tbuckley/cabot-search huggingface dataset:
Abstract 492: A Novel QUATRAMER sustained injectable suspension for the intracellular delivery of Salinomycin, a stem cell inhibitor (HSB-1216), for the treatment of triple negative breast cancer
Authors: Surender M. Kharbanda, Anees Mohammad, Bhawana Gupta, Sireesh Appajosyula, Sandeep Laumas, Jugnu Jain, Donald Kufe, Harpal Singh
Journal: Cancer Research (2020)

Abstract Triple-negative breast cancer (TNBC) accounts for approximately 15-20 % of all breast cancers, is an aggressive disease with a poor prognosis, and lacks targeted therapy. Recent studies suggest that cancer stem cells (CSCs) play an important role in TNBC progression and tumorigenesis and that targeting CSCs may be a promising, novel strategy for the treatment of this disease. Both CD44+/CD24- and CD44+/CD24 low CSCs are enriched in TNBCs and may contribute to chemotherapy resistance, emphasizing the need to target this population. In this regard, recent studies have shown that salinomycin (SAL) preferentially targets CSCs; however, the preclinical toxicity associated with this agent has limited its clinical development.In the current studies, we have generated novel biodegradable QUATRAMER polymeric nanoparticles comprised of a polyethylene glycol (PEG)-polypropylene glycol (PPG)-PEG modified polylactic acid (PLA)-tetra-block copolymer (SAL-NPs; HSB-1216) for the intracellular delivery of SAL. Treatment of human TNBC MDA-MB-231 cells with HSB-1216 was associated with significant cell death with an IC50 of around 2 uM. Similar results were obtained when other TNBC cell line SUM149 was treated with HSB-1216 (IC50 ~ 0.5 uM). Based on the characteristic formation of TNBC mammospheres in in vitro 3D culture conditions, the mammosphere formation assay has become an essential tool for quantifying CSC activity. Cultured MDA-MB-231 mammospheres were therefore exposed to different concentrations and durations of HSB-1216. Our results demonstrate dose-dependent inhibition of mammosphere formation in response to HSB-1216. Additionally, CD44+/CD24- enriched CSCs were isolated from a TNBC patient tumor biopsy, grown as 3D culture/mammospheres and then treated with HSB-1216. Interestingly, in contrast to Paclitaxel, treatment with HSB-1216 was associated with nearly complete inhibition of mammosphere formation. Taken together, these results demonstrate an effective method for sustained delivery of a potent stem cell inhibitor, SAL, and its potential for the treatment of TNBC. Citation Format: Surender M. Kharbanda, Anees Mohammad, Bhawana Gupta, Sireesh Appajosyula, Sandeep Laumas, Jugnu Jain, Donald Kufe, Harpal Singh. A Novel QUATRAMER sustained injectable suspension for the intracellular delivery of Salinomycin, a stem cell inhibitor (HSB-1216), for the treatment of triple negative 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 492.
Abstract 1332: Cancer-Immu portal: An open resource for exploring immunotherapy-related multidimensional cancer genomic profiles
Authors: Jing Yang, Qi Liu, Yu Shyr
Journal: Cancer Research (2020)

Abstract Cancer immunotherapy that blocks immune checkpoint molecules, such as cytotoxic T lymphocyte-associated antigen-4 (CTLA-4) and programmed cell death protein-1 /ligand-1 (PD-1/PD-L1), has revolutionized anticancer therapy. Since the first approval of ipilimumab (anti-CTLA-4) for the treatment of unresectable or metastatic melanoma, FDA has granted dozens of approval of immune checkpoint blockade (ICB) drugs for many cancers, including non-small cell lung cancer, urothelial cancer, renal cell carcinoma, Hodgkin's lymphoma, head and neck cancer, microsatellite instability or mismatch repair deficient cancers, gastric cancer, colorectal cancer, hepatocellular carcinoma and Merkel cell carcinoma. Although patients with advanced-stage cancers have opportunity to get durable benefits from ICB treatment, only a minority of them responds to ICB, which highlights the need of the predictive biomarkers for guiding the selection of patients. Meanwhile, driven by the advances of technologies, such as next-generation sequencing and single-cell technologies, the field of immunotherapy-related cancer genomic is evolving rapidly, providing unprecedented opportunities to draw a comprehensive picture about immuno-genomic connection. In recent years, large amount of immuno-genomic data were generated, however, most of them are scattered in literatures and are not readily accessible to the community. To provide easy access to those valuable immuno-genomic datasets, we developed Cancer-Immu (http://bioinfo.vanderbilt.edu/database/Cancer-Immu/), which collected 2799 samples from 13 cancer types with both ICB response outcome and genomic profiling by either bulk sequencing or single-cell technologies Cancer-Immu allows interactive exploration of associations between ICB responsiveness and a variety of known and novel genomic features (genetic, transcriptomics, immune cell, and single cell populations) across multiple cancer types. Additionally, Cancer-Immu enables users to analyse their own datasets independently or co-analyse with existing data to identify and validate signatures of interest. Cancer-Immu, provides a platform for immunotherapy response evaluations, reduces barriers between researchers and complex genomic data, and facilitates discoveries in cancer immunotherapy, such as guiding combination treatments, repositioning existing drugs, and even developing novel agents. Citation Format: Jing Yang, Qi Liu, Yu Shyr. Cancer-Immu portal: An open resource for exploring immunotherapy-related multidimensional cancer genomic profiles [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 1332.
Abstract 3568: Ferroptosis induced by xCT abrogation is dependent on GPX4 protein expression regulated by L-cystine/cysteine metabolism
Authors: Yanyu Zhang, Peng Huang
Journal: Cancer Research (2020)

Abstract Nutrients in the tumor microenvironment play an essential role in tumor development and proudly impact cancer metabolism. The xCT antiporter, which mediates cellular uptake of L-cystine coupled with glutamate export, has been considered as a promising therapeutic target due in part to its high expression in cancer cells to promote L-cystine uptake as a precursor for glutathione (GSH) synthesis to maintain redox homeostasis. Although inhibition of xCT has been shown to have anticancer effect in multiple models, emerging evidence also reveals that blocking xCT function could confer survival advantages to cancer cells. These opposite observations suggest that xCT inhibition could be a double-edged sword, and its impact on the overall outcome (cancer-inhibitory or tumor-promoting) is likely context-dependent via yet unknown mechanisms. Here, we show that the expression of glutathione peroxidase 4 (GPX4) is a key molecular determinant that decides the cell fate when xCT is suppressed. In cells with low or no expression of GPX4, inhibition of xCT causes severe ROS stress leading to massive cell death via ferroptosis. In contrast, high expression of GPX4 confers cancer cells the ability to escape ROS-induced ferroptosis. Mechanistic study suggests that the intracellular L-cysteine plays a major role in regulating GPX4 protein level, likely via direct binding to GPX4 and stabilize the protein. Pharmacological and genetic disruption of xCT in cancer cells induces dramatic ferroptosis in culture conditions lacking L-cysteine, whereas the presence of L-cysteine in culture or in vivo renders cancer cells resistance to xCT abrogation. Importantly, genetic knockout of xCT by CRISPR/cas9 reduces cancer cell proliferation in culture but promotes tumor growth in vivo, suggesting that the metabolic changes induced by xCT disruption favor cell growth in vivo. Biochemical and molecular analyses show that the in vivo microenvironment containing L-cysteine enables the xCT-disrupted cells to maintain a high GPX4 level, and thus prevents ferroptosis. Furthermore, metabolic flux using U-13C5 glutamine reveals that xCT abrogation leads to intracellular accumulation of more glutamate, which promotes cancer cell survival and proliferation in the low glucose tissue microenvironment in vivo. Our study has identified GPX4 as a key molecule that determines cell fate under metabolic stress induced by xCT suppression, and suggests that modulation of L-cystine/cysteine metabolism might be an effective strategy to overcome ferroptosis-resistant cancer cells. Citation Format: Yanyu Zhang, Peng Huang. Ferroptosis induced by xCT abrogation is dependent on GPX4 protein expression regulated by L-cystine/cysteine metabolism [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 3568.
Abstract 101: Studies on the flavonoid metabolite 2,4,6-trihydroxybenzoic acid as a CDK inhibitor and anti-proliferative agent: Potential role in cancer prevention
Authors: Ranjini Sankaranarayanan, Chaitanya K. Valiveti, Severine van Slambrouck, Siddharth S. Kesharwani, D. Ramesh Kumar, Teresa Seefeldt, Hemachand Tummala, Jayarama B. Gunaje
Journal: Cancer Research (2020)

Abstract Colorectal cancer (CRC) is the second highest cause of cancer deaths in the United States according to Center for Disease Control. Increasing evidences suggest that a diet rich in fruits and vegetables will reduce incidences of colorectal adenomas. We hypothesize that the natural compounds present in fruits and vegetables, along with their metabolites generated by the gut microbiota, could be responsible for cancer prevention by targeting the cell cycle proteins. Previous studies conducted in the laboratory have identified 2,4,6- Trihydroxybenzoic acid (2,4,6-THBA), one of the degradation products of flavonoids, as a potential chemo-preventive agent mediating its effect through inhibition of cyclin dependent kinases (CDKs). Transport of monocarboxylic acids like 2,4,6-THBA is mediated by the Solute Ligand Carrier (SLC) family of transporters; in particular SLC5A8 and SLC5A12 have been implicated as tumor suppressor proteins that are down-regulated/non-functional in various cancers. In this study, we investigated the ability of the monocarboxylic acid transporter SLC5A8 to transport 2,4,6-THBA into the mammalian cells. Our pilot studies show that the cells expressing SLC5A8 transporters have the capacity to transport 2,4,6-THBA leading to upregulation of p21 and p27 as measured by western blots and qPCR. This was associated with decreased cell number as well as decreased colony formation as measured through clonogenic assays. We suggest that chemo-preventive actions of dietary compounds containing flavonoids may occur through 2,4,6-THBA, contributing largely to the prevention of CRC. Citation Format: Ranjini Sankaranarayanan, Chaitanya K. Valiveti, Severine van Slambrouck, Siddharth S. Kesharwani, D. Ramesh Kumar, Teresa Seefeldt, Hemachand Tummala, Jayarama B. Gunaje. Studies on the flavonoid metabolite 2,4,6-trihydroxybenzoic acid as a CDK inhibitor and anti-proliferative agent: Potential role in cancer prevention [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 101.
Abstract 6006: Total body irradiation and graft-versus-host disease: A meta-analysis
Authors: Kittika Poonsombudlert, Chattip Prueksapraopong, Jakrin Kewcharoen, Nath Limpruttidham
Journal: Cancer Research (2020)

Abstract Objective: Total Body Irradiation (TBI) has been one of the standard conditioning regimens since the early development of allogeneic hematopoietic stem cell transplant (HSCT). Some studies have suggested a correlation between the use of TBI and the development of acute and chronic graft-versus-host disease (aGVHD and cGVHD) but there is currently no meta-analysis to confirm the association. Therefore, we conducted a meta-analysis to evaluate the association between TBI and GVHD. Method: We performed a comprehensive literature search in MEDLINE, Cochrane Library and EMBASE database from inception to February 2019 for studies that evaluated the association between TBI and aGVHD or cGVHD. We calculated pooled odd ratios (OR) with 95% confidence interval (CI) and I2 statistic using the random-effects model (Odd Ratio) of aGVHD and cGVHD in the TBI group versus the non-TBI group. Result: Thirteen studies were included involving a total of 19,303 participants (TBI=10,222, non-TBI 9,081).There was a significant association between TBI use and development of aGVHD (pooled OR 1.32, 95% CI 1.09-1.60, I2=76.7 %) and cGVHD (pooled OR 1.32, 95% CI 1.12-1.54, I2=46.2%) Conclusion: The results of our meta-analysis suggested that the use of TBI is significantly associated with aGVHD and cGVHD in the setting of allogeneic hematopoietic stem cell transplant. Citation Format: Kittika Poonsombudlert, Chattip Prueksapraopong, Jakrin Kewcharoen, Nath Limpruttidham. Total body irradiation and graft-versus-host disease: A meta-analysis [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 6006.
Abstract 4426: Redox regulation of tumor cell heterogeneity in the PyMT mammary tumor model revealed by single cell RNA sequencing
Authors: Zuen Ren, Malindrie Dharmaratne, Ameya Kulkarni, Atefeh Taherian Fard, Jessica Mar, Phillip M. Galbo, Yang Liu, Deyou Zheng, Huizhi Liang, Outhiriaradjou Benard, Kimita Suyama, Michael B. Prystowsky, Larry Norton, Rachel B. Hazan
Journal: Cancer Research (2020)

Abstract Tumor heterogeneity is known to drive breast cancer progression and metastasis. Current therapies target mostly inter-tumor heterogeneity (different patients) without taking into consideration intratumor heterogeneity (individual tumor). Hypoxia is a hallmark of aggressive tumors that is known to select for intratumor cells that are prone for metastasis. Here we show that knockdown of a ROS scavenging enzyme, Glutathione Peroxidase 2, in the PyMT mammary tumor model results in highly hypoxic and metastatic tumors. Single cell RNA-seq on both GPx2 knockdown and control tumors revealed a high degree of intratumor heterogeneity resulting in several clusters that were either of luminal/epithelial or basal-like/mesenchymal type shared by both tumors. Interestingly, GPx2 loss caused increases in a mesenchymal-like/quiescent and a highly proliferative luminal population, implying that GPx2 loss might drive a cancer stem-like population that is conducive of metastasis. Metascape pathway analysis of differentially expressed genes identified pathways that were significantly overrepresented in GPx2 knockdown tumors involving mitochondrial oxidative phosphorylation and response to hypoxia, consistent with the high levels of reactive oxygen species in these tumors. Finally, differential gene expression analysis on mesenchymal and luminal subpopulations predicts novel candidate gene signatures stimulated by GPx2 loss, that might be used to identify or target metastatic cells in tumors. In sum, our data imply that oxidative stress conveys a metastatic phenotype via effects on tumor cell heterogeneity. Citation Format: Zuen Ren, Malindrie Dharmaratne, Ameya Kulkarni, Atefeh Taherian Fard, Jessica Mar, Phillip M. Galbo, Yang Liu, Deyou Zheng, Huizhi Liang, Outhiriaradjou Benard, Kimita Suyama, Michael B. Prystowsky, Larry Norton, Rachel B. Hazan. Redox regulation of tumor cell heterogeneity in the PyMT mammary tumor model revealed by single cell RNA sequencing [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 4426.
Abstract 3126: Serum miR-4687-3p as the diagnostic biomarker for NSCLC
Authors: Man Liu, Jun Ouyang, Qiufang Si, Yulin Wang, Ting Yang, Xue Zhang, Di Jiang, Jianying Zhang, Liping Dai
Journal: Cancer Research (2020)

Abstract Objective: The lack of useful biomarker contributes to the increased morbidity and mortality of non-small cell lung cancer (NSCLC) partly. However, biomarkers in blood have become increasingly appreciated in diagnosis of NSCLC. This study, we aimed to identify serum miRNAs for diagnosing NSCLC. Methods: Microarray were used to detect 2549 miRNAs in serum from NSCLC patients (n=10) and healthy individuals (n=10) and gain differentially expressed miRNAs. Quantitative reverse-transcription polymerase chain reaction (qRT-PCR) assay were applied to validate the expression of selected miRNAs in validation set consisting of sera from 60 participants. Area under the receiver operating characteristic curve (AUC) was used to evaluate diagnostic accuracy of the chosen miRNAs. Tissue expression of the selected miRNA was analyzed based on TCGA database. Subsequently, the target gene of the miRNAs were predicted by TargetScan and Gene ontology (GO) and KEGG pathway enrichment analysis tested by R (clusterProfiler package). The effect of miR-4687-3p on proliferation, invasion, and metastasis of lung cancer cells were investigated through CCK-8 and Transwell assay. Results: We identified serum miR-4687-3p that provided a high diagnostic accuracy of NSCLC (AUC=0.69, 95%CI: 0.543-0.815) in validation data set. According to TCGA database, we also found that the tissue miR-4687-3p level were significantly higher in NSCLC tissues than normal tissues (p&amp;lt;0.05). GO and KEGG pathway enrichment analysis showed that postsynaptic specialization and TGF-β signaling pathway were significantly enriched. Up-regulated miR-4687-3p by miR-4687-3p mimic could promote the proliferation, invasion, and metastasis of the NSCLC cells, compared with mimic negative control. Meanwhile, applying miR-4687-3p inhibitor could suppressed the proliferation, invasion, and metastasis of the NSCLC cells. Conclusion: Our study on the first reported that serum miR-4687-3p levels may have clinical potentials as a novel non-invasive diagnostic biomarker for NSCLC patients. Key words: NSCLC, miR-4687-3p, microarray, bioinformatics, biomarker Citation Format: Man Liu, Jun Ouyang, Qiufang Si, Yulin Wang, Ting Yang, Xue Zhang, Di Jiang, Jianying Zhang, Liping Dai. Serum miR-4687-3p as the diagnostic biomarker for NSCLC [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 3126.
Abstract 1324: Genomic and clinical characteristics of MET exon14 alterations in 26,391 Chinese cancer patients
Authors: Sisi Liu, Danni Song, Xiaoling Tong, Xue Wu, Xiaonan Wang, Yang Washington Shao
Journal: Cancer Research (2020)

Abstract Background: Alterations in MET exon 14 (METex14) and its flanking intronic regions have been identified in a variety of cancers, and suggested to cause enhanced MET activity and oncogenesis. Clinical evidences suggested that patients with METex14 alterations often benefit from MET inhibitors such as crizotinib. Given the unique mutation profiles of Chinese lung cancer patients, it is necessary to investigate the prevalence of METex14 alterations in a large cohort of cancer patients. Patients and methods: Cases carrying METex14 alterations were screened from 26,391 Chinese cancer patients, and the clinicopathologic and molecular characteristics of the cohort were reviewed. PD-L1 immunohistochemistry and the treatment response to MET inhibitors were also analyzed for cases with such information available. Results: Compared to Western cancer population (3~7%), the frequency of METex14 alterations is much lower in Chinese cancer patients (0.7%, n=184) and in Chinese lung cancer patients (1.1%, n=175). Seventy-eight distinct METex14 alterations were detected, with majority of alterations are base substitutions at splice donor site (42%) and insertion/deletions (indels) in intron 13 (28%). Concurrent MET copy gain and non-exon14 MET mutations were found in 4% and 11% of cases, respectively. Other driver alterations, such as EGFR copy gain (11%) and mutations (8%), KRAS (5%) and PIK3CA (5%), appeared in a mutually exclusive pattern. In 71 patients sequenced by 425-gene panel, gene copy gains were prevalent in MDM2 (24%), CDK4 (14%), MCL1 (13%), TERT (13%), MYC (11%), CD274 (7%) and CDK6 (6%). Female patients contain much less TP53 mutations than male patients (65% vs. 24%, FDR = 0.01). Of 9 tissue specimens having PD-L1 immunohistochemistry (IHC) results, 5 of them (55.5%) were found PD-L1 positive, indicating the option for immunotherapy. In 14 patients who received crizotinib-treatment, the median progression free survival (mPFS) was 7 months with the longest PFS of 17 months. Upon resistance to crizotinib, two patients acquired secondary mutations in MET and one patient acquired BRAF p.K601E that can be a novel resistance mechanism to crizotinib treatment. Conclusion: Chinese cancer patients have a relatively lower frequency of METex14 alterations compared to Western patients, and these patients can be potentially treated by immunotherapy and crizotinib. Citation Format: Sisi Liu, Danni Song, Xiaoling Tong, Xue Wu, Xiaonan Wang, Yang Washington Shao. Genomic and clinical characteristics of MET exon14 alterations in 26,391 Chinese cancer patients [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 1324.
NICE reconsiders esketamine for depression
Authors: Elisabeth Mahase
Journal: BMJ (2020)

The National Institute for Health and Care Excellence (NICE) has launched a second consultation on the use of esketamine for treatment resistant depression, after feedback showed that it could benefit some patients.

Guidance published in January 2020 did not recommend esketamine for treatment resistant depression and said that the drug should not be made available on the NHS because of uncertainties over its clinical efficacy and cost effectiveness.1

However, NICE has now said that a second consultation is required, as “comments from the first consultation suggested esketamine may be used in …