tbuckley/cabot-search huggingface dataset:
Abstract 3059: UHRF1 deficiency exerts anti-tumor immune responses in non-small cell lung cancer
Authors: Handan Xiang, Junying Chen, Xiao-Fan Wang
Journal: Cancer Research (2017)

Abstract Immune surveillance is essential for effective tumor clearance. However, the tumor microenvironment is typically impermissive for proper stimulation of both innate and adaptive immune populations. Epigenetic inhibitors have recently been shown to function as immune sensitizing reagents in the suppressive microenvironment. In our search for novel epigenetic regulators with immunomodulatory functions, we found ubiquitin-like with PHD and ring finger domain-containing protein 1 (UHRF1) being crucial for the suppression of immune activation. Loss of UHRF1 in cancer cells led to significant reduction of tumor masses in a syngeneic lung cancer model. The tumor shrinkage was due to increased infiltration of T cells with the enhanced ability to proliferate and produce IFN-gamma. Mechanistically, lung cancer cells deficient of UHRF1 had elevated expression of endogenous retrovirus genes due to DNA demethylation, which associated with enhanced type I interferon responses. Type I interferons are potent antitumor effector molecules by promoting immune cell infiltration into the tumor microenvironment, yet they can also dampen T cell activation by upregulating PD-L1 expression in tumor cells. Surprisingly, UHRF1 deficient cancer cells failed to upregulate PD-L1 even in the presence of excessive type I interferons, indicative of additional regulatory pathways for PD-L1. We further found that UHRF1 directly interacted with PD-L1 promoter regions and that UHRF1 promoted PD-L1 transcription. Therefore, the inhibition of UHRF1 augmented type I interferon responses while diminished PD-L1 expression, which synergistically contributed to the immune activation phenotype. Moreover, in non-small cell lung cancer (NSCLC) patients, UHRF1 expression was positively correlated with PD-L1 expression as well as poor prognosis. Together, our data suggested that UHRF1 represents a novel immuno-oncology target for NSCLC. Citation Format: Handan Xiang, Junying Chen, Xiao-Fan Wang. UHRF1 deficiency exerts anti-tumor immune responses in non-small cell lung cancer [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 3059. doi:10.1158/1538-7445.AM2017-3059
A Survey of Radiation Protection In Hospitals
Journal: JNCI Journal of the National Cancer Institute (1941)

Journal Article A Survey of Radiation Protection In Hospitals Get access Dean B. Cowie, Dean B. Cowie research fellow National Cancer Institute, National Institute of Health, United States Public Health Service Search for other works by this author on: Oxford Academic PubMed Google Scholar Leonard A. Scheele Leonard A. Scheele passed assistant surgeon National Cancer Institute, National Institute of Health, United States Public Health Service Search for other works by this author on: Oxford Academic PubMed Google Scholar JNCI: Journal of the National Cancer Institute, Volume 1, Issue 6, June 1941, Pages 767–787, https://doi.org/10.1093/jnci/1.6.767 Published: 01 June 1941
Abstract 5201: PSMA-targeted alpha radioimmunotherapy for prostate cancer with 225Ac-J591
Authors: Jaspreet S. Batra, He Liu, Sae Kim, Vicente N. Navarro, Shankar Vallabhajosula, Scott T. Tagawa, Neil H. Bander
Journal: Cancer Research (2017)

Abstract Background: Prostate cancer (PC) is a radiosensitive disease. In addition to external beam and brachytherapy, systemic bone-seeking radioisotopes have been utilized clinically for many years, with radium-223 leading to overall survival benefits. However, the available beta and alpha emitting particles in the clinic target tumors / stroma in bone only. Biologically targeted radiopharmaceutical treatment has shown promising results in our earlier multiple clinical trials using beta-emitting anti-PSMA therapy with Leutetium-177 radiolabeled anti-PSMA monoclonal antibody (mAb) J591, with accurate targeting and tumor response, but treatment is limited by myelosuppression. Both beta and alpha-small molecule PSMA ligand directed therapy has been utilized anecdotally outside of the US, but has not been systemically studied. Based upon their biodistribution, targeting of salivary glands and potentially proximal renal tubules may pose longer term toxicity issues. mAb-based targeted alpha-particle delivery may be advantageous with less expected myelosuppression than seen with β-emitters. Experimental procedures: To optimize labeling of humanized DOTA-J591 mAb, actinium-225 (225Ac) nitrate was obtained from Oak Ridge National Laboratories and was dissolved in HCl solution and then mixed with trimethyl ammonium acetate and L-ascorbic acid. This preparation was incubated with DOTA-J591. The labeling efficiency (LE) was determined by ITLC-SG. If the LE is &amp;gt;60%, 225Ac-DOTA-J591 mAb was purified by gel filtration and sterilized by membrane filtration. In a pilot pre-clinical study, we studied the toxicity in non-tumor bearing BALB/c mice. Results: The radiochemical purity is &amp;gt;95% and the immunoreactivity was &amp;gt;80%. Twenty-five BALB/c mice received from 2.1 to 6.3 KBq of 225Ac-J591. Treatment was well tolerated, with all mice alive and healthy at Day 26. Conclusions: A stable alpha emitting-antibody complex has been produced with 225Ac-J591. Initial mouse safety experiments have been successful. A RIT dose escalation study of PSMA-targeted alpha emitter in a LNCaP xenograft model is underway. Citation Format: Jaspreet S. Batra, He Liu, Sae Kim, Vicente N. Navarro, Shankar Vallabhajosula, Scott T. Tagawa, Neil H. Bander. PSMA-targeted alpha radioimmunotherapy for prostate cancer with 225Ac-J591 [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 5201. doi:10.1158/1538-7445.AM2017-5201
Abstract 4036: Induction of detrimental aneuploidy in basal breast cancer cells treated by MPS1 inhibitors in combination with paclitaxel
Authors: Simon J. Anderhub, Grace WY Mak, Amir Faisal, Katie Walsh, Mark Gurden, Liz Day, Paolo Innocenti, Hannah L. Woodward, Isaac M. Westwood, Kwai-Ming J. Cheung, Sebastien Naud, Angela Hayes, Gary Box, Alexis de Haven Brandon, Melanie R. Valenti, Lisa O’Fee, Harry Saville, Rosemary Burke, Rob LM van Montfort, Florence I. Raynaud, Suzanne A. Eccles, Julian Blagg, Swen Hoelder, Spiros Linardopoulos
Journal: Cancer Research (2017)

Abstract Basal-like breast cancer has received considerable attention in recent years, but despite all efforts, conventional chemotherapy remains the main therapeutic option in the clinic with taxane therapy, the most frequently prescribed treatment. A significant reason for the lack of effective therapeutics may be related to the high degree of heterogeneity and aneuploidy which is characteristic for basal-like breast cancer. A new approach in this field is the concept that cancer cells may be targeted by the introduction of a detrimental level of aneuploidy. Inhibition of one of the main spindle assembly checkpoint kinases, MPS1 is a rational choice to achieve this goal. We report here the identification of a synergistic effect between the novel, oral, highly potent and selective MPS1 inhibitor CCT289346 and paclitaxel. We demonstrate robust synergism in multiple basal-like breast cancer cell lines and provide mechanistic insights into how both compounds’ individual properties work together to maximise mitotic defects thereby increasing aneuploidy and cell death in a single round of mitosis. Additionally, in vivo studies in basal-like breast cancer xenograft models, including patient derived xenografts and systemic metastatic models, using clinically relevant doses of paclitaxel with well-tolerated doses of CCT289346, demonstrate significant benefit of combination of the two agents in comparison to paclitaxel alone. Citation Format: Simon J. Anderhub, Grace WY Mak, Amir Faisal, Katie Walsh, Mark Gurden, Liz Day, Paolo Innocenti, Hannah L. Woodward, Isaac M. Westwood, Kwai-Ming J. Cheung, Sebastien Naud, Angela Hayes, Gary Box, Alexis de Haven Brandon, Melanie R. Valenti, Lisa O’Fee, Harry Saville, Rosemary Burke, Rob LM van Montfort, Florence I. Raynaud, Suzanne A. Eccles, Julian Blagg, Swen Hoelder, Spiros Linardopoulos. Induction of detrimental aneuploidy in basal breast cancer cells treated by MPS1 inhibitors in combination with paclitaxel [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 4036. doi:10.1158/1538-7445.AM2017-4036
An Integrative Scoring System for Survival Prediction Following Umbilical Cord Blood Transplantation in Acute Leukemia
Authors: Roni Shouval, Annalisa Ruggeri, Myriam Labopin, Mohamad Mohty, Guillermo Sanz, Gerard Michel, Jürgen Kuball, Patrice Chevallier, Amal Al-Seraihy, Noel-Jean Milpied, Cristina Diaz de Heredia, William Arcese, Didier Blaise, Vanderson Rocha, Joshua Fein, Ron Unger, Frederic Baron, Peter Bader, Eliane Gluckman, Arnon Nagler
Journal: Clinical Cancer Research (2017)

Purpose: Survival of acute leukemia (AL) patients following umbilical cord blood transplantation (UCBT) is dependent on an array of individual features. Integrative models for risk assessment are lacking. We sought to develop a scoring system for prediction of overall survival (OS) and leukemia-free survival (LFS) at 2 years following UCBT in AL patients.Experimental Design: The study cohort included 3,140 pediatric and adult AL UCBT patients from the European Society of Blood and Marrow Transplantation and Eurocord registries. Patients received single or double cord blood units. The dataset was geographically split into a derivation (n = 2,362, 65%) and validation set (n = 778, 35%). Top predictors of OS were identified using the Random Survival Forest algorithm and introduced into a Cox regression model, which served for the construction of the UCBT risk score.Results: The score includes nine variables: disease status, diagnosis, cell dose, age, center experience, cytomegalovirus serostatus, degree of HLA mismatch, previous autograft, and anti-thymocyte globulin administration. Over the validation set an increasing score was associated with decreasing probabilities for 2 years OS and LFS, ranging from 70.21% [68.89-70.71, 95% confidence interval (CI)] and 64.76% (64.33-65.86, 95% CI) to 14.78% (10.91-17.41) and 18.11% (14.40-22.30), respectively. It stratified patients into six distinct risk groups. The score's discrimination (AUC) over multiple imputations of the validation set was 68.76 (68.19-69.04, range) and 65.78 (65.20-66.28) for 2 years OS and LFS, respectively.Conclusions: The UCBT score is a simple tool for risk stratification of AL patients undergoing UCBT. Widespread application of the score will require further independent validation. Clin Cancer Res; 23(21); 6478-86. ©2017 AACR.
Abstract 2678: Novel host-pathogen interactions of Helicobacter pylori and their implications to gastric cancer
Authors: Emine Guven Maiorov, Ruth Nussinov, Chung-Jung Tsai
Journal: Cancer Research (2017)

Abstract About 20% of the cancer incidences worldwide have been estimated to be associated with infections. There is a strong correlation of some pathogens with various cancer types. Although presence of commensal microbiome helps chemotherapy to be more effective, pathogenic microbiota increases the cancer risk. Invading pathogens interact with the host mainly through proteins. To subvert host defense, pathogens hijack host pathways by mimicking the binding surfaces (interfaces) of host proteins. This similarity in interfaces permits the pathogenic protein to compete with host proteins to bind to a target protein, alter the physiological signaling and cause persistent infections as well as cancer. Detection of host-pathogen interactions (HPIs) and mapping the re-wired HPI network - along with its structural details - is critical for in-depth understanding of the underlying pathogenesis mechanisms of infections and pathogen-triggered cancers, and developing efficient therapeutics. Here, we developed a novel computational approach to identify novel HPIs by employing “interface mimicry”, We applied this approach to Helicobacter pylori, dominant species in gastric microbiome that greatly increases the gastric cancer risk in order to understand how they modulate host immunity and lead to tumorigenesis. We found that its proteins interfere with the functioning of host apoptosis pathway, cytokine and chemokine pathways, and also cell-cell adhesions. Our results shed light on the molecular mechanisms of resistance to apoptosis, immune evasion and loss of cell junctions that are seen in Helicobacter pylori-infected host cells. In conclusion, HPIs can help us unravel which human pathways are targeted by the pathogenic proteins and how they contribute to pathogenesis of infections and pathogen-triggered cancer. With a better grasp on immunomodulatory strategies of pathogens, we can develop better therapies against them. Citation Format: Emine Guven Maiorov, Ruth Nussinov, Chung-Jung Tsai. Novel host-pathogen interactions of Helicobacter pylori and their implications to gastric cancer [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 2678. doi:10.1158/1538-7445.AM2017-2678
Abstract 3489: Noncoding RNA distribution in clear cell renal cell cancer: small RNA-seq data
Authors: Srinivas V. Koduru, Dino J. Ravnic
Journal: Cancer Research (2017)

Abstract Small noncoding RNAs (sncRNAs) play pivotal roles in biological processes and may prove to be a tool in cancer diagnosis, prognosis, and treatment. Noncoding RNAs such as microRNAs (miRNAs), piwi-interacting-RNAs (piRNAs), long noncoding RNA (lncRNAs) and small nuclear/nucleolar RNAs (sn/snoRNAs) have recently been investigated to identify their role in cancer. Approximately 62,700 new cases of kidney cancer are expected each year in the United States leading to 14,240 deaths, with rates rising over the past 20 years. Nearly 90% of all kidney cancers will be renal cell carcinoma, of which 70% will be a clear cell renal cell carcinoma (ccRCC) subtype. When detected early most cases can be treated effectively, however there is a lack of early detection tests. We sought to identify molecular markers for early detection and diagnosis. We downloaded publically available (NIH bioproject PRJNA162397) ccRCC small RNA sequence raw data for noncoding RNA analysis. 22 ccRCC and 11 non-tumor renal cortex patient samples were evaluated. Data was analyzed by PartekFlow software. sRNA-seq data was annotated to miRNAs with 69 miRNAs aberrantly expressed in ccRCC with 37 being upregulated (top five: miR-122, miR-210, miR155, miR-224 and miR-21) and 32 being downregulated (top five: miR-200c, miR-502, miR-20b, miR10a and miR-204). Utilizing MetaCore software for pathway analysis the majority of expressed miRNAs were involved in metabolism related signaling pathways. Examining data for piRNAs revealed 22 which were significantly expressed (8 upregulated and 14 downregulated). Investigation of lncRNAs revealed 15 to be downregulated and 27 upregulated. We also uncovered 2 mitochondrial rRNAs, 10 miscRNAs, 1 snRNA, 7 snoRNAs, and 5 rRNAs in ccRCC samples. Our comprehensive analysis of publically available small RNA-seq data identified numerous sncRNAs associated with ccRCC. Pending further validation, they may prove useful as early detection biomarkers in this common cancer. Citation Format: Srinivas V. Koduru, Dino J. Ravnic. Noncoding RNA distribution in clear cell renal cell cancer: small RNA-seq data [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 3489. doi:10.1158/1538-7445.AM2017-3489
Abstract 614: VB4-845 tumor cell killing in a combination study with the anti-PD-1, Nivolumab
Authors: Rachelle Lee Dillon, Shilpa Chooniedass, Arjune Premsukh, Glen MacDonald, Jeannick Cizeau, Gregory A. Adams
Journal: Cancer Research (2017)

Abstract VB4-845 is a Targeted Protein Therapeutic (TPT) comprised of a scFv fragment specific for the Epithelial Cell Adhesion Molecule (EpCAM) genetically fused to a truncated form of Pseudomonas exotoxin A (ETA), via a flexible linker. Due to the inherent immunogenicity of the ETA moiety, VB4-845 is only used for the treatment of loco-regionally accessible tumors and is currently in a Phase III clinical trial for the treatment of high grade, non-muscle invasive bladder cancer. In a Phase I study in late stage squamous cell carcinoma of the head and neck, direct injection of VB4-845 led to shrinkage of the principal injected tumor, as well as non-targeted tumors in some patients, suggesting the activation of a T cell-mediated anti-tumor response through cross-priming. Only cells undergoing immunogenic cell death, or ICD, are capable of stimulating cross-priming. ICD is characterized by distinct “eat-me” signals such as the release of ATP and HMGB1, and cell surface translocation of calreticulin, an endoplasmic reticulum chaperone protein. To evaluate whether VB4-845-mediated cell killing results in ICD events, treated tumor cell lines were assessed for these distinct signaling molecules. In vitro studies using flow cytometry and ELISA showed both translocation of calreticulin and release of ATP and HMGB1 by VB4-845-treated tumor cells. Immune T cell activation via an ICD pathway suggests a complimentary outcome when combined with checkpoint inhibitors. A study was performed in PDX tumor-bearing NOG mice reconstituted with a human immune system to assess the combination of intratumoral injection of VB4-845 with an anti-PD1 antibody, Nivolumab, given i.p. VB4-845 showed growth suppression of the injected tumor whereas the growth delay of the contralateral, non-injected tumor was more pronounced with the addition of Nivolumab. In summary, the data presented suggests that VB4-845 mediates tumor cell killing by an ICD pathway and that the resulting cross-priming effect can enhance the anti-tumoral activity of immune checkpoint inhibitors. Citation Format: Rachelle Lee Dillon, Shilpa Chooniedass, Arjune Premsukh, Glen MacDonald, Jeannick Cizeau, Gregory A. Adams. VB4-845 tumor cell killing in a combination study with the anti-PD-1, Nivolumab [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 614. doi:10.1158/1538-7445.AM2017-614
Abstract 3247: Discovery of a novel drug that affects centrosome clustering
Authors: Dilan B. Jaunky, Kevin Larocque, Javier Porro Suardiaz, Dan Yang, Emma J. Furze, Pat Forgione, Alisa Piekny
Journal: Cancer Research (2017)

Abstract Our goal is to identify molecular regulators of a mechanism that occurs uniquely in cancer cells, and to develop a selective anti-cancer drug. Most chemotherapies are non-selective, causing severe side-effects. In additions, cancers often develop resistance to some of the more commonly used chemotherapies. To expand the repertoire of available drugs, and to design drugs that are selective, we need to identify molecules that regulate the physiological changes that occur primarily in cancer cells. For example, cancer cells in many hard-to-treat cancers have aberrant centrosomes, which may be supernumerary or fragmented. During mitosis, these aberrant centrosomes must cluster to form bipolar spindles for successful division. Thus, targeting a process like centrosome clustering is ideal, since it is not necessary in healthy cells. We synthesized a small, stable scaffold with amenability to structure-activity-relationship studies, and found several analogues with IC50 values &amp;lt; 50 nM, depending on the cancer cell line. Preliminary tests showed that these compounds prevent tumors from forming and/or cause their regression in vitro. We performed cell biological studies to characterize their mechanism of action. In several different types of cancer cells, these compounds cause mitotic arrest and centrosome declustering at concentrations where they have little affect on non-cancerous cells. Live imaging revealed that within minutes of adding the compounds to HeLa cells expressing GFP-tagged tubulin, we observed rapid microtubule depolymerization and centrosome declustering. After washing out the compound, microtubule polymerization recovered, but the mitotic spindles were multipolar. Adding similar concentrations of Nocodazole, a microtubule-depolymerizing drug, also caused rapid microtubule depolymerization, but after washing out the drug, the spindles were bipolar. We are in the process of identifying the molecular target of these compounds to provide crucial insight to the mechanism governing centrosome clustering, and are continuing to perform SAR studies to obtain compounds with higher efficacy and selectivity. Citation Format: Dilan B. Jaunky, Kevin Larocque, Javier Porro Suardiaz, Dan Yang, Emma J. Furze, Pat Forgione, Alisa Piekny. Discovery of a novel drug that affects centrosome clustering [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 3247. doi:10.1158/1538-7445.AM2017-3247