tbuckley/cabot-search huggingface dataset:
Abstract 3709: miR-21-3p: A potential oncomir in breast cancer
Authors: Arsalan Amirfallah, Adalgeir Arason, Bjarni A. Agnarsson, Oskar Th Johannsson, Bylgja Hilmarsdottir, Rosa Bjork Barkardottir, Inga Reynisdottir
Journal: Cancer Research (2020)

Abstract MIR21 is a well known oncomir in many cancer types including breast cancer. Most studies that have described the oncogenic properties of MIR21 have focused on the leading strand miR-21-5p. Fewer studies have focused on the passenger strand miR-21-3p, but in a few types of cancer it has been shown to have oncogenic properties. A handful of studies suggest that miR-21-3p could be a biomarker in breast cancer. MIR21 is located at 17q23.1, a region which is often amplified in breast tumors. It overlaps the 3´ end of VMP1 but it has its own distinct promoter. The aim of this study was to analyze whether miR-21-3p associated with prognostic factors in breast cancer. The levels of miR-21-5p and miR-21-3p were measured by qPCR in 144 breast tumors from a cohort of breast cancer patients (cohort 1). The association of expression levels with clinical and pathological factors was analyzed by Student´s t-test and Anova, and with survival by Kaplan-Meier, the log-rank test, and the Cox proportional hazards test. To confirm the results, available data were used from breast cancer cohorts from The Cancer Genome Atlas (TCGA) (n=256) and METABRIC (n=1286). The mean expression levels of miR-21-5p were significantly higher than those of miR-21-3p in breast tumors from cohort 1 (p=2.2e−10). However, only miR-21-3p was more highly expressed in tumors than normal breast tissue (p=0.003), and in all three cohorts there was a strong positive correlation between MIR21 copy number and miR-21-3p expression levels. There was a significant higher expression of miR-21-3p in HER2 positive tumors compared to HER2 negative tumors in the two larger cohorts (p &amp;lt; 0.05), and high miR-21-3p levels associated with higher histograde in the largest cohort (9.2e−14). A shorter breast cancer specific survival was associated with higher miR-21-3p expression in the METABRIC cohort (HR 1.338, CI 1.104-1.622, p=0.003). HER2 was the largest confounding factor but even after adjustment for HER2 positivity the effect remained significant (HR 1.260, CI 1.036-1.532, p = 0.021). Our data show that miR-21-3p is expressed in breast tissue and tumors. Furthermore, our preliminary data suggest that miR-21-3p may be an indicator of worse outcome for breast cancer patients. However, additional work is needed to elucidate the association of miR-21-3p expression with distinct prognostic factors in breast cancer. Citation Format: Arsalan Amirfallah, Adalgeir Arason, Bjarni A. Agnarsson, Oskar Th Johannsson, Bylgja Hilmarsdottir, Rosa Bjork Barkardottir, Inga Reynisdottir. miR-21-3p: A potential oncomir in breast cancer [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 3709.
Abstract 2445: Epigenetic modulation of tumor cell tolerance to chemotherapy
Authors: Jephesson Alex Alex dos Santos, Carolina Nunes Santo, Luiza Cherobini Pereira
Journal: Cancer Research (2020)

Abstract Cancer represents a set of diseases that are dynamic and heterogeneous. Their cells are phenotypically and genetically different from each other and, exhibit stochastic fluctuations in their phenotype. Investigations of isogenic populations of tumor cells reveal that tolerance also may emerge through non-genetic mechanisms, often through stochastic fluctuations in key factors in response to drugs. The objective of this work is to measure the dynamics of chemotherapy tolerance phenotype and modulate these dynamics in tumor cells to potentiate the therapy. Glioma cell lines and primary gliomas were plated at low density and after the formation of colonies, cells were treated with Temozolomide (TMZ) for 3 days. Growth rate of individual colonies was measured and the variance of growth rate of colonies with the same size was used to determine the dynamics of the phenotype. We developed a method to measure the dynamics of phenotype called DynaFit and defined a proportion of phenotypic chance in fitness until generation 6 called rCoDyFF (relative Colony DynaFit Factor 6), which is a value between 0% (stable phenotype) and 100% (dynamic phenotype). The untreated glioma cell lines (U251 and A172) and primary gliomas (LS12 and LS17) had rCoDyFF6 of 40%, 33%, 41%, 33% and treatment with 50uM TMZ produced an rCoDyFF6 67% in U251 cells. However, when cells were treated with a combination of epigenetic modulators and chemotherapy agent, 0.5µM Saha plus 3µM Azacytidine, and 50µM TMZ, the rCoDyFF6 result in - 23%, showing a drastic reduction, indicating stabilization of the phenotype. This treatment also increases sensitivity to TMZ. The result demonstrates that epigenetic modulators were able to induce a phenotypically stable state in U251 cells, leading to the copy of the tolerance phenotype of the colony founder cell to all the cells in the colony. Here we showed tumor cells fluctuate their fitness levels in the absence or presence of chemotherapy and this fluctuations can be stabilized by the inhibition of chromatin and DNA modifying enzymes. Citation Format: Jephesson Alex Alex dos Santos, Carolina Nunes Santo, Luiza Cherobini Pereira. Epigenetic modulation of tumor cell tolerance to chemotherapy [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 2445.
Abstract 3108: Combined cfDNA and cfRNA NGS testing for cancer patient care
Authors: Yong Huang, Yue Zhang, Binggang Xiang, Zhixin Zhao, Xiaohong Wang, Feng Xie, Reza Moktari, Kemin Zhou, Pan Du, Shidong Jia, Jianjun Yu
Journal: Cancer Research (2020)

Abstract Background: NGS based liquid biopsy has its unique advantage in cancer patient care/monitoring as it allows repeated testing of a spectrum of target sites at multiple time points. However, cfDNA assays usually can only cover focused genomic regions. In order to monitor dynamic fusion and alternative splicing variants, we developed and validated a cfRNA assay which can be used in combination with cfDNA assays to get clear snapshots of mutation landscapes in cancer patients. Here we introduce our application of the combined cfDNA and cfRNA approach to cancer patient care. Method: A single tube of blood is taken from cancer patients, which is used to extract both cfDNA and cfRNA. Predicine proprietary cfDNA and cfRNA NGS assays and analysis pipelines are used to detect SNV/INDEL, CNV as well as fusion and alternative RNA splicing variants from cancer samples, collected at multiple time points from patients during or after treatment. Results: The cfDNA+cfRNA combined approach allows the cross-validation of results from both methods, which greatly elevated the confidence level of our testing results. For example, a case in which EML4-ALK fusion was detected at cfDNA level but only with fairly low allele frequency was confidently confirmed, as EML4-ALK fusion was also detected at cfRNA level. On the other hand, the cfDNA+cfRNA combined approach allows us to study the broad mutation landscape from both cfDNA and cfRNA levels. For example, for a cohort of prostate samples, the changes of AR alternative splicing forms and the cfDNA mutation landscape can be observed from the same tube of blood samples. In general, the cfDNA+cfRNA combined approach provides a more complete molecular biomarker profiles and extract more information that can be used to instruct cancer patient care. Citation Format: Yong Huang, Yue Zhang, Binggang Xiang, Zhixin Zhao, Xiaohong Wang, Feng Xie, Reza Moktari, Kemin Zhou, Pan Du, Shidong Jia, Jianjun Yu. Combined cfDNA and cfRNA NGS testing for cancer patient care [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 3108.
Abstract 2657: Sphingosine-1-phosphate receptor 1 signalling modulates macrophage recruitment to diffuse large B cell lymphomas and the phagocytosis of rituximab-opsonized tumor cells
Authors: Tracey Adams Perry, Lauren Lupino, Katerina Vrzalikova, Navta Masand, Pamela R. Kearns, Paul G. Murray
Journal: Cancer Research (2020)

Abstract Diffuse large B cell lymphoma (DLBCL) is the most common form of non-Hodgkin lymphoma. Currently, approximately 40% of DLBCL patients treated with standard of care therapies, which include a combination of immunotherapy (rituximab; R) and chemotherapy (CHOP), will have disease that is refractory or will relapse. Tumor-associated macrophages can phagocytose opsonised DLBCL tumor cells and are therefore centrally important in determining therapeutic outcomes for patients treated with R-CHOP. Recent data from our lab and from others suggests that the modulation of sphingosine-1-phosphate (S1P) signalling may therapeutically benefit some patients with this tumor. Here, we have investigated the effects of S1P on macrophage functions relevant to DLBCL. We show that S1P signalling through the major receptor, S1P-receptor 1 (S1PR1), suppresses the phagocytosis of rituximab-opsonized DLBCL cells. However, we also show that chemotherapy potently induces monocyte recruitment to DLBCL tumors in vivo and that S1PR1 is a primary mediator of monocyte migration both in vitro and in vivo. According to our data, S1PR1 signalling inhibitors could improve the therapeutic efficacy of rituximab-based therapies for DLBCL patients. However, our data suggests that these drugs should be given only after chemotherapy and before rituximab administration so as to maximize the S1P-mediated recruitment of therapeutic macrophages to the tumor site. Citation Format: Tracey Adams Perry, Lauren Lupino, Katerina Vrzalikova, Navta Masand, Pamela R. Kearns, Paul G. Murray. Sphingosine-1-phosphate receptor 1 signalling modulates macrophage recruitment to diffuse large B cell lymphomas and the phagocytosis of rituximab-opsonized tumor cells [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 2657.
Abstract 2540: Chemoprevention of aerosolized Let-7b in mouse lung cancer model
Authors: Qi Zhang, Jing Pan, Yian Wang, Mark S. Miller, Alberto Izzotti, Ming You
Journal: Cancer Research (2020)

Abstract The delivery of microRNA (miRNA) via inhalation is a potential strategy for lung cancer prevention in high risk individuals such as current and former smokers. Previous studies have shown that intratracheal or intranasal exposure of genetically engineered mice to viral vectors expressing let-7 miRNA resulted in a reduced lung tumor burden. However, these studies were done in genetically engineered mouse models that developed highly aggressive tumors more relevant for a treatment regimen. In this study, we investigated the efficacy of let-7b in lung cancer prevention. An aerosolized let-7b miRNA formulation was tested in the benzo(a)pyrene (B[a]P) mouse model. The particle size of the let-7b miRNA aerosol has been systematically characterized as particles with sizes between 1.9 to 35 nm (average size of 29.0 nm). Following the aerosol formulation evaluation, the biodistribution of let-7b in the lung by tail vein injection and aerosolized delivery were compared. The distribution of the aerosolized let-7b produced higher levels of the miRNA in the lung compared with systematic delivery. The aerosol delivery of let-7b had no effect on animal body weight nor were there any other signs of toxicity. The development of an aerosolized let-7b formulation inhibited B[a]P - induced lung adenoma volume by 72% in A/J mice. Collectively, these findings show that aerosolized miRNA is a promising approach for lung cancer prevention. Citation Format: Qi Zhang, Jing Pan, Yian Wang, Mark S. Miller, Alberto Izzotti, Ming You. Chemoprevention of aerosolized Let-7b in mouse lung cancer model [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 2540.
Abstract 6313: A transcription block survival assay for the discovery of functional inhibitors of transcription factors
Authors: Sarah K. Madden, Jody M. Mason
Journal: Cancer Research (2020)

Abstract Transcription factor dysregulation is often key to oncogenesis and cancer progression. Direct inhibition of transcription factors provides a logical therapeutic strategy but the broad and shallow interaction interfaces of their protein-protein and protein-DNA interactions are challenging to target using traditional small-molecule approaches. The larger size of peptides provides an opportunity to span such interfaces with the exquisite affinity and selectivity required, and a number of peptide-based inhibitors are starting to emerge. In this study we focused on inhibiting basic leucine zipper transcription factors (bZIPs) as proof of principle. A key therapeutically relevant protein-protein interaction of bZIPs is the dimerization interface. Developing efficient peptide inhibitors of bZIP transcription factors has generally focused on either rational design or screen-based assays to identify peptides best able to inhibit dimerization. However, a major step in which bZIPs induce cancer initiation and progression is through DNA binding and the most effective inhibitors of bZIP dimerization do not necessarily translate into those best able to block the bZIP-DNA interaction. An assay that is able to screen for peptides that inhibit dimerization of the target transcription factor and – importantly – also selects according to the ability to inhibit protein-DNA interactions, holds significant promise in the development of more potent inhibitors. To achieve this aim we have developed a Transcription Block Survival assay. Here key binding sites are placed into a gene essential for E.coli survival. The target transcription factor then blocks transcription of this essential gene by binding to these sites, leading to cell death. When a peptide inhibitor from a peptide library is introduced into the system that is able to effectively inhibit DNA binding of the transcription factor, the gene is transcribed, restoring growth. Libraries can have up to two million peptides and allow the assay to select for peptides that not only bind to the target transcription factor, but that are also able to differentiate peptides on their ability to inhibit the transcription factor from binding DNA. The assay has been fully optimized for one bZIP target, and is currently undergoing the final stages of optimization for two other bZIP targets. Future work will focus on screening peptide libraries against these systems. This assay provides a route towards more efficient selection of potent inhibitors of transcription factors for the treatment of cancer. Citation Format: Sarah K. Madden, Jody M. Mason. A transcription block survival assay for the discovery of functional inhibitors of transcription factors [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 6313.
Abstract 899: Remarkable anti-tumor response in a HCC transgenic mouse model treated with GNS561 in combination with anti-PD1
Authors: Madani Rachid, Annemilaï Tijeras-Raballand, Cindy Serdjebi, Sonia Brun, Christelle Ansaldi, Eric Raymond, Philippe Halfon
Journal: Cancer Research (2020)

Abstract Introduction:Hepatocellular carcinoma (HCC) is the most frequent primary liver cancer, leading to 75,000 deaths annually. Immunotherapeutic intervention has emerged as a novel effective treatment to delay the progression of aggressive tumors and suppress tumor recurrence and metastasis. However, few clinical immunotherapy trials have been conducted in HCC patients and there is an unmet need for novel therapeutic strategies. Combinations of conventional and novel treatments with immune-oncologic agents are now regarded as a therapy that can dramatically improve the outcome of patients with HCC.GNS561 is a lysosomotropic small molecule that was investigated in the context of antitumor activity alone or in combination with a PD-1 inhibitor using a transgenic immunocompetent mouse model (ASV-B). Materials and Methods: 40 ASV-B mice were treated with either the vehicle (p.o. water pH= 4, 5 days per week), GNS561 (p.o. 50 mg/kg/5 days per week), mouse anti-PD1 antibody (i.p. 10 mg/kg/twice a week [BIW]) or a combination of GNS561 and mouse anti-PD1 (p.o. 50 mg/kg/5 days per week and i.p. 10 mg/kg/BIW respectively) for 8 weeks. Tumor burden was evaluated by measuring the liver volume and blood flow velocity in the coeliac trunk by US/doppler 4 and 8 weeks (W8) after treatment start, the macronodules count and liver weight at sacrifice (W8). Intra and peritumoral CD8+ cells were counted. Results: All treatments were well tolerated. No significant response was observed with the anti-PD1 monotherapy compared with the vehicle. At W8, GNS561 alone or in combination with an anti-PD-1 showed a significant rapid and durable tumor response based on the macronodule count, decreased liver blood flow in the coeliac trunk, liver volume and weight (-59% and -77%; -18% and -31%; -36% and -37%; -37% and -52%, respectively). Based on preliminary mechanistic data, GNS561 alone or in combination showed an increase in the count of CD8+ cells penetrating the tumor site compared to the vehicle and the anti-PD1 alone, suggesting GNS561 may reinstore the anti-PD1 activity by facilitating CD8+ cells to reach the tumor site to exert their antitumoral activity. Conclusion: GNS561 alone or in combination with an anti-PD1 showed a significant antitumoral response. A combination of GNS561 with an anti-PD1 could then be of clinical interest in the treatment of hepatocelullar carcinoma. Citation Format: Madani Rachid, Annemilaï Tijeras-Raballand, Cindy Serdjebi, Sonia Brun, Christelle Ansaldi, Eric Raymond, Philippe Halfon. Remarkable anti-tumor response in a HCC transgenic mouse model treated with GNS561 in combination with anti-PD1 [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 899.
Abstract 1877: Hypoxia induces EGFR inhibitor resistance in lung cancer cells by upregulation of fibroblast growth factor receptor 1 (FGFR1) via MAPK pathway
Authors: Yuhong Lu, Yanfeng Liu, Sebastian Oeck, Gary J. Zhang, Peter M. Glazer
Journal: Cancer Research (2020)

Abstract The development of small molecule tyrosine kinase inhibitors (TKIs) specific for epidermal growth factor receptors (EGFRs) with activating mutations has led to a new paradigm in the treatment of non-small cell lung cancer (NSCLC) patients. However, most patients eventually develop resistance. Hypoxia is a key micro-environmental stress in solid tumors that is associated with poor prognosis due in part to acquired resistance to conventional therapy. In our previous study, we showed that long-term, moderate hypoxia promotes resistance to the EGFR TKI, gefitinib, in the NSCLC cell line, HCC827, which harbors an activating EGFR mutation. In this study, we found that hypoxia also induces third generation EGFR TKI, osimertinib (AZD9291), resistance in the NSCLC cell line, H1975, which had developed resistance to first and second generation of EGFR TKIs by harboring second EGFR mutation, T790M. Following growth in hypoxia, hypoxia-induced gefitinib resistant HCC827 clones and hypoxic H1975 cells show increased N-cadherin expression and decreased E-cadherin expression, characteristics of an epithelial-mesenchymal transition (EMT), coordinated by an increased expression of ZEB1, an EMT activator. Mechanistically, we show that hypoxia induces increased fibroblast growth factor receptor 1 (FGFR1) expression in HCC827 and H1975 cells, and that knockdown of the FGFR1 by shRNA can attenuate hypoxia induced EGFR TKI resistance in both HCC827 and H1975 cells. We also found the upregulated expression of FGFR1 by hypoxia is mediated through the MAPK pathway to lead to EGFR TKI resistance. In keeping with this, inhibition of FGFR1 function by the selective small molecular inhibitor, BGJ398, attenuates hypoxia-induced EGFR TKI resistance and promotes upregulation of BIM levels. Similarly, inhibition of MEK activity by the inhibitor, trametinib, shows similar effects. In vivo in tumor xenografts in mice, BGJ398 treatment or trametinib treatment suppresses tumor growth and enhances AZD9291 response. These results suggest that hypoxia is a driving force for acquired resistance to EGFR TKIs through increased FGFR1 expression and coordination of EMT in NSCLC. The combination of EGFR TKIs and FGFR1 or MEK inhibitors may offer an attractive therapeutic strategy for NSCLCs. Citation Format: Yuhong Lu, Yanfeng Liu, Sebastian Oeck, Gary J. Zhang, Peter M. Glazer. Hypoxia induces EGFR inhibitor resistance in lung cancer cells by upregulation of fibroblast growth factor receptor 1 (FGFR1) via MAPK pathway [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 1877.