tbuckley/cabot-search huggingface dataset:
Integration of Antiangiogenic Therapy with Cisplatin and Gemcitabine Chemotherapy in Patients with Nasopharyngeal Carcinoma
Authors: Wan Qin Chong, Chwee Ming Lim, Arvind Kumar Sinha, Chee Seng Tan, Gloria Hui Jia Chan, Yiqing Huang, Nesaretnam Barr Kumarakulasinghe, Raghav Sundar, Anand D. Jeyasekharan, Woei Shyang Loh, Joshua K. Tay, Kritika Yadav, Lingzhi Wang, Andrea L. Wong, Li Ren Kong, Ross Andrew Soo, Jieying Amelia Lau, Yu Yang Soon, Robby Miguel Goh, Francis Cho Hao Ho, Siew Meng Chong, Soo Chin Lee, Kwok Seng Loh, Bee Choo Tai, Yaw Chyn Lim, Boon Cher Goh
Journal: Clinical Cancer Research (2020)

Induction cisplatin and gemcitabine chemotherapy is a standard treatment for locally advanced nasopharyngeal carcinoma (NPC). Inhibition of VEGF axis has been shown to promote maturation of microvasculature and improve perfusion. We conducted a four-arm study to assess the effect of two doses of either sunitinib or bevacizumab with chemotherapy in NPC.Patients with treatment-naïve locally advanced NPC were treated with three cycles of 3-weekly cisplatin and gemcitabine preceded by 1 week of anti-VEGF therapy for each cycle, followed by standard concurrent chemoradiation: arm A patients received 7 days of 12.5 mg/day sunitinib; arm B 7 days of 25 mg/day sunitinib; arm C bevacizumab 7.5 mg/kg infusion; arm D bevacizumab 2.5 mg/kg infusion. Patients with metastatic NPC were treated with up to six cycles of similar treatment without concurrent chemoradiation.Complete metabolic response (mCR) by whole body 18FDG PET was highest in arm C (significant difference in four groups Fisher exact test P = 0.001; type 1 error = 0.05), with 42% mCR (95% confidence interval, 18-67) and 3-year relapse-free survival of 88% in patients with locally advanced NPC. Significant increase in pericyte coverage signifying microvascular maturation and increased immune cell infiltration was observed in posttreatment tumor biopsies in Arm C. Myelosuppression was more profound in sunitinib containing arms, and tolerability was established in arm C where hypertension was the most significant toxicity.Bevacizumab 7.5 mg/kg with cisplatin and gemcitabine was well tolerated. Promising tumor response was observed and supported mechanistically by positive effects on tumor perfusion and immune cell trafficking into the tumor.
The NGAL iron delivery pathway coupling with extracellular matrix signal modulates E-cadherin cellular localization and colon cancer cell invasion
Authors: Limei Hu, Hong Zheng, Stanley Hamilton, Wei Zhang
Journal: Cancer Research (2007)

3951  Expression of neutrophil gelatinase-associated lipocalin (NGAL)/lipocalin2, a recently recognized iron-binding protein, is increased in colorectal cancer.However, the effects of NGAL on colorectal cancer cells are unknown. Identifying these effects formed the purpose of the study we report here. We have generated several stable over-expressing NGAL cell lines using KM12C colon carcinoma cell line and examined the effects of the protein in the aspects of cell growth, motility and invasion. We found that NGAL over-expression in KM12C colon carcinoma cells did not affect the cell growth rate, however, it resulted in cytoskeleton rearrangement, the translocation of E-cadherin and α-catenin proteins to the cytoplasm, decreased RhoA activity, increased cell motility and invasion. To investigate the mechanism of the protein function, we treated NGAL over-expressing cells with either ferric chloride or iron chelator. Interestingly, we found that different extracellular matrix signals differentially modulate NGAL effects on the cells through its iron delivery pathway. Coupling with type IV collagen signal, ferric chloride treatment of the cells proved to promote E-cadherin cytoplasmic distribution and cell invasion. In contrast, iron chelator treatment of the cells restored E-cadherin to the cell-cell junctions and inhibited the cell invasion ability. We conclude from our findings that the NGAL iron-delivery system coupling with extracellular matrix signal, most likely integrin signals, is a key mechanism for altering the location of E-cadherin in the cells and for promoting colon cancer cell motility and invasion.
Evaluation of antitumor activity and biomarkers for MBP-426 in human pancreatic cancer xenograft models in vivo
Authors: Elzbieta Izbicka, Armando Diaz, David Campos, Michael Wick, Chris Takimoto, M Nagasawa, C Hashimoto
Journal: Cancer Research (2007)

5586  MBP-426 is a novel oxaliplatin-encapsulated transferrin (Tf) -conjugated N-glutaryl phosphatidylethanolamine (NGPE)-liposome. MBP-426 demonstrated potent anticancer preclinical activity and has recently entered clinical trials. Direct drug binding to Tf receptor (TfR) was demonstrated in human cancer cells in vitro; the drug delivery is thought to be enhanced via uptake by TfR. This study investigated activity of MBP-426 alone and in combination with gemcitabine or erlotinib in the PANC-1 human pancreas tumor xenograft model. Significant endpoints included mean tumor growth inhibition or regression, weight loss, and agent toxicity. In groups treated with MBP-426 alone and in combination with gemcitabine we further evaluated expression of biomarkers (TfR, cleaved caspase-3, PARP, survivin, CD31, Hif1a in tumor tissue; VEGF, TNF-a, bFGF, IL-6, MMP-2 and MMP-9 in serum) by immunostaining and multiplexed immunoassays, respectively. In vivo treatment with gemcitabine (40 mg/kg) resulted in reversible weight loss and moderate tumor growth inhibition (TGI=25%); no weight loss or TGI was reported for 50 mg/kg erlotinib. MBP-426 alone was inactive but the group co-treated with 40 mg/kg gemcitabine and 4 mg/kg MBP-426 reported significant (p 20% inhibition, p=0.011) in the 4 mg/kg MBP-426 plus gemcitabine treatment group. TNF-a was significantly suppressed by gemcitabine (50% inhibition, p=0.007), the low dose of MBP-426 alone (35% inhibition, p=0.043) and in combination with gemcitabine (38% inhibition, p=0.027). Taken together, these results demonstrate additive combinatorial effects of MBP-426 with gemcitabine and erlotinib in pancreatic adenocarcinoma in vivo. Serum TNF-a and MMP-2 levels might be pursued as potential biomarkers of drug efficacy in clinical trials. Supported by Mebiopharm
Abstract IA10: Developing rational combination therapy with checkpoint inhibitors
Authors: Megan M. Tu, Francis Y. F. Lee, Robert T. Jones, Abigail K. Kimball, Elizabeth Saravia, Robert F. Graziano, Brianne Coleman, Krista Menard, Jun Yan, Erin Michaud, Han Chang, Hany A. Abdel-Hafiz, Andrii I. Rozhok, Jason E. Duex, Neeraj Agarwal, Ana Chauca-Diaz, Linda K. Johnson, Terry L. Ng, John C. Cambier, Eric T. Clambey, James C. Costello, Alan J. Korman, Dan Theodorescu
Journal: Clinical Cancer Research (2020)

Abstract Targeting antibodies to programmed cell death protein-1 (PD-1) is an effective treatment across multiple cancer types. While a subset of patients receiving these therapies experience favorable responses, many still show disease progression, highlighting the importance of other mechanisms influencing immune responsiveness in these tumors. Therefore, combining therapies that enhance antitumor immunity has been an area of great interest to the entire cancer community. We have recently tackled this challenge in the rapidly evolving field of cancer immunotherapy by using in vivo functional genomics to identify genes whose inhibition potentiates the response to anti-PD-1 immunotherapy. Using an in vivo screening approach with a customized shRNA pooled library, we identified a number of candidates including DDR2 as promising targets for the enhancement of response to anti-PD-1 immunotherapy. In the case of DDR2, using isogenic in vivo murine models across five different tumor histologies—bladder, breast, colon, sarcoma, and melanoma—we show that DDR2 depletion increases sensitivity to anti-PD-1 treatment compared to monotherapy. Combination treatment of tumor-bearing mice with anti-PD-1 and dasatinib, a tyrosine kinase inhibitor of DDR2, also led to tumor load reduction and in some cases, complete clearance. RNAseq and CyTOF analysis revealed higher CD8+ T-cell populations in tumors with DDR2 depletion and those treated with dasatinib when either was combined with anti-PD-1 treatment. Our work provides strong scientific rationale for targeting DDR2 in combination with PD-1 inhibitors. In addition, a number of other potential druggable targets have been identified in our screen that we are currently pursuing. Citation Format: Megan M. Tu, Francis Y. F. Lee, Robert T. Jones, Abigail K. Kimball, Elizabeth Saravia, Robert F. Graziano, Brianne Coleman, Krista Menard, Jun Yan, Erin Michaud, Han Chang, Hany A. Abdel-Hafiz, Andrii I. Rozhok, Jason E. Duex, Neeraj Agarwal, Ana Chauca-Diaz, Linda K. Johnson, Terry L. Ng, John C. Cambier, Eric T. Clambey, James C. Costello, Alan J. Korman, Dan Theodorescu. Developing rational combination therapy with checkpoint inhibitors [abstract]. In: Proceedings of the AACR Special Conference on Bladder Cancer: Transforming the Field; 2019 May 18-21; Denver, CO. Philadelphia (PA): AACR; Clin Cancer Res 2020;26(15_Suppl):Abstract nr IA10.
Safety and Clinical Activity of MEDI0562, a Humanized OX40 Agonist Monoclonal Antibody, in Adult Patients with Advanced Solid Tumors
Authors: Bonnie S. Glisson, Rom S. Leidner, Robert L. Ferris, John Powderly, Naiyer A. Rizvi, Bhumsuk Keam, Reva Schneider, Sanjay Goel, James P. Ohr, Jennifer Burton, Yanan Zheng, Steven Eck, Matthew Gribbin, Katie Streicher, Danielle M. Townsley, Sandip Pravin Patel
Journal: Clinical Cancer Research (2020)

Immune checkpoint blockade has demonstrated clinical benefits across multiple solid tumor types; however, resistance and relapse often occur. New immunomodulatory targets, which are highly expressed in activated immune cells, are needed. MEDI0562, an agonistic humanized mAb, specifically binds to the costimulatory molecule OX40. This first-in-human study evaluated MEDI0562 in adults with advanced solid tumors.In this phase I, multicenter, open-label, single-arm, dose-escalation (3+3 design) study, patients received 0.03, 0.1, 0.3, 1.0, 3.0, or 10 mg/kg MEDI0562 through intravenous infusion every 2 weeks, until confirmed disease progression or unacceptable toxicity. The primary objective evaluated safety and tolerability. Secondary endpoints included antitumor activity, pharmacokinetics, immunogenicity, and pharmacodynamics.In total, 55 patients received ≥1 dose of MEDI0562 and were included in the analysis. The most common tumor type was squamous cell carcinoma of the head and neck (47%). Median duration of treatment was 10 weeks (range, 2-48 weeks). Treatment-related adverse events (TRAEs) occurred in 67% of patients, most commonly fatigue (31%) and infusion-related reactions (14%). Grade 3 TRAEs occurred in 14% of patients with no apparent dose relationship; no TRAEs resulted in death. Two patients had immune-related partial responses per protocol and 44% had stable disease. MEDI0562 induced increased Ki67+ CD4+ and CD8+ memory T-cell proliferation in the periphery and decreased intratumoral OX40+ FOXP3+ cells.MEDI0562 was safely administered at doses up to 10 mg/kg in heavily pretreated patients. On-target pharmacodynamic effects were suggested in this setting. Further evaluation with immune checkpoint inhibitors is ongoing.
Revised DIPSS-Plus: A Composite Clinical, Cytogenetic and Molecular Prognostic System for Primary Myelofibrosis
Authors: Ayalew Tefferi, Paola Guglielmelli, Terra L. Lasho, Francesca Gesullo, Christy Finke, Francesco Mannelli, Animesh Pardanani, Curtis A. Hanson, Rhett P. Ketterling, Naseema Gangat, Alessandro M. Vannucchi
Journal: Blood (2017)
SP0019 How the clinician can use the cochrane library
Authors: P Tugwell, J McGowan, V Welch, B Shea, G Wells
Journal: Annals of the Rheumatic Diseases (2001)

<h3>Objectives</h3> To demonstrate online searching of The Cochrane Library for clinicians and illustrate how The Cochrane Library can be used in practice. The Cochrane Library is the single best source of updated systematic reviews of health care interventions. There are now 37 published Cochrane reviews relating to Musculoskeletal Diseases. The abstracts can be accessed for free on the internet and lay summaries written in consultation with consumers are also available on the internet (www.arthritis.ca). The first part of this workshop will demonstrate how to use text words to search for consumer and scientific abstracts available for free on the internet. In addition, the web interface for the full Cochrane Library will be shown. The second purpose of this workshop is to provide examples of how to use Cochrane reviews in clinical practice. For example, the University of Ottawa has developed hospital-wide access to the Cochrane Library, and these can be accessed by clinicians from any computer with an internet connexion. The pooled estimate of efficacy and side effects is the best estimate from all published randomised controlled trials. The direction and statistical significance of this estimate can be easily interpreted. The second part of the workshop will illustrate the interpretation of the magnitude and direction of the pooled estimate. In addition, the workshop will illustrate how these estimates can be used as part of evidence based practice.
Abstract B02: TP63 isoform expression landscape associations with bladder cancer patient outcomes
Authors: Armand Bankhead, Thomas McMaster, Phillip L. Palmbos
Journal: Clinical Cancer Research (2020)

Abstract Bladder cancer will cause an estimated 17,000 deaths this year in the United States. Transformation-related protein 63 (TP63) is a p53 family transcription factor that has been shown to be important for development and is commonly expressed in bladder cancer. However, the relationship of TP63 to bladder cancer patient outcome remains unclear. Some studies have associated TP63 expression with a positive patient outcome, while others have shown TP63 expression is associated with reduced survival. One potential explanation for this discrepancy is that TP63 is expressed as one of at least 15 unique isoforms, of which there are two main types (TAp63 and DNp63) exhibiting unique functional domains. In this work we define the landscape of TP63 isoform expression and quantify its association with bladder cancer patient outcome using RNA sequencing data from the TCGA bladder cancer cohort and other human bladder cancer samples. To examine the TP63 isoform landscape in bladder cancer, we utilized annotations from Refgene and Ensembl databases and used Cufflinks to identify two potentially novel TP63 isoforms not represented in current TP63 gene annotations. To quantitate isoform expression, we used multiple RNA-Seq expression quantification algorithms (Cufflinks, Kallisto, and Salmon) to infer isoform expression estimates of 15 TP63 isoforms for 408 bladder cancer patients from TCGA. We experimentally validated our findings using a collection of 14 bladder cancer cell lines and show that results translated to an additional collection of 19 primary bladder cancer tumor samples. We find that DNp63 is significantly higher in patients with luminal papillary and basal squamous subtypes, while TAp63 was selectively expressed in patients with basal squamous bladder cancer. Analysis of TP63 isoform expression with clinical data demonstrated that DNp63 trends with improved patient survival (HR=0.94, CI=0.88,1.006, P=0.082), whereas TAp63 is associated with worse patient survival (HR = 1.8, CI=1.38,2.4, P=0.00022) in human bladder cancer. Taken together, this work represents a comprehensive assessment of TP63 isoform expression in the TCGA bladder cancer cohort using contemporary, extended gene isoform annotations and quantifications—underscoring the need for profiling additional bladder cancer cohorts with RNA-Seq for further insight to isoform-specific expression. It also implicates TP63 isoform expression as a potential biomarker of clinical patient outcomes. Citation Format: Armand Bankhead III, Thomas McMaster, Phillip L. Palmbos. TP63 isoform expression landscape associations with bladder cancer patient outcomes [abstract]. In: Proceedings of the AACR Special Conference on Bladder Cancer: Transforming the Field; 2019 May 18-21; Denver, CO. Philadelphia (PA): AACR; Clin Cancer Res 2020;26(15_Suppl):Abstract nr B02.
Sex Differences in All-Cause Mortality in the Decade Following Complex Coronary Revascularization
Authors: Hironori Hara, Kuniaki Takahashi, David van Klaveren, Rutao Wang, Scot Garg, Masafumi Ono, Hideyuki Kawashima, Chao Gao, Michael Mack, David R. Holmes, Marie-Claude Morice, Stuart J. Head, Arie Pieter Kappetein, Daniel J.F.M. Thuijs, Yoshinobu Onuma, Thilo Noack, Friedrich W. Mohr, Piroze M. Davierwala, Patrick W. Serruys
Journal: Journal of the American College of Cardiology (2020)
In vivo efficacy investigations of an siRNA-containing nanoparticle formulation targeting the m2 subunit of ribonucleotide reducatse (rrm2) in tumor-bearing mice
Authors: Jeremy Heidel, Joannna Liu, Ryan Zeidan, Youngchao Liang, Shyam Rele, Mark Davis
Journal: Cancer Research (2008)

1382  Calando Pharmaceuticals is developing siRNA-containing nanoparticle formulations and its leading formulation that will enter the clinic in 2008 contains the human transferrin protein as a targeting ligand and siRNA targeting the M2 subunit of ribonucleotide reductase (RRM2). As part of the pre-clinical investigations, a number of in vivo studies of this formulation in mice have been performed to determine the effects of dose level, dose schedule, and tumor type (e.g., HCC, melanoma, etc.) on efficacy. The results of these studies will be presented and include evidence of tumor growth delay and tumor regression. Efficacy is only obtained when the targeted version of the nanoparticles are employed. Results from numerous studies will be provided to support the claim that RRM2 inhibition by the RNAi mechanism (RACE analyses) is the cause of the tumor growth suppression rather than other off target effects.
Abstract B30: A living biomarker from urine to predict drug efficacy and recurrence of bladder cancer
Authors: Xuefeng Liu
Journal: Clinical Cancer Research (2020)

Abstract The culture of cancer cells from urine samples is a simple, noninvasive technique that has the potential to advance the diagnosis, treatment, and monitoring of patients with bladder cancer, and the generation of such urine-derived cultures can provide both genetic and phenotypic data for precision medicine. In this study we collected urine and/or tumor biopsies from 23 bladder cancer patients and used conditional reprogramming (CR) to generate cell cultures from each of these sources. Using this CR technique, the overall success rate of culturing primary bladder cancer cells from the urine of bladder cancer patients was 96% (22/23), with 100% (18/18) of high-grade bladder cancers and 80% (4/5) of low-grade cancers generating cultures. No CR cultures (0/7) were generated from the urine of cancer-free participants. We characterized CR cells at cellular and genetic levels. The therapeutic responses of urine CRCs and tumor CRCs were also distinguishable from different patients and displayed similar patterns if derived from the same patient. This rapid, efficient, and noninvasive method for generating cultures of bladder cancer cells can be used potentially for high-throughput drug screening, predicting patient clinical responses, and monitoring tumor initiation and recurrence. Citation Format: Xuefeng Liu. A living biomarker from urine to predict drug efficacy and recurrence of bladder cancer [abstract]. In: Proceedings of the AACR Special Conference on Bladder Cancer: Transforming the Field; 2019 May 18-21; Denver, CO. Philadelphia (PA): AACR; Clin Cancer Res 2020;26(15_Suppl):Abstract nr B30.
Cancer Cell CD44 Mediates Macrophage/Monocyte-Driven Regulation of Head and Neck Cancer Stem Cells
Authors: Karina E. Gomez, FangLong Wu, Stephen B. Keysar, J. Jason Morton, Bettina Miller, Tugs-Saikhan Chimed, Phuong N. Le, Cera Nieto, Farshad N. Chowdhury, Anit Tyagi, Traci R. Lyons, Christian D. Young, Hongmei Zhou, Hilary L. Somerset, Xiao-Jing Wang, Antonio Jimeno
Journal: Cancer Research (2020)

Tumor-associated macrophages (TAM) in the tumor microenvironment (TME) cooperate with cancer stem cells (CSC) to maintain stemness. We recently identified cluster of differentiation 44 (CD44) as a surface marker defining head and neck squamous cell carcinoma (HNSCC) CSC. PI3K-4EBP1-SOX2 activation and signaling regulate CSC properties, yet the upstream molecular control of this pathway and the mechanisms underlying cross-talk between TAM and CSC in HNSCC remain largely unknown. Because CD44 is a molecular mediator in the TME, we propose here that TAM-influenced CD44 signaling could mediate stemness via the PI3K-4EBP1-SOX2 pathway, possibly by modulating availability of hyaluronic acid (HA), the main CD44 ligand. HNSCC IHC was used to identify TAM/CSC relationships, and in vitro coculture spheroid models and in vivo mouse models were used to identify the influence of TAMs on CSC function via CD44. Patient HNSCC-derived TAMs were positively and negatively associated with CSC marker expression at noninvasive and invasive edge regions, respectively. TAMs increased availability of HA and increased cancer cell invasion. HA binding to CD44 increased PI3K-4EBP1-SOX2 signaling and the CSC fraction, whereas CD44-VCAM-1 binding promoted invasive signaling by ezrin/PI3K. In vivo, targeting CD44 decreased PI3K-4EBP1-SOX2 signaling, tumor growth, and CSC. TAM depletion in syngeneic and humanized mouse models also diminished growth and CSC numbers. Finally, a CD44 isoform switch regulated epithelial-to-mesenchymal plasticity as standard form of CD44 and CD44v8-10 determined invasive and tumorigenic phenotypes, respectively. We have established a mechanistic link between TAMs and CSCs in HNSCC that is mediated by CD44 intracellular signaling in response to extracellular signals. SIGNIFICANCE: These findings establish a mechanistic link between tumor cell CD44, TAM, and CSC properties at the tumor-stroma interface that can serve as a vital area of focus for target and drug discovery.
Abstract IA20: Intravesical versus systemic therapy: Win, lose, or draw—the future is now for multidisciplinary NMIBC drug development
Authors: Noah M. Hahn
Journal: Clinical Cancer Research (2020)

Abstract In recent years, we have witnessed an explosion in both therapeutic drug development and our understanding of the key biologic drivers and targets in bladder cancer. While new drug approvals have thus far been confined to metastatic patients, several promising agents have fully accrued key FDA registration studies in the BCG-unresponsive non-muscle invasive bladder cancer (NMIBC) population. Initial early-response data in the carcinoma in situ (CIS) populations demonstrate clear signals of activity with long-term follow-up ongoing to assess response durability. Agents administered by either intravesical or systemic routes are among those being assessed. While urologists, medical oncologists, and radiation oncologists have long worked together in the care of muscle-invasive bladder cancer (MIBC) and metastatic bladder cancer patients, an established template of multidisciplinary collaboration in the care of NMIBC patients is lacking. This unknown frontier creates both challenges and immense opportunities. True lasting, impactful progress rarely happens in isolation. This session will utilize data and example cases to illustrate specialty-specific skills and perceptions that define us, must be acknowledged for the biases they create, and ultimately should be embraced as a vehicle to establish functional and collaborative multidisciplinary drug development and clinical care models for NIMIBC patients. Citation Format: Noah M. Hahn. Intravesical versus systemic therapy: Win, lose, or draw—the future is now for multidisciplinary NMIBC drug development [abstract]. In: Proceedings of the AACR Special Conference on Bladder Cancer: Transforming the Field; 2019 May 18-21; Denver, CO. Philadelphia (PA): AACR; Clin Cancer Res 2020;26(15_Suppl):Abstract nr IA20.