinformatics algorithm for mRNA-4157 is able to predict and select neoantigens with pre-existing TIL reactivities based on human ex vivo assays for vaccine designs with high accuracy. [1] Parkhurst MR, et al. Unique Neoantigens Arise from Somatic Mutations in Patients with Gastrointestinal Cancers. Cancer Discov. 2019 Aug;9(8):1022-1035. Citation Format: Shan Zhong, Ben Breton, Wei Zheng, Iain McFadyen, Kristen Hopson, Joshua Frederick, Robert S. Meehan, Tal Zaks. Bioinformatics algorithm of mRNA-4157 identifies neoantigens with pre-existing TIL reactivities in colorectal tumors [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 6539.
Abstract 3044: The novel bi-specific antibody CKD-702 is a potential agent for NSCLC patients with aberrant cMET and EGFR signaling
Authors: kyu jin park, Eun-Ju Jeon, Ji-Hye Choi, Kwan-Woo Lee, Kyung-Woo Lee, Gun-Woo Park, Hae-Jin Hong, In-Chang Hwang, Seung-Kee Moon, Yeo-Wook Koh
Journal: Cancer Research (2020)

Abstract Development of drug resistance is one of the main causes of poor prognosis and therapeutic failure in NSCLC. Mutual synergism between cMET and EGFR is known to promote acquired drug resistance. In NSCLC, cMET gene amplification is reported in 2-4% previously untreated patients and in 5-20% of patients with EGFR mutation and acquired resistance to EGFR TKIs. Because of this crosstalk between cMET and EGFR pathways, dual inhibition of these targets holds promise as a treatment for NSCLC patients, especially those with acquired cMET activation. CKD-702 is a bispecific antibody designed to dually target cMET and EGFR. It is tetravalent IgG1-like bispecific antibody, in which single-chain variable fragment specific to EGFR is genetically fused to the c-terminus of a conventional IgG1 of a cMET. The antibody binds to extracellular domains of cMET and EGFR with high affinity and inhibits signaling by blocking ligand binding. CKD-702 also induces internalization and degradation of both receptors. There are various types of cMET activation in NSCLC patients, including point mutations and amplification. An emerging aberrant cMET activation is through a splice site mutation of cMET that leads to skipping of exon 14, inducing prolonged signaling and oncogenic activity. In this study, we carried out genetic analysis of cMET activation in cancer cell line as well as PDX model with or without EGFR mutation, and the efficacy of CKD-702 in each model for NSCLC was determined. CKD-702 showed complete tumor regression as monotherapy in tumor models that have primary/secondary activating EGFR mutations and cMET amplification. Also, CKD-702 resulted in complete tumor regression in models where cMET is activated by either skipping of exon 14 or amplification. Interestingly, unlike other previously developed EGFR-targeting agents, CKD-702 showed limited skin rash in GLP toxicity study. In summary, CKD-702 is confirmed to inhibit tumors with activated cMET pathway such as cMET amplification and exon 14 skipping as well as with EGFR-activating mutations. This profile of preclinical data supports the clinical trial of CKD-702 as monotherapy in selected lung cancer patients with aberrant cMET and EGFR signaling. A Phase I study of CKD-702 is planned to initiate in 2020. Citation Format: kyu jin park, Eun-Ju Jeon, Ji-Hye Choi, Kwan-Woo Lee, Kyung-Woo Lee, Gun-Woo Park, Hae-Jin Hong, In-Chang Hwang, Seung-Kee Moon, Yeo-Wook Koh. The novel bi-specific antibody CKD-702 is a potential agent for NSCLC patients with aberrant cMET and EGFR signaling [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 3044.
Abstract 1577: Gene expression studies using microgel embedded pancreatic cancer spheroids
Authors: Saumya Prasad, Anil Chandra, Enza Lonardo, Erika Parasido, Christopher Albanese, Loretta L. del Mercato
Journal: Cancer Research (2020)

Abstract Pancreatic ductal adenocarcinoma (PDAC) is known to be one of the deadliest cancers due to its late diagnosis and faster metastasis rate1. Thus, the time required to test the patient-derived cancer cells against different therapeutics becomes extremely crucial. Gene expression analysis using real-time PCR is vital, typically when designing patient-specific therapeutics. 2D tumor models do not represent the true picture of the tumor in vivo. In order to perform these gene expression studies, robust 3D cancer models are required2. The traditional techniques of generating cancer spheroids using U-bottom wells and hanging drop methods are effective but are limited by scalability as well as the limitations associated with the traditional organoid architecture. Gene expression studies of spheroids under different combinations of drug treatment thus requires many well defined and easy to handle spheroids. Here, we are trying to perform real-time PCR studies to access the gene expression changes on MIA PaCa-2 microgel based spheroids generated using co-axial droplet microfluidics with or without stromal cells. This 3D platform will enable gene expression studies in miniature co-culture tumor models. In addition, PCR and single-cell sequencing analyses will define the gene expression changes in the recently described conditionally reprogramed, patient-derived, primary PDAC cultures3. The establishment and analysis of this 3D model is fast, reproducible and can be easily scaled to enable high-throughput screening, thereby providing an opportunity to design patient-specific precision medicine. The research leading to these results received funding from the European Research Council (ERC) under the European Union's Horizon 2020 research and innovation programme (grant agreement No 759959, ERC-StG “INTERCELLMED”). References: (1) Adamska, A.; Domenichini, A.; Falasca, M. Pancreatic Ductal Adenocarcinoma: Current and Evolving Therapies. Int. J. Mol. Sci. 2017, 18 (7). (2) Moreira, L.; Bakir, B.; Chatterji, P.; Dantes, Z.; Reichert, M.; Rustgi, A. K. Pancreas 3D Organoids: Current and Future Aspects as a Research Platform for Personalized Medicine in Pancreatic Cancer. Cell. Mol. Gastroenterol. Hepatol. 2018, 5 (3), 289-298. (3) Parasido, E.; Avetian, G. S.; Naeem, A.; Graham, G.; Pishvaian, M.; Glasgow, E.; Mudambi, S.; Lee, Y.; Ihemelandu, C.; Choudhry, M.; et al. The Sustained Induction of C-MYC Drives Nab-Paclitaxel Resistance in Primary Pancreatic Ductal Carcinoma Cells. Mol. Cancer Res. 2019, 17 (9), 1815-1827. Citation Format: Saumya Prasad, Anil Chandra, Enza Lonardo, Erika Parasido, Christopher Albanese, Loretta L. del Mercato. Gene expression studies using microgel embedded pancreatic cancer spheroids [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 1577.
Abstract 1666: A comprehensive DLBCL lymphoma PDX collection to evaluate the efficacy and resistant mechanism of rituximab
Authors: Hui Qi, Xuzhen Tang, Zhiyuan Zou, Ying Fang, Li Wang, Weili Zhao, Qingyang Gu, Qunsheng Ji
Journal: Cancer Research (2020)

Abstract Rituximab has shown great efficacy in B-cell non-Hodgkin's lymphoma (NHL), by binding CD20 to induce cell destruction through activating apoptosis, complement and cell-mediated cytotoxity. However, the response rate of patients with relapsed or refractory CD20-positive NHL to standard rituximab treatment is less than 50%, and the non-responders, especially DLBCL patients, still could express high levels of CD20. Therefore, a translational in vivo platform to understand the mechanisms behind Rituximab resistance is in urgent need. We established and characterized a series of DLBCL lymphoma PDX. Eleven non-GCB DLBCL PDX models were selected for the Rituximab efficacy study, of which 3 are relapse DLBCL. IHC and RNAseq were conducted to evaluate CD20 status and expression of other genes. The anti-tumor efficacy of Rituximab in 11 PDX models revealed that 5 of them were sensitive to rituximab and 6 had a poor response. All these models are CD20 positive judged by IHC. By analyzing the correlation of tumor growth inhibition (TGI) and the genomic background of these PDX models, we identified several candidate genes such as BCL2L1, PDK1, TGF-β, Lgalsl and p56/p53Lyn that may contribute to drug resistance mediated by elevated apoptotic threshold, modulation of complement activity or diminished cellular cytotoxicity. Further validation studies are in progress. We established a series of DLBCL lymphoma PDX; with advanced genomic profiling method and validation, these models can be precisely used for subtype-specific therapy evaluation and the investigation of the mechanism of drug resistance. Citation Format: Hui Qi, Xuzhen Tang, Zhiyuan Zou, Ying Fang, Li Wang, Weili Zhao, Qingyang Gu, Qunsheng Ji. A comprehensive DLBCL lymphoma PDX collection to evaluate the efficacy and resistant mechanism of rituximab [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 1666.
Abstract 6433: Dual targeting MYC G-quadruplex and topoisomerase I: Lead discovery indenoisoquinolines for cancer therapy
Authors: Kaibo Wang
Journal: Cancer Research (2020)

Abstract G-quadruplexes are noncanonical four-stranded DNA or RNA secondary structures that have emerged as novel therapeutic targets. MYC is one of the most important oncogenes and is overexpressed in a number of human cancers. The G-quadruplex formed in the MYC oncogene promoter (MycG4) is a transcriptional silencer and amenable to small molecule targeting. Indenoisoquinolines are human topoisomerase I inhibitors with improved physicochemical and biological properties as compared to the clinically used camptothecin anticancer drugs. Three indenoisoquinolines, indotecan (LMP400), indimitecan (LMP776), and LMP744, have entered phase I clinical trials in adults with relapsed solid tumors and lymphomas. However, some indenoisoquinolines showed potent anticancer activity without being strong topoisomerase I inhibition activity, suggesting additional mechanisms of action. Herein, we demonstrate that a large number of anticancer indenoisoquinolines strongly bind and stabilize MycG4 in vitro, using fluorescence, nuclear magnetic resonance (NMR), and circular dichroism (CD) spectroscopy, as well as gel electromobility shift assay (EMSA). In addition, MycG4-interactive indenoisoquinolines lower MYC mRNA and protein levels in vivo, as shown by western blotting and quantitative reverse transcription-polymerase chain reaction (qRT-PCR) experiments. These results indicate that targeting the MYC promoter G4 to downregulate MYC is a likely mechanism of action for the anticancer activities of these particular indenoisoquinolines. In addition, structure-activity-relationships of MycG4 recognition by indenoisoquinolines were investigated and elucidated the essential structural requirements for strong binding. The analysis of indenoisoquinoline derivatives for their MYC inhibitory, topoisomerase I inhibitory, and anticancer activity led to the discovery of a synergistic effect of MYC inhibition and topoisomerase I inhibition on anticancer activity. In conclusion, our result reveals MYC downregulation by MycG4 binding as a new mechanism of action for anticancer indenoisoquinolines. Moreover, we suggest dual targeting of MycG4 and topoisomerase I as a novel strategy for cancer therapy. Citation Format: Kaibo Wang. Dual targeting MYC G-quadruplex and topoisomerase I: Lead discovery indenoisoquinolines for cancer therapy [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 6433.
Abstract LB-087: Blockade of β-catenin-induced CCL28 suppresses gastric cancer progression via inhibition of Treg cell infiltration
Authors: Lu Ji, Helen He Zhu, Bin Ma, Wei-Qiang Gao
Journal: Cancer Research (2020)

Abstract Dysregulation of Wnt/β-catenin signaling is frequently observed in human gastric cancer. Elucidation of tumor immune microenvironment is essential for the understanding of tumorigenesis and the development of immunotherapeutic strategies. However, it remains unclear how β-catenin signaling regulates stomach tumor immune microenvironment. Our in vitro study unraveled CCL28 as a direct transcriptional target gene of β-catenin/T cell factor (TCF). Protein levels of β-catenin and CCL28 were positively correlated in human gastric adenocarcinoma. β-Catenin-activated CCL28 was able to recruit Regulatory T (Treg) cells in transwell migration assay. In a clinically relevant mouse gastric cancer model established by Helicobacter (H.) felis infection and MNU treatment, inhibition of β-catenin/TCF activity by a pharmacological inhibitor iCRT14 suppressed CCL28 expression and Treg cell infiltration in the stomach. Moreover, anti-CCL28 antibody attenuated Treg cell infiltration and tumor progression in H. felis/MNU mouse models. Diphtheria toxin (DT)-induced Treg cell ablation restrained gastric cancer progression in H. felis/MNU-treated DEREG (Foxp3-DTR) mice, clarifying the tumor-promoting role of Treg cells. Thus, the β-catenin-CCL28-Treg cell axis may serve as an important mechanism for immunosuppression of the stomach tumor microenvironment. Our findings highlighted an immunoregulatory role of β-catenin signaling in stomach tumors and the therapeutic potentials of CCL28 blockade for the treatment of gastric cancer. Citation Format: Lu Ji, Helen He Zhu, Bin Ma, Wei-Qiang Gao. Blockade of β-catenin-induced CCL28 suppresses gastric cancer progression via inhibition of Treg cell infiltration [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr LB-087.
The effects of liraglutide and dapagliflozin on cardiac function and structure in a multi-hit mouse model of heart failure with preserved ejection fraction
Authors: Coenraad Withaar, Laura M G Meems, George Markousis-Mavrogenis, Cornelis J Boogerd, Herman H W Silljé, Elisabeth M Schouten, Martin M Dokter, Adriaan A Voors, B Daan Westenbrink, Carolyn S P Lam, Rudolf A de Boer
Journal: Cardiovascular Research (2020)

Abstract Aims Heart failure with preserved ejection fraction (HFpEF) is a multifactorial disease that constitutes several distinct phenotypes, including a common cardiometabolic phenotype with obesity and type 2 diabetes mellitus. Treatment options for HFpEF are limited, and development of novel therapeutics is hindered by the paucity of suitable preclinical HFpEF models that recapitulate the complexity of human HFpEF. Metabolic drugs, like glucagon-like peptide receptor agonist (GLP-1 RA) and sodium-glucose co-transporter 2 inhibitors (SGLT2i), have emerged as promising drugs to restore metabolic perturbations and may have value in the treatment of the cardiometabolic HFpEF phenotype. We aimed to develop a multifactorial HFpEF mouse model that closely resembles the cardiometabolic HFpEF phenotype, and evaluated the GLP-1 RA liraglutide (Lira) and the SGLT2i dapagliflozin (Dapa). Methods and results Aged (18–22 months old) female C57BL/6J mice were fed a standardized chow (CTRL) or high-fat diet (HFD) for 12 weeks. After 8 weeks HFD, angiotensin II (ANGII), was administered for 4 weeks via osmotic mini pumps. HFD + ANGII resulted in a cardiometabolic HFpEF phenotype, including obesity, impaired glucose handling, and metabolic dysregulation with inflammation. The multiple hit resulted in typical clinical HFpEF features, including cardiac hypertrophy and fibrosis with preserved fractional shortening but with impaired myocardial deformation, atrial enlargement, lung congestion, and elevated blood pressures. Treatment with Lira attenuated the cardiometabolic dysregulation and improved cardiac function, with reduced cardiac hypertrophy, less myocardial fibrosis, and attenuation of atrial weight, natriuretic peptide levels, and lung congestion. Dapa treatment improved glucose handling, but had mild effects on the HFpEF phenotype. Conclusions We developed a mouse model that recapitulates the human HFpEF disease, providing a novel opportunity to study disease pathogenesis and the development of enhanced therapeutic approaches. We furthermore show that attenuation of cardiometabolic dysregulation may represent a novel therapeutic target for the treatment of HFpEF.