tbuckley/cabot-search huggingface dataset:
Abstract 2784: Driver genes network promotes mesenchymal to epithelial transition and organ-specific metastasis
Authors: Ming Chang, Xin Huang, Songjian Lu, Wei Zhang, Weiping Liang, Evan Keller, Xinghua Lu, Jian Zhang
Journal: Cancer Research (2019)

Abstract Metastasis, a major characteristic of malignancy, causes high mortality. Accumulating evidence suggests that cancer intends to metastasize to specific organ, however the molecular mechanisms remain unknown. Others and us have demonstrated that epithelial to mesenchymal transition (EMT) plays key roles in initiation of primary tumor adherent, migration, and invasion, whereas mesenchymal to epithelial transition (MET) revokes “sleeping” disseminated tumor cell (DTC) to colonization at distant metastatic organ sites and facilitates the tumor cell proliferation. We have successfully generated the lung-specific metastatic subclones of human prostate cancer PC3 and murine RM1 cells. Through omic bench work and data analysis and comparison with TCGA database, we, for the first time, identified a preliminary network of “driver genes” that potentially promotes the reversible EMT/MET process We utilized cutting-edge tools of data analysis to identify the selected driver genes (LAMA, SPP1, ITGB3, S100A8, SERPINE, DKK2) and further characterized the gene functions via in vitro bioassay of cell proliferation, migration, invasion, cell cycle, and apoptotic testing etc, and in vivo with our unique cell and animal metastatic models. We observed that the rate of organ-specific metastasis was dramatically reduced when these gene expression levels were changed. Finally, we confirmed our findings using TMA slides, Our results may provide novel mechanisms of metastasis and clinical targets of cancer therapy. Supported by NSFC projects 81773146; Guangdong Provincial Key Laboratory of Cell Microenvironment and Disease Research (2017B030301018); JCYJ20170412152943794, JCYJ20170412154619484, JCYJ20170307105128101, JCYJ2017030711041760 Note: This abstract was not presented at the meeting. Citation Format: Ming Chang, Xin Huang, Songjian Lu, Wei Zhang, Weiping Liang, Evan Keller, Xinghua Lu, Jian Zhang. Driver genes network promotes mesenchymal to epithelial transition and organ-specific metastasis [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 2784.
Abstract 253: Protein-tyrosine phosphatase 1B (PTP1B) as a therapeutic target in glioblastoma
Authors: Ruben Bartolomé, Marta Jaén, Miranda Burdiel, Irina V. Balyasnikova, Ignacio Casal
Journal: Cancer Research (2019)

Abstract New targeted therapies are urgently needed in glioblastoma (GBM). IL13Rα2 receptor is considered a highly specific receptor for GBM cells and has been proposed for therapeutic purposes. Here, we aimed to identify the protein interaction network of IL13Rα2 and its mediators in GBM searching for novel associated therapeutic targets. We investigated the IL13Rα2 protein interaction network in U251 GBM cells using immunoprecipitation followed by mass spectrometry. Different cell lines were used for validation. Two glioblastoma cell lines were used for testing proliferation, adhesion, migration and invasion. Claramine, a PTP1B inhibitor, was tested to study inhibition of GBM cells growth in cultured cells and in animal experiments. In vivo experiments with NSG mice were performed after treatment with PTP1B inhibitors. Using a proteomic approach, we identified the association of the PTP1B phosphatase with IL13Rα2 in U251 GBM cells. Although GBM cell lines were positive for PTP1B, the highest PTP1B expression was found in GBM clinical samples. Moreover, “in silico” dataset analysis showed PTP1B association with poor outcome in GBM patients. PTP1B silencing inhibited the IL-13-promoted activation of Src (Tyr419), AKT and ERK1/2 in all the cell lines tested causing a significant effect on IL-13-mediated migration and invasion, and proliferation at a lower extent, of GBM cells. Therefore, PTP1B-silencing reverted most of the pro-metastatic capacities of the IL-13/ IL13Rα2 signaling axis. Further immunoprecipitation of PTP1B showed its association with a large number of NF-κB and NOTCH-related proteins in GBM cells. Both pathways are highly relevant for cancer proliferation and invasion. Claramine, a selective inhibitor of PTP1B, caused similar results to PTP1B silencing, inhibiting the dephosphorylation of Src Tyr527, migration and invasion in GBM. Moreover, treatment with Claramine caused a complete regression of GBM xenografts in NSG mice and total inhibition of liver metastatic growth in nude mice inoculated with colorectal cancer cells. In conclusion, our results provide new insights into the mechanisms underlying IL13Rα2-driven GBM aggressiveness after identifying PTP1B as a critical mediator of IL-13/IL13Rα2 signaling. A PTP1B inhibitor such as Claramine showed a great value as a therapeutic candidate in GBM. PTP1B inhibitors might be highly effective to prevent GBM progression and invasion. Citation Format: Ruben Bartolomé, Marta Jaén, Miranda Burdiel, Irina V. Balyasnikova, Ignacio Casal. Protein-tyrosine phosphatase 1B (PTP1B) as a therapeutic target in glioblastoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 253.
Abstract 358: Inhibition of AKT phosphorylation in acute myeloid leukemia by ISC 4
Authors: Shreya Thakur, Charyguly Annageldiyev, Srinivasa Ramisetti, Trupti Patel, Saumya Iyer, Pavan Dhanyamraju, Shantu Amiin, Arun Sharma, David Claxton, Arati Sharma
Journal: Cancer Research (2019)

Abstract Acute myeloid leukemia (AML) is a heterogeneous disease with percent remission of 35-40% for younger patients and 5-15% for older patients and a survival of 5-10 months if left untreated. This emphasizes the urgent unmet need for new therapeutics in AML. The activation of PI3K/AKT signaling pathway plays an important role in cellular survival, proliferation and regulation of apoptosis in cancer cells including leukemia. Recent studies showed that activation of AKT may correlate with poor prognosis in AML. Furthermore, mutations such as FLT3-ITD in the PI3K-AKT pathway causing constitutive activation of AKT, are very common in AML, therefore, it remains as an important target for AML treatment. Phenylbutyl isoselenocyanate (ISC-4), a small drug-like molecule that is developed by our group through optimization of naturally occurring isothiocyanates, targets the P13K-AKT pathway in melanoma and other gastrointestinal malignancies. In this study, we demonstrated potent activity of ISC-4 against AML. We tested the cytotoxicity of ISC-4 in various human AML cell lines (n=6) and in samples collected from AML patients (n=8). AML cell lines exhibited dose-dependent sensitivity to ISC-4 in the low micromolar range (IC50: 2-5 uM) as did most primary AML cases. Western blotting showed a dose dependent decrease in AKT phosphorylation in MV-4-11 and AML-OCI3 cell lines, and lead to an increase in cleaved PARP levels, indicating the induction of apoptosis. Furthermore, ISC-4 treatment reduced the clonogenicity of primary AML cells at relatively low concentrations. Future studies will aim to further develop ISC-4 as a single agent and in combination with anti-leukemic agents and demonstrate the preclinical efficacy in AML animal models including AML patient derived xenografts (PDXs). Together, these data demonstrates the therapeutic potential of ISC-4 that can be a promising drug candidate for further development as a novel therapy for AML. Citation Format: Shreya Thakur, Charyguly Annageldiyev, Srinivasa Ramisetti, Trupti Patel, Saumya Iyer, Pavan Dhanyamraju, Shantu Amiin, Arun Sharma, David Claxton, Arati Sharma. Inhibition of AKT phosphorylation in acute myeloid leukemia by ISC 4 [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 358.
Abstract LB-276: Farnesyltransferase inhibitor (FTI)-induced growth inhibition of HRAS-mutant head and neck cancers is enhanced by concurrently inhibiting compensatory upregulation of the ERK-MAPK kinase cascade
Authors: Sehrish Javaid, Victoria V. Nguyen, Andrew M. Waters, Craig M. Goodwin, Channing J. Der, Adrienne D. Cox
Journal: Cancer Research (2019)

Abstract Activating mutations in the HRAS oncogene are present in 5-11% of head and neck squamous cell carcinomas (HNSCC), but whether mutant HRAS drives HNSCC growth was not known. The clinical candidate FTI, tipifarnib, is currently under investigation in HRAS-mutant HNSCC, but whether patient responses to tipifarnib are due to blocking HRAS membrane association or due to action on another FTI target/s is also unclear. We found that the FTIs tipifarnib and lonafarnib inhibited the growth of HRAS-mutant HNSCC in a target-dependent manner, blocking HRAS farnesylation and membrane association. We also found that genetic depletion of mutant HRAS inhibited the anchorage-dependent and -independent growth of HRAS-mutant HNSCC cell lines in vitro and robustly induced apoptosis, indicating HNSCC dependence on mutant HRAS and a correlation between FTI-mediated growth inhibition and blockade of HRAS function. Tumor types driven by other RAS isoforms, such as KRAS-driven pancreatic cancer, are highly dependent on the ERK MAPK effector pathway and are sensitive to pharmacological inhibitors of ERK1/2 (ERKi: SCH772984, BVD-523). In contrast, we found that HRAS-driven HNSCC was resistant to growth inhibition by ERKi alone, despite strong target inhibition as indicated by decreases in pRSK and MYC protein levels. Consistent with this finding, genetic depletion of HRAS not only failed to reduce MAPK signaling but instead caused compensatory upregulation. Similarly, FTI treatment also induced upregulation of MAPK signaling, which is typically growth-promoting. We therefore speculated that the addition of ERKi would enhance responses to FTIs, and indeed found that ERKi synergistically enhanced FTI-mediated apoptosis and growth inhibition. Our results provide a mechanistic rationale for adding ERKi to FTI to improve clinical responses in HRAS-mutant HNSCC, and suggest that monitoring MAPK pathway activation may be a useful marker for emerging FTI resistance in this patient population. Citation Format: Sehrish Javaid, Victoria V. Nguyen, Andrew M. Waters, Craig M. Goodwin, Channing J. Der, Adrienne D. Cox. Farnesyltransferase inhibitor (FTI)-induced growth inhibition of HRAS-mutant head and neck cancers is enhanced by concurrently inhibiting compensatory upregulation of the ERK-MAPK kinase cascade [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr LB-276.
Retinol binding protein 3 is increased in the retina of patients with diabetes resistant to diabetic retinopathy
Authors: Hisashi Yokomizo, Yasutaka Maeda, Kyoungmin Park, Allen C. Clermont, Sonia L. Hernandez, Ward Fickweiler, Qian Li, Chih-Hao Wang, Samantha M. Paniagua, Fabricio Simao, Atsushi Ishikado, Bei Sun, I-Hsien Wu, Sayaka Katagiri, David M. Pober, Liane J. Tinsley, Robert L. Avery, Edward P. Feener, Timothy S. Kern, Hillary A. Keenan, Lloyd Paul Aiello, Jennifer K. Sun, George L. King
Journal: Science Translational Medicine (2019)

The Joslin Medalist Study characterized people affected with type 1 diabetes for 50 years or longer. More than 35% of these individuals exhibit no to mild diabetic retinopathy (DR), independent of glycemic control, suggesting the presence of endogenous protective factors against DR in a subpopulation of patients. Proteomic analysis of retina and vitreous identified retinol binding protein 3 (RBP3), a retinol transport protein secreted mainly by the photoreceptors, as elevated in Medalist patients protected from advanced DR. Mass spectrometry and protein expression analysis identified an inverse association between vitreous RBP3 concentration and DR severity. Intravitreal injection and photoreceptor-specific overexpression of RBP3 in rodents inhibited the detrimental effects of vascular endothelial growth factor (VEGF). Mechanistically, our results showed that recombinant RBP3 exerted the therapeutic effects by binding and inhibiting VEGF receptor tyrosine phosphorylation. In addition, by binding to glucose transporter 1 (GLUT1) and decreasing glucose uptake, RBP3 blocked the detrimental effects of hyperglycemia in inducing inflammatory cytokines in retinal endothelial and Müller cells. Elevated expression of photoreceptor-secreted RBP3 may have a role in protection against the progression of DR due to hyperglycemia by inhibiting glucose uptake via GLUT1 and decreasing the expression of inflammatory cytokines and VEGF.
Abstract 1049A: Deregulation of MITF in the context of inactive MC1R leads to melanocyte transformation
Authors: Tine Norman Alver, Timothy J. Lavelle, Karen-Marie Heintz, Patrik Wernhoff, Vegard Nygaard, Geir F. Øy, Sigurd L. Bøe, Alfonso Urbanucci, Eivind J. Hovig
Journal: Cancer Research (2019)

Abstract MC1R, the cAMP pathway and the response to solar UV are all elements involved in the growth, differentiation and survival of melanocytes and in malignant melanoma. Here we present a model of melanomagenesis based on the forced expression of MITF-M in the context of MC1R-inactivating variants in a way not dependent on sun exposure. We demonstrate that lentiviral transduction of MITF-M alone leads to consistent transformation of the Hermes4C cell line with inactive MC1R, but not the Hermes3C cell line having a wild type background. Hermes 4c cells transduced with MITF-M are able to form tumors in mice. We mapped MITF binding to chromatin and found that 4C cells displayed enhanced MITF chromatin binding compared to 3C. Expression analysis revealed that the altered binding pattern leads to enhanced transcription of epithelial to mesenchymal transition genes and consequent repression of key melanocyte-specific genes e.g. involved in pigmentation in the background of inactive MC1R. We observed a marked deregulation of AXL and EGFR, which is accompanied by downregulation of PTEN and increased phosphorylation of ERK and PI3K-AKT pathway. In conclusion, we show that MITF-M is a molecular switch in the context of MC1R-inactivating variant which leads to cell reprogramming and melanomagenesis. Citation Format: Tine Norman Alver, Timothy J. Lavelle, Karen-Marie Heintz, Patrik Wernhoff, Vegard Nygaard, Geir F. Øy, Sigurd L. Bøe, Alfonso Urbanucci, Eivind J. Hovig. Deregulation of MITF in the context of inactive MC1R leads to melanocyte transformation [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 1049A.
Abstract 2713: Discovery and characterization of AZD8701, a high affinity antisense oligonucleotide targeting FOXP3 to relieve immunosuppression in cancer
Authors: Charles Sinclair, Alexey S. Revenko, R B. Johnson, Alison Peter, Molly A. Taylor, Lisa A. Hettrick, Stephanie Klein, Anisha Solanki, Melissa Chapman, James Yates, Helen K. Angell, Andrew Watt, Danielle Gattis, Brett P. Monia, Simon T. Barry, Paul Lyne, Mark Edbrooke, Frederick Goldberg, A R. Macleod
Journal: Cancer Research (2019)

Abstract Regulatory T cells (Treg) critically maintain immuno-suppression in the tumor microenvironment, representing an attractive immuno-oncology target. The Treg lineage is defined by expression of the FOXP3 transcription factor, which controls immune-suppressive functions. We have developed the clinical candidate AZD8701, a next-generation antisense oligonucleotide inhibitor of FOXP3 (utilizing the Ionis Gen 2.5 cEt-modified ASO platform). AZD8701 treatment knocked down FOXP3 in primary human Tregs via free uptake (IC50 65nM), which was also associated with modulation of known FOXP3 target genes including 25-50% reduction in CTLA4, ICOS, CCR8 and GITR. Tregs treated with AZD8701 further exhibited reduced suppressive functions in in vitro suppression assays, which confirmed the functional effects of FOXP3 modulation. Finally, AZD8701 promoted dose-dependent knockdown of FOXP3 in humanized mice, including &amp;gt;50% FOXP3 knockdown at doses that can be feasibly achieved with the Gen 2.5 ASO platform in the clinic. To support the importance of FOXP3 in immuno-oncological settings, we characterized murine surrogate FOXP3 ASOs in the context of syngeneic tumour bearing mice. Murine FOXP3 ASOs similarly promoted &amp;gt;50% FOXP3 knockdown in mice and were well tolerated with no overt toxicological findings at high doses, over a maximum of 12 weeks of treatment. Murine FOXP3 ASOs significantly attenuated tumour growth in A20 and ID8-VEGF syngeneic models, which was associated with some complete tumour regressions. Moreover, we found that mouse surrogate FOXP3 ASOs promoted additive/enhanced therapeutic effects when combined with immune checkpoint blockade. Collectively, FOXP3 ASOs represent a first-in-class strategy to target Tregs in cancer in a highly selective manner. The clinical application of AZD8701 may provide therapeutic benefit to patients either as a monotherapy or in combination with immune checkpoint blocking agents. Citation Format: Charles Sinclair, Alexey S. Revenko, R B. Johnson, Alison Peter, Molly A. Taylor, Lisa A. Hettrick, Stephanie Klein, Anisha Solanki, Melissa Chapman, James Yates, Helen K. Angell, Andrew Watt, Danielle Gattis, Brett P. Monia, Simon T. Barry, Paul Lyne, Mark Edbrooke, Frederick Goldberg, A R. Macleod. Discovery and characterization of AZD8701, a high affinity antisense oligonucleotide targeting FOXP3 to relieve immunosuppression in cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 2713.
Phase I, Open-Label, Dose-Escalation Study of the Safety, Pharmacokinetics, Pharmacodynamics, and Efficacy of GSK2879552 in Relapsed/Refractory SCLC
Authors: Todd M. Bauer, Benjamin Besse, Alex Martinez-Marti, Jose Manuel Trigo, Victor Moreno, Pilar Garrido, Geraldine Ferron-Brady, Yuehui Wu, Jennifer Park, Therese Collingwood, Ryan G. Kruger, Helai P. Mohammad, Marc S. Ballas, Arindam Dhar, Ramaswamy Govindan
Journal: Journal of Thoracic Oncology (2019)

This first-time-in-humans study assessed the safety, pharmacokinetics (PK), pharmacodynamics (PD), and clinical activity of GSK2879552 in patients with relapsed or refractory SCLC.This phase I, multicenter, open-label study (NCT02034123) enrolled patients (≥18 years old) with relapsed or refractory SCLC (after ≥1 platinum-containing chemotherapy or refusal of standard therapy). Part 1 was a dose-escalation study; Part 2 was a dose-expansion study. Dose escalations were based on safety, PK, and PD. The primary end point (Part 1) was to determine the safety, tolerability, and recommended dose and regimen of GSK2879552. Secondary end points were to characterize PK and PD parameters and measure disease control rate at week 16. Part 2 was not conducted.Between February 4, 2014, and April 18, 2017, a total of 29 patients were allocated to one of nine dose cohorts (0.25 mg-3 mg once daily and 3-mg or 4-mg intermittent dosing). In all, 22 patients completed the study; 7 withdrew, primarily owing to adverse events (AEs). Most patients (24 of 29 [83%]) had at least one treatment-related AE, most commonly thrombocytopenia (12 of 29 [41%]). Twelve serious AEs (SAEs) were reported by nine patients; six were considered treatment related, the most common of which was encephalopathy (four SAEs). Three patients died; one death was related to SAEs. PK was characterized by rapid absorption, slow elimination, and a dose-proportional increase in exposure.GSK2879552 is a potent, selective inhibitor of lysine demethylase 1A and has demonstrated favorable PK properties but provided poor disease control and a high AE rate in patients with SCLC. The study was terminated, as the risk-benefit profile did not favor continuation.
Abstract 3675: Elucidating the role and function of APOBEC3 DNA deaminases in myeloproliferative neoplasms
Authors: Jane Isquith, Qingfei Jiang, Raymond Diep, Jessica Pham, Frida Holm, Catriona Jamieson
Journal: Cancer Research (2019)

Abstract The prevalence of upregulated apolipoprotein B mRNA editing enzyme, catalytic polypeptide-like 3 (APOBEC3) transcripts as well as a distinct mutational signature has been identified and presented extensively in numerous cancer types. Previously, this family of cytidine deaminases has been studied in innate immunity, as they are active in the conversion of cytosine to uracil to restrict retroviral replication. Recent studies employing whole exome sequencing of multiple cancer types have shown a significant increase in both APOBEC3 transcript level as well as an increase in mutations indicated as a result of APOBEC3 driven mutagenesis. However, the expression and role of these enzymes in cancer initiation and progression as well as the mechanisms by which the APOBEC3 enzymes elicit a response in the cancer microenvironment remains unknown, especially in hematopoietic malignancies. Here, we elucidate the APOBEC3 mutation phenotype in Myeloproliferative Neoplasms (MPNs) as well as the naïve cell populations of CD34+ cord blood and normal aged samples. Through RNA sequencing we have found a cell type and context specific nature of these enzymes, notably the upregulation of APOBEC3G (A3G) in the Myelofibrosis (MF) stem and progenitor cell population as compared to normal aged counterparts. There is also significant differential expression of APOBEC3C (A3C), APOBEC3D (A3D), and APOBEC3F (A3F) in MF disease states compared to normal controls. By cloning the APOBEC3 enzymes into lentiviral expression vectors, we can now study the physiological effects of changes in APOBEC3 transcript level in relation to the known changes in expression seen in many cancers, focusing on the upregulation of A3G through lentiviral overexpression. Using these techniques, we will also elucidate the mutation signature of APOBEC3G in CD34+ cord blood as compared to the known mutagenesis pattern derived from the editing signature of APOBEC3B. Upon APOBEC3G overexpression we can connect the prevalence and proposed activity of the enzymes to the physiological deregulation present in hematopoietic malignancies. We have found that A3G induces a proliferative burst in normal CD34+ cord blood, which leads us to study the effects of APOBEC3 upregulation in regards to proliferation, differentiation and self-renewal in normal and malignant cells as well as their potential function in disease initiation and progression in MPNs. Citation Format: Jane Isquith, Qingfei Jiang, Raymond Diep, Jessica Pham, Frida Holm, Catriona Jamieson. Elucidating the role and function of APOBEC3 DNA deaminases in myeloproliferative neoplasms [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 3675.
Strengths and Weaknesses of the Committee Approach
Authors: Nevin S. Scrimshaw
Journal: New England Journal of Medicine (1976)

The 1971 Joint FAO/WHO Expert Committee on Energy and Protein RequirementsWe are now able to return to the controversial actions taken by the 1971 Joint FAO/WHO Expert Committee on Energy and Protein Requirements. This committee met in Rome in late March and early April, 1971, and I participated as a member. It had the advantage of most of the additional data cited above, and began by reassessing the factorial calculation based on the new information from MIT and California.As shown in Table 5, it concluded that obligatory urinary and fecal losses plus the minimal integumental losses measured by Calloway . . .