tbuckley/cabot-search huggingface dataset:
Abstract 4593: Glycoengineered antibodies for click chemistry applications
Authors: Drishti Sehgal, Stephen Kalscheuer, Tanmoy Sadhukha, Jayanth Panyam
Journal: Cancer Research (2017)

Abstract Antibody-drug conjugates (ADC) hold considerable promise as anticancer agents. A critical determinant of the effectiveness of ADCs is the chemistry that is used to conjugate the payload. Currently used approaches include primarily conjugation to either side-chain amine or carboxylic acid groups or conjugation to thiols. Because these reactions are not site specific and not easily controlled, these chemistries can result in reduced affinity for the target antigen. Further, these conjugation reactions lack selectivity and can result in heterogeneous mixtures of products that differ in the sites and stoichiometry of modification. We investigated a glycoengineering strategy that enables the introduction of artificial azide groups in the antibody without affecting their antigen affinity. This is based on the observation that glycosyltransferases can incorporate non-natural sugars (e.g., azido mannose) at different sites on an IgG molecule. The azide groups inthese artificial sugars are then available to react with alkynes through copper-catalyzed ‘click’ chemistry or with strained alkynes such as dibenzyl cyclooctyne (DBCO) allowing for biorthogonal, copper-free ‘click’ chemistry. Because the sugars are added reproducibly and at asite that does not affect antigen binding, the glycoengineering technology would overcome problems associated with traditional conjugation strategies. Using this approach, azide groups were introduced in anti-CD133 and anti-perlecan antibodies. Further, the azide groups were available to react with various DBCO conjugates including fluorophores, drug molecules and nanoparticles. Importantly, the addition of artificial sugar and subsequent azide-alkyne reactiondid not affect the affinity of the antibody for the target antigen. Conjugation of nanoparticles to antibodies using this approach resulted in enhanced cellular uptake of the nanoparticles. Similarly, conjugation of a cytotoxin to the antibody resulted in enhanced cell kill in vitro. Weexpect that this glycoengineering strategy will prove to be a unique platform technology that will have a significant impact on antibody-based therapeutics. Citation Format: Drishti Sehgal, Stephen Kalscheuer, Tanmoy Sadhukha, Jayanth Panyam. Glycoengineered antibodies for click chemistry applications [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 4593. doi:10.1158/1538-7445.AM2017-4593
Abstract 5852: DUOX2, a key player for chemopotentiation by low-dose fractionated radiation therapy in gastric cancer cells
Authors: Palak R. Parekh, Elizabeth Chang, Navesh K. Sharma, France Carrier
Journal: Cancer Research (2017)

Abstract One of the most conventional therapy for solid tumors is radiotherapy. Still, this modality presents a challenge when it comes to managing highly disseminated gastrointestinal cancers due to increased toxicity to surrounding tissues. Recent laboratory and clinical data indicate that Low Dose Fractionated Radiation Therapy (LDFRT) can potentiate systemic chemotherapy and presents the possibility to revisit the concept of Whole Abdominal Radiotherapy (WART) for disseminated intra-abdominal gastric cancers. Earlier work considered LDFRT ineffective for tumor removal but we now know that LDFRT induces hyper-radiosensitivity (HRS) in a number of proliferating cells. We have recently shown that dual oxidase (DUOX2) is a major contributor to induce HRS at radiation doses as low as 0.15 Gy and sensitize human gastric cancer cells to chemotherapy. The aim of our study is to determine the utility of DUOX2 as a potential biomarker for the clinical application of chemopotentiation by LDFRT. First, we performed immunohistochemistry (IHC) on 48 human gastric samples with progressive grades. Our data indicate that only about 50% of human gastric cancers are positive for DUOX2. The reason for DUOX2 variability of expression is not clear but may be linked to inflammation since six of the seven (86%) gastritis samples we examined expressed strong levels of DUOX2 in the surface of epithelial cells. Our data also indicate that expression of DUOX2 significantly increases the levels of macrophages infiltration in tissue expressing DUOX2 as well as in the stroma surrounded by cells expressing DUOX2. This suggests that expression of DUOX2 could impact on the dynamic of the tumor microenvironment. Expression of DUOX2 in response to LDFRT is conserved since we also observed this in mice primary gastric cancer cells as well as cancer stem cells. Furthermore, as a first step to develop DUOX2 as an accessible biomarker, we studied DUOX2 activity by measuring the accumulation of oxidative serum proteins in gastric cancer cells media. Our data indicate that down regulation of DUOX2 significantly reduces the levels of serum protein oxidation. Taken together these data suggest that DUOX2 could potentially be used as a biomarker to stratify patients and follow the efficiency of clinical application of chemopotentiation by LDFRT. Citation Format: Palak R. Parekh, Elizabeth Chang, Navesh K. Sharma, France Carrier. DUOX2, a key player for chemopotentiation by low-dose fractionated radiation therapy in gastric cancer cells [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 5852. doi:10.1158/1538-7445.AM2017-5852
Abstract 1824: Endothelial mTORC2 deficiency inhibits tumor angiogenesis, tumor progression and metastasis in non-small cell lung cancer (NSCLC)
Authors: Shan Wang
Journal: Cancer Research (2017)

Abstract Vascular endothelial cells (ECs) are specialized components of the tumor microenvironment that orchestrates tumor growth and invasion. They form tumor-associated blood vessels (angiogenic) that supply nutrients and oxygen, remove waste products, and also provide an entry site for tumorigenic cells to spread to secondary sites in various organs. One of the major signaling events in tumor vessels is PI3K/PDK-AKT-mTOR activation. mTOR is a serine/threonine kinase that functions in two distinct complexes, mTORC1 and mTORC2,which regulate a diverse array of cellular processes including cell growth, survival and metabolism. Although mTORC1, and to lesser extent, mTORC2, has been broadly studied in cancers and diseases, little is known regarding the relative contributions of mTORC1 versus mTORC2 in tumor endothelium. Using mouse model of endothelium-specific Rictor (a mTORC2 specific cofactor) gene targeting, we discovered that endothelial Rictor deletion decreased tumor neovascularization, suppressed tumor growth, and prevented metastasis in vivo. Direct co-culture of endothelial cells and NSCLC tumor cells in vitro showed that knockdown of endothelial Rictor inhibited tumor cell proliferation while Raptor (a mTORC1 specific cofactor) depletion had a modest effect. However, loss of endothelial Rictor or Raptor both markedly decreased tumor cell extravasation in response to endothelial cells, and also inhibited tumor spheroid formation in a direct co-culture system. Furthermore, a screen of phospho-kinase arrays revealed that Raptor or Rictor depletion in endothelial cells decreased various phosphor-RTKs in tumor cells that were co-cultured with ECs, including members of the Eph receptor family, Insulin receptor family and FGF receptor family. Additionally, endothelial Rictor knockdown suppressed phosphorylation levels of nerve growth factor receptors TrkB and TrkC in tumor cells. Collectively, these data suggest that endothelial mTORC1 and mTORC2 play critical roles in regulating tumor progression through distinct signaling pathways. Note: This abstract was not presented at the meeting. Citation Format: Shan Wang. Endothelial mTORC2 deficiency inhibits tumor angiogenesis, tumor progression and metastasis in non-small cell lung cancer (NSCLC) [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 1824. doi:10.1158/1538-7445.AM2017-1824
Abstract 2677: Role of CLEC4D in inflammation-driven liver carcinogenesis
Authors: Elena Riboldi, Luca Di Tommaso, Nausicaa Clemente, Chiara Raggi, Elisa Forti, Simone Merlin, Fabio Pasqualini, Antonia Follenzi, Antonio Sica
Journal: Cancer Research (2017)

Abstract Hepatocellular carcinoma (HCC) accounts for approximately 90% of all primary liver tumors and is the second most deadly cancer in the world. HCC commonly arises in a chronically damaged liver that contains large amounts of inflammation and fibrosis. Indeed, interactions among hepatocytes, stromal, and inflammatory cells create a complex microenvironment permissive to tumor development. Myeloid cells are crucial players in cancer-related inflammation. From transcriptional profiling of liver myeloid cells, we identified the gene encoding for the C-type lectin receptor CLEC4D as one of the genes upregulated during the inflammatory response that precedes cancer development in a spontaneous model of murine HCC. We hypothesized that CLEC4D may be involved in the molecular mechanisms that drive HCC pathogenesis. We used the murine model of diethylnitrosamine (DEN)-induced liver carcinogenesis and evaluated tumor growth in genetically modified mice lacking CLEC4D (CLEC4D KO mice), as compared to C57BL/6 wild type (WT) mice. We observed that tumor burden (number of tumors per mouse and tumor dimensions) was reduced in CLEC4D KO mice compared to WT mice. Gene expression analysis of tumor lesions showed that the tumor microenvironment of CLEC4D KO mice was less inflammatory. CLEC4D expression was then evaluated in surgical specimens and tissue microarrays from HCV+ HCC patients. CLEC4D-positive inflammatory cells (macrophages and granulocytes) were present both in the peritumor and in the tumor areas. The percentage of intratumor CLEC4D-positive cells inversely correlated with the degree of the lesion: CLEC4D expression was higher in dysplastic nodules compared to high grade HCCs. Our results indicate that the CLEC4D-dependent pathway contributes to the initiation and the progression of HCC. By targeting CLEC4D, we could modulate immune responses and provide an environment less favorable to tumor growth. An intervention at this level could represent a chemopreventive strategy to arrest the development of HCC in a cirrhotic liver.This work has been supported by Fondazione Cariplo, grant n° 2014-0962. Citation Format: Elena Riboldi, Luca Di Tommaso, Nausicaa Clemente, Chiara Raggi, Elisa Forti, Simone Merlin, Fabio Pasqualini, Antonia Follenzi, Antonio Sica. Role of CLEC4D in inflammation-driven liver carcinogenesis [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 2677. doi:10.1158/1538-7445.AM2017-2677
Abstract CT051: Tumor treating fields in pediatric recurrent high-grade glioma and ependymoma
Authors: Stewart Goldman, Arzu Onar-Thomas, Ira Dunkel, Eugene Hwang
Journal: Cancer Research (2017)

Abstract Background Recurrent or progressive pediatric CNS tumors have a poor prognosis under current treatment regimens. For children with high-grade gliomas (HGG), once progression occurs, most patients cannot be cured, and median survival remains &amp;lt; 1-2 years; overall survival of recurrent/progressive ependymoma is also poor in children. Tumor Treating Fields (TTFields) is an anti-mitotic cancer therapy for the treatment of recurrent (supratentorial) glioblastoma (GB).) A phase 3 clinical trial comparing TTFields monotherapy with physician’s choice chemotherapy in adult patients with recurrent GB demonstrated comparable overall survival and improved quality of life. In this multicenter feasibility trial we plan to examine the feasibility and device-related toxicity of TTFields in children with supratentorial HGG and ependymoma. The secondary objectives include: response rate, Event-Free Survival, compliance on use of device and Quality of Life (QoL) of tehe children (aged 8+) and families. Methods The Optune device will be worn ≥ 18 hours/day for at least 23 days out of 28 days of cycle one. Patients will have Brain MRI with and without contrast performed prior to therapy, after cycles 2, 4, 6, 9, then every 3 cycles thereafter until time of progression or completion of treatment. For those patients who complete at least 9 cycles of therapy, an MRI will be performed every 3 cycles for 2 years then every 4 months after completion of treatment.Treatment may continue up to 26 cycles pending observed benefit and safety. A sample size of 20 patients is needed with an interim analysis conducted after the first 11 patients. Kaplan-Meier estimates of EFS for all eligible patients who use the device for &amp;lt; 1 day will be provided separately for the HGG and Ependymomahistology-based cohorts. We will also estimate the rates of confirmed sustained objective responses (CR+PR) observed during treatment. All PROMIS and Neuro-QoL scores will be reported using T-score matrix (mean=50 and SD=10). The projected accrual rate is 1.5-2.5 patients per month. Patients will be followed for 2 years. Citation Format: Stewart Goldman, Arzu Onar-Thomas, Ira Dunkel, Eugene Hwang. Tumor treating fields in pediatric recurrent high-grade glioma and ependymoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr CT051. doi:10.1158/1538-7445.AM2017-CT051
Abstract 1523: The mechanism of action of BCL6 in glioblastoma
Authors: Nicole M. Jones, Marie-Sophie Fabre, Dinindu Sachindra Senanayake, Katerina Hatzi, Ari M. Melnick, Melanie J. McConnell
Journal: Cancer Research (2017)

Abstract Glioblastoma (GBM) is the most common and most deadly brain tumor to occur in adults. Initially patients respond to radiation and chemotherapy, which primarily work by causing large amounts of DNA damage, causing apoptosis of the cells. However, this process does not happen effectively in GBM and understanding how these cells resist cell death in response to therapy is key to improving the efficacy of treatment. BCL6 is a transcription factor that stops cell death in response to DNA damage. Recent work in our lab has shown BCL6 to be present in untreated GBM tumors and up-regulated in treated GBM cells. This evidence indicates that BCL6 may be used as a mechanism of therapy resistance by GBM cells. In this study, the objective was to determine the mechanism of action of BCL6 in GBM cells using luciferase reporter assays, quantitative chromatin immunoprecipitation (qChIP) and RNA sequencing. We observed that BCL6 was transcriptionally active in GBM as shown by a reduction in luciferase activity when BCL6 was present. qChIP experiments revealed that BCL6 binding changed over time and was different with different types of DNA-damaging treatment. Preliminary analysis of our RNA sequencing data has identified a unique subset of genes which are upregulated when BCL6 is inhibited and downregulated in response to chemotherapy. These changes indicate that these genes may be regulated by BCL6 in chemotherapy treated cells. All of these results illustrate that BCL6 appears to have an active and relevant function in GBM cells, which demonstrates that BCL6 is an attractive therapeutic target in GBM. Citation Format: Nicole M. Jones, Marie-Sophie Fabre, Dinindu Sachindra Senanayake, Katerina Hatzi, Ari M. Melnick, Melanie J. McConnell. The mechanism of action of BCL6 in glioblastoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 1523. doi:10.1158/1538-7445.AM2017-1523
Epigenetic dysregulation in chronic myeloid leukaemia: A myriad of mechanisms and therapeutic options
Authors: Steffen Koschmieder, David Vetrie
Journal: Seminars in Cancer Biology (2017)

The onset of global epigenetic changes in chromatin that drive tumor proliferation and heterogeneity is a hallmark of many forms of cancer. Identifying the epigenetic mechanisms that govern these changes and developing therapeutic approaches to modulate them, is a well-established avenue pursued in translational cancer medicine. Chronic myeloid leukemia (CML) arises clonally when a hematopoietic stem cell (HSC) acquires the capacity to produce the constitutively active tyrosine kinase BCR-ABL1 fusion protein which drives tumor development. Treatment with tyrosine kinase inhibitors (TKI) that target BCR-ABL1 has been transformative in CML management but it does not lead to cure in the vast majority of patients. Thus novel therapeutic approaches are required and these must target changes to biological pathways that are aberrant in CML − including those that occur when epigenetic mechanisms are altered. These changes may be due to alterations in DNA or histones, their biochemical modifications and requisite ‘writer’ proteins, or to dysregulation of various types of non-coding RNAs that collectively function as modulators of transcriptional control and DNA integrity. Here, we review the evidence for subverted epigenetic mechanisms in CML and how these impact on a diverse set of biological pathways, on disease progression, prognosis and drug resistance. We will also discuss recent progress towards developing epigenetic therapies that show promise to improve CML patient care and may lead to improved cure rates.
Abstract 1233: WNT inhibitor ICG-001 prevents visceral metastatic triple negative breast cancer in a chemo-resistant patient derived xenograft -PDX-model
Authors: Iram Fatima, Ikbale El Ayachi, Chidi Zacheaus, Joseph Kerby Gray, Raya Krutilina, Tiffany N. Seagroves, Susan A. Krum, Gustavo A. Miranda-Carboni
Journal: Cancer Research (2017)

Abstract Triple negative breast cancer (TNBC) is characterized by absence of the estrogen receptor (ER) and progesterone receptor (PR), and human epidermal growth factor receptor 2 (HER2) amplification. Such cancers are highly aggressive and frequently metastasize to the lung and brain. Unlike other breast cancer subtypes such as, ER+, PR+ and/or HER2+, TNBCs have no specific targeted-therapeutics; therefore, studies should be directed for development of targeted therapies to treat this condition. Recent studies indicate that Wnt/β-catenin signaling is particularly activated in TNBC and is associated with reduced overall survival in all patients. Therefore, pharmacological targeting of Wnt signaling pathway constitutes an ideal approach for treating TNBC and various Wnt inhibitors are currently in use in clinical trials, such as; ICG-001 in metastatic colon cancer. The inhibitory effects of ICG-001 have not been tested in chemoresistant TNBC PDX tumors. Herein, we report for the first time that ICG-001 compound selectively inhibited the growth of several European American (EA) and African American (AA) triple negative breast cancer subtypes MSL and BSL-1 cell lines both in vitro and in vivo models. To further investigate the precise mechanisms of action in the regulation of Wnt/β-catenin signaling by ICG-001, we performed Western blot analysis, apoptosis assays, cell cycle assays and quantitative real-time reverse transcriptase- polymerase chain reactions in human triple negative breast cancer cells. This compound significantly interfered with Wnt/β-catenin signaling, and its inhibition led to downregulation of important downstream targets such as Axin2, HMGA2, PCNA, c-myc and Cyclin D1, which in turn led to inhibition of proliferation, cell cycle progression and metastasis confirming our previous results too. In addition ICG-001 inhibited the invasion and motility of tumor cells and showed inhibition and prevention of visceral metastatic PDX tumors from both chemoresistant EA and AA women. These results indicate that the Wnt inhibitor ICG-001 could constitute a powerful new chemotherapeutic agent against triple negative breast cancer. Citation Format: Iram Fatima, Ikbale El Ayachi, Chidi Zacheaus, Joseph Kerby Gray, Raya Krutilina, Tiffany N. Seagroves, Susan A. Krum, Gustavo A. Miranda-Carboni. WNT inhibitor ICG-001 prevents visceral metastatic triple negative breast cancer in a chemo-resistant patient derived xenograft -PDX-model [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 1233. doi:10.1158/1538-7445.AM2017-1233
Platelet-Targeted Delivery of Peripheral Blood Mononuclear Cells to the Ischemic Heart Restores Cardiac Function after Ischemia-Reperfusion Injury
Authors: Melanie Ziegler, Xiaowei Wang, Bock Lim, Ephraem Leitner, Franco Klingberg, Victoria Ching, Yu Yao, Dexing Huang, Xiao-Ming Gao, Helen Kiriazis, Xiao-Jun Du, Jody J. Haigh, Alex Bobik, Christoph E. Hagemeyer, Ingo Ahrens, Karlheinz Peter
Journal: Theranostics (2017)

One of the major hurdles in intravenous regenerative cell therapy is the low homing efficiency to the area where these cells are needed. To increase cell homing toward areas of myocardial damage, we developed a bispecific tandem single-chain antibody (Tand-scFvSca-1+GPIIb/IIIa) that binds with high affinity to activated platelets via the activated glycoprotein (GP)IIb/IIIa receptor, and to a subset of peripheral blood mononuclear cells (PBMC) which express the stem cell antigen-1 (Sca-1) receptor. Methods: The Tand-scFvSca-1+GPIIb/IIIa was engineered, characterized and tested in a mouse model of ischemia-reperfusion (IR) injury applying left coronary artery occlusion for 60 min. Fluorescence cell tracking, cell infiltration studies, echocardiographic and histological analyses were performed. Results: Treatment of mice undergoing myocardial infarction with targeted-PBMCs led to successful cell delivery to the ischemic-reperfused myocardium, followed by a significant decrease in infiltration of inflammatory cells. Homing of targeted-PBMCs as shown by fluorescence cell tracking ultimately decreased fibrosis, increased capillary density, and restored cardiac function 4 weeks after ischemia-reperfusion injury. Conclusion: Tand-scFvSca-1+GPIIb/IIIa is a promising candidate to enhance therapeutic cell delivery in order to promote myocardial regeneration and thereby preventing heart failure.