bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 2307: Targeted agents and chemotherapeutic treatments of genetically engineered Basal-like breast cancer mouse model
Authors: Contreras Cristina M. , Silva Grace O. , Pfefferle Adam D. , Perou Charles M. 
Published: August 2015

Abstract
Background: Genomic characterization of human breast tumors has resulted in the identification of at least five distinct tumor subtypes (Luminal A and B, HER2-enriched, Claudin-low, and Basal-like). These subtypes each show their own unique biology, which correlates with distinct patient outcomes. Basal-like Breast Cancer (BLBC) is associated with high grade, BRCA1 mutation status, younger patient age, and increased frequency in African Americans. In order to identify novel therapeutic strategies for BLBC, we developed a genetically engineered mouse model based upon two common human BLBC genetic events, namely BRCA1 and TP53 loss.
Results: We developed a genetically engineered mouse (GEM) model of breast cancer by inactivating TP53 and BRCA1 genes using Cre-LOX technology in the mammary gland (K14-cre / TP53 L/L / BRCA1 L/L). As part of the characterization of this GEM model, we performed gene expression profiling and DNA copy number analysis using aCGH arrays on the Basal-like tumors from this model (25/27 total tumors were Basal-like). We found a number of chromosomal regions that were similarly altered and found to be specific to mouse and human BLBC including gains of mouse chromosome 1q and 12q and losses in chromosomes 3F1 and 15q. Subsequently two tumors from the murine Basal-like group were taken and expanded into an orthotopic syngeneic model where they passaged in wild type FVB mice. These two tumors lines were then tested extensively with chemotherapeutics (Doxorubicin, Carboplatin, Cytoxan, Paclitaxel) and biologically targeted agents (MEK inhibitor/AZD6244, PI3K Inhibitor/BEZ235, PARP Inhibitor/ABT888 and mTOR Inhibitor/Everolimus). The DNA damaging agents exhibited exceptional efficacy (i.e. ABT888, Cytoxan, and Carboplatin), whereas the biologically targeted agents tended to at best, only slow tumor growth, even in combination.
Conclusions: Genetic engineering of mice using TP53 and BRCA1 loss results in tumors of predominantly the Basal-like subtype phenotype. As expected, these tumors were exquisitely sensitive to DNA damaging chemotherapeutics including cytoxan and carboplatin, yet generally insensitive to the 3 tested kinase inhibitors. Novel combinations of targeted agents and chemotherapeutics are now being tested.
Citation Format: Cristina M. Contreras, Grace O. Silva, Adam D. Pfefferle, Charles M. Perou. Targeted agents and chemotherapeutic treatments of genetically engineered Basal-like breast cancer mouse model. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 2307. doi:10.1158/1538-7445.AM2015-2307
Abstract 2308: The role of LKB1 in development of lung squamous cell carcinoma in mice
Authors: Liu Jian , Cho Sung-Nam , Zhang Yiqun , Creighton Chad J. , DeMayo Francesco J. 
Published: August 2015

Abstract
LKB1 is frequently dysregulated in human lung cancer and has been shown to be one of the critical genes controlling the development of lung squamous cell carcinoma (SCC) in mice1,2. However, it's unclear that the contribution of LKB1 in the development of lung SCC in mice. Here we took advantage of our new enhanced Cre (CCSPiCre) to efficiently deplete Lkb1 in the mouse airway epithelial cells. Although ablation of Lkb1 failed to show any discernable morphological changes, microarray analysis revealed 503 genes and 202 LincRNAs were significantly altered after single ablation of Lkb1. Ingenuity Pathway Analysis (IPA) showed that LXR/RXR activation and inflammatory pathways were significantly dysregulated by ablation of Lkb1. Using the CCSPiCre mouse, we ablated Pten in addition to Lkb1. As previously reported by Xu and coworkers who used Adenoviral delivery of Cre recombinase to achieve Lkb1 and Pten ablation2, the resulting phenotype was SCC while much rapider tumor initiation age, higher mouse metastasis ratio and a worse mortality were observed in this efficient mouse model. Analysis of the tumor development showed progression from mucous cell hyperplasia of the large airways to a papillary transition stage, then to the SCC phenotype. Mice with airway specific loss of Lkb1 and only one allele of Pten (CCSPiCrePtenf/+Lkb1f/f) showed slower tumor progression with the strong metastasis ability to multiple organs, such as liver, uterus, intestine and spleen. Comparison of the microarrays of CCSPiCrePtenf/f and CCSPiCrePtenf/fLkb1f/f in the pretumor stage showed 1463 genes and 339 LincRNAs were significantly altered. Again the major altered pathways were inflammatory and cholesterol biosynthesis. Using this model the developmental progression of lung SCC and the contribution of LKB1 to lung SCC progression were determined.
References
1.
Ji, H., et al. LKB1 modulates lung cancer differentiation and metastasis. Nature 448, 807-810 (2007).
2.
Xu, C., et al. Loss of Lkb1 and Pten leads to lung squamous cell carcinoma with elevated PD-L1 expression. Cancer cell 25, 590-604 (2014).
Citation Format: Jian Liu, Sung-Nam Cho, Yiqun Zhang, Chad J. Creighton, Francesco J. DeMayo. The role of LKB1 in development of lung squamous cell carcinoma in mice. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 2308. doi:10.1158/1538-7445.AM2015-2308
Abstract 2320: Prox1 marks a stem cell population that promotes tumor progression in intestinal adenomas
Authors: Wiener Zoltan , Högström Jenny , Hyvönen Ville , Kallio Pauliina , Heino Sarika , Alitalo Kari 
Published: August 2015

Abstract
Colorectal cancer (CRC) initiation and growth is often attributed to stem cells, yet little is known about the regulation of this cell population. We have shown that a subpopulation of cells expressing the Prox1 transcription factor have stem cell activity in intestinal adenomas, but not in the normal intestine. Using in vivo models and 3D ex vivo organoid cultures of mouse adenomas and human CRC, we found that Prox1 deletion reduced the number of stem cells and cell proliferation and decreased intestinal tumor growth in multiple CRC model systems. Loss of Prox1 also decreased autophagy and the survival of hypoxic tumor cells in tumor transplants. Thus, Prox1 is essential for the expansion of the stem cell pool in intestinal adenomas and CRC without being critical for the normal functions of the gut. To further study the adenoma stem cells in relation to the Prox1-positive cell population, we analyzed Apc-mutant intestinal organoids derived from Prox1-CreER; tdTomatoflox/Stop/flox; Apcmin/+ mice. In this lineage tracing model, the induction of Cre activity results in the expression of the red fluorescent protein tdTomato only in the Prox1-positive adenoma cells. FACS sorted tdTomato-positive cell population displayed a highly elevated capability to form new organoids compared to the tdTomato-negative cells, consistent with stem cells enrichment in the Prox1-positive cell population. Gene expression analysis provided new clues about the identity of the Prox1 positive cells.
Citation Format: Zoltan Wiener, Jenny Högström, Ville Hyvönen, Pauliina Kallio, Sarika Heino, Kari Alitalo. Prox1 marks a stem cell population that promotes tumor progression in intestinal adenomas. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 2320. doi:10.1158/1538-7445.AM2015-2320
Abstract 2324: The histone acetyltransferase inhibitor CPTH6 selectively targets lung cancer stem-like cells
Authors: Di Martile Marta , Desideri Mariannna , De Luca Teresa , Gabellini Chiara , Eramo Adriana , Milella Michele , Secci Daniela , Carradori Simone , Buglioni Simona , Del Bufalo Donatella , Trisciuoglio Daniela 
Published: August 2015

Abstract
Targeting epigenetic regulators is emerging as a promising strategy for cancer therapy. In this context, we recently identified the thiazole derivative 3-methylcyclopentylidene-[4-(4′-chlorophenyl)thiazol-2-yl]hydrazone (CPTH6) as a novel pCAF and GCN5 histone acetyltransferase inhibitor. CPTH6 exerts in vitro anti-tumoral effect in a panel of human tumor cell lines derived from different histotypes. In this study, we evaluated the efficacy of CPTH6 as a novel drug that targets Lung Cancer Stem-like Cells (LCSC) derived from non-small cell lung cancer (NSCLC) patients. We found that CPTH6 has a stronger growth-inhibitory effect in patient-derived LCSC than in established NSCLC lines. Unlike LCSC models, in which CPTH6 treatment induces cell cycle perturbation and apoptosis even at low doses, in established NSCLC lines CPTH6 triggers a cell cycle perturbation associated to DNA damage only at higher concentrations. Of note, differentiated progeny of LCSC lines are more resistant to CPTH6 cytoxicity when compared to their undifferentiated counterparts. Interestingly, CPTH6 treatment is also associated with reduced expression of the CD133 stemness marker in LCSC lines. Analysis of the CD133+ subpopulation in LCSC lines indicates that CD133+ cells not only undergo apoptosis following CPTH6 treatment but also shift toward a more differentiated phenotype. Furthermore, the growth inhibitory effect seems to be tightly related to baseline expression of acetylated alpha-tubulin, which was particularly prominent in sensitive LCSC lines. In vivo experiments confirmes the antitumor efficacy of CPTH6, particularly in LCSC-derived models, where a pronounced apoptosis induction and growth inhibitory effect is observed after CPTH6 treatment. Overall, our studies propose histone acetyltransferase inhibition as an attractive target for cancer therapy of NSCLC.
Citation Format: Marta Di Martile, Mariannna Desideri, Teresa De Luca, Chiara Gabellini, Adriana Eramo, Michele Milella, Daniela Secci, Simone Carradori, Simona Buglioni, Donatella Del Bufalo, Daniela Trisciuoglio. The histone acetyltransferase inhibitor CPTH6 selectively targets lung cancer stem-like cells. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 2324. doi:10.1158/1538-7445.AM2015-2324
Abstract 2342: Characterization of inflammatory markers and mast cells in association with prostate cancer
Authors: Hempel Heidi , Kulac Ibrahim , Cuka Nathan S. , Cornish Toby C. , Platz Elizabeth A. , DeMarzo Angelo M. , Sfanos Karen S. 
Published: August 2015

Abstract
Evidence suggests that there is a strong association between chronic inflammation and prostate cancer development and/or progression. While chronic inflammation is known to serve as an “enabling characteristic” in many cancers, the mechanism whereby it contributes to carcinogenesis and progression is still very controversial. This is particularly true for cells of the innate immune system, such as mast cells, that have been shown to possess both pro- and anti-tumor properties. The role of mast cells in prostate cancer is of particular interest, as evidence suggests that they influence cancer progression and immune modulation. The current study seeks to characterize mast cell density and mast cell-to-epithelial ratio in relation to prostate cancer recurrence using a unique set of tissue microarrays (TMAs) from a case-control study nested in a cohort of prostate cancer patients who underwent radical prostatectomy. These studies are aided by novel digital image analysis using a software framework integrating whole slide imaging, virtual microscopy, and ImageJ based analysis algorithms. Our preliminary results, obtained via analysis of a prostate cancer TMA containing matched cancer and benign tissues from 727 cases of radical prostatectomy patients, correlated with the literature in that the mast cell density (mast cell number/total tissue area) was significantly higher in cancer versus benign (p = 0.0016). We will expanded this study to determine if mast cell number correlates with epithelial area in the same cohort and to examine mast cell density in correlation to the presence, grade, or progression of prostate cancer. Furthermore, we will be examining this in a large full tissue slide cohort in relation to Gleason grade and stage. Finally, we are expanding this study to explore a possible role for mast cells in the racial disparity in prostate cancer incidence and prognosis.
Citation Format: Heidi Hempel, Ibrahim Kulac, Nathan S. Cuka, Toby C. Cornish, Elizabeth A. Platz, Angelo M. DeMarzo, Karen S. Sfanos. Characterization of inflammatory markers and mast cells in association with prostate cancer. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 2342. doi:10.1158/1538-7445.AM2015-2342
Abstract 2361: TGFβ signaling deficiency enhances tumor associated inflammation in colon cancer
Authors: Principe Daniel R. , DeCant Brian , Mangan Riley J. , Wayne Elizabeth A. , Diaz Andrew M. , Vitello Dominic , Munshi Hidayatullah G. , Grippo Paul , Jung Barbara 
Published: August 2015

Abstract
In early colon cancer development, there is considerable evidence suggesting that transforming growth factor-β (TGFβ) serves as a tumor suppressor due to its growth-inhibitory effects in the epithelium. This is in contrast to observations suggesting that in advanced disease, TGFβ promotes tumor progression by contributing to metastasis. Therefore, to better understand the effects of TGFβ signaling on colon cancer, we examined the effect of global or epithelial reduction in TGFβ signaling on tumor progression in the APC murine model of colon cancer. Initially, we examined the relationship between TGFβ signaling and inflammation in human colon cancer specimens. We found that loss of SMAD4 in epithelial cells correlates with increased inflammation in tissue from colon cancer patients. Moreover, APC mice with global TGFBR deficiency (ATG mice) demonstrated increased inflammation that was also associated with loss of SMAD4 in epithelial cells. In contrast, APC mice with epithelial loss of TGFBR signaling (ATC mice) do not demonstrate loss of SMAD4, but have even more pronounced inflammation concomitant with rectal bleeding and prolapse, significant weight loss, the presence of crypt abscesses and lymphoid aggregates, and increased mortality. Similarly, ATC mice, in contrast to the ATG and the APC mice, show markedly increased tumor infiltrating macrophages, splenic macrophages, and serum levels of the cancer-associated cytokines IL8, TGFβ1, and TNFα. Overall, these findings demonstrate that loss of TGFβ signaling, particularly in epithelial cells, dramatically worsens tumor progression. Yet, the attempt to reduce metastasis by treating colon cancer patients with TGFβ inhibitors may result in worse outcome by invoking a robust inflammatory response.
Citation Format: Daniel R. Principe, Brian DeCant, Riley J. Mangan, Elizabeth A. Wayne, Andrew M. Diaz, Dominic Vitello, Hidayatullah G. Munshi, Paul Grippo, Barbara Jung. TGFβ signaling deficiency enhances tumor associated inflammation in colon cancer. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 2361. doi:10.1158/1538-7445.AM2015-2361
Abstract 2412: Assessment of clinical applications of circulating tumor DNA using an enhanced TAm-Seq platform
Authors: Lawson Andrew RJ , Plagnol Vincent , Fahem Abdelaziz , Forshew Tim , Brenton James D. , Gale Davina , Rosenfeld Nitzan 
Published: August 2015

Abstract
Novel biomarkers are required to assess tumor burden and response in cancer as conventional biopsies are invasive, costly and only provide a snapshot of the mutational profile at a given time and location. A promising biomarker is the detection of genomic material released from tumors into the blood plasma of patients, known as circulating tumor DNA (ctDNA). ctDNA has been detected in plasma for a wide range of solid tumors and can be distinguished from other (germline) cell-free DNA by the presence of tumor-specific DNA alterations or known hotspot mutations. However, the potential of ctDNA as a biomarker has not yet been fully realized due to technical challenges associated with its detection and analysis, including the short fragment sizes (140-170 bp), small number of amplifiable copies and low/variable allele fractions of ctDNA.
We have developed an enhanced platform for tagged-amplicon deep sequencing (TAm-Seq™). Using a combination of improved library preparation and bespoke data analysis methods, this platform can be used to sequence established cancer hotspots and the entire coding regions of selected genes, while preserving high levels of specificity and sensitivity. Using this approach, we have developed an assay that analyzes ∼20 kb of the genome (including regions of interest in more than 30 genes) with sensitivity down to a few mutant copies. Performance of this assay has been demonstrated using spike-in experiments, dilution series and clinical sample cohorts. Proof of concept studies have shown the potential of ctDNA to be used to assess tumor mutation status, monitor tumor dynamics, assess response to treatment and identify mutations associated with acquired drug resistance and disease progression. This non-invasive approach - a “liquid biopsy” - offers a revolution in how cancer can be detected, monitored and treated.
Citation Format: Andrew RJ Lawson, Vincent Plagnol, Abdelaziz Fahem, Tim Forshew, James D. Brenton, Davina Gale, Nitzan Rosenfeld. Assessment of clinical applications of circulating tumor DNA using an enhanced TAm-Seq platform. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 2412. doi:10.1158/1538-7445.AM2015-2412
Abstract 2426: JAK inhibitors as new drugs for treatment of paclitaxel-resistant anaplastic thyroid cancer
Authors: Fujita Tomoyuki , Sasaki Takayuki , Wang Zheng , Koshikawa Kayoko , Nishimura Hajime , Fujimori Minoru 
Published: August 2015

Abstract
Background: Anaplastic thyroid carcinoma (ATC) is a rare but particularly aggressive solid tumor that has a poor prognosis, despite multimodal treatment approaches. New chemotherapy agents are being developed and taxanes have efficacy against ATC. Targeted agents including fosbretabulin, imatinib, erlotinib and gefitinib have also been examined, but were unsuccessful. These results suggest that innovative strategies are required for treatment of ATC. Therefore, our primary aim was to determine the genes and pathways related to sensitivity to paclitaxel as biomarkers in ATC. Our secondary aim was to identify new genes and pathways as therapeutic targets in ATC.
Materials and Methods: We analyzed differences in gene expression profiles before and after treatment with paclitaxel in two ATC cell lines: KTA-3 cells, which are sensitive to paclitaxel, and TTA-2 cells, which are resistant to paclitaxel. Parametric Analysis of Gene Set Enrichment (PAGE) using the Kyoto Encyclopedia of Genes and Genomes (KEGG) and the Transcriptional Regulatory Element Database (TRED) were performed to detect significant differences at the level of functional categories such as pathway genes and transcriptionally regulated genes.
Results: Genes in the Janus kinase/signal transducer and activator of transcription (JAK-STAT) pathway (KEGG classification) were downregulated significantly in KTA-3 cells compared with TTA-2 cells after treatment with paclitaxel. PAGE showed that breast cancer susceptibility gene (BRCA)1-related genes including Janus kinase (JAK)1, JAK2 and signal transducer and activator of transcription (STAT)3 were downregulated most significantly in KTA-3 cells compared with TTA-2 cells after paclitaxel treatment. Several JAK inhibitors inhibited cell growth in paclitaxel-resistant ATC cells.
Conclusions: JAK-STAT pathway may be a biomarker of paclitaxel sensitivity in ATC and may represent a new target in drug development for ATC therapy.
Citation Format: Tomoyuki Fujita, Takayuki Sasaki, Zheng Wang, Kayoko Koshikawa, Hajime Nishimura, Minoru Fujimori. JAK inhibitors as new drugs for treatment of paclitaxel-resistant anaplastic thyroid cancer. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 2426. doi:10.1158/1538-7445.AM2015-2426
Abstract 2428: Translational study of F14512, a novel vectorised epipodophyllotoxin, which demonstrates a marked activity on ovarian cancer models from patients
Authors: Thibault Benoît , Zorza Gregoire , Meignan Samuel , Guilbaud Nicolas , Bailly Christian , Delord Jean-Pierre , Couderc Bettina , Kruczynski Anna , Ferre Pierre , Annereau Jean-Philippe 
Published: August 2015

Abstract
Epithelial ovarian cancer is the fourth cause of death among cancer-bearing women, frequently associated with carboplatin resistance, underlining the need of more efficient and targeted therapies. F14512 is a novel concept of drug vectorization that we propose here to investigate in ovarian cancer models. F14512 is an epipodophyllotoxin-core linked to a spermine chain, which enters selectively tumor cells via the polyamine transport system (PTS), currently in clinical phase II evaluation in AML. We compared the effects of F14512 versus etoposide against OVCAR-3, IGROV-1, SKOV-3, A2780S and A2780R cancer cell lines. Using the F17073 PTS fluorescent probe, we determined the PTS activity of these cells and of 18 clinical samples. As results, F14512 displayed strong anti-proliferative and pro-apoptotic activities in carboplatin-resistant models, being increased in cell lines with high levels of PTS. Consistently, at a dose of 1.25 mg/kg, F14512 significantly inhibited tumor growth in cisplatin-resistant SKOV-3 xenograft model. Interestingly, ex vivo analysis indicated that 15 patients sample out of 18 presented a higher F17073 fluorescent probe incorporation into CD326-positive tumor cells as compared to normal cells, even in the case of 2 platinum-refractory patients. Therefore, F14512 is a targeted drug with a potent anti-tumor efficacy regardless the status of cisplatin resistance. The high PTS activity detected in fresh clinical samples highlights the potential of F14512 as a new therapy for PTS-positive and platinum resistant ovarian cancer patients.
Citation Format: Benoît Thibault, Gregoire Zorza, Samuel Meignan, Nicolas Guilbaud, Christian Bailly, Jean-Pierre Delord, Bettina Couderc, Anna Kruczynski, Pierre Ferre, Jean-Philippe Annereau. Translational study of F14512, a novel vectorised epipodophyllotoxin, which demonstrates a marked activity on ovarian cancer models from patients. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 2428. doi:10.1158/1538-7445.AM2015-2428