bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 5749: Interleukin-1 (IL-1) induces a treatment-resistant gene expression pattern in prostate cancer (PCa)
Authors: Thomas-Jardin Shayna Elizabeth , Kanchwala Mohammed , Jacob Joan , Meade Rachel , Gahnim Nagham , Delk Nikki 
Published: August 2018

Abstract
Inflammation promotes the development and progression of cancer, where inflammatory cytokines secreted by infiltrating immune cells and tumor cell autocrine signaling are usurped to promote tumor cell survival and disease progression. The interleukin-1 (IL-1) inflammatory cytokine is elevated in prostate cancer (PCa) patient tissue and serum, where it promotes PCa metastasis and bone colonization. Performing in vitro analysis on PCa cell lines and RNA sequencing, we found that IL-1 concomitantly upregulates many pro-survival and lineage proteins, and represses the hormone receptor, androgen receptor (AR). Despite AR loss, a subpopulation of PCa cells remain viable. Our observation could reflect a role for IL-1 in the de novo accumulation of AR- PCa subpopulations. Indeed, AR- PCa subpopulations, such as stem and neuroendocrine cells, are implicated in PCa resistance to AR-targeted therapies. Thus, we hypothesize that IL-1 may reprogram AR+ PCa cells into treatment-resistant AR- PCa cells that survive hormone receptor repression through the upregulation of pro-survival pathways. To begin to address this hypothesis, we performed RNA sequencing and pathway analysis to identify an IL-1-conferred expression pattern in the LNCaP AR+ PCa cell line that mimics the PC3 AR- PCa cell line. We identified canonical inflammatory and immune response pathways, including NFκB, IL-8, and iNOS signaling cascades, likely facilitating PCa cell survival in an inflammatory tumor microenvironment. We also identified novel IL-1-regulated proteins that are known to promote PCa cell survival, such as SQSTM1/p62, SOX9, and ELF3. Experiments are underway to determine the functional significance of our IL-1-conferred gene expression profile in cell line and PDX models. Our investigation will provide insight into the mechanistic function of IL-1 in PCa resistance to AR-targeted therapies
Citation Format: Shayna Elizabeth Thomas-Jardin, Mohammed Kanchwala, Joan Jacob, Rachel Meade, Nagham Gahnim, Nikki Delk. Interleukin-1 (IL-1) induces a treatment-resistant gene expression pattern in prostate cancer (PCa) [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 5749.
Abstract 5750: Underlying inflammatory processes in non-neoplastic female thyroid serve as an immunological basis for the sex disparity in papillary thyroid cancer
Authors: Gupta Anvita , Singh Karnika , O'Connell Timmy J. , Jones Melanie , Rasamny JK , Schwarcz Monica , Moscatello Augustine , Shin Edward , Tiwari Raj , Geliebter Jan 
Published: August 2018

Abstract
Background: The American Cancer Society (ACS) estimated 56,870 new cases of thyroid cancer in the United States in 2017, with roughly 2,010 deaths attributed to the disease. The incidence of thyroid cancer has been increasing steadily over the past three decades, with Papillary Thyroid Cancer (PTC) being the most prevalent form of this endocrine malignancy, comprising of about 90% of all cases. Appreciably, Surveillance, Epidemiology, and End Results (SEER) and the ACS indicate that the incidence of PTC in the age group of 20-49 years is three to four times more prevalent in women than in men. This epidemiologic finding suggests that the female thyroid is at a higher risk of developing PTC.
Methods: The Cancer Genome Atlas (TCGA) database provides the means to address the differences between male and female thyroids on the molecular level. Using the normalized Level 3 RNA Seq Data and patient pathology reports available on the TCGA Data Portal, differential gene expression of 56 non-neoplastic/normal thyroid samples (40 women; 16 men) was investigated using the biological analysis software, Subio platform, version v1.20.5031. (Subio Inc., Tokyo, Japan).
Results: Immune/inflammatory genes exhibited a higher expression in uninflamed, normal thyroid tissue of women than in men (&gt;1.5 fold; p&lt;0.05). The expression levels of these genes were increased in male PTC samples, compared to their matched normal tissue. The level of expression of immune/inflammatory genes in women approximated their expression levels in matched PTC tissue of women and men, indicating that normal thyroid tissue in women exhibits a neoplastic level of inflammation.
Conclusions: Our data suggest that the female thyroid may be “at-risk” for developing PTC due to underlying and on-going immune/inflammatory processes.
Citation Format: Anvita Gupta, Karnika Singh, Timmy J. O'Connell, Melanie Jones, JK Rasamny, Monica Schwarcz, Augustine Moscatello, Edward Shin, Raj Tiwari, Jan Geliebter. Underlying inflammatory processes in non-neoplastic female thyroid serve as an immunological basis for the sex disparity in papillary thyroid cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 5750.
Abstract 5768: MG1122, a whole IgG-like bispecific antibody targeting mesothelin and CD3, induces T cell-mediated killing of MSLN-expressing tumor cells
Authors: Lee Yun-Jung , Lim Okjae , Kim Munkyung , Lee Jeewon , Kim Kisu , Jung Junhong , Lee SuA , Kim Sung Keun , Kwon Haenaem , Lim Yangmi , Park Yong Yea , Won Jonghwa 
Published: August 2018

Abstract
Mesothelin (MSLN) is an antigen overexpressed in several malignancies, including mesothelioma and ovarian and pancreatic adenocarcinoma. It has been studied as a marker for diagnosis and a target for immunotherapy. Here, we adopted a bispecific antibody format for recruiting cytotoxic T cells to kill tumor cells. MG1122 is a novel, whole IgG-like bispecific antibody which recognizes CD3 on T cells and MSLN on tumor cells. MG1122 induced effective killing of MSLN-expressing tumor cells. This response was associated with robust activation of T cells as shown by nuclear factor of activated T cells (NFAT) activation, CD25 and CD69 upregulation and increased cytokine release. In addition, using a live cell analysis system, we found that levels of activated caspase 3/7 were amplified in the tumor cells by MG1122 treatment. Although MSLN is a surface antigen, it also exists as a secreted isoform, which can lead to tumor evasion against MSLN targeting antibodies. However, despite the high concentration of soluble MSLN, MG1122 still effectively bound and showed strong killing effects against MSLN-expressing tumor cells. Taken together, our MSLN/CD3 bispecific antibody, MG1122 offers a promising opportunity to redirect T cells to kill MSLN-expressing cancer cells.
Citation Format: Yun-Jung Lee, Okjae Lim, Munkyung Kim, Jeewon Lee, Kisu Kim, Junhong Jung, SuA Lee, Sung Keun Kim, Haenaem Kwon, Yangmi Lim, Yong Yea Park, Jonghwa Won. MG1122, a whole IgG-like bispecific antibody targeting mesothelin and CD3, induces T cell-mediated killing of MSLN-expressing tumor cells [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 5768.
Abstract 577: Oral microbiome biomarker panel to detect oral and oropharyngeal cancers in a clinical setting
Authors: Lim Yenkai , Fukuma Naoki , Totsika Makrina , Kenny Liz , Morrison Mark , Punyadeera Chamindie 
Published: August 2018

Abstract
Oral microbiome plays a role in the instigation of oral diseases that affect other systemic conditions. These associations encourage the exploration of oral dysbiosis leading to the pathogenesis of cancers. In this study, saliva was used to characterise the oral microbiome fluctuation associated with oral and oropharyngeal cancers. The study cohort consists of normal healthy controls (n = 10, between 20 to 30 years of age; n = 10, above 50 years of age), high-risk individuals (n = 11, above 50 years of age with bad oral hygiene and/or oral diseases) and oral and oropharyngeal cancer patients (n = 31, HPV-positive; n = 21, HPV-negative). Saliva samples were analysed using 16S rRNA gene amplicon sequencing on the MiSeq platform. Kruskal-Wallis rank test was used to identify genera associated with oral and oropharyngeal cancers. A logistic regression analysis was carried out to determine the performance of these genera as a biomarker panel to detect oral and oropharyngeal cancers. In addition, a two-fold cross-validation with a bootstrap procedure was carried out on R to investigate how well the panel would perform in a real clinical scenario. Our data indicates that the oral microbiome is able to predict the presence of oral and oropharyngeal cancers with sensitivity and specificity of 100% and 90% respectively. With further validation, the panel could potentially be implemented into clinical workflow as oral and oropharyngeal cancers diagnostic and prognostic biomonitors.
Citation Format: Yenkai Lim, Naoki Fukuma, Makrina Totsika, Liz Kenny, Mark Morrison, Chamindie Punyadeera. Oral microbiome biomarker panel to detect oral and oropharyngeal cancers in a clinical setting [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 577.
Abstract 5785: EML4-ALK variant E6a/b;A20 positive NSCLC cell lines are associated with growth upon blocking MEK-ERK pathway
Authors: Hallberg Bengt , Palmer Ruth H. , Umapathy Ganesh , Gustafsson Dan E. , Siaw Joachim T. , Alam Wasi , Guan Jikui , Doebele Robert , Le Anh T. , Doak Andrea 
Published: August 2018

Abstract
Background:
The protein kinase B (PKB/AKT) and RAF/MEK/ERK signaling pathways are activated in a wide range of human cancer types. In many cases, concomitant inhibition of both pathways is necessary to block proliferation and induce cell death and tumor shrinkage. Several feedback mechanisms have been described in which inhibition of one pathway leads to activation of a parallel signaling pathway, thereby decreasing the effectiveness of targeted monotherapies.
Materials and Methods:
In order to determine which signalling core should be blocked for combinatorial treatment, we treated a panel of EML4-ALK positive lung cancer cell lines using MEK-ERK inhibitors. Resazurin assay was performed to evaluate cell viability. Protein levels were determined using western blotting.
Results:
In this study, we describe a feedback mechanism in which MEK-ERK inhibition leads to increased activation of AKT signaling in EML4-ALK variant (E6a/b;A20) positive NSCLC cell lines. Interestingly, EML4-ALK variant (E13;A20) NSCLC cell lines responds to MEK-ERK inhibitors and shows synergism when combined with ALK tyrosine kinase inhibitors. We found that feedback response in EML4-ALK variant (E6a/b;A20) positive NSCLC cells was mediated by the mammalian target of rapamycin complex 2-associated protein SIN1, resulting in increased survival and proliferation that depended on AKT signaling.
Conclusions:
Taken together, these results elucidate an important feedback network and contraindicate the use of MEK inhibitors as effective therapeutic strategy in EML4-ALK variant (E6a/b;A20) positive NSCLC.
Citation Format: Bengt Hallberg, Ruth H. Palmer, Ganesh Umapathy, Dan E. Gustafsson, Joachim T. Siaw, Wasi Alam, Jikui Guan, Robert Doebele, Anh T. Le, Andrea Doak. EML4-ALK variant E6a/b;A20 positive NSCLC cell lines are associated with growth upon blocking MEK-ERK pathway [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 5785.
Abstract 5806: Combination of the miniature drug conjugate PEN-866 with PARP inhibitors as a rational approach to overcoming limitations of PARP inhibitor monotherapy
Authors: Perino Samantha , Quinn James M. , Callahan Marrissa , Sharma Gitanjali , White Brian , Bilodeau Mark , Alland Leila , Whalen Kerry , Wooster Richard 
Published: August 2018

Abstract
PEN-866 is a novel miniature drug conjugate comprised of a Heat Shock Protein 90 (HSP90) targeting ligand attached through a cleavable linker to SN-38, the active metabolite of the approved topoisomerase I inhibitor, irinotecan. The conjugate accumulates and is retained in tumor cells through the HSP90 targeting ligand. PEN-866 linker cleavage provides sustained release of SN-38 at a high local tumor concentration leading to DNA damage and apoptosis of tumor cells resulting in broad preclinical antitumor activity. Reducing the DNA repair activity in tumor cells is an opportunity to significantly potentiate the efficacy of PEN-866.
Poly ADP ribose polymerase (PARP) has an important role in the repair of DNA. PARP inhibitors have shown activity in the clinical setting, both in patients whose cancers harbor mutations in BRCA1 and BRCA2, and in those that are BRCA1/2 wildtype, and are approved as monotherapy for use in treatment of patients with advanced ovarian cancers. Combining PARP inhibitors with other therapeutics has been challenging due to dose limiting toxicities. Combining PARP inhibitors with PEN-866 is mechanistically appealing with the potential for greater efficacy as compared to these agents used alone and the potential to mitigate the toxicity of the combination of a PARP inhibitor with conventional cytotoxic therapy due to the high levels of accumulation and retention of PEN-866 in xenograft tumors.
To evaluate these hypotheses, we have combined PEN-866 and PARP inhibitors in preclinical models of human cancer. Efficacy studies were carried out in both BRCA mutant and BRCA wildtype tumor xenografts combining PEN-866 and PARP inhibitors, and the combinations resulted in greater efficacy than that of the single agent in tumors with both genetic backgrounds. In addition, a pharmacodynamic assessment of DNA damage was performed in tumors responsive to the combination treatment. These data demonstrate that combination of PEN-866 and PARP inhibitors provide greater efficacy than single agent activity alone, including BRCA wildtype tumors, and support the evaluation of such combinations in the clinical setting. The authors acknowledge David Proia, Weiwen Ying and others from Synta Pharmaceuticals who contributed to this work.
Citation Format: Samantha Perino, James M. Quinn, Marrissa Callahan, Gitanjali Sharma, Brian White, Mark Bilodeau, Leila Alland, Kerry Whalen, Richard Wooster. Combination of the miniature drug conjugate PEN-866 with PARP inhibitors as a rational approach to overcoming limitations of PARP inhibitor monotherapy [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 5806.
Abstract 5814: Synthetic lethal therapy to overcome resistance to AURKA inhibition in HPV-negative head and neck cancer
Authors: Deneka Alexander Y. , Einarson Margret B. , Lee Jong Woo , Nikonova Anna S. , Burtness Barbara , Golemis Erica A. 
Published: August 2018

Abstract
Head and neck squamous cell carcinomas (HNSCC) affect more than a half million people annually worldwide. Most currently available treatments, which include cisplatin and irradiation, are associated with significant morbidity, while many targeted inhibitors show limited single agent efficacy: novel therapeutic approaches which combine efficacy and limited toxicity are needed. The most common mutational event in human papillomavirus (HPV)-negative HNSCC is mutation of TP53. As control of the G1/S transition is entirely p53-dependent, cells with TP53 mutations lose the G1/S checkpoint, and evade radiation- and cisplatin-induced cellular senescence. Targeting the serine/threonine mitotic kinase Aurora-A (AURKA) emerged as a promising synthetic lethal approach in this setting. AURKA is negatively regulated by p53, which causes upregulation of AURKA in the majority of cases of HNSCC, correlating with poor prognosis and cisplatin resistance. The single agent AURKA inhibitor MLN8237 (alisertib) had a 9% monotherapy response rate in treatment-refractory HNSCC, with all responses occurring in HPV-negative or -unknown disease. In our study, we used initial high throughput screening in multiple genomically characterized HNSCC cell lines to identify synergistic combinations involving AURKA inhibitors and 20 other inhibitors of cell cycle, and cell cycle checkpoint controls. This work has identified has several effective combinations, particularly in between alisertib (targeting AURKA), danusertib (AURKA and AURKB), LY2606368/prexasertib (CHK1), and reversine (MPS1). Multiplexing analysis with measures of cell metabolism, direct visualization of mitotic nuclei, and additional assays has allowed us to dissect distinct execution points for different drug combinations. We will describe in detail mechanistic interactions between specific combinations of value for HNSCC. These drug combinations are likely to represent a new and effective modality for treating TP53-mutated cancers.
Citation Format: Alexander Y. Deneka, Margret B. Einarson, Jong Woo Lee, Anna S. Nikonova, Barbara Burtness, Erica A. Golemis. Synthetic lethal therapy to overcome resistance to AURKA inhibition in HPV-negative head and neck cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 5814.
Abstract 582: Accelerating drug development with a CLIA approved functional test using patient derived organoids
Authors: Schaub Franz X. , Churchill Michael J. , Swan Hallie A. , Rosati Rachele , Watt Roland M. , Shaw Reid C. , Murphy Stephanie A. , Diaz Robert L. , Pereira Shalini C. , Grandori Carla 
Published: August 2018

Abstract
The pool of targeted therapies is expanding steadily providing novel treatment opportunities. However, the process of expanding indications and including additional cancer types after initial approval is slow. Here we present an in vitro clinical trial platform using the data from the first CLIA-approved Precision Medicine Platform using high-throughput screening (P.A.R.I.S. Assay, SEngine Precision Medicine, Seattle, WA).
Briefly, patient-derived tumor cells from biopsies are expanded as living organoids, and functionally evaluated using a high-throughput drug screen. The drug library currently includes FDA approved and experimental drugs. Results are integrated with known genomic information and reported to the clinician to highlight treatment options of an individual patient. Combining this data from multiple patients enables the discovery of novel indications and biomarkers. To date we have acquired data from a wide range of tumor types including hard-to-treat cancers, rare tumor types and tumors from heavily pretreated patients. In addition, we also have collected data from more than 100 patient derived cell lines.
Using the data analysis platform developed in R, the drug responses across all patient screens of a given drug can be analyzed to find common indicators of sensitivities. For instance, a BRD4 inhibitor (CPI-203), which was tested on 8 different primary tumor samples, was selectively active in a subset of the patients. Interestingly, most of the responding tumor types are ovarian and breast cancer cases with mutations in BRCA1 or EZH2. However, there are currently no clinical trials investigating the more developed BRD4 inhibitor CPI-0610 for breast or ovarian cancer. Non-responders, on the other hand, are spread between multiple cancer types.
The number of patients receiving the P.A.R.I.S. test is steadily increasing and these patient cases contribute to our knowledge base. As this test is used to inform clinicians about potential treatment opportunities, we are also accumulating information on how these patients respond to treatment. Overall, this platform will provide real world data for optimal drug combinations and novel biomarkers to quickly expand indications of existing drugs.
Citation Format: Franz X. Schaub, Michael J. Churchill, Hallie A. Swan, Rachele Rosati, Roland M. Watt, Reid C. Shaw, Stephanie A. Murphy, Robert L. Diaz, Shalini C. Pereira, Carla Grandori. Accelerating drug development with a CLIA approved functional test using patient derived organoids [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 582.
Abstract 5842: Oxidative stress and protein carbonylation towards multi-drug resistance in cancer
Authors: Aryal Baikuntha P. , Gillet Jean-Pierre , Rao V Ashutosh 
Published: August 2018

Abstract
Reactive oxygen species (ROS) are constantly produced under normal as well as stress conditions and play important roles in cell signaling and homeostasis. An elevated level of ROS has been reported in most cancers which may play a critical role in both cancer progression or cancer suppression. One proposed therapeutic strategy is to alter the oxidative stress from ROS-induced tumor promoting event to a ROS-induced apoptotic signaling. Most ROS inducing therapeutic agents initially induce ROS to kill cancer cells by apoptosis; however, prolonged exposure of drugs may result in reduced ROS level and an adaptive microenvironment that makes cancer cells resistant to the same ROS-inducing therapeutic drugs. Chronic exposure of ROS may also upregulate the multidrug resistance protein expression in cancer cells. We hypothesize that differences in oxidative stress and the antioxidant response between drug sensitive and drug resistance cells may play a key role in drug resistance to redox-active drugs. We used two pairs of cell lines, a mitoxantrone sensitive and resistance MCF7 human breast adenocarcinoma (MCF7/MCF7MX) and H460 non-small lung cancer cell lines (H460/H460MX) for our experiments. We employed western blot and ELISA assays to determine the total and specific protein oxidation by carbonylation. Both MCF7MX and H460MX showed slightly lower level of total protein carbonylation compared to their mitoxantrone sensitive counterparts. In western blot analysis, we observed two specific proteins that were differentially carbonylated in MCF7MX compared to and MCF7. Both cytoskeletal and multifunctional proteins were identified by mass spectrometry and confirmed by two-color western blot analysis. Investigation of the potential roles of these specific protein carbonylation in drug resistance will be presented.
Citation Format: Baikuntha P. Aryal, Jean-Pierre Gillet, V Ashutosh Rao. Oxidative stress and protein carbonylation towards multi-drug resistance in cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 5842.