tbuckley/cabot-search huggingface dataset:
Abstract 1894: Role of IGF1R in mediating resistance to MAPK pathway inhibitors in BRAF-mutant melanoma
Authors: Hima Patel, Rosalin Mishra, Natasa Broit, Nour Yacoub, Long Yuan, Samar Alanazi, Nicholas Hayward, Peter Johansson, Joan T. Garrett
Journal: Cancer Research (2020)

Abstract Melanoma is the most aggressive form of skin cancer originating in the pigment producing melanocytes of the skin. The five year survival rate for patients diagnosed with metastatic melanoma is only 23%. Around 60% of the melanomas encompass the active BRAFV600E oncoprotein, which is critical for survival and proliferation of the melanoma cells as a consequence of hyperactivation of theMAPK pathway. This opened up avenues for development of BRAF inhibitors and subsequently the development of MEK inhibitors. Co-targeting of BRAF and MEK with Dabrafenib and Trametinib respectively, results in a response rate of about 70% in patients harboring the BRAF mutation. The use of these inhibitors is limited as patients relapse on treatment typically within 6 months due to the development of acquired resistance. Recent studies have identified various resistance mechanisms including involvement of various receptor tyrosine kinases. In order to decipher novel mechanisms of resistance, we generated double resistant cell lines to BRAF and MEK inhibitor in WM115, WM983 and A375 human melanoma cell lines harboring BRAFV600 mutations using Dabrafenib and Trametinib over a course of 9-11 months. The drug resistant cell lines exhibited increased viability and maintenance of downstream p-ERK protein as compared to their drug sensitive counterparts. Receptor tyrosine kinase array revealed an increase in phosphorylated HER3, AXL, EGFR and IGF1R in the drug resistant cells versus drug sensitive cells. Quantitative PCR data revealed an upregulation of these molecules along with an increase in the expression of some of their ligands at the mRNA level. RNA-seq analysis identified IGF1R and IGF2BP2 to be upregulatedin the resistant cell lines compared to parental cell lines.IGF2BP2 is a tumor promoter and drives cancer proliferation in a variety of malignancies and is correlated with poor survival.Our next experiments are focused on testing the efficacy of IGF1R inhibitors in the drug resistant cell lines and their downstream effector signaling molecules in vitro and in vivo. Further, we aim to decipher the mechanism by which IGF2BP2 regulates the IGF1R signaling pathway in MAPK inhibitors resistant melanoma setting. Delineating the role of IGF1R in mediating resistance to BRAF and MEK inhibitors will help expand possible treatment options to aid in long-term success for BRAF-mutant melanoma patients. Citation Format: Hima Patel, Rosalin Mishra, Natasa Broit, Nour Yacoub, Long Yuan, Samar Alanazi, Nicholas Hayward, Peter Johansson, Joan T. Garrett. Role of IGF1R in mediating resistance to MAPK pathway inhibitors in BRAF-mutant melanoma [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 1894.
Abstract 227: Maltose enhanced the growth of bladder and colon cancer cells unlike some other disaccharides: Cellobiose, isomaltose, lactose, and sucrose
Authors: Michael A. Lea, Charles desBordes
Journal: Cancer Research (2020)

Abstract The addiction of most cancer cells to the metabolism of glucose is well known. The metabolism by cancer cells of other saccharides is less well characterized. We have studied the impact on growth of human bladder and colon cancer cells of mono- and disaccharides. The standard RPMI 1640 medium contains 2 mg glucose per ml. Substitution for glucose by other monosaccharides (fructose, galactose and mannose) resulted in similar growth in some cell lines but greatly diminished growth in others. For the Caco-2 and HT29 colon cancer cells, co-incubation with 2-deoxyglucose was more inhibitory for growth with fructose than with glucose as substrate. There was a similar situation with some bladder cancer cell lines (5637, HT1197 and RT4) whereas with other bladder cancer cells (HT1376, T24 and UM-UC-3) 2-deoxyglucose caused greater inhibition with glucose. In those cell lines in which alkaline phosphatase activity could be induced after incubation with butyrate (Caco-2, HT29, 5637, HT1197 and HT1376), induction by butyrate was observed with any of the monosaccharides. Similarly with the disaccharides lactose, maltose and trehalose there was induction of alkaline phosphatase by butyrate. In the course of this work it was apparent that maltose could enhance growth to an extent that was sometimes not significantly different to that seen with glucose and was not seen with cellobiose, isomaltose, lactose or sucrose. HT29 cells were the only cell line to have a substantial increased growth with trehalose. The increased growth with maltose was inhibited by 2-deoxyglucose. In conclusion, maltose increased growth of bladder and colon cancer cells without a period of adaptation. Citation Format: Michael A. Lea, Charles desBordes. Maltose enhanced the growth of bladder and colon cancer cells unlike some other disaccharides: Cellobiose, isomaltose, lactose, and sucrose [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 227.
Abstract 6011: Mesenchymal stem cells promote PD-L1 expression in lung cancer cells
Authors: Hui Zhao, Hui Yang, Jinqiu Sun, Guoqiang Liang, Qianqian Zhao, Xiufang Zhang, Shengxian Liang, Rui Guo, Li Zhong
Journal: Cancer Research (2020)

Abstract Background Effects of mesenchymal stem cells (MSCs) on tumors have been extensively studied in recent years, but results still remain controversial. In this study we investigated the roles of MSCs on the expression of programmed death-ligand 1 (PD-L1) in lung cancer cells. Since overexpression of PD-L1 has been found to attenuate body's immune system against tumor cells, PD-1/PD-L1 blockages have become the most effective immunotherapy to the late stage non-small cell lung cancer (NSCLC). Therefore, understanding the effects of MSCs on PD-L1 expression is critical in managing immunotherapy for NSCLC patients. Method PD-L1 expressions were tested in two NSCLC cell lines, A549 and H1299 using qRT-PCR and Western Blot to qualitatively measure mRNA and protein levels, respectively. MSCs were isolated from umbilical cord blood and co-cultured with A549 and H1299 cells in complete medium using Transwell filters for 24-h, 48-h and 72-h. Then both A549 and H1299 cells were collected and PD-L1 expressions were tested. MSC-Conditioned Medium (MSC-CM) was generated by culturing 80% confluence of MSCs with serum-free medium. After 48 h, the medium was collected as MSC-CM. Both A549 and H1299 were then cultured in MSC-CM for 24-h, 48-h and 72-h, and PD-L1 expressions were measured from these two cell lines separately. Result Both MSCs and MSC-CM significantly increased the PD-L1 mRNA levels in the two NSCLC cells, while the MSC-CM had stronger stimulation to PD-L1 expressions (P &amp;lt; 0.0001) comparing to MSCs treatment (P&amp;lt;0.01). A549 cells reached the most significant effect at 48-h, while H1299 cells attended the same effect at 24-h treatment. The similar results were observed with PD-L1 protein levels. Both cell lines showed increased PD-L1 protein expressions after treating with MSCs and MSC-CM, but the augmented scales were smaller than the mRNA levels. The PD-L1 protein expressions in A549 cells increased significantly (p &amp;lt; 0.05) at 48-h when treating with MSCs, while increased much higher when treating with MSC-CM (P &amp;lt; 0.01). H1299 cells also showed the similar increase in PD-L1 protein expressions after 24-h treatment. Conclusion Both MSCs and MSC-CM significantly increase PD-L1 expressions in lung cancer cells, which ultimately attenuate the immune system against tumor cells. Citation Format: Hui Zhao, Hui Yang, Jinqiu Sun, Guoqiang Liang, Qianqian Zhao, Xiufang Zhang, Shengxian Liang, Rui Guo, Li Zhong. Mesenchymal stem cells promote PD-L1 expression in lung cancer 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 6011.
Abstract 5838: RNA methylation regulates autophagy via unfolded protein response in cancers
Authors: Panneerdoss Subbarayalu, Pooja Yadav, Manjeet Rao
Journal: Cancer Research (2020)

Abstract N6-methyladenosine (m6A) RNA methylation is a dynamic, reversible and most abundant epitranscriptomic modification found on mRNA and long-non coding RNAs. M6A is regulated by methyl transferases (writes m6A), demethylases (erases m6A) and read by specific RNA binding proteins known as m6A readers that can modulate the fate of specific transcript. Recent studies have suggested that RNA methylation affects several fundamental cellular and molecular functions including mRNA splicing, stability, export, stem cell fate, circadian rhythms, DNA repair and cell survival. In addition, we and others have shown that RNA methylation plays an important role in tumor growth and progression. Here, we discovered that m6A may regulate tumorigenesis by regulating autophagy in cancer cells. Our results revealed that altering the levels of m6A methylation led to increased levels of LC3, which is a universal marker for autophagy. In addition, autophagy initiation protein ULK1 and other autophagy complex proteins including ATG5, ATG12, ATG16L1, and LAMP1 levels were significantly increased in cells with altered m6A methylation. Importantly, we discovered that change in m6A levels by altering the RNA demethylase protein induced the unfolded protein response (UPR) pathway, which is a known activator of autophagy. To understand the molecular mechanism of autophagy induction, we looked into three branches of UPR pathways and discovered that protein kinase RNA like kinase (PERK) UPR signaling pathway is highly activated in ALKBH5 depleted cancer cells and might regulate autophagy induction and cancer cell survival. In conclusion, our study is the first investigation to show that RNA methylation plays an important role in cancer growth by regulating autophagy via UPR. Citation Format: Panneerdoss Subbarayalu, Pooja Yadav, Manjeet Rao. RNA methylation regulates autophagy via unfolded protein response in cancers [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 5838.
Liver transplantation for secondary liver tumours: The difficult balance between survival and recurrence
Authors: Pål-Dag Line, Svein Dueland
Journal: Journal of Hepatology (2020)

Assessing the balance between survival and recurrence after transplantation for secondary liver tumours should be based on the type of cancer in question. For neuroendocrine liver metastases, high recurrence rates are clearly related to reduced long-term survival. For colorectal liver metastases, experience to date indicates that pulmonary recurrence alone has a modest impact on survival outcomes. Further studies focusing on this group of patients will be important for the development of this field of transplant oncology. Liver transplantation for secondary liver tumours should be implemented in accordance with stringent transplant criteria and preferably in the context of prospective trials. Expansion of the donor pool by utilising extended criteria donors and partial liver transplantation could be considered for this indication.
Abstract 198: Molecular genetic characterization of primary breast cancer via clinical next-generation sequencing
Authors: Jung Ho Park, Seung Yeon Ko, Sang Hwa Kim, Ho Young Kim, Sung Hoon Ko, Lee Su Kim
Journal: Cancer Research (2020)

Abstract Targeting appropriate driver genes is crucial in cancer precision medicine. To find oncogenic drivers, targeted next-generation sequencing is becoming widely used in the clinical field. Using targeted next-generation sequencing, we aimed to detect targetable genetic alterations and characterize mutational profiles of breast cancer. We analyzed breast cancer biopsy specimens using customized 50-gene panel. In total, 196 patients of primary operable breast cancer patients were selected from single institution in South Korea. Among the 196 patients, 22 kinds of genes were significantly mutated or amplified. They comprised 161 nonsynonymous missense mutations, 54 frameshift mutations, 29 missense mutations and 5 small indels; 64 gene amplifications and 2 deletions. The most frequently mutated gene was PIK3CA (n=81/196; 41.3%), followed by TP53 (n=62; 31.6%), AKT1 (n=21; 10.7%), GATA3 (n=17; 8.7%) and PTEN (n=14; 7.1%). The most frequently amplified gene was ERBB2 (n=25/196; 12.8%), followed by FGFR1 (n=11; 5.6%), MYC (n=9; 4.6%), FGFR2 (n=3; 1.5%) and FGFR3 (n=3; 1.5%). Targeted next-generation sequencing can be readily performed in daily clinical practice. The most commonly found targetable genetic alterations were mutations of PI3K/AKT/mTOR pathway genes and FGFR family gene amplifications. Despite the limited number of available targeted agents, our study shows the feasible application of precision medicine in breast cancer. Citation Format: Jung Ho Park, Seung Yeon Ko, Sang Hwa Kim, Ho Young Kim, Sung Hoon Ko, Lee Su Kim. Molecular genetic characterization of primary breast cancer via clinical next-generation 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 198.
Engineering transplantable jejunal mucosal grafts using patient-derived organoids from children with intestinal failure
Authors: Laween Meran, Isobel Massie, Sara Campinoti, Anne E. Weston, Riana Gaifulina, Lucinda Tullie, Peter Faull, Michael Orford, Anna Kucharska, Anna Baulies, Laura Novellasdemunt, Nikolaos Angelis, Elizabeth Hirst, Julia König, Alfonso Maria Tedeschi, Alessandro Filippo Pellegata, Susanna Eli, Ambrosius P. Snijders, Lucy Collinson, Nikhil Thapar, Geraint M. H. Thomas, Simon Eaton, Paola Bonfanti, Paolo De Coppi, Vivian S. W. Li
Journal: Nature Medicine (2020)
Abstract 2978: Cyclic GMP-independent inhibition of colon cancer cell growth by phosphodiesterase inhibitors
Authors: Bianca N. Islam, Yali Hou, Namratha Mylarapu, Kaylin A. Browning, Kenneth J. Vega, Darren D. Browning
Journal: Cancer Research (2020)

Abstract There is growing interest in the potential use of phosphodiesterase (PDE) inhibitors for colon cancer chemoprevention, but the tumor suppressive mechanism is not understood. The present study has tested the idea that PDE inhibitors can suppress growth and promote apoptosis of colon cancer cell lines by increasing cGMP and activating cGMP-dependent protein kinase (PKG). Treatment of LS174T, Caco2, and HCT116 colon cancer cells with membrane permeable 8Br-cGMP had no effect on cell proliferation or viability. Endogenous PKG was undetectable in any of these cells using phosphorylation of the PKG substrate vasodilator-stimulated phosphoprotein (VASP) as a readout. Ectopic expression of PKG2 conferred modest inhibition of proliferation by cGMP treatment (15-25% over 3 days), but did not affect cell viability. The lack of effect of cGMP on colon cancer proliferation is incongruous with many reported effects of PDE inhibitors. To understand the reason for the discrepant observations, colon cancer cells were treated with sildenafil, PF-0447943, and TAK-063 that are specific inhibitors of the cGMP-targeting PDE5, 9, 10a (respectively). At clinically unachievable concentrations exceeding 10μM, all of these drugs reduced proliferation to various degrees in the different cell lines. TAK-063 was the most effective, and the only one that reduced cell viability. Notably, growth-inhibition by the PDE inhibitors was independent of PKG expression, and surprisingly, none of them increased cGMP levels. The inability of the PDE inhibitors to increase cGMP was due to the lack of endogenous cGMP generation, because treatment with the guanylyl-cyclase C agonist linaclotide conferred a robust cGMP response to a physiological dose of sildenafil (1µM). The growth inhibitor effects of high, non-physiological levels of PDE inhibitors is likely due to off-target effects, but apart from a transient inhibition of the ERK pathway, no common mechanism was identified. Taken together, these results refute the idea that cGMP elevating agents prevent colon carcinogenesis by inhibiting cancer cell growth, and support the inhibition of tumor initiation as a more likely mechanism. Citation Format: Bianca N. Islam, Yali Hou, Namratha Mylarapu, Kaylin A. Browning, Kenneth J. Vega, Darren D. Browning. Cyclic GMP-independent inhibition of colon cancer cell growth by phosphodiesterase inhibitors [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 2978.
Abstract 2124: Hotspots of sequence variability in gut microbial metagenomic datasets and their association with colorectal cancer
Authors: Rachell M. Martinez-Ramirez, Miguel M. Girod-Hoffman, Abiel Roche-Lima, Kelvin Carrasquillo-Carrión, Josué Pérez-Santiago, Abel Baerga-Ortiz
Journal: Cancer Research (2020)

Abstract The gut microbiome has been found to impact host predisposition to disease. Previous research shows that certain species of microbes, encoding pro-inflammatory factors, increase the probability of developing dysplasia and colorectal cancer (CRC). Recently, through the oligotyping approach, we found genetic variants for an amplified region of usp, a genotoxic protein made by E. coli in the gut. These different variants were present in healthy, adenoma and CRC clinical stool samples. To our surprise, the same positions of genetic variability found experimentally were confirmed by BLAST analyses of shotgun metagenomic data from a case-control study conducted in France and Washington D.C. In this work, using the same metagenomics data, we searched for hotspots of genetic variability in the sequences for five genes with known pro-inflammatory and toxicity profiles: usp, tcpC, gelE, clbB, and clbN. More importantly, we extended our analyses to cover the entire length of these genes using a command line approach to BLAST+. The sequence reads for both clbB and clbN lacked coverage, rendering their analysis unquantifiable. The output data for both tcpC and gelE showed high levels of homology between the sequences of the healthy and CRC patients. However, we found twenty-nine hotspots in the usp gene, thirteen of which cause a modification in the primary structure of the protein. Among these thirteen positions, nine were different in cases and controls suggesting that these hotspots of variation are associated with CRC. All these results provide insight into both the link between variability and pathogenicity, and the viability of shotgun sequencing for such types of analyses. Citation Format: Rachell M. Martinez-Ramirez, Miguel M. Girod-Hoffman, Abiel Roche-Lima, Kelvin Carrasquillo-Carrión, Josué Pérez-Santiago, Abel Baerga-Ortiz. Hotspots of sequence variability in gut microbial metagenomic datasets and their association with colorectal 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 2124.
Abstract 1757: Developing sensitive assays to facilitate hit identification of RNA modifying enzymes
Authors: Chris Tomlinson, Rachel Lawrence, Stuart Best, Grace Boden, Thomas Alanine, James Wasp, Bethany Smith, Ross Wilkie, Stuart Thomson, John Unitt, Scott Pollack, Allan M. Jordan
Journal: Cancer Research (2020)

Abstract N-6-methyladenosine (m6A) is the most abundant RNA chemical modification found in the eukaryotic transcriptome. It is a dynamic and reversible modification which plays a role in RNA function across a wide range of biological processes. Dysregulation of the m6A modification and the readers, writers and erasers involved in these processes have been implicated in the progression of multiple types of cancer and metabolic disease. RNA modifying enzymes are therefore emerging as exciting therapeutic targets. To facilitate and accelerate drug discovery efforts in this area, we have developed several sensitive and robust assays suitable for identifying and assessing chemical matter against the RNA modifying enzymes, fat mass and obesity associated protein (FTO) and methyltransferase-like 3/14 (METTL3/14). Specifically, a robust Microscale Thermophoresis (MST) assay was developed, validated, and used to screen 100 compounds from the LOPAC for novel human FTO small molecule binders. Five compounds, which displayed reproducible, concentration-dependent binding in the MST screen, were tested for inhibition of human FTO RNA demethylation activity and revealed a single, novel FTO inhibitor. To further profile emerging FTO hit matter, we are also developing sensitive and robust mass spectrometry assays to demonstrate target inhibition and proof of mechanism. Our progress in this area will be reported. Additionally, we have developed a highly sensitive and robust LC-MS/MS assay to monitor the METTL3/14 catalysed conversion of S-adenosylmethionine (SAM) to S-adenosylhomocysteine (SAH). This assay is suitable for identifying either substrate competitive or allosteric METTL3/14 inhibitors. In summary, our proof of concept studies describe the development of several robust and sensitive assays suitable for hit identification and further characterisation of inhibitors of key RNA modifying enzymes and offer a platform for the discovery and development of novel therapeutics in this emerging area of research. Citation Format: Chris Tomlinson, Rachel Lawrence, Stuart Best, Grace Boden, Thomas Alanine, James Wasp, Bethany Smith, Ross Wilkie, Stuart Thomson, John Unitt, Scott Pollack, Allan M. Jordan. Developing sensitive assays to facilitate hit identification of RNA modifying enzymes [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 1757.