bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 4222: Targeting HMGA2 suppresses GBM stemness, invasion and tumorigenicity
Authors: Kaur Harpreet , Hütt-Cabezas Marianne , Taylor Isabella , Asnaghi Laura , Rodriguez Fausto , Orr Brent A. , Eberhart Charles G. , Raabe Eric H. 
Published: August 2015

Abstract
Glioblastoma Multiforme (GBM) causes the majority of brain tumor-related deaths in the United States. The high invasiveness of GBM prevents complete surgical resection, allowing tumor recurrence. The lack of curative treatment highlights a dire need to develop specific targeted therapeutics. Identifying and targeting novel molecular markers in glioma stem-like cells (GSCs) thought to be critical for tumor invasion and recurrence could lead to development of better therapies. HMGA2, a non-histone transcriptional modulator, is a regulator of normal and cancer stem cells. The significance of HMGA2 as a potential therapeutic target in GBM has not been investigated. We found increased HMGA2 expression in a subset of primary human GBM tumors, in multiple patient-derived GBM neurosphere and adherent cell lines, and in the mesenchymal subgroup of GBM in The Cancer Genome Atlas (TCGA) database. Lentiviral short hairpin RNA (shRNA)-lowered HMGA2 protein levels and significantly reduced invasion and clonogenicity of GBM cell lines in transwell invasion and soft agar colony formation assays. Pharmacological inhibition of HMGA proteins using the DNA minor-groove binding drug Netropsin significantly inhibited growth of the U-87 MG GBM cell line (P&lt;0.01) in MTS assays. Mice bearing orthotopic GBM neurosphere xenograft lines transduced with HMGA2 shRNA lived longer (median survival = 108 days) compared to control shRNA (median survival = 67.5 days) (P&lt;0.0001 by log-rank analysis). Conversely, lentiviral-mediated overexpression of HMGA2 in GBM cell lines increased invasion, clonogenicity and resistance to radiation in vitro (P&lt;0.01). Overexpression of HMGA2 also promoted GBM tumor formation in vivo in orthotopic xenografts. To elucidate the molecular mechanism by which HMGA2 promotes invasion and stemness in GBM, we performed mRNA expression profiling on GBM neurosphere lines lentivirally transduced to express HMGA2 or empty vector control. We found increased CD44 expression in HMGA2-overexpressing GBM neurosphere lines compared to control, and confirmed this result by western blotting. Together, our results suggest an oncogenic role of HMGA2 in promoting GBM tumorigenicity by increasing invasiveness and a stem cell-like state, and show that HMGA2 is a potential therapeutic target in GBM.
Citation Format: Harpreet Kaur, Marianne Hütt-Cabezas, Isabella Taylor, Laura Asnaghi, Fausto Rodriguez, Brent A. Orr, Charles G. Eberhart, Eric H. Raabe. Targeting HMGA2 suppresses GBM stemness, invasion and tumorigenicity. [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 4222. doi:10.1158/1538-7445.AM2015-4222
Abstract 4242: Metformin suppresses GRP78-dependent PI3-Kinase activity in clonogenic side population to enhance the anti-myeloma benefit of bortezomib
Authors: Driscoll James J. , Jagannathan Sajjeev , Abdel Malek Mohamed AY , Vad Nikhil , Malek Ehsan 
Published: August 2015

Abstract
Multiple myeloma (MM) patients invariably relapse through mechanisms that remain elusive. Disease recurrence after treatment suggests that rare, tumor-initiating subpopulations with chemoresistant phenotypes persist or emerge to propagate and mediate tumor regrowth. Stem cell-like side population (SP) cells were isolated from myeloma cell lines and patient samples and exhibited resistance to proteasome inhibitors relative to the main population (MP). SP cell-based high-throughput screening detected pharmacologics that enhanced the anti-proliferative effect of bortezomib and revealed the anti-diabetic agent metformin. Bortezomib treatment increased levels of the molecular chaperone glucose-regulated protein GRP78 but metformin co-treatment suppressed bortezomib-induced GRP78 upregulation. Bortezomib treatment also promoted GRP78 co-localization with the signal transducer phosphatidylinositol-3-kinase (PI3K) that activates cell growth and survival pathways. SP cells displayed greater levels of the PI3K product phosphatidylinositol (3,4,5)-trisphosphate (PIP3) and enhanced PI3K-mediated phosphorylation of protein kinase B/AKT compared to MP cells. Metformin treatment or knockdown of GRP78-encoding HSPA5 enhanced sensitivity to bortezomib preferentially in SP cells. Tumor growth was significantly delayed and overall survival prolonged after metformin co-treatment with bortezomib in mice injected with parental or SP cells. Taken together, the results support the pharmacologic repositioning of metformin to inhibit GRP78 induction in therapy-resistant cells and enhance the anti-myeloma benefit of bortezomib.
Note: This abstract was not presented at the meeting.
Citation Format: James J. Driscoll, Sajjeev Jagannathan, Mohamed AY Abdel Malek, Nikhil Vad, Ehsan Malek. Metformin suppresses GRP78-dependent PI3-Kinase activity in clonogenic side population to enhance the anti-myeloma benefit of bortezomib. [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 4242. doi:10.1158/1538-7445.AM2015-4242
Abstract 4249: High-Frequency of TMPRSS2-ERG fusion gene identifies a non-random androgen-driven event of chromosomal instability in BRCA mutated prostate cancer
Authors: Castro Elena , Van de Poll Floortje , Piñeiro Elena , Nombela Paz , Bancroft Elizabeth , Govindasami Koveela , Guy Michelle , Kovacs G , Ellis Steve , Antoniu Antonis , Easton Douglas , Kote-Jarai Zsofia , Al-Sharour Fatima , Olmos David , Eeles Rosalind 
Published: August 2015

Abstract
INTRODUCTION:
Germline BRCA mutations are an independent prognostic factor for PrCa prognosis and treatment outcomes. BRCA tumours are associated with chromosomal instability due to underlying DNA repair deficiency; however, recurrent patterns of genomic aberrations in this context have not been explored.
METHODS:
We collected PrCa formalin-fixed paraffin-embedded samples from diagnostic biopsies and/or prostatectomies from 5 BRCA1 and 24 BRCA2 germline mutation carriers, which were matched with at least 1 sporadic PrCa (ie PrCa with no germline mutation) by stage and treatment. All samples were reviewed by an expert pathologist, and the tumour relevant areas were selected for further analyses. Recurrent chromosomal abnormalities in PrCa were also analyzed using previously described fluorescence in situ hybridization (FISH) “break-apart” and/or “fusion” assays, including a novel FISH “combined break-fusion” assay for TMPRSS2-ERG designed with probes flanking 3´and 5´of ERG and 5´of TMPRSS2. Genomic abnormalities were confirmed by a second method (qPCR or IHC) whenever possible.
RESULTS:
No differences in Gleason score between mutation carriers and non-carriers were seen (p = 0.134). Neuroendocrine phenotype was not identified in any sample. The “break-apart” assay identified interstitial deletion of genomic sequences between TMPRSS2 and ERG in all BRCA mutated tumours in at least one focus (100%), compared with 45% of non-carriers (P&lt;0.001). The novel “break-fusion” assay allowed us to identify TMPRSS2 as the fusion partner in all cases, excluding other potential partners previously described. ETV1 rearrangements were identified in 3.5% of carriers and in 4% of non-carriers (P = 0.662).
CONCLUSIONS:
The presence of TMPRRSS2-ERG fusion gene in all BRCA mutated tumours in our series identifies a non-random androgen-driven event on the background of high chromosomal instability. Our findings suggests that BRCA mutated PrCa is androgen-dependent which may have important implications for the management of these patients.
Citation Format: Elena Castro, Floortje Van de Poll, Elena Piñeiro, Paz Nombela, Elizabeth Bancroft, Koveela Govindasami, Michelle Guy, G Kovacs, Steve Ellis, Antonis Antoniu, Douglas Easton, Zsofia Kote-Jarai, Fatima Al-Sharour, David Olmos, Rosalind Eeles. High-Frequency of TMPRSS2-ERG fusion gene identifies a non-random androgen-driven event of chromosomal instability in BRCA mutated 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 4249. doi:10.1158/1538-7445.AM2015-4249
Abstract 4280: Utilizing a selective agonist of the intermediate-affinity IL-2 receptor with an improved pharmacokinetic profile leads to an enhanced immunostimulatory response With reduced toxicity in mice
Authors: Losey Heather C. , Lopes Jared E. , Dean Reginald L. , Flick Heather , Gomes Madison , Huff Michael R. , Moroso Rosemarie A. , Sun Lei , Wang Chunhua , Waters Julie F. , Alvarez Juan C. 
Published: August 2015

Abstract
RDB 1450 is an engineered fusion protein which selectively activates the intermediate-affinity IL-2 receptor present on NK cells and memory CD8 T cells. In rodents, RDB 1450 has a half-life of 6-8 hours, compared to a half-life of minutes for recombinant human IL-2 (rhIL-2). Repeat daily dosing (QD) of RDB 1450 in mice results in marked expansion of NK cells and CD8+CD44high T cells, with minimal expansion of CD4+ regulatory T cells (Tregs). Higher QD doses elicit more pronounced effector cell expansion with modest pulmonary edema. TID delivery of the same total daily dose of RDB 1450 enhances the immunological responses in the absence of pulmonary edema. These results suggest that prolonged delivery of reduced concentrations of RDB 1450 drive the desired immune responses with improved tolerability. In contrast, high circulating concentrations of rhIL-2 are required to stimulate effector cells due to its preferential activation of Tregs at lower concentrations. The selectivity profile and favorable pharmacokinetics of RDB 1450 highlight its potential as a novel, differentiated immunotherapeutic agent for the treatment of cancer.
Citation Format: Heather C. Losey, Jared E. Lopes, Reginald L. Dean, Heather Flick, Madison Gomes, Michael R. Huff, Rosemarie A. Moroso, Lei Sun, Chunhua Wang, Julie F. Waters, Juan C. Alvarez. Utilizing a selective agonist of the intermediate-affinity IL-2 receptor with an improved pharmacokinetic profile leads to an enhanced immunostimulatory response With reduced toxicity 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 4280. doi:10.1158/1538-7445.AM2015-4280
Abstract 4281: Determination of the Relative Potency of a Selective Agonist of the Intermediate-Affinity IL-2 Receptor on Lymphocytes from Human, Cynomolgus Monkey and Mouse
Authors: Rosentrater Emily E. , Flick Heather , Lopes Jared E. , Losey Heather C. , Wang Chunhua , Alvarez Juan C. 
Published: August 2015

Abstract
RDB 1450 is an engineered fusion protein designed to selectively activate the intermediate-affinity IL-2 receptor versus the high-affinity IL-2 receptor. The potencies of RDB 1450 and IL-2 for activation of distinct subsets of effector and regulatory lymphocytes from murine, non-human primate and human donors were determined. Splenocytes isolated from mice or leukocytes isolated from human or cyno blood were stimulated with either RDB 1450 or IL-2. Multicolor flow cytometry was used to identify distinct subpopulations and the extent of phosphorylation of STAT5 was measured. Whereas IL-2 is 2-3 orders of magnitude more potent on immunosuppressive Tregs relative to NK cells and memory CD8 T cells, RDB 1450 induces activation of NK cells, memory CD8 T cells and Tregs at comparable concentrations within each species. The non-differentiated potency of RDB 1450 on the lymphocyte subpopulations examined suggests that its effects are mediated through the intermediate affinity receptors even on CD25-expressing Tregs. The preferential activation of Tregs by IL-2 may lead to immunosuppression and limit its antitumor efficacy. In contrast, RDB 1450 does not exhibit the same preference for Treg activation and is expected to be more effective in driving antitumor immune responses. These results highlight the differentiated immunological profile of RDB 1450 and support its potential as a novel human immunotherapy.
Citation Format: Emily E. Rosentrater, Heather Flick, Jared E. Lopes, Heather C. Losey, Chunhua Wang, Juan C. Alvarez. Determination of the Relative Potency of a Selective Agonist of the Intermediate-Affinity IL-2 Receptor on Lymphocytes from Human, Cynomolgus Monkey and Mouse. [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 4281. doi:10.1158/1538-7445.AM2015-4281
Abstract 4290: Potent and selective next generation inhibitors of indoleamine-2,3-dioxygenase (IDO1) for the treatment of cancer
Authors: Powers Jay P. , Walters Matthew J. , Noubade Rajkumar , Young Stephen W. , Marshall Lisa , Melom Jan , Park Adam , Shah Nick , Bjork Pia , Fridman Jordan S. , Beck Hilary P. , Chian David , McKinnell Jenny V. , Osipov Maksim , Reilly Maureen K. , Shunatona Hunter P. , Walker James R. , Zibinsky Mikhail , Jaen Juan C. 
Published: August 2015

Abstract
The IDO1 pathway has been proposed to mediate immunosuppressive effects in the tumor microenvironment through its role in the catabolism of tryptophan, resulting in effects on the differentiation and proliferation of T cells. IDO1 inhibition has shown promising clinical benefit as well as exacerbated toxicity in the treatment of melanoma, when combined with the anti-CTLA-4 antibody ipilimumab.
We have discovered a novel class of highly selective small molecule inhibitors of IDO1 which surpass the potency of the compounds currently in clinical development. These compounds potently inhibit IDO1 activity in IFN-γ stimulated HeLa cells with single digit nM potency. Importantly, they also retain their potency in the presence of human serum, with IC50 values ranging between 5 and 15 nM in this more physiologically relevant media. Consistent with the role of IDO1+ dendritic cells in the suppression of T cell proliferation, this series of molecules is capable of restoring the proliferative capacity of human T cells (which is inhibited by allogeneic IDO1+ dendritic cells) with EC50 values of 2-3 nM. The molecules exhibit preclinical PK characteristics that are suitable for assessing the contribution of IDO1 to tumor growth in murine models, both alone and in combination with other therapeutic agents. The compounds have high metabolic stability against cultured human hepatocytes and exhibit preclinical PK and ADME characteristics consistent with once-daily dosing in humans. The full preclinical profile of one of these molecules, selected for clinical evaluation, will be the focus of this presentation.
In conclusion, we have discovered a novel class of small molecule inhibitors of IDO1, which provides a preclinical basis for the clinical evaluation of a next generation IDO1 inhibitor in combination with other therapeutic agents.
Citation Format: Jay P. Powers, Matthew J. Walters, Rajkumar Noubade, Stephen W. Young, Lisa Marshall, Jan Melom, Adam Park, Nick Shah, Pia Bjork, Jordan S. Fridman, Hilary P. Beck, David Chian, Jenny V. McKinnell, Maksim Osipov, Maureen K. Reilly, Hunter P. Shunatona, James R. Walker, Mikhail Zibinsky, Juan C. Jaen. Potent and selective next generation inhibitors of indoleamine-2,3-dioxygenase (IDO1) for the treatment of 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 4290. doi:10.1158/1538-7445.AM2015-4290
Abstract 4293: Histamine dihydrochloride as an immune modulator for solid tumors
Authors: Newick Kheng , O'Brien Shaun , Kapoor Veena , Wang Liang-chuan , Moon Edmund , Sterman Daniel , Albelda Steven 
Published: August 2015

Abstract
Our recent adoptive T cell transfer trial for mesothelioma revealed a striking anti-tumor response in a patient which was accompanied by anaphylaxis, suggesting endogenous histamine release. In animal models, histamine has direct and immune-based anti-tumor effects. In fact, histamine dihydrochloride is approved in Europe in combination with interleukin-2 (IL2) for leukemia treatment. We thus explored the anti-tumor role of histamine in mesothelioma and lung cancer. An in vitro MTT assay was used to measure cell proliferation. Daily doses of histamine (1 mg/kg) - alone, or in combination with other immunotherapies - was used to treat four subcutaneous flank tumor models in three different mouse strains. Flow cytometric analyses were subsequently performed on tumors. Histamine had in vitro anti-tumor activity against all five cell lines tested with an IC50 of 0.1 mg/ml. Histamine also significantly reduced tumor volume in all four in vivo models without toxic side effects. Immunodepletion studies revealed that the effect was partially due to T cells. When combined with two immunotherapy approaches (adenovirally-delivered interferon-α or a tumor antigen), anti-tumor efficacy was augmented. Histamine resulted in more interferon-γ and IL2 production by tumor-infiltrating lymphocytes, downregulation of CD206 expression on tumor-infiltrating macrophages, and reduced numbers of T regulatory cells (Tregs). This pre-clinical data suggests that histamine alone, or in combination with immunotherapy, should be explored in the treatment of mesothelioma, lung cancer, and perhaps other cancers.
Citation Format: Kheng Newick, Shaun O'Brien, Veena Kapoor, Liang-chuan Wang, Edmund Moon, Daniel Sterman, Steven Albelda. Histamine dihydrochloride as an immune modulator for solid tumors. [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 4293. doi:10.1158/1538-7445.AM2015-4293
Abstract 4299: MicroRNA 200c regulates cytochrome P450 1B1-mediated docetaxel resistance in renal cell cancers
Authors: Chang Inik , Mitsui Yozo , Fukuhara Shinichiro , Gill Ankurpreet , Wong Darryn K. , Yamamura Soichiro , Shahryari Varahram , Tabatabai Z. Laura , Dahiya Rajvir , Shin Dong Min , Tanaka Yuichiro 
Published: August 2015

Abstract
Cytochrome P450 1B1 (CYP1B1) is up-regulated in many types of cancer. It has been suggested that CYP1B1 may be a general tumor biomarker and have an important function in cancers. Despite its high protein expression and enzymatic activity in renal cell cancer (RCC), functional significance of CYP1B1 has not been elucidated. Here we explored the functional role and regulatory mechanism of CYP1B1 in RCC. Reduction of CYP1B1 levels fail to prevent in vitro tumorigenicity such as proliferation, apoptosis, and cell cycle progression of RCC cells. Moreover, the expression levels are not associated with tumor type, stage, Fuhrman grade and 5-year survival probability after surgery. Instead, alteration of CYP1B1 expression regulates the chemosensitivity of RCC cells to docetaxel suggesting its critical contribution to the RCC chemoresistance. Additionally, miR-200c, which is significantly down-regulated in RCC tissues and cell lines regulates CYP1B1 mRNA, protein and enzyme activity. An inverse association was also observed between the expression levels of miR-200c and CYP1B1 protein in RCC tissues. Thus, high expression of CYP1B1 could be a result of decreased miR-200c expression in RCC. Finally, alteration of miR-200c levels affects the chemosensitivity of RCC cells. Restoration of docetaxel resistance by exogenous expression of CYP1B1 in miR-200c-over-expressing cells indicates that CYP1B1 is a functional target of miR-200c. These results suggest that CYP1B1 up-regulation mediated by low miR-200c is one of the mechanisms underlying resistance of RCC cells to docetaxel. Therefore, expression of CYP1B1 and miR-200c in RCC may be useful as a prediction for docetaxel response.
Citation Format: Inik Chang, Yozo Mitsui, Shinichiro Fukuhara, Ankurpreet Gill, Darryn K. Wong, Soichiro Yamamura, Varahram Shahryari, Z. Laura Tabatabai, Rajvir Dahiya, Dong Min Shin, Yuichiro Tanaka. MicroRNA 200c regulates cytochrome P450 1B1-mediated docetaxel resistance in renal cell cancers. [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 4299. doi:10.1158/1538-7445.AM2015-4299
Abstract 4326: Co-amplification of FGF receptors and ligands in FGFR inhibitor-sensitive cell lines
Authors: Bell Katherine , Gaffney Dana , Martinez-Cardona Gabriela , Karkera Jayaprakash , Platero Suso 
Published: August 2015

Abstract
The fibroblast growth factor receptors (FGFR) play a key role during development and in adult function. FGFRs belong to a family of receptor tyrosine kinases which are single-pass transmembrane receptors with extracellular ligand binding domains and an intracellular tyrosine kinase domain. Upon binding of the ligand the kinase domain activates intracellular signaling networks that coordinate cellular processes such as proliferation, growth, differentiation, migration and survival. Fibroblast growth factors (FGFs) are a family of 18 ligands which are able to bind and activate distinct FGFRs. Deregulated FGFR activity, through mutations or translocations, is often associated with oncogenic events. Overexpression of FGFR or FGF may lead to increased cell proliferation, growth, differentiation, migration or survival, thus making it an interesting target.
In this study we optimized a TaqMan qRT-PCR-based approach to evaluate the copy number variation for several FGFRs (FGFR1, FGFR2, FGFR3 and FGFR4) and several FGF ligands (FGF1, FGF2, FGF3, FGF4, FGF10, FGF12, and FGF19) on a panel of 23 cell lines. The cell types covered a variety of diseases including bladder, breast, endometrial, gastric, kidney, liver, lymphoma, melanoma, sarcoma, small cell lung carcinoma and squamous cell carcinoma. These cell lines had been tested for sensitivity to the JNJ FGFR small molecule inhibitor JNJ42541707 which is a pan-FGFR inhibitor. We observed in the sensitive (IC50&lt;100nm) and moderately sensitive (IC50 100 nM - 1000 nM) cell lines a co-amplification of FGF receptor and ligand. Two of the most sensitive cell lines to FGFR inhibitor treatments had the greatest amplification of FGFR2 with a copy number value greater than 100. This finding that co-amplification occurs in receptor and ligand offers a new potential biomarker for patients that may be sensitive to small molecule FGFR inhibitors.
Citation Format: Katherine Bell, Dana Gaffney, Gabriela Martinez-Cardona, Jayaprakash Karkera, Suso Platero. Co-amplification of FGF receptors and ligands in FGFR inhibitor-sensitive cell lines. [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 4326. doi:10.1158/1538-7445.AM2015-4326