tbuckley/cabot-search huggingface dataset:
Pathologic Considerations and Standardization in Mesothelioma Clinical Trials
Authors: Ming-Sound Tsao, Michele Carbone, Francoise Galateau-Salle, Andre L. Moreira, Andrew G. Nicholson, Anja C. Roden, Alex A. Adjei, Marie-Christine Aubry, Dean A. Fennell, Daniel Gomez, David Harpole, Mary Hesdorffer, Fred R. Hirsch, Geoffrey Liu, Shakun Malik, Anna Nowak, Tobias Peikert, Ravi Salgia, Peter Szlosarek, Emanuela Taioli, Haining Yang, Anne Tsao, Aaron S. Mansfield
Journal: Journal of Thoracic Oncology (2019)
Abstract 1247: Screening the membrane proteome to determine antibody specificity and discover new immunomodulatory targets
Authors: Duncan Huston-Paterson
Journal: Cancer Research (2019)

Abstract The Membrane Proteome Array (MPA) is a cell-based expression array of more than 5,300 membrane proteins that enables the screening of preclinical antibodies for off-target binding and the deorphaning of phenotypic antibodies to identify their associated targets. Each membrane protein is expressed in live cells in its native conformation with appropriate post-translational modifications. Binding interactions are tested and validated using high-throughput flow cytometry, providing a comprehensive assessment of antibody binding across the membrane proteome. Membrane proteins in the MPA are fully functional and can be used for phenotypic screening to identify new therapeutic targets. Using a T-cell co-culture approach, we identified dozens of novel co-stimulatory proteins, as well as many well-validated proteins known to be involved in T-cell activation. The proteins identified in this screen represent novel therapeutic targets across multiple membrane protein classes and likely function on diverse axes of T-cell regulation. Citation Format: Duncan Huston-Paterson. Screening the membrane proteome to determine antibody specificity and discover new immunomodulatory targets [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 1247.
Abstract 4841: Rapid screening of cyclotide-based libraries for the selection of potent E3 ligase antagonists
Authors: Julio A. Camarero
Journal: Cancer Research (2019)

Abstract We report novel methods for the biosynthesis of natively-folded MCoTI-based cyclotides inside live E. coli cells using a split protein splicing unit. The cyclotide MCoTI-cylotides are potent trypsin inhibitors recently isolated from the seeds of Momordica cochinchinensis, a plant member of cucurbitaceae family. Biosynthesis of genetically encoded cyclotide-based libraries opens the possibility of using single cells as microfactories where the biosynthesis and screening of a particular inhibitor can take place in a single process within the same cellular cytoplasm. The cyclotide scaffold has a tremendous potential for the development of therapeutic leads based on their extraordinary stability and potential for grafting applications. We will show an example, where a large cyclotide-based genetically-encoded library was used to screen for low nanomolar antagonists for the Hdm2-HdmX RING-mediated E3 ligase activity. We will also present different strategies to improve the cellular uptake and pharmacokinetic profiles of bioactive cyclotides. Citation Format: Julio A. Camarero. Rapid screening of cyclotide-based libraries for the selection of potent E3 ligase antagonists [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 4841.
The technology specialist: a 21st century support role in clinical care
Authors: Valerie A. Noel, Elizabeth Carpenter-Song, Stephanie C. Acquilano, John Torous, Robert E. Drake
Journal: npj Digital Medicine (2019)

Mental health clinicians, clients, and researchers have shown keen interest in using technology to support mental health recovery. However, technology has not been routinely integrated into clinical care. Clients use a wide range of digital tools and apps to help manage their mental health, but clinicians rarely discuss this form of self-management in clinical interactions. This absence of communication is concerning because the safety and quality of the digital tools and apps people use may negatively affect their mental health outcomes. Mental health systems could benefit from someone to help identify technology-based supports that reflect current evidence and minimize privacy and security concerns. This technology specialist may also enhance the therapeutic bond between the client and the clinician. In working with a technology specialist, clients may begin to gain a sense of control over their mental health, and perhaps use fewer mental health services.
Efficacy and tolerability of the combination of Liposomal irinotecan and 5-fluorouracil/leucovorin in advanced pancreatic cancers: post-approval clinic experience
Authors: R. Paluri, A. Kasi, T. Mcginnis, C. Smith, G. Williams, R. Jacob, U. Manne, O. Gbolahan, G. Naik
Journal: Annals of Oncology (2019)
Abstract 4128: Identification and characterization of LHC165, a TLR7 agonist designed for localized intratumoral therapies
Authors: Jonathan A. Deane, German A. Cortez, Chun Li, Nora Eifler, Shailaja Kasibhatla, Nehal Parikh, Shifeng Pan, Steven Bender
Journal: Cancer Research (2019)

Abstract Checkpoint inhibition has transformed immunotherapy by alleviating T cell exhaustion in a subset of patients. However, an important component of effective immune targeting to expand the benefit of immune response requires engagement of both innate and adaptive responses. Our understanding of safe and effective engagement of the innate immune system is evolving, with multiple preclinical and clinical agents targeting pathways such the Toll-like Receptors. Here we disclose the structure and preclinical activity of LHC165, a benzonapthyridine TLR7 agonist that is adsorbed to aluminum hydroxide. The interaction between LHC165 and aluminum hydroxide allows for a slow release from the injection site resulting in improved efficacy in mouse models compared with free LHC165. This localization allows for immune activation at the site of the tumor and also results in lower systemic exposure and cytokine induction. Intratumoral studies in syngeneic preclinical studies show single agent activity and a benefit when dosed in combination with checkpoint blockade. LHC165 as a single agent and in combination with PDR001 is currently enrolling patients with advanced malignancies in CLHC165X2101. Citation Format: Jonathan A. Deane, German A. Cortez, Chun Li, Nora Eifler, Shailaja Kasibhatla, Nehal Parikh, Shifeng Pan, Steven Bender. Identification and characterization of LHC165, a TLR7 agonist designed for localized intratumoral therapies [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 4128.
Abstract 1744: SAMHD1 expression and impact on clinical outcome in diffuse large B-cell lymphoma: a potential therapeutic target
Authors: Waaqo Daddacha
Journal: Cancer Research (2019)

Abstract Diffuse large B-cell lymphoma (DLBCL) is the most common subtype of non-Hodgkin lymphoma. While standard treatment with rituximab, cyclophosphamide, doxorubicin, vincris- tine, and prednisone (R-CHOP) can cure DLBCL, failed patients have poor outcome. Thus, a search for stand-alone or adjuvant therapy to improve patient’s outcome is important. Sam and HD domain-containing protein 1 (SAMHD1) is a well-established deoxyribonucleotide triphosphate (dNTP) triphosphohydrolase. Its dNTPase activity has been associated with cellular defence mechanism against infection by depleting cellular dNTP pool bellow level required for viral replication. SAMHD1 mutations have been associated with Aicardi Goutières (AGS) and cancers such as chronic lymphocytic leukemia (CLL), demonstrating its relevance beyond viral infection. In addition, it has been shown that SAMHD1 expression in Recently, our lab has defined a novel role for SAMHD1 in DNA end resection to facilitate DNA double strand break (DSB) repair by homologous recombination (HR). SAMHD1 expression and its diagnostic or therapeutic relevance in DLBCL is not known. Thus, we analyzed SAMHD1 expression in patients with DLBCL and determined its correlation with clinical outcome. In addition, we studied the SAMHD1 expression in germinal center B cell (GCB) and activated B cell (ABC) DLBCL cells lines. Also, we examined the possibility of depleting SAMHD1 using a virus like particles (VLPs) containing viral protein x (Vpx) in DLBCL cell lines. Finally, we determined the effect on cells sensitivity to standard DLBCL therapy, R-CHOP, and other DNA damage inducing agents. Low SAMHD1 expression correlates with improved overall survival. SAMHD1 was downregulated in ABC as compared to GCB DLBCL cell lines and SAMHD1 depletion sensitizes DLBCL cell lines to R-CHOP and other DNA damage inducing agents. These findings suggest that SAMHD1 is a potential therapeutic target to improve the DLBCL patient’s clinical outcome. Citation Format: Waaqo Daddacha. SAMHD1 expression and impact on clinical outcome in diffuse large B-cell lymphoma: a potential therapeutic target [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 1744.
Abstract 4151: Siglec-15 is a novel immunomodulatory effector of adaptive immune evasion in acute lymphoblastic leukemia
Authors: Claire Pillsbury, Jairo A. Fonseca, Jodi Dougan, Lori Gardner, Jennifer Rabe, Christy Gearheart, Chris C. Porter
Journal: Cancer Research (2019)

Abstract Despite advances in therapy for acute lymphoblastic leukemia (ALL), it remains a leading cause of illness-related death in children and has poor long term disease-free survival and prognosis in recurrence in adults. Recent developments in immune-based therapies, such as CAR T cells, have shown great promise, but immune evasion mechanisms of leukemia remain poorly understood, and alternative strategies to engage the immune system are needed. Our group has characterized a role for calcineurin (CN) as a driver of a potent immune escape mechanism in an aggressive murine model of BCR-ABL+ ALL. We performed RNA-seq analysis of control and CN-deficient ALL cells to identify downstream mediators of this effect. Siglec-15 emerged as one of the most differentially expressed genes, being preferentially downregulated in the more immunogenic CN-deficient cells. The role of this Siglec-family immunomodulator is yet unstudied in the context of leukemia and could represent a novel mechanism for immune evasion. We first validated lower expression of Siglec-15 in CN-deficient leukemia cells by RT-qPCR. We next mined publicly available databases, which revealed higher expression of Siglec-15 in primary B-ALL and AML leukemias as compared to normal PBMCs, as well as in post-chemotherapy MRD samples as compared to at-diagnosis samples. Western blot analysis of human leukemia cell lines demonstrated upregulation of Siglec-15 expression in B-ALL, some AML, as well as DLBCL, as compared to normal PBMCs. To determine if Siglec-15 mediates immune evasion in vivo, we knocked down Siglec-15 in the murine model of BCR-ABL+ ALL, which resulted in rapid suppression of the leukemia following engraftment in immunocompetent mice, an effect lost in immunocompromised counterparts. Preliminary studies with cells in which Siglec-15 was knocked-out using CRISPR/Cas9 revealed similar results. Importantly, Siglec-15-deficient cells do not have any changes in proliferation or susceptibility to DNA damage-induced apoptosis. To address the capacity for therapeutic targeting of Siglec-15, mice with parental leukemia were treated with a monoclonal blocking antibody against Siglec-15, yielding an overall reduction in leukemic burden and prolonged survival. Taken together, these results suggest that Siglec-15 is a novel immunomodulatory effector and has a therapeutically exploitable role in immune evasion of ALL. Citation Format: Claire Pillsbury, Jairo A. Fonseca, Jodi Dougan, Lori Gardner, Jennifer Rabe, Christy Gearheart, Chris C. Porter. Siglec-15 is a novel immunomodulatory effector of adaptive immune evasion in acute lymphoblastic leukemia [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 4151.
Chemoradiation with capecitabine and mitomycin-C for locally advanced anal squamous cell carcinoma: experience of a single Portuguese institution
Authors: I. Miguel, A. Monteiro, I. Oliveira, T. Marques, I. Rosa, M. Limbert, G. Fernandez, R. Barroca, I. Marques, R. Fonseca, L. Mirones, T. Ferreira, J. Venâncio, A. Moreira, J. Freire
Journal: Annals of Oncology (2019)
Abstract 4516: Suppression of metastasis by inhibiting nanoscale physical communication of cancer cell and the endothelium
Authors: Chinmayee Dash, Tanmoy Saha, Sachin Khiste, Shiladitya Sengupta
Journal: Cancer Research (2019)

Abstract The progression of metastasis proceeds through the physical communication of cancer cells with the endothelium via tunneling nanotubes (TNTs). Restriction on the cancer cell and the endothelium communication by inhibiting TNT formation can lead to breakthrough advancement in the treatment of metastasis. However, the mechanistic interpretation about the formation of TNTs between the cancer cells and the endothelium has been poorly defined in literature. Our study integrates the investigation of mechanism behind the TNT formation and introduction of a pharmacological inhibitor for TNT formation. The nanobridges are primarily composed of cytoskeletal elements such as actin and tubulin, which originates from the energy dependent remodeling of membrane cytoskeletal elements. Here, we propose that the members of Rho-family of GTPases, Cdc42, Ral and Rac along with exocyst complex, are involved in the actin polymerization based on their localization to the nanobridges between the metastatic cancer cells and the endothelium. A significant decrease in mitochondrial transfer and TNT formation has been observed when the inhibitor for Cdc42/Rac1 GTPase inhibitor (ML141), and a geranylgeranyltransferase 1 inhibitor (L-778,123) has been employed in the co-culture. The amount of mitochondrial transfer was evaluated with flow cytometry and the number of TNT formation was counted from imaging, which in case of inhibitors was highly reduced. Simultaneously the involvement of exocyst complex was confirmed through imaging. The proteins involved in the exocyst complex co-localize with the nanotubes and was further validated by siRNA-based knock down study. The nanotubular pathways are the primary mode of communication between cancer cell and endothelium, which leads to the conversion of healthy endothelium to a pathological one. Hindering the TNT mediated communication via pharmacological inhibitors can reduce the chance of metastasis. Conclusion: Investigation of molecular mechanism behind the TNT formation and employing innovative ways to have restriction over that can be a potential next generation therapeutic module for controlling metastasis. Reference: Connor Y, Tekleab S, Nandakumar S, Walls C, Tekleab Y, Reiberger T, Husain A, Gadish O, Sabbisetti V, Kaushik S, Sehrawat S, Kulkarni A, Dvorak H, Zetter B, Jain RK, Edelman E, Sengupta S. Physical nanoscale conduits-mediated communication between tumor cells and endothelium enables a metastatic hijack. Nature Communications (2015) 6:8671. Citation Format: Chinmayee Dash, Tanmoy Saha, Sachin Khiste, Shiladitya Sengupta. Suppression of metastasis by inhibiting nanoscale physical communication of cancer cell and the endothelium [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 4516.
Abstract 5241: Whole transcriptome TempO-Seq profiling of focal areas of H&amp;E stained FFPE: Differentiation of normal colon and cancer phenotypes between donors
Authors: Christy Trejo, Elliot Imler, Milos Babic, Peter Shepard, Raymond Nagle, Joanne Yeakley, Bruce Seligmann
Journal: Cancer Research (2019)

Abstract Profiling gene expression from small amounts of FFPE using methods that require extraction of RNA from the tissue, such as RNA-seq, have been problematic. We report use of a modification of the whole transcriptome TempO-Seq® assay (Yeakley et al, PLOSone, 2017; DOI:10.1371/journal.pone.0178302) to profile 2 mm2 areas of 5 μm thick FFPE sections by scraping the tissue and assaying lysates directly without extracting the RNA. Duration of fixation and the amount of sample down to a 2 mm2 area do not impact the performance of the assay. Good results can be achieved using FFPE blocks that are up to 30 years old. As a consequence of the ability to assay areas as small as 2 mm2 from H&amp;E stained tissue, we were able to scrape and profile areas of colorectal cancer vs adjacent normal and obtain replicates within donors, and then compare between donors. The assay shows excellent reproducibility, with R2 &amp;gt; 0.95 between biological replicates (separate samples taken from the same patient and lysed/processed separately). While the normal tissues from the patients exhibited a range of expression variability, they all clustered very tightly when analyzed via principal component analysis. The cancer tissue profile from each patient was not only substantially different from the normal tissue profile of that patient, but substantially different from all profiles within the normal tissue cluster of all patients. Furthermore, the cancer tissue profiles were separated into distinct subgroups. Changes in regulatory pathways leading to oncogenesis could be directly distinguished between patients. These results demonstrate the ability to use whole transcriptome TempO-Seq profiling to investigate molecular subtypes of colon cancer using archival FFPE samples. We are expanding the cohort of patients being profiled to investigate these signatures further, and to draw out signatures which allow direct subtype classification purely from expression data. Citation Format: Christy Trejo, Elliot Imler, Milos Babic, Peter Shepard, Raymond Nagle, Joanne Yeakley, Bruce Seligmann. Whole transcriptome TempO-Seq profiling of focal areas of H&amp;E stained FFPE: Differentiation of normal colon and cancer phenotypes between donors [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 5241.
Abstract 4808: Preclinical studies of the combination of ONC201, radiotherapy and Temozolomide against GBM, DIPG and ATRT cell lines
Authors: Lanlan Zhou, Wafik S. El-Deiry
Journal: Cancer Research (2019)

Abstract The American Cancer Society predicts, in 2018, there will be ~23,880 new cases and 16,830 deaths caused by primary cancer of the brain and spinal cord, in the US. CNS tumors are the most common cause of cancer-related deaths in adolescents and young adults. First-in-class small-molecule imipridone ONC201 can act as a dual inhibitor of ERK/AKT and can induce an integrated stress response (ISR), pro-apoptotic TRAIL receptor DR5 activation, cancer stem cell depletion, and growth arrest. ONC201 crosses the blood brain barrier and has demonstrated clinical benefits in glioblastoma patients. Radiation therapy is used alone or in combination with surgery and/or chemotherapy such as Temozolomide in the treatment of primary or metastatic brain tumors. We hypothesized that ONC201 may synergize with radiotherapy and Temozolomide in brain tumor treatment. Glioblastoma (GBM), diffuse intrinsic pontine glioma (DIPG) and atypical teratoid rhabdoid tumor (ATRT) cell lines were tested in this study. Cell viability and colony formation assays were performed with ONC201 alone up to 20 μM or in combination with radiotherapy up to 8 Gy and Temozolomide up to 100 μM. Western blots were used to document apoptosis of treated cells. We observed synergy between ONC201 and radiation and between ONC201 and Temozolomide with the best combination indices of 0.51 and 0.21 respectively. Further studies are evaluating the role of dopamine receptors engaged by ONC201, the ISR and TRAIL pathway in the synergistic effect that would support further development of the triple combination therapy in brain tumors. Citation Format: Lanlan Zhou, Wafik S. El-Deiry. Preclinical studies of the combination of ONC201, radiotherapy and Temozolomide against GBM, DIPG and ATRT cell lines [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 4808.
A whole-brain map of long-range inputs to GABAergic interneurons in the mouse medial prefrontal cortex
Authors: Qingtao Sun, Xiangning Li, Miao Ren, Mengting Zhao, Qiuyuan Zhong, Yuqi Ren, Pan Luo, Hong Ni, Xiaoyu Zhang, Chen Zhang, Jing Yuan, Anan Li, Minmin Luo, Hui Gong, Qingming Luo
Journal: Nature Neuroscience (2019)
Abstract 2389: Role of Midkine in molecular targeted therapy to TIP1 for lung cancer treatment
Authors: Vaishali Kapoor, Abhay K. Singh, Dinesh Thotala, Dennis Hallahan
Journal: Cancer Research (2019)

Abstract Non-small cell lung cancer (NSCLC) ranks among the highest cancer-related mortalities world-wide. Targeted therapy has been a growing topic of investigation to improve therapeutic efficacy for NSCLC. A few targeted therapies that exploit aberrant protein expression profiles have been approved for NSCLC. However, marginal improvement in efficacy observed with these therapeutic approaches highlights the need for discovery of additional therapeutic targets. We identified Tax interacting protein 1 (TIP1) which is overexpressed in various cancers as a molecular targets. We focused on antibody-based targeting of the chaperone protein TIP1. The functional domain of TIP1 (PDZ domain) caps the C-terminus of many cellular proteins that regulate important cellular functions. Knocking down TIP1 revealed that it plays an important role in cell signaling, cancer development, and progression. Comparing antibodies targeting different epitopes of TIP1, we found that antibodies against the PDZ domain of TIP1 were most effective in inducing cytotoxicity of lung cancer cells but not normal cells. Anti-PDZ/TIP1 antibodies injected into mice bearing lung cancer bind specifically to cancer and substantially enhance tumor control. A mass spectrometry-based approach identified Midkine (MDK) as a putative protein that modulates this cytotoxicity by anti-TIP1 antibodies. Additional studies suggested that the β-catenin/Wnt signaling may be involved in induction of MDK after blocking of TIP1. These studies led to the hypothesis that MDK is upregulated by the anti-PDZ/TIP1 antibody via the β-catenin/Wnt signaling pathway, which subsequently modulates downstream signaling mechanisms. This project will systematically characterize the mechanisms of cytotoxicity by the anti-PDZ/TIP1 antibodies. To achieve this, a number of novel methodologies including genome-wide CRISPR knockout, proteomics and mass cytometry to characterize the link between TIP1 and MDK will be applied. The project will guide development of combination therapies to optimize efficacy of NSCLC treatment. One strategy proposed, is dual-targeting of TIP1 and MDK for enhanced efficacy. This project will lead to identification of novel molecular targets for NSCLC treatment that have never been considered before. Citation Format: Vaishali Kapoor, Abhay K. Singh, Dinesh Thotala, Dennis Hallahan. Role of Midkine in molecular targeted therapy to TIP1 for lung cancer treatment [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 2389.