bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 2619: Novel biomarkers and molecular alterations for breast cancer initiation and susceptibility
Authors: Marino Natascia , Johnson Mariah L. , Tanaka Hiromi , Wu Xi , Mathieson Theresa , Henry Jill E. , Ivan Mircea , Liu Yunlong , Rufenbarger Connie , Storniolo. Anna Maria V. 
Published: July 2016

Abstract
Background: Despite significant advances in diagnosis and treatment, breast cancer remains the leading cause of cancer-related death in women worldwide. Therefore, there is a critical need to identify molecular mechanisms responsible for cancer initiation and progression. To date, there have been attempts to identify biomarkers that can predict progression of pre-malignant lesions (i.e. DCIS) to invasive carcinoma. Our study aims to identify earliest markers of breast cancer initiation.
Methods: We evaluated local (breast tissue) and systemic (serum/plasma) molecular alterations associated with breast cancer susceptibility using the unique resources available at the Komen Normal Tissue Bank at IUSCC. Human specimens (serum/plasma and breast tissue) donated by women before their cancer was clinically detectable were used to identify circulating biomarkers that are associated with breast cancer risk. Specimens from age-matched controls were used for comparison. Sera/plasma were analyzed for circulating miRNAs and telomeric level in the cell-free circulating DNA (cfDNA). We employed next generation sequencing to obtain transcriptome in the “normal” breast of women who eventually developed breast cancer and age-matched control normal breast.
Results/Discussion: Serum/plasma of women who developed breast cancer showed variation in circulating miRNAs as well as telomeric cfDNA levels as compared to the healthy control group. Among 385 microRNAs detected in circulation, 10 miRNAs were present at different levels in the susceptible group. In addition, susceptible group displayed reduced levels of plasma telomeric cfDNA and telomere shortening in breast epithelium.
Transcriptome analysis of microdissected breast epithelium and stroma revealed molecular alterations in the “normal” breast tissue associated with cancer development. Pathway analyses of these differentially expressed genes are underway to determine the mechanisms associated with breast cancer initiation.
Conclusion/Impact: Functional analysis of biomarkers identified in this study may help in cancer risk assessment and improvement of preventive therapy.
Citation Format: Natascia Marino, Mariah L. Johnson, Hiromi Tanaka, Xi Wu, Theresa Mathieson, Jill E. Henry, Mircea Ivan, Yunlong Liu, Connie Rufenbarger, Anna Maria V. Storniolo. Novel biomarkers and molecular alterations for breast cancer initiation and susceptibility. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 2619.
Abstract 262: Combination therapy of folate-targeted chemotherapeutics with anti-PD-1 antibody against folate receptor-positive tumors in immunocompetent murine models
Authors: Lu Yingjuan June , Wheeler Leroy W. , Cross Vicky , Westrick Elaine , Lloyd Alex , Leamon Christopher P. 
Published: July 2016

Abstract
The PD-1/PD-L1 (programmed cell death protein 1; programmed death-ligand 1) pathway plays a key role in immunological tolerance and autoimmunity. PD-1 is primarily expressed on activated T and B cells while its receptor, PD-L1, is expressed in a variety of cell types including resting lymphocytes, DCs, and macrophages. Recently, multiple human solid tumor types (melanoma, NSCLC, RCC, ovarian, and colorectal cancer) have been found to overexpress PD-L1 within its tumor microenvironment. More importantly, PD-1/PD-L1 blocking agents (pembrolizumab, nivolumab, lambrolizumab, MPDL3280A) have been found active as a single agent or in combination with chemotherapy and some have produced durable clinical responses. On the other hand, human epithelial tumors are also known to overexpress the high-affinity folate receptor (FR)-alpha that is capable of bringing folate-linked drugs into the cell cytosol via endocytosis. Using flow cytometry, we assessed PD-L1 expression in various FR-positive syngeneic mouse tumor models (M109, Renca, L1210A, 4T1-Cl2, ID8-Cl15). PD-L1 expression was found to vary significantly among different tumor types and could be found not only on CD45- malignant cells but also on tumor stromal cells such as F4/80+CD11b+ tumor-associated macrophages. Using a rat anti-mouse PD-1 antibody (clone RMP1-14), we studied in-vivo efficacy of a folate-targeted chemotherapy in combination with PD-1/PD-L1 blockage in PD-L1-expressing tumor models. In syngeneic models with high PD-L1 expression and tumor-infiltrating lymphocytes, a synergistic and curable anti-tumor effect was observed and the animals developed tumor-protective immunity against rechallenge. Thus, our preliminary results suggest that folate-targeted chemotherapeutics may also be enhanced by PD-1/PD-L1 blockage by means of overcoming tumor-mediated immune suppression
Citation Format: Yingjuan June Lu, Leroy W. Wheeler, Vicky Cross, Elaine Westrick, Alex Lloyd, Christopher P. Leamon. Combination therapy of folate-targeted chemotherapeutics with anti-PD-1 antibody against folate receptor-positive tumors in immunocompetent murine models. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 262.
Abstract 2643: Discovery and characterization of a selective TrkA inhibitor for the treatment of TrkA-driven cancers
Authors: Tirunagaru Vijaya G. , Nagaswamy Kumaragurubaran , Mitra Sayan , Maddi Srinivas , Adluri Ram Sudheer , Joshi Hemant , Gupta Jang B. 
Published: July 2016

Abstract
Kinase gene fusions have been implicated as oncogenic drivers promoting cell survival and proliferation. TrkA gene fusions have been reported in a number of cancer types including lung, colorectal, papillary thyroid, sarcoma, cholangiocarcinoma and other tumors. We have identified novel, potent, selective and orally bioavailable TrkA inhibitors for the treatment of TrkA-driven cancers. One of the inhibitors, GVK-TrkI showed potent activity with an IC50 of 0.8 nM and 1.5 nM in the cell based assays for WT TrkA (AD293 cells expressing TrkA) and TPM3-NTRK1 fusion (KM12 cells) respectively. Potent activity of 12.5 nM IC50 was observed in TrkA Z-lyte kinase assay. Significant change in TrkA Z-lyte kinase IC50 was not observed at multiple ATP concentrations ranging from 100 uM to 1 mM suggesting non-ATP competitive mode of inhibition. Excellent selectivity (&gt;1000x) was observed towards TrkB and TrkC in the cell based assays. GVK-TrkI inhibited TrkA autophosphorylation in a concentration dependent manner up to 24 h in KM12 cells in vitro. GVK-TrkI inhibited cell proliferation in KM12 cells with a GI50 of 34 nM while exhibiting no activity in cell lines without TrkA fusion. Comparable activity was observed in Ba/F3 cell line expressing MPRIP-NTRK1 fusion, demonstrating inhibition of TrkA driven cell proliferation irrespective of the N-terminal fusion with a different gene, MPRIP. In the KM12 xenograft model, treatment with GVK-TrkI at various doses and dosing regimens of 20 mpk bid, 50 mpk bid and 100 mpk qd resulted in dose dependent inhibition with almost 100% tumor growth inhibition (TGI) at 100 mpk qd with 3 out of 8 mice showing complete tumor regression. Besides, at 50 mpk in various dosing regimens of qd, bid and bid alternate day showed good correlation of TGI with compound exposure. GVK-TrkI was well-tolerated, causing no weight loss or death compared with vehicle control. Based on the evidence of ATP binding site mutations contributing to clinical resistance with kinase inhibitor drugs, GVK-TrkI is predicted to be effective as a second generation TrkA inhibitor with a non-ATP binding site mechanism compared to pan-Trk inhibitors currently being pursued in clinic. These results suggest that GVK-TrkI is an effective therapeutic option in TrkA driven cancers with TrkA gene fusions, activating mutations and cancers with NGF/TrkA overexpression resulting in constitutive activation of TrkA pathway.
Citation Format: Vijaya G. Tirunagaru, Kumaragurubaran Nagaswamy, Sayan Mitra, Srinivas Maddi, Ram Sudheer Adluri, Hemant Joshi, Jang B. Gupta. Discovery and characterization of a selective TrkA inhibitor for the treatment of TrkA-driven cancers. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 2643.
Abstract 2652: Pan-cancer analysis of programmed death-ligand 1 (PD-L1) amplifications
Authors: Budczies Jan , Bockmayr Michael , Klauschen Frederick , Weichert Wilko , Denkert Carsten , Stenzinger Albrecht 
Published: July 2016

Abstract
PD-L1, located in the chromosomal region 9p28, is a ligand of programmed cell death protein 1 (PD-1) and has been described as immune checkpoint regulator that allows cancers to evade the host immune system. To stratify patients for treatment with PD-1 inhibitors, PD-L1 expression is currently intensively studied on RNA and protein levels. However, no comprehensive study of PD-L1 amplifications including many cancer types has been performed so far.
We investigated PD-L1 amplifications in eighteen cancer types that were copy number profiled, gene expression profiled and clinically characterized by the TCGA consortium: Acute Myeloid Leukemia (LAML), Bladder Urothelial Carcinoma (BLCA), Brain Lower Grade Glioma (LGG), Breast invasive carcinoma (BRCA), Cervical squamous cell carcinoma and endocervical adenocarcinoma (CESC), Colorectal adenocarcinoma (COADREAD), Glioblastoma multiforme (GBM), Head and Neck squamous cell carcinoma (HNSC), Kidney renal clear cell carcinoma (KIRC), Liver hepatocellular carcinoma (LIHC), Lung adenocarcinoma (LUAD), Lung squamous cell carcinoma (LUSC), Ovarian serous cystadenocarcinoma (OV), pancreatic adenocarcinoma (PAAD), Sarcoma (SARC), Skin Cutaneous Melanoma (SKCM), Stomach adenocarcinoma (STAD) and Uterine Corpus Endometrial Carcinoma (UCEC).
We found a diverse landscape of focal PD-L1 amplification, 9p chromosome arm amplifications and polysomy 9. Focal amplifications had the highest incidence in OV (10.7%), LUSC (9.8%), HNSC (8.6%), BLCA (8.3%), SARC (8.2%), CESC (7.1%), STAD (6.8%) and BRCA (5.3%). 9p amplifications were most frequently found in OV (12.6%), BLCA (7.4%), BRCA (6.8%) and LUAD (5.2%). Polysomy 9 had the highest incidence in COADREAD (14.0%), HNSC (13.6%), CESC (11.2%), SARC (9.4%) and STAD (7.2%), BLCA (5.9%) and GBM (5.5%). In a pooled analysis of focal and non-focal alterations, PD-L1 amplifications positively correlated with gene expression in nine cancer types and significantly (p &lt; 0.05) shortened overall survival in five cancer types.
In summary, PD-L1 amplifications represent a frequent genetic alteration that occurs in many cancer types and could potentially be exploited for patient stratification and immune therapy.
Citation Format: Jan Budczies, Michael Bockmayr, Frederick Klauschen, Wilko Weichert, Carsten Denkert, Albrecht Stenzinger. Pan-cancer analysis of programmed death-ligand 1 (PD-L1) amplifications. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 2652.
Abstract 2664: Eradication of neuroblastoma by suppressing the expression of a single long noncoding RNA
Authors: Tee Andrew E. , Liu Pei Y. , Milazzo Giorgio , Vandesompele Jo , Marshall Glenn M. , Perini Giovanni , Mestdagh Pieter , Dinger Marcel , Liu Tao 
Published: July 2016

Abstract
Neuroblastoma is the most common solid tumour in early childhood, and accounts for approximately 15% of all childhood cancer death. N-Myc gene amplification occurs in one quarter to one third of human neuroblastoma tissues, and the majority of patient with neuroblastoma due to N-Myc gene amplification die of the disease. We performed RNA sequencing experiments, and identified 5 transcripts, including RP1X, which were considerably differentially expressed between N-Myc gene amplified and non-amplified human neuroblastoma cell lines. Affymetrix microarray studies revealed that DEPD was one of the few genes considerably down-regulated in neuroblastoma cells after RP1X depletion. Chromatin immunoprecipitation assays showed that knocking-down RP1X expression reduced histone H3 lysine 4 trimethylation, a marker for active gene transcription, at the DEPD gene promoter. Depletion of RP1X or DEPD significantly reduced ERK protein phosphorylation, N-Myc protein phosphorylation at Serine 62, N-Myc protein stabilization, neuroblastoma cell proliferation and survival. Clonogenic assays showed that knocking-down RP1X with doxycycline completely abolished colony formation capacity of neuroblastoma cells stably transfected with doxycycline-inducible RP1X shRNA. Importantly, treatment with doxycycline in mice xenografted with neuroblastoma cells stably transfected with doxycycline-inducible RP1X shRNA, led to tumour eradication. In human neuroblastoma tissues from 600 neuroblastoma patients, high levels of RP1X gene expression correlated with DEPD gene expression and poor patient prognosis. In conclusion, this study identifies the novel long noncoding RNA RP1X as an important regulator of N-Myc protein stability and neuroblastoma tumourigenesis.
Citation Format: Andrew E. Tee, Pei Y. Liu, Giorgio Milazzo, Jo Vandesompele, Glenn M. Marshall, Giovanni Perini, Pieter Mestdagh, Marcel Dinger, Tao Liu. Eradication of neuroblastoma by suppressing the expression of a single long noncoding RNA. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 2664.
Abstract 267: Preclinical investigation of the HSP90 inhibitor, ganetespib, in combination with FDA-approved cytotoxic agents for their potential anti-tumor effects on human neuroendocrine tumors
Authors: Wong Chung , Vosburgh Evan , Levine Arnold , Proia David , Xu Eugenia 
Published: July 2016

Abstract
The gastroenteropancreatic neuroendocrine tumor (GEP-NET) system is comprised of a heterogeneous group of tumors with increasing incidence. Current standard of care cytotoxic agents have limited efficacy, which necessitates the need for innovative therapeutic approaches. Heat shock protein 90 (HSP90) is overexpressed in a wide range of tumor types including human pancreatic neuroendocrine tumors (PanNETs). Ganetespib is a second-generation HSP90 inhibitor that is well tolerated in cancer patients (dosed into &gt;1500 patients) and is currently being evaluated in several investigator sponsored clinical trials including acute myeloid leukemia (AML), ovarian cancer, breast cancer, and other tumor types.
Here, we show that ganetespib inhibits the proliferation of NET cells and induces apoptosis in vitro with potency comparable to another second-generation HSP90 inhibitor (NVP-AUY922), but with potency two- to seven-fold more than first generation inhibitors (17-AAG, IPI-504) in BON-1, CM and H727 cell lines, and thirty-fold more in QGP-1 cell line. In mice bearing PanNET tumor xenografts, single agent ganetespib reduced the growth of tumors without signs of toxicity. Tumors from ganetespib treated animals demonstrated reduced phospho-AKT and phospho-ERK expression, and elevated HSP70 expression, supportive of exposures necessary for functional activity. In an effort to identify clinically meaningful agents that could further potentiate the antitumor activity of ganetespib, we performed in vitro combination screens evaluating proliferation in four NET cell lines with ganetespib and forty FDA approved anticancer agents. Ganetespib showed synergistic effects when combined with inhibitors of mTOR, topoisomerase I or II, or DNA synthesis. Results from our ongoing in vivo combination studies with ganetespib and these three classes of anticancer agents will be presented.
Citation Format: Chung Wong, Evan Vosburgh, Arnold Levine, David Proia, Eugenia Xu. Preclinical investigation of the HSP90 inhibitor, ganetespib, in combination with FDA-approved cytotoxic agents for their potential anti-tumor effects on human neuroendocrine tumors. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 267.
Abstract 2677: Unfolded protein response is required for EMT-driven metastasis by inducing CREB3L1
Authors: Feng Yuxiong , Jin Dexter X. , Gupta Piyush B. 
Published: July 2016

Abstract
Cancer initiates and progresses in the presence of a diversity of stresses ranging from nutrient deficiency, low oxygen supply to pH fluctuations. A set of stress response pathways, termed unfolded protein response (UPR), was evolved to maintain homeostasis of the endoplasmic reticulum (ER) from disruption by the above stressors. While it is broadly acknowledged that the UPR is involved in tumorigenesis, as tumor cells can employ the UPR as a critical survival strategy to grow and resist chemotherapy, the role of UPR in metastasis remains largely elusive. Epithelial-to-mesenchymal transition (EMT) is a cell transdifferentiation program frequently hijacked by cancer cells to migrate and invade. Here we showed cancer cells that have undergone an EMT employ the PERK-ATF4 branch of the UPR to drive metastasis, since loss of ATF4 abrogates the cell invasion upon an EMT. By conducting gene expression profiling, we found that the PERK-ATF4 pathway mediates the expression of a subset of the essential pro-invasion EMT-signature genes. In particular, CREB3L1, an ER-associated transcription factor (TF), is highly induced upon EMT in an ATF4-dependent manner. Knockdown of CREB3L1 effectively inhibits the EMT-driven invasion, while overexpression of CREB3L1 not only promotes invasion but also rescues the decrease of invasion caused by loss of ATF4. Mechanistically, CREB3L1 facilitates invasion through an ECM-FAK cascade. In breast cancer patients, the expression of CREB3L1 is significantly upregulated in breast cancer metastases compared to primary lesions, and predicts a poor prognosis. Most importantly, unlike other EMT-TFs, CREB3L1 could be inhibited by known chemicals, since the activation of CREB3L1 is mediated by the S1P- and S2P- dependent proteolysis. In an orthotopic breast cancer model, we found that chemical inhibition of CREB3L1 drastically suppresses lung metastasis. As a summary, we discovered that an ER stress-associated transcription factor CREB3L1 is required for cancer metastasis, and the susceptibility of CREB3L1 to chemical inhibition makes it a valuable target for drug development.
Citation Format: Yuxiong Feng, Dexter X. Jin, Piyush B. Gupta. Unfolded protein response is required for EMT-driven metastasis by inducing CREB3L1. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 2677.
Abstract 2682: Sympathetic activation alters the bone vasculature: implication for osteotropic breast cancer metastasis
Authors: Mulcrone Patrick L. , Campbell J. Preston , Anbinder Ana Lia , Sterling Julie A. , Elefteriou Florent 
Published: July 2016

Abstract
Emotional stresses chronically activate the Hypothalamic-Pituitary-Adrenal axis and the sympathetic nervous system (SNS), and have been associated with the progression and recurrence of breast cancer, as well as with reduced survival of breast cancer patients. We observed that isoproterenol (ISO), a β1/2 adrenergic receptor (βAR) agonist used to mimic sympathetic activation, induced the expression of Vegfa in mouse bone in vivo and in osteoblast cultures in vitro. Because VEGF is pro-angiogenic, and tumor cells depend on the vasculature to form distant metastases, we hypothesized that SNS chronic activation may increase bone marrow vascular density via an effect on β2AR-expressing osteoblasts, thus promoting the possibility of metastatic breast cancer establishment in the skeleton. To address this question, we measured the formation of CD31+ vessels in femurs in vivo by histomorphometric analyses, following daily ISO treatment of adult mice for 6 weeks. Vessel number was significantly increased by ISO treatment in WT mouse femurs, and this effect was blunted in mice lacking the β2AR. Further supporting our hypothesis, we found that the conditioned media (CM) from MC3T3 osteoblasts treated with ISO augmented blood vessel formation in an ex vivo metatarsal assay as compared to the CM of PBS-treated osteoblasts. Lastly, the CM of ISO-treated MC3T3 osteoblasts promoted primary bone endothelial cell tube formation, and inhibition of Vegf:Vegfr2 interaction with the antibody mcr84 reduced this formation. These results suggest that the effect of chronic stress on metastatic breast cancer cell establishment in the skeleton may be mediated in part due to changes in the bone microenvironment, specifically an increase in osteoblastic VEGF that changes host bone marrow vascular density.
Citation Format: Patrick L. Mulcrone, J. Preston Campbell, Ana Lia Anbinder, Julie A. Sterling, Florent Elefteriou. Sympathetic activation alters the bone vasculature: implication for osteotropic breast cancer metastasis. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 2682.