tbuckley/cabot-search huggingface dataset:
Abstract LB-144: Deletion of Map4k4 enhances CD8 T cell function
Authors: Emel Esen, Weilan Ye, Rajiv Jesudason, Ismail Sergin
Journal: Cancer Research (2019)

Abstract Map4k4 is broadly expressed across different cell types and its function is cell type and context dependent. Although it is expressed in multiple types of immune cells, its specific function in different subsets of lymphocytes and myeloid cells have yet to be determined. Here we demonstrate that reducing MAP4K4 activity can enhance CD8 T cell functions in the context of anti-tumor and anti-viral responses. Inducible deletion of Map4k4 increases CD8 T cell activation, proliferation, cytokine production, and target cell killing in vitro, and enhances CD8 T cell-mediated suppression of tumor growth as well as antigen-specific response to viral infection in vivo. Intratumoral T cells showed evidence of enhanced activation and produced more inflammatory cytokines when stimulated ex vivo. Simultaneously reducing MAP4K4 activity and blocking PDL1 resulted in additive anti-tumor efficacy. Our data suggests that MAP4K4 could be a potential target to augment anti-tumor and immunity. Citation Format: Emel Esen, Weilan Ye, Rajiv Jesudason, Ismail Sergin. Deletion of Map4k4 enhances CD8 T cell function [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-144.
Seeking light-chain amyloidosis very early: The SAVE trial—identifying clonal lambda light chain genes in patients with MGUS or smoldering multiple myeloma.
Authors: Ping Zhou, Adin Kugelmass, Denis Toskic, Amandeep Godara, Teresa Fogaren, Cindy Varga, Ray Comenzo
Journal: Journal of Clinical Oncology (2019)

8010 Background: In systemic AL amyloidosis (AL), caused by clonal Ig free light chains (LC) produced in 75% of cases by λ clones, patients often present with advanced organ damage, making earlier diagnosis a critical unmet need. Five λ IGLV germline genes account for 75% of AL λ-type ( IGLV 6-57, 1-44, 2-14, 1-51, 3-1) (Blood 2017;129:299), representing 56% of all AL patients. Relative risk of AL versus MM with these clonal genes can be high (7.3, 6-57; 2.5, 1-44), intermediate (1.7, 2-14; 1.2, 1-51) or low (0.8, 3-1) (Amyloid 2009;16:1). Progression to AL from smoldering multiple myeloma (SMM) or monoclonal gammopathy of undetermined significance (MGUS) occurs but is not well appreciated (JCO 2014; 32:2679). SAVE is a trial for λ SMM or λ MGUS patients with a κ:λ FLC ratio &lt; 0.26 and difference between involved and uninvolved FLC &gt; 23mg/L (JCO 2014;32:2699). Methods: Eligible patients ship peripheral blood (PB) or bone marrow (BM) samples to us for RT-PCR with cDNA from CD138+ cells, using primers for the Vλ families (Blood 2001;98:714). Amplicons are sequenced and the IGLV germline genes identified in IMGT (ImMunoGene-Tics, www.imgt.org). If the germline gene is AL-related, further evaluation is pursued. Results: Twenty asymptomatic λ patients from 18 states have been enrolled (3M, 17F) and 23 PB and 4 BM specimens obtained. Medians of months from diagnosis, involved FLC, κ:λ ratios, MNC and CD138-selected cells were 20.5 months, 113mg/L, κ:λ 0.06, 8.1x10 6 (0.8-24) and 3x10 5 (0-30), respectively. Seventeen patients have had IGLV genes identified, 12 with the first and 5 with additional specimens including 4 BM. Increased risk of AL was identified in 7 patients, 2 of whom had undiagnosed AL (both with IGLV2-14 germline genes). One patient with SMM diagnosed in 2016 had AL λ-type with GI involvement and is 9 months status post MEL 200 stem cell transplant (SCT), and the second with SMM diagnosed in 2009 had cardiac AL λ-type by heart biopsy with an NT-proBNP 171 (but with a suggestive MRI) and is en route to SCT. Conclusions: The SAVE trial enables early diagnosis of AL λ-type based on the λ IGLV gene used by the clonal plasma cells. By RT-PCR in this pilot study we identified the clonal λ gene 85% of the time. Earlier diagnosis will enable treatment with effective therapy such as MEL 200 SCT. Clinical trial information: NCT02741999.
First-in-human phase I study of the liposomal RNAi therapeutic Atu027 in patients with advanced cancer.
Authors: Beate Schultheis, Dirk Strumberg, Ansgar Santel, Frank Gebhardt, Michael Khan, Oliver Keil, Klaus Giese, Jörg Kaufmann
Journal: Journal of Clinical Oncology (2013)

2508 Background: Atu027 is a novel vascular stabilising, anti-metastatic, RNAi therapeutic, targeting systemic endothelial cell function and the tumor vasculature. Atu027 comprises a liposomal particle, containing an siRNA, which silences expression of the PKC pathway signalling molecule PKN3. Atu027 was previously shown to restrict tumor growth, local invasion and both, lymph node as well as pulmonary metastasis in mouse xenograft models. Methods: 34 patients with advanced cancer received 10 escalating doses of Atu027 without pre-medication as single and repeated i.v. infusions (qw2x4 per 28-d cycle) with a 3-wks dose intermission. Primary end points were safety, pharmacokinetics and -dynamics (biomarker identification). Response was monitored by CT/MR imaging at baseline, after treatment and at final follow-up (EoS) and was assessed according to RECIST. Results: Atu027 was well tolerated up to 0.336 mg/kg (around twice the predicted effective siRNA plasma levels). An MTD was not achieved. Around 50% of patients experienced disease stabilization according to RECIST. 8 patients had stable disease at EoS and 2 with neuroendocrine cancer had disease stabilization for 9 or 22 months. Partial regression of pulmonary metastasis and a regression of liver metastases were observed in subjects with neuroendocrine and breast cancer, respectively. An improved ECOG performance status was observed in patients of higher dose levels. Most AEs were low grade toxicities (1 or 2), including fatigue and increased lipase. Transient complement system activation was observed for certain factors. Area exposure levels of siRNA strands were dose-proportional and peaks were reached during 4 h-infusion. Of 102 plasma proteins assessed, sFLT1 (sVEGF-R1) was the most promising as a potential biomarker, with decreases from baseline in most pts from dose level 4-10 after treatment. Conclusions: Atu027 was well tolerated and there was suggestion of a clinically meaningful antitumor activity. In view of this further clinical trials can be initiated at a dose of up to 0.336 mg/kg and sFLT1 will be investigated as a potential biomarker. Clinical trial information: NCT00938574.
Abstract LB-005: Allosteric SHP2 phosphatase inhibition: Multiple mechanisms and chemotypes
Authors: Matthew J. LaMarche, Jeff Bagdanoff, Mike Acker, Ying-Nan Chen, Homan Chan, Michael Dore, Brant Firestone, Michelle Fodor, Jorge Garcia-Fortanet, Murphy Hentemann, Mitsunori Kato, Robert Koenig, Laura La Bonte, Shumei Liu, Movarid Mohseni, Rukundo Ntaganda, Patrick Sarver, Troy Smith, Martin Sendzik, Travis Stams, Stan Spence, Chris Towler, Hongyun Wang, Ping Wang, Sarah Williams, Zhouliang Chen, Huaixiang Hao, Gang Liu, Chen Liu, Eric McNeill, Bing Yu
Journal: Cancer Research (2019)

Abstract Protein tyrosine phosphatase SHP2 is an oncoprotein associated with cancer as well as a potential immune modulator due to its role in the programmed cell death PD-L1/PD-1 pathway. Small molecule inhibition of SHP2 has been widely investigated including our previous reports describing SHP099, which binds to a tunnel-like allosteric binding site. To broaden our approach to allosteric inhibition of SHP2, we conducted additional hit finding, evaluation, and structure-based scaffold morphing. These studies led to the identification of multiple, potent inhibitor chemotypes, an additional and distinct allosteric binding site, and the identification of SHP394, an orally efficacious inhibitor of SHP2 with improved potency and enhanced pharmacokinetic properties. Overall, this work improves upon our previously described allosteric inhibitors, and exemplifies and extends the range of permissible chemical templates that inhibit SHP2 via the allosteric mechanism. Citation Format: Matthew J. LaMarche, Jeff Bagdanoff, Mike Acker, Ying-Nan Chen, Homan Chan, Michael Dore, Brant Firestone, Michelle Fodor, Jorge Garcia-Fortanet, Murphy Hentemann, Mitsunori Kato, Robert Koenig, Laura La Bonte, Shumei Liu, Movarid Mohseni, Rukundo Ntaganda, Patrick Sarver, Troy Smith, Martin Sendzik, Travis Stams, Stan Spence, Chris Towler, Hongyun Wang, Ping Wang, Sarah Williams, Zhouliang Chen, Huaixiang Hao, Gang Liu, Chen Liu, Eric McNeill, Bing Yu. Allosteric SHP2 phosphatase inhibition: Multiple mechanisms and chemotypes [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-005.
Epithelial HIF-1α/claudin-1 axis regulates barrier dysfunction in eosinophilic esophagitis
Authors: Joanne C. Masterson, Kathryn A. Biette, Juliet A. Hammer, Nathalie Nguyen, Kelley E. Capocelli, Bejan J. Saeedi, Rachel F. Harris, Shahan D. Fernando, Lindsay B. Hosford, Caleb J. Kelly, Eric L. Campbell, Stefan F. Ehrentraut, Faria N. Ahmed, Hiroshi Nakagawa, James J. Lee, Eóin N. McNamee, Louise E. Glover, Sean P. Colgan, Glenn T. Furuta
Journal: Journal of Clinical Investigation (2019)

Epithelial barrier dysfunction is a significant factor in many allergic diseases, including eosinophilic esophagitis (EoE). Infiltrating leukocytes and tissue adaptations increase metabolic demands and decrease oxygen availability at barrier surfaces. Understanding of how these processes impact barrier is limited, particularly in allergy. Here, we identified a regulatory axis whereby the oxygen-sensing transcription factor HIF-1α orchestrated epithelial barrier integrity, selectively controlling tight junction CLDN1 (claudin-1). Prolonged experimental hypoxia or HIF1A knockdown suppressed HIF-1α-dependent claudin-1 expression and epithelial barrier function, as documented in 3D organotypic epithelial cultures. L2-IL5OXA mice with EoE-relevant allergic inflammation displayed localized eosinophil oxygen metabolism, tissue hypoxia, and impaired claudin-1 barrier via repression of HIF-1α/claudin-1 signaling, which was restored by transgenic expression of esophageal epithelial-targeted stabilized HIF-1α. EoE patient biopsy analysis identified a repressed HIF-1α/claudin-1 axis, which was restored via pharmacologic HIF-1α stabilization ex vivo. Collectively, these studies reveal HIF-1α's critical role in maintaining barrier and highlight the HIF-1α/claudin-1 axis as a potential therapeutic target for EoE.
Abstract 4006: Effect of Prior Cancer on Trial Eligibility and Treatment Outcomes in Nasopharyngeal Carcinoma: Implications for Clinical Trial Accrual
Authors: Ya-Qin Wang, Jia-Wei Lv, Ling-Long Tang, Xiao-Jing Du, Lei Chen, Wen-Fei Li, Xu Liu, Ying Guo, Ai-Hua Lin, Yan-Ping Mao, Ying Sun, Yu-Pei Chen, Jun Ma
Journal: Cancer Research (2019)

Abstract Background: In cancer trials, prior cancer is a common exclusion criterion. We evaluated the characteristics of prior cancer exclusion criteria in nasopharyngeal carcinoma (NPC) trials and determined its prognostic effect on patients with NPC. Methods: We reviewed NPC trials for prior cancer exclusion criteria. Then we estimated the effect of prior cancer among NPC patients using the Surveillance, Epidemiology, and End Results database. Propensity score-matching was used to compensate for differences in baseline characteristics between patients with and without prior cancer. Results: There were 109 clinical trials involving 10,437 patients; 49 trials (45%) excluded patients with prior cancer. Prior cancer exclusion was more common in recent or phase III trials. We identified 10,195 NPC patients; 6.2% had prior cancer. More than 70% of these cancers were in situ/localized/regional and diagnosed relatively close to the NPC diagnosis (median 3.3 years). Patients with certain prior cancer type (prostate, breast, gynecological, hematological), time of diagnosis (&amp;gt;5 years ago), or stage (in situ/localized) did not have inferior survival compared with patients with no prior cancer. We tested one form of prior cancer exclusion criteria in an NPC cohort resembling a modern trial population: it did not adversely affect overall and NPC-specific survival. Conclusions: Many NPC trials excluded patients with prior cancer, which impacts trial accrual and generalizability. Our findings suggest that broader inclusion in trials of patients with NPC with prior cancer might not affect trial outcomes. More research is needed to understand the appropriateness of this exclusion policy across cancer types and trials. Citation Format: Ya-Qin Wang, Jia-Wei Lv, Ling-Long Tang, Xiao-Jing Du, Lei Chen, Wen-Fei Li, Xu Liu, Ying Guo, Ai-Hua Lin, Yan-Ping Mao, Ying Sun, Yu-Pei Chen, Jun Ma. Effect of Prior Cancer on Trial Eligibility and Treatment Outcomes in Nasopharyngeal Carcinoma: Implications for Clinical Trial Accrual [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 4006.
Abstract 894: A Self-Immobilizing NIR Probe for <i>in vivo</i>Imaging of Chemotherapy Induced Senescence
Authors: Xiaowei Ma, Jun Liu, Ying Wang, Chao Cui, Philip Deenik
Journal: Cancer Research (2019)

Abstract Post-treatment relapse and distant metastasis are significant causes of mortality by cancers. Previous research has demonstrated that cancer treatments, such as chemotherapy, can sometimes stimulate tumor spread. This phenomenon is associated with an essential process that some cells are resistant to apoptosis by entering premature senescence after therapy. Thus, chemotherapy-induced cellular senescence may play a critical role in cancer recurrence and metastasis. To monitor the cellular senescence induced by chemotherapy, we developed a self-immobilizing near infrared (NIR) probe (4-152) that can be activated by senescence-associated beta-galactosidase (β-gal) and get immobilized at site of activation, allowing the monitoring of chemotherapy-induced senescence in vivo. We first verified our approach in vitro, when cervical cancer cells (HeLa) were treated with camptothecin (CPT), followed by fluorescence imaging with 4-152. The results demonstrated that our designed probe exhibited a dramatic NIR fluorescent response in cells receiving CPT treatment. The fluorescent western blot showed that the probe could be activated by β-gal and attached to the enzyme. The confocal microscopy imaging and flow cytometry results further demonstrated the 4-152 could accumulate in the CPT-induced senescent cancer cells. We then investigated the in vivo imaging ability of the probe for senescence detection in tumor xenografts treated with CPT. After treatment with CPT or saline (as control), 4-152 was administrated to the mice by tail vein injection. NIR imaging was then performed on the IVIS Spectrum in vivo imaging system. The imaging showed that the 4-152 could quickly distribute to the tumor and accumulated for over 24 hours. The fluorescence intensity of the CPT treated tumors was significantly higher than the untreatment tumors. After imaging, tumors and major organs were resected for ex vivo imaging. The fluorescent intensity of tumors showed 6.27-fold higher than liver. Ex vivo immunofluorescence staining and X-gal staining further confirmed the correlation of probe 4-150 and senescence cells.In conclusion, we have developed an activatable self-immobilizing NIR probe for the monitoring of chemotherapy-induced cellular senescence in vivo. This probe may be used for the treatment effect monitoring and therapeutic regimen optimization in the future. Reference1. Ebos JM. Prodding the beast: assessing the impact of treatment-induced metastasis. Cancer Res 2015; 75: 3427-3435. Citation Format: Xiaowei Ma, Jun Liu, Ying Wang, Chao Cui, Philip Deenik. A Self-Immobilizing NIR Probe for in vivoImaging of Chemotherapy Induced Senescence [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 894.
Abstract 4391: Disruption of the translation initiation complex by eIF4A mutant inhibits prostate tumor growth <i>in vivo</i>
Authors: Puja Singh, Hanyong Chen, Hanxuan Li, Young-In Chi, Bin Liu, Junxuan Lu, Wei Li, Zigang Dong, Yibin Deng
Journal: Cancer Research (2019)

Abstract Translation initiation in cancer cells is the rate-limiting step of oncogenic mRNAs translation/protein synthesis and is primarily mediated by the eukaryotic translation initiation factor 4 F (eIF4F) complex that consists of three subunits: eIF4E, which binds the cap of mRNA; eIF4A, an RNA helicase implicated in unwinding mRNA structure; and a scaffold protein eIF4G. Our prior crystal structure determination of human eIF4A in complex with Heat 1 domain of eIF4GI (722-999) revealed that eIF4G interacts with both N- and C-terminal domains of human eIF4A (eIF4A1-NTD and eIF4A1-CTD). Utilizing structural information gained from this complex, we generated a series of eIF4A mutants (eIF4A1-NTD: E41K, R45D, Y48A and eIF4A1-CTD: T271A, R324D, D296A/T298A) in order to identify the crucial site(s) of interaction with eIF4G Heat 1 domain. Using in vitro binding studies, we demonstrated that amongst various mutants tested, eIF4A-CTD (eIF4A1R324D) mutant disrupted the eIF4A/eIF4G Heat 1 complex formation, mirroring the binding residue E809K mutant of eIF4G that also interrupted eIF4A/eIF4G Heat 1 interaction. Given that eIF4G has an additional eIF4A-binding site named Heat 2 domain, we further investigated whether eIF4A1R324D mutant is able to disrupt binding to full-length eIF4G protein in vivo. Surprisingly, overexpression of Flag-tagged eIF4A1R324D in prostate cancer cell line blocked interaction with exogenous eIF4G as well as endogenous eIF4G. Taken together, these results strongly suggest that eIF4A1R324 residue plays a crucial role in mediating eIF4A/eIF4G complex formation in vivo. Furthermore, overexpression of eIF4A1R324D mutant significantly blocked oncogene c-myc and Bcl-2 mRNA translation thereby inhibiting prostate tumor growth in vivo. To conclude, our studies provide a previously unexplored strategy to identify small-molecule compounds disrupting eIF4A-eIF4G complex by targeting the pocket spanning eIF4AR324 and its binding site residues on eIF4G for cancer therapy. Citation Format: Puja Singh, Hanyong Chen, Hanxuan Li, Young-In Chi, Bin Liu, Junxuan Lu, Wei Li, Zigang Dong, Yibin Deng. Disruption of the translation initiation complex by eIF4A mutant inhibits prostate tumor growth in vivo [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 4391.
Matt Morgan: Fixing our broken wards
Authors: Matt Morgan
Journal: BMJ (2019)

As I reach the top of the staircase a faded sign reads, “Block A, Tower 3, Wards 7F and 6G.” Nobody really knows what these characters mean or how they help to navigate the twists of an ever changing, expanding hospital. A patient looks up and down at a clutched paper letter, wondering if they’re going the right way. A hospital porter senses their disorientation and points them back towards the way they’ve already come.

As I approach the door of the ward, I see a line of relatives huddled around a buzzer with “ONLY PRESS ONCE” taped over its scratched buttons. Once a minute, once an hour, once a day? A busy nurse, looking after patients and supporting families, hears the buzzer’s call but can’t …
Lobectomy should remain the first choice for treating early stage nonsmall cell lung cancer
Authors: Han-Yu Deng, Qinghua Zhou
Journal: European Respiratory Journal (2019)

Stereotactic body radiotherapy (SBRT), also known as stereotactic ablative radiotherapy, is characterised as a highly noninvasive precise radiotherapy that is performed by applying an external focused beam guided by high-resolution imaging to target well-defined small tumours [1]. Because of its high local control and survival with acceptable toxicity, SBRT has become the guideline-recommended choice for treating early stage nonsmall cell lung cancer (NSCLC) patients who are not fit for surgery [2]. However, recently, SBRT has also imposed great challenges to surgery in treating operable patients with early stage NSCLC [3]. However, in the absence of completed randomised controlled trials, the currently available evidence for comparing the efficacy of SBRT and surgery for treating early stage NSCLC has all come from observational studies with propensity score-matched analysis [4]. A recent study by Detillon et al. [5] has compared the efficacy of SBRT with video-assisted thoracoscopic (VATS) lobectomy for treating stage I NSCLC in elderly patients by applying propensity score-matched analysis. They included a total of 792 elderly patients (≥65 years old) with clinical stage I NSCLC undergoing SBRT or VATS lobectomy. In the analysis of unmatched cohorts, with significant baseline characteristics imbalance between the two groups, they found that VATS lobectomy yielded significantly better overall survival than SBRT (77 months versus 38 months; p<0.001). In the analysis of matched cohorts, with well-balanced characteristics between the two groups, VATS lobectomy yielded similar overall survival to SBRT in the first 15 months of follow-up, but significantly better overall survival than SBRT after 15 months of follow-up in both primary and secondary analyses with different matching covariates [5]. Therefore, their study again added to the evidence that patients with clinical stage I NSCLC receiving VATS lobectomy had better overall survival than patients receiving SBRT. Lobectomy should remain the first choice for treating early stage nonsmall cell lung cancer <http://bit.ly/2M982Il>
IL-27 enhances IL-15/IL-18-mediated activation of human natural killer cells
Authors: Yeon Ho Choi, Eun Jin Lim, Se Wha Kim, Yong Wha Moon, Kyung Soon Park, Hee-Jung An
Journal: Journal for ImmunoTherapy of Cancer (2019)

<h3>Background</h3> Natural killer (NK) cells are an emerging new tool for cancer immunotherapy. To develop NK cell therapeutics from peripheral blood mononuclear cells (PBMCs) of healthy donors, substantial expansion of primary NK cells is necessary because of the very low number of these cells in peripheral blood. In this study, we aimed to investigate the effect of various cytokine alone or combinations, in expanded NK cells and to analyze the synergetic effect of cytokine combinations. <h3>Methods</h3> Human NK cells were isolated from healthy donor PBMC. Purified NK cells were stimulated with single cytokines or combinations of IL-2, IL-15, IL-18, and IL-27. The expanded NK cells were characterized by flow cytometry, cytotoxicity assay, calcein AM assay and Western blot. <h3>Results</h3> We investigated the synergistic effects of each cytokine, namely, IL-2, IL-15, IL-18, and IL-27, on human NK cells isolated from PBMCs of healthy donors and cultured for 21 days. We identified that IL-15/IL-18/IL-27-mediated activation of NK cells most potently increased NK cell proliferation, cytotoxicity, and IFN-ɣ secretion compared with the activation observed with other treatments, including IL-2, IL-15, and IL-15/IL-18. Additionally, the expression of DNAM-1, NKG2D, CD69, and natural cytotoxicity receptors (NCRs; NKp30 and NKp44) increased on day 21 compared to that on day 0, demonstrating the activation of NK cells. In vitro, expanded NK cells were highly cytotoxic against cancer cells, displaying increased perforin and granzyme B accumulation. <h3>Conclusions</h3> Taken together, these results indicated that IL-27 can synergize on NK cell expansion and activation with IL-15 and IL-18. In addition, we described an improved culture method for ex vivo expansion of human NK cells with IL-15/IL-18/IL-27 stimulation and characterized the response of NK cells to this stimulation.