bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract LB-260: A small molecule Myc inhibitor has therapeutic effects on mouse pancreatic and other cancers
Authors: Stellas Dimitris , Szabolcs Matthias , Koul Sanjay , Li Zhe , Polyzos Alexander , Anagnostopoulos Constantinos , Cournia Zoe , Tamvakopoulos Constantin , Klinakis Apostolos , Efstratiadis Argiris 
Published: August 2015

Abstract
Mouse models faithfully simulating human cancer are valuable for genetic identification of potential drug-targets but, among them, the most advantageous for practical use in subsequent preclinical testing of candidate therapeutic regimes are those exhibiting rapid tumor development. Considering that pancreatic ductal adenocarcinoma (PDA) is the deadliest of the major malignancies and an unresolved clinical problem, and that a KRAS mutation (predominantly in codon 12, such as KRASG12D; KRAS*) occurs with high frequency (∼90%) in PDA cases, we sought to develop a mouse PDA model that would exhibit high tumor incidence and short latency by ectopic overexpression of Kras*. This transgenic modification caused by two weeks postpartum the appearance of pancreatic intraepithelial neoplasia (PanIN), which evolved into invasive PDA within a week later, and resulted in a moribund condition at one month of age. Interestingly, however, this aggressive form of pancreatic tumorigenesis was effectively prevented by genetic ablation of Myc specifically in the pancreas On the basis of this observation, causally demonstrating that Kras* oncogenicity fully depends on unperturbed Myc activity, we tested with positive results the effective treatment of our mouse PDA model by using orally-administered Mycro3, a small-molecule inhibitor of Myc-Max dimerization. PET/CT image analysis demonstrated marked shrinkage of PDA, while immunohistochemical analyses showed an increase in cancer cell apoptosis and reduction in cell proliferation. Tumor growth was also drastically attenuated in Mycro3-treated NOD/SCID mice carrying orthotopic or heterotopic xenografts of human pancreatic cancer cells. In addition, Mycro3 was efficacious in treating xenografts generated either heterotopically or orthotopically (by tail-injection) using a human lung carcinoma cell line (KRASG12D) and also in treating KRAS-driven mouse mammary tumors. These results provide strong justification for eventual clinical evaluation of anti-Myc drugs as potential chemotherapeutic agents for the treatment of PDA and other Myc-dependent cancers.
Citation Format: Dimitris Stellas, Matthias Szabolcs, Sanjay Koul, Zhe Li, Alexander Polyzos, Constantinos Anagnostopoulos, Zoe Cournia, Constantin Tamvakopoulos, Apostolos Klinakis, Argiris Efstratiadis. A small molecule Myc inhibitor has therapeutic effects on mouse pancreatic and other 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 LB-260. doi:10.1158/1538-7445.AM2015-LB-260
Abstract LB-267: Role of VEGFR-1 signaling in obesity-induced tumor progression
Authors: Incio Joao , Tam Joshua , Rahbari Nuh , Suboj Priya , McManus Daniel , Chin Shan , Vardan-Kaur Trupti , Batista Ana , Babycutty Suboj , Jung Keehoon , Khachatryan Anna , Shibuya Masabumi , Soares Raquel , Duda Dan , Jain Rakesh K. , Fukumura Dai 
Published: August 2015

Abstract
Background: Obesity associates with angiogenesis and increased macrophage infiltration in adipose tissues during weight gain. Whether these effects also occur in cancer to promote tumor progression in obese condition remains unclear. We have shown that the vascular endothelial growth factor receptor-1 (VEGFR-1) pathway can modulate tumor angiogenesis and recruitment of tumor-associated macrophages (TAMs). Here, we tested the emerging hypothesis that obesity enhances tumor progression and metastasis by augmenting angiogenesis and TAM recruitment via activation of the VEGFR-1 pathway.
Methods: We used a high-fat diet-induced obesity model in either wild type (WT) or VEGFR-1 tyrosine kinase null (Flt1TK-/-) C57BL/6 mice. Then, we implanted orthotopically syngeneic pancreatic (PAN02) or breast (E0771) carcinomas. We evaluated the role of VEGFR-1 activity on systemic metabolism, tumor angiogenesis and immune environment, and tumor growth and metastasis.
Results: Obesity increased p38-MAPK activation and TAM infiltration, tumor growth (p = 0.001) and metastasis (p = 0.035) in PAN02 tumors. VEGFR-1 inhibition reduced tumor growth (p = 0.007) and metastasis (p = 0.017) in obese but not lean mice. This was associated with a decreased p38-MAPK activity and a shift in TAM polarization towards the M1 phenotype with reduced secretion of pro-tumor cytokines, but no change in vascular density or number of TAMs. In the E0771 model, VEGFR-1 inhibition reduced MMP-9 expression and decreased lung metastatic burden (p = 0.026) in obese mice. In addition to these tumor effects, VEGFR-1 inhibition reduced weight gain, but caused metabolic disorder-hyperinsulinemia-during obesity. Combining metformin with VEGFR-1 inhibition not only prevented this metabolic alteration, but also by recruiting cytotoxic cells further decreased tumor growth in the PAN02 model (p = 0.047).
Conclusion: Inactivation of VEGFR-1 signaling prevents weight gain and obesity-induced acceleration of tumor progression in pancreatic and breast cancer models. Targeting VEGFR-1 signaling axis in combination with an anti-diabetic drug such as metformin might be a considerable cancer therapeutic option in the obese setting.
Note: This abstract was not presented at the meeting.
Citation Format: Joao Incio, Joshua Tam, Nuh Rahbari, Priya Suboj, Daniel McManus, Shan Chin, Trupti Vardan-Kaur, Ana Batista, Suboj Babycutty, Keehoon Jung, Anna Khachatryan, Masabumi Shibuya, Raquel Soares, Dan Duda, Rakesh K. Jain, Dai Fukumura. Role of VEGFR-1 signaling in obesity-induced tumor progression. [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 LB-267. doi:10.1158/1538-7445.AM2015-LB-267
Abstract LB-298: The multiple-myeloma associated snoRNA, ACA11 increases oxidative stress and cell proliferation
Authors: Mahajan Nitin , Maggi Leonard B. , Tomasson Michael H. , Weber Jason D. 
Published: August 2015

Abstract
Multiple myeloma (MM) is an incurable malignancy of antibody secreting plasma B cells. The t(4;14) translocation is detected in 20% of MM and is associated with shortened patient survival. Although the t(4;14) is known to up regulate the MMSET proteins, its role in MM remains unclear. Previously, we identified a novel orphan box H/ACA class small nucleolar RNA (snoRNA), that is located within intron 19 of MMSET, and is expressed in MM cells harboring the t(4;14) translocation. H/ACA small RNAs are an evolutionarily conserved class of abundant noncoding RNAs (ncRNA) involved in a diverse range of processes including posttranslational modifications of functional RNAs, preribosomal RNA processing, and telomere maintenance, yet their contribution to human disease remains largely unexplored. In this study, t(4:14) positive and negative MM patient tumor cells were analyzed by RNA sequencing. This revealed a unique signature of up regulated genes involved in mitochondrial respiration and oxidative stress. Our hypothesis is ACA11 plays critical role in MM cell proliferation and cell transformation by increasing oxidative stress. We found that acute ACA11 overexpression leads to the increased oxidative stress in primary splenic B-cells, established myeloma cell lines, as well as embryonic fibroblasts. In particular, cells overexpressing ACA11 showed enhanced proliferation, significantly larger colony sizes in soft agar assays, and elevated ERK1/2 phosphorylation, a downstream consequence of oxidative stress. In addition, we found that the transcription factor nuclear factor erythroid-derived 2-related factor 2 (Nrf2), which regulates anti-oxidant signaling, dissociated from Keap1 and translocated to the nucleus, but failed to activate anti-oxidant downstream targets in ACA11 overexpressing cells. Furthermore, ACA11 up regulated TXNIP, which encodes an inhibitor of ROS scavenger thioredoxin. In conclusion, we propose that acute overexpression of ACA11 up regulates TXNIP and suppresses the ability of Nrf2 to induce target anti-oxidants genes, resulting in increased oxidative stress and cell proliferation. These changes may be critical events in the development and/or progression of multiple myeloma.
Citation Format: Nitin Mahajan, Leonard B. Maggi, Michael H. Tomasson, Jason D. Weber. The multiple-myeloma associated snoRNA, ACA11 increases oxidative stress and cell proliferation. [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 LB-298. doi:10.1158/1538-7445.AM2015-LB-298
Abstract LB-299: Gene knockdown by EpCAM aptamer-siRNA chimeras suppresses epithelial breast cancers and their tumor-initiating cells
Authors: Gilboa-Geffen Adi , Hamar Peter , Wheeler Lee Adam , Trifonova Radiana , Petrocca Fabio , Wittrup Anders , Lieberman Judy 
Published: August 2015

Abstract
Effective therapeutic strategies for in vivo siRNA delivery to knockdown genes in cells outside the liver are needed to harness RNA interference for treating cancer. EpCAM is a tumor-associated antigen highly expressed on common epithelial cancers and their tumor-initiating cells (T-IC, also known as cancer stem cells). Here we show that aptamer-siRNA chimeras (AsiC, an EpCAM aptamer linked to an siRNA sense strand and annealed to the siRNA antisense strand) are selectively taken up and knockdown gene expression in EpCAM+ cancer cells in vitro and in human cancer biopsy tissues. PLK1 EpCAM-AsiCs inhibit colony and mammosphere formation (in vitro T-IC assays) and tumor initiation by EpCAM+ luminal and basal-A triple negative breast cancer (TNBC) cell lines, but not EpCAM- mesenchymal basal-B TNBCs, in nude mice. Subcutaneously administered EpCAM-AsiCs concentrate in EpCAM+ Her2+ and TNBC tumors and suppress their growth. Thus EpCAM-AsiCs provide an attractive approach for treating epithelial cancer.
Note: This abstract was not presented at the meeting.
Citation Format: Adi Gilboa-Geffen, Peter Hamar, Lee Adam Wheeler, Radiana Trifonova, Fabio Petrocca, Anders Wittrup, Judy Lieberman. Gene knockdown by EpCAM aptamer-siRNA chimeras suppresses epithelial breast cancers and their tumor-initiating 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 LB-299. doi:10.1158/1538-7445.AM2015-LB-299
Abstract LB-300: Reintroduction of tumor-suppressor miR-34a shows therapeutic efficacy in triple-negative breast cancer
Authors: Adams Brian D. , Wali Vikram , Cheng Chris , Inukai Sachi , Rimm David , Pusztai Lajos , Saltzman Mark , Slack Frank 
Published: August 2015

Abstract
Triple-negative breast cancer (TNBC) accounts for a disproportionate share of the total breast cancer morbidity because of its aggressive behavior and lack of effective targeted therapies to treat the disease. MicroRNAs, global regulators of survival and proliferation pathways important in tumor development and maintenance, are highly dysregulated in cancer. We identified miR-34a to be aberrantly lost in TNBC lines when compared to both a luminal cancer subtype as well as normal breast cells. Re-introduction of miR-34a in TNBC lines results in inhibition of cell proliferation and invasion, reactivation of senescence, and enhanced sensitivity to apoptosis inducing agents. Furthermore, intratumoral delivery of miR-34a into subcutaneous tumors in nude mice, as well as systemic delivery of poly(amine-co-ester) PACE-loaded miR-34a in an orthotopic setting, delayed tumor growth. In conclusion, re-introduction of miR-34a in TNBC promotes potent anti-tumorigenic phenotypes in vitro and in vivo, and could be a promising targeted therapeutic agent to treat the disease.
Citation Format: Brian D. Adams, Vikram Wali, Chris Cheng, Sachi Inukai, David Rimm, Lajos Pusztai, Mark Saltzman, Frank Slack. Reintroduction of tumor-suppressor miR-34a shows therapeutic efficacy in triple-negative breast 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 LB-300. doi:10.1158/1538-7445.AM2015-LB-300
Abstract SY07-01: New targets in combination cancer immunotherapies
Authors: Smyth Mark J. 
Published: August 2015

Abstract
Cancer immunotherapy may become the treatment backbone in many cancers over the next decade. The demonstration that an intratumor TH1 immune polarity is prognostic of good clinical outcome and the recent success with co-immune checkpoint blockade in humans now sets the stage for rational tailoring of immunotherapies to treat specific cancer types. The recently approved anti-PD-1 monoclonal antibody (mAb)(pembrolizumab) and other mAbs targeting PD-L1 have revolutionized the field. Pre-clinical data and combinations between anti-CTLA-4 (ipilimumab) and anti-PD-1 (Nivolumab) in advanced malignant melanoma demonstrate the anti-tumor potential and dangers of targeting more than one immune evasion pathway. There are four different types of tumor microenvironment based on the presence or absence of tumor infiltrating lymphocytes and programmed death-ligand 1 (PD-L1) expression. This stratification may be an approach for rationally designing ideal combinations between various new immunotherapies and conventional cancer treatments. This seminar will discuss our recent work to determine which tumors are responsive to anti-PD-1 and what pathways are necessary for, or an impediment to, anti-PD-1 anti-tumor activity. Our efforts to pre-clinically examine two new target pathways including immune checkpoints CD96/TIGIT and the immune suppressive metabolite adenosine will be described. Their combination with anti-PD-1 therapies will be detailed. Further, the ability of some targeted therapies to act in part via host immunity has created opportunities to rationally combine these approaches with immunotherapy in humans. These and other pre-clinical studies of combinations that concurrently relieve Treg- and M2 macrophage-mediated immune suppression will be discussed. Mouse models for combination treatment sequencing in the context of adjuvant therapy and safety in relation to immune related adverse events will be presented.
Citation Format: Mark J. Smyth. New targets in combination cancer immunotherapies. [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 SY07-01. doi:10.1158/1538-7445.AM2015-SY07-01
Abstract SY27-04: Induction of cancer stemness and drug resistance by EGFR blockade
Authors: Cheresh David A. 
Published: August 2015

Abstract
Tumor drug resistance is often accompanied by genetic and biological changes in the tumor cell population reflecting the acquisition of a stem-like state. However, it is not clear whether cancer therapies select for the growth of drug resistance cancer stem cells and/or directly induce the reprograming of tumor cells to a cancer stem-like, drug resistance state. We provide evidence that breast, pancreas and lung carcinomas in the presence of prolonged exposure to EGFR inhibitors undergo an epigenetic reprogramming resulting in a drug resistant stem-like tumor population expressing the cell surface marker CD61 (b3 integrin). In fact, CD61 in the context of KRAS, is necessary and sufficient to account for drug resistance, tumor initiation, self-renewal and expression of the pluripotent genes Oct 4 and Nanog. Once expressed, CD61 in the unligated state recruits KRAS to the plasma membrane leading to the activation of RalB, TBK1 and c-Rel driving both stemness and EGFR inhibitor resistance. Pharmacological targeting this pathway with drugs such as bortezomib or revlimid not only reverses stemness but resensitizes these epithelial tumors to EGFR inhibition. This epigenetic pathway can also be initiated by range of cellular stresses found within the tumor microenvironment such as hypoxia, nutrient deprivation, low pH, and oxidative stress. In normal tissues CD61 is induced during tissue remodeling and repair. For example, CD61 was found to be critical for mammary gland remodeling during pregnancy and as a mediator of pathological neovascularization. Together these findings reveal a stress-induced epigenetic pathway characterized by the upregulation of CD61 that promotes the remodeling of normal tissues but in tumors contributes to EGFR inhibitor resistance and tumor progression.
Citation Format: David A. Cheresh. Induction of cancer stemness and drug resistance by EGFR blockade. [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 SY27-04. doi:10.1158/1538-7445.AM2015-SY27-04
Abstract SY30-02: Understanding the proteome through the chaperome: From mechanisms to diagnostics and drugs
Authors: Chiosis Gabriela 
Published: August 2015

Abstract
Malignant cellular function is maintained by a functionally altered proteome. Helping the proteome in this context is the chaperome, a network of molecular chaperones and folding enzymes. This talk will discuss how, by using chemical tools that selectively target the stress chaperome, one may perform mechanistic and therapeutic investigations into the tumor proteome. Specifically, using chemical tools as affinity-purification baits or as global perturbers of the altered proteome one may inquire into its nature (i.e., identify and investigate). By attacking specifically the stress chaperome, one may inactivate the altered proteome, and thus revert or slow the disease phenotype (i.e., treat).
In summary, I will discuss how by chemically sensing the stress chaperome one may investigate, understand and destabilize the tumor proteome.
Citation Format: Gabriela Chiosis. Understanding the proteome through the chaperome: From mechanisms to diagnostics and drugs. [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 SY30-02. doi:10.1158/1538-7445.AM2015-SY30-02
Abstract SY33-04: Integrated omic analysis of lung cancer reveals metabolism-proteome signatures with prognostic impact
Authors: Moran Michael F. , Li Lei , Wei Yuhong , Taylor Paul , To Christine , Tong Jiefei , Ignatchenko Vladimir , Pintilie Melania , Pham Nhu-An , Zhang Wen , Muthuswamy Lakshmi , Shepherd Frances A. , Kislinger Thomas , Tsao Ming S. 
Published: August 2015

Abstract
Cancer results from processes prone to selective pressure and dysregulation acting along the sequence-to- phenotype continuum DNA→RNA→Protein→Disease. An Omics Array integrating DNA gene copy number, mRNA transcriptome, and quantified proteome was assembled into a genetic map representing non-small cell lung carcinoma (NSCLC). Data were collected from patient-matched normal lung, primary tumors, and patient tumor-derived xenograft (PDX) tumors. Dysregulated proteins not previously implicated as cancer drivers were found encoded throughout the genome including but not limited to regions of recurrent DNA amplification/deletion in NSCLC. Unsupervised clustering revealed signatures comprising metabolism proteins particularly highly recapitulated between matched primary and PDX tumors, and which distinguished between the major NSCLC histological subtypes adenocarcinoma (ADC) and squamous cell carcinoma (SCC). Interrogation of The Cancer Genome Atlas (TCGA) revealed sizeable cohorts of NSCLC patients with DNA alterations in genes encoding the metabolism proteome signatures, and accompanied by differences in survival. Similar to the proteome signatures from which they were extrapolated, the gene mutation signatures with prognostic impact discriminated between the lung ADC and SCC subtypes. Serine hydroxymethyltransferase 2 (SHMT2), a key enzyme in serine/glycine and folate- dependent one-carbon metabolism, is upregulated in the proteomes of NSCLC primary and PDX tumours, and is implicated as a driver of recurrent chromosome 12q14.1 amplification in NSCLC. SHMT2, along with other enzymes implicated as anti-folate targets, is also part of a metabolism proteome signature associated with poor outcome in lung ADC. The interrogation of cancer genomes and proteomes for alterations that are related products of selective pressures driving the cancer phenotype may be a general approach to uncover and group together cryptic, polygenic cancer drivers, which might represent new anti-cancer therapeutic targets.
Citation Format: Michael F. Moran, Lei Li, Yuhong Wei, Paul Taylor, Christine To, Jiefei Tong, Vladimir Ignatchenko, Melania Pintilie, Nhu-An Pham, Wen Zhang, Lakshmi Muthuswamy, Frances A. Shepherd, Thomas Kislinger, Ming S. Tsao. Integrated omic analysis of lung cancer reveals metabolism-proteome signatures with prognostic impact. [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 SY33-04. doi:10.1158/1538-7445.AM2015-SY33-04
Rate of Contrast Extravasation on Computed Tomographic Angiography Predicts Hematoma Expansion and Mortality in Primary Intracerebral Hemorrhage
Authors: Brouwers H. Bart , Battey Thomas W.K. , Musial Hayley H. , Ciura Viesha A. , Falcone Guido J. , Ayres Alison M. , Vashkevich Anastasia , Schwab Kristin , Viswanathan Anand , Anderson Christopher D. , Greenberg Steven M. , Pomerantz Stuart R. , Ortiz Claudia J. , Goldstein Joshua N. , Gonzalez R. Gilberto , Rosand Jonathan , Romero Javier M. 
Published: August 2015

Background and Purpose—
In primary intracerebral hemorrhage, the presence of contrast extravasation after computed tomographic angiography (CTA), termed the spot sign, predicts hematoma expansion and mortality. Because the biological underpinnings of the spot sign are not fully understood, we investigated whether the rate of contrast extravasation, which may reflect the rate of bleeding, predicts expansion and mortality beyond the simple presence of the spot sign.

Methods—
Consecutive intracerebral hemorrhage patients with first-pass CTA followed by a 90-second delayed postcontrast CT (delayed CTA) were included. CTAs were reviewed for spot sign presence by 2 blinded readers. Spot sign volumes on first-pass and delayed CTA and intracerebral hemorrhage volumes were measured using semiautomated software. Extravasation rates were calculated and tested for association with hematoma expansion and mortality using uni- and multivariable logistic regressions.

Results—

One hundred and sixty-two patients were included, 48 (30%) of whom had ≥1 spot sign. Median spot sign volume was 0.04 mL on first-pass CTA and 0.4 mL on delayed CTA. Median extravasation rate was 0.23 mL/min overall and 0.30 mL/min among expanders versus 0.07 mL/min in nonexpanders. Extravasation rates were also significantly higher in patients who died in hospital: 0.27 mL/min versus 0.04 mL/min. In multivariable analysis, the extravasation rate was independently associated with in-hospital mortality (odds ratio, 1.09 [95% confidence interval, 1.04–1.18],
P
=0.004), 90-day mortality (odds ratio, 1.15 [95% confidence interval, 1.08–1.27];
P
=0.0004), and hematoma expansion (odds ratio, 1.03 [95% confidence interval, 1.01–1.08];
P
=0.047).

Conclusions—
Contrast extravasation rate, or spot sign growth, further refines the ability to predict hematoma expansion and mortality. Our results support the hypothesis that the spot sign directly measures active bleeding in acute intracerebral hemorrhage.