bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract IA17: TSLP-driven inflammation fosters development of epithelial tumors
Authors: Palucka Anna Karolina , Xu Kangling , Pedroza Alexander Gonzalez , Wu Te-Chia , Zurawski Sandra , Marches Florentina , Zurawski Gerard , Liu Yong-Jun , Banchereau Jacques 
Published: March 2013

Abstract
Solid tumors are often associated with aseptic inflammation. There are two types of inflammation that have opposing effects on tumors, chronic inflammation that promotes cancer cell survival, and metastasis, and acute inflammation which triggers cancer cell destruction. Chronic inflammation is often linked with the presence of type 2-polarized macrophages (M2), which are induced by Th2 cytokines, IL-4 and IL-13.
Our recent studies have demonstrated the presence in breast cancer tumors of inflammatory Th2 cells, which produce IL-13, IL-4, and TNF. These CD4+ T cells appear to play a key role in the disease as they accelerate breast tumor development in a xenograft model through the production of IL-13. Breast tumors appear to play a critical role in conditioning the infiltrating myeloid DCs (mDCs) to induce such inflammatory Th2 cells. Our most recent results suggest that thymic stromal lymphopoetin (TSLP) secreted by cancer cells plays a role in mDCs conditioning. Breast cancer cell lines and primary tumors from patients show TSLP protein expression. TSLP-neutralizing antibodies block the upregulation of OX40L by mDCs exposed to tumor supernatant and consequently block mDCs capacity to generate inflammatory Th2 cells in vitro. The TSLP production is mediated by PAR2-signaling in cancer cells. PAR2 is expressed by all 4 breast cancer cell lines, and TSLP production can be induced upon PAR2-agonist peptide treatment. Similar observations were made by us and others in pancreatic cancer as well as lung cancer. Thus, TSLP could serve as therapeutic target in tumors of epithelial origin.
Abstract IA6: Gene fusions in lung cancer
Authors: Beer David G. 
Published: March 2013

Abstract
Gene fusions represent one type of genetic alteration recently detected in lung cancer that results from chromosomal rearrangements. A fusion joining the echinoderm microtubule-associated protein-like 4 (EML4) and anaplastic lymphoma kinase (ALK) genes was detected as a transforming gene in a small subset of lung adenocarcinomas. Importantly, patients with these fusions show responsiveness to ALK kinase inhibitors. Additional studies have identified multiple EML4-ALK gene fusion variants and the histopathological characteristics of the lung tumors identified. Various methods utilized to detect lung gene fusions have included retrovirus-mediated expression screening with 3T3 cell transformation assays, FISH, mRNA/protein expression, RACE-coupled PCR sequencing, massively parallel paired-end and transcriptome sequencing. Additional novel gene fusion events in lung cancer have recently been identified using these and newly defined approaches in small percentages of primary lung tumors. Potential mechanisms underlying the production and triggers for gene fusion events will be discussed.
Abstract IA8: Role of biomarkers in the early detection of lung cancer
Authors: Massion Pierre P. 
Published: March 2013

Abstract
While lung cancer remains the leading cause of cancer-related death in the world with a 16% overall survival rate, we now know that early detection by low dose chest CT saves lives. The implementation of screening programs represents a huge challenge. Research is needed to address who will benefit from screening, for how long, and with what frequency we should screen. Using biomarkers to select the most at-risk population, to detect the disease while measurable and yet not clinically apparent, and to predict survival, has been the goal of many investigations. Recent advances in molecular strategies and analytical platforms including genomics, epigenomics, proteomics, and metabolomics, have identified increasing numbers of potential biomarkers. These molecular approaches are applied to a variety of samples collected by non invasive methods including blood, urine, exhaled breath condensate, bronchial specimens, saliva, and sputum. None have yet moved to the clinical setting. In this presentation, we will define clinical contexts where diagnostic biomarkers may have utility in the management of lung cancer, we will review the state of development of candidate diagnostic biomarkers, and finally, we will discuss critical aspects of study design in biomarkers research.
Abstract PR5: A phase II study of sorafenib in patients with stage IV non-small cell lung cancer (NSCLC) with a K-Ras mutation
Authors: Mellema Wouter W. , Dingemans Anne-Marie C. , Groen Harry J.M. , van Wijk Atie , Burgers Sjaak , Kunst Peter W.A. , Thunnissen Frederik B. , Heideman Daniëlle A.M. , Smit Egbert F. 
Published: March 2013

Abstract
Background: In a pilot study (1) we found sorafenib to display clinical activity against patients with K-Ras positive NSCLC, sufficient for formal phase II testing. Methods: Patients with K-Ras mutated NSCLC that progressed after at least 1 platinum containing regimen with adequate organ reserve, ECOG 0–2, who provided written informed consent according to local IRB regulations were eligible. A tumor biopsy confirming the presence of a K-Ras mutation was mandatory. Treatment consisted of sorafenib 400 mg BID until disease progression or unacceptable toxicity. Dose reductions and delays were specified per protocol in the face of CTC toxicities grade 3 and 4. Primary endpoint: Rate of No Progression (NPR) at 6 weeks. Secondary endpoints: duration of response, progression free survival (PFS), overall survival and treatment related toxicities. A 2-stage design was implemented (Simon's optimal design; p0=40%, p1=60%, alpha=0.05, beta=0.20) for a total number of 48 pts. Results: 59 patients were entered between May 1st 2010 and February 18 2011. Median age was 58 (range 46–79) years, 17 Male/42 Female, ECOG PS 0/1/2 23/32/4. 57 patients started treatment. At 6 weeks 5 PR, 25 SD, 27 PD were observed; NPR 52.6%. Fifteen patients stopped treatment before 6 weeks, of which 10 patients stopped due to (clinical) progression. Median duration of treatment was 9 (range 0–62) weeks, 2 patients are still on treatment. Median duration of response was 32 (range 5–58) weeks. Median PFS was 2.3 months, median OS was 4.9 months, 14 patients still alive. Dose modifications were realized in 21 patients, of whom 4 discontinued treatment. Most reported adverse events were fatigue (6.4%), hand-foot reaction (5.7%), dyspnea (5.6%), anorexia (3.7%) diarrhea (3.6%) and cough (3.6%). Sorafenib related grade 3-4 toxicity was reported in 10 patients. Five patients with grade 3 skin toxicity, 4 patients with grade 3 gastrointestinal toxicity and 1 patient with both grade 3 metabolic abnormalities and a grade 3 pneumonitis. Conclusion: Treatment with sorafenib has relevant clinical activity in patients with K-Ras mutational status. Further randomized study with this agent is warranted.
This abstract is also presented as Poster B18.
Abstract A17: Loss of DEPTOR increases resistance to EGFR tyrosine kinase inhibitors by upregulating EGFR and MAPK signaling
Authors: Cowell Catherine F. , De Bruin Elza C. , Howell Michael , Downward Julian 
Published: March 2013

Abstract
Epidermal growth factor (EGFR) activating mutations occur in 10% to 40% of non-small cell lung cancer (NSCLC), and can be successfully targeted with EGFR tyrosine kinase inhibitors (EGFR-TKIs), achieving up to 80% response rate in patient populations selected for presence of activating mutations. However, almost all patients develop resistance to treatment within a year, and in at least 30% of cases the cause of resistance is unknown. To identify novel mechanisms of resistance we executed a genome-wide siRNA screen in PC9 cells, an EGFR-TKI sensitive NSCLC cell line. We completed the screen in untreated and drug treated conditions, and selected hits as those genes that had a significantly different effect on survival in drug treated conditions compared to untreated controls. RNAi-mediated knockdown of DEPTOR, a negative regulator of mTOR, increased resistance of PC9 cells to erlotinib (an EGFR-TKI). Cells depleted of DEPTOR have higher levels of mTOR signaling as seen by greater phosphorylation of AKT, and SGK1 substrate NDRG1. DEPTOR loss leads to enhanced resistance to erlotinib treatment by increasing abundance of EGFR protein, thereby augmenting MAPK signaling in basal and erlotinib treated conditions. This upregulation of EGFR appears dependent on mTOR activation, as mTOR kinase inhibitors can resensitize DEPTOR deficient cells to erlotinib treatment. Also, combination treatment of erlotinib with a MEK inhibitor restores sensitivity to erlotinib of cells in which DEPTOR expression has been reduced, indicating increased MAPK signaling contributes to resistance in these cells. mTOR activation is known to cause DEPTOR degradation, therefore our results may have implications for a wide subset of NSCLC where mTOR signaling is upregulated.
Abstract A19: A qPCR assay, OncoScore Colon, predicts resistance to cetuximab in formalin-fixed, paraffin-embedded colorectal cancer tissue independent of KRAS status
Authors: Eddy Sean , Lee Byung-In , Macarulla Teresa , Tabernero Josep , Monforte Joseph , Rhodes Daniel R. , Williams Paul , Tomilo Mark , Sadis Seth , Wyngaard Peter , Vo Lien , Oades Kahuku , Kim Hyunsoo , Wang Yipeng 
Published: March 2013

Abstract
Gene expression modules derived from an unsupervised analysis of 20 independent microarray datasets comprising more than 2,000 colorectal cancer patients were identified. Each module represents a set of highly co-expressed genes related to an important aspect of underlying cancer variability. Modules containing genes related to epithelial and mesenchymal biology associated with sensitivity and resistance to EGFR family targeted inhibitors (gefitinib and lapatinib), respectively. In retrospective analysis of clinical samples, the epithelial-mesenchymal axis associated with cetuximab response in two independent patient cohorts. The first study was a Phase II clinical trial (Khambata-Ford et al., J Clin Oncol, 2007) with accompanying microarray data from pre-treatment metastatic colorectal tumor biopsies. Expression of the modules was determined by normalizing and averaging co-expressed module genes. Patients with a more epithelial and less mesenchymal module expression profile were enriched for cetuximab response. An independent cohort of patients was analyzed using module scores that were generated from a qPCR gene expression module test, OncoScore™ Colon, which quantifies modules by averaging three representative module genes relative to housekeeping genes using formalin-fixed-paraffin-embedded primary tumor samples. In these patients, presence of the mesenchymal module was significantly associated with a decrease in progression free survival. Notably, the status of the mesenchymal module was independent of KRAS mutation status—as KRAS mutations occurred in both mesenchymal module-positive and -negative patients. Further clinical studies are ongoing to continue to support the development of the OncoScore™ Colon assay and to further test the predictive capacity of the module with regards to cetuximab resistance and other MAPK pathway inhibitors. This study demonstrates the value of a gene expression module-based qPCR panel for stratifying colorectal cancer patients for treatment response, and suggests that our approach may have immediate utility for cetuximab treatment response prediction.
Abstract A31: Roles of Nogo-B receptor (NgBR) in regulating Ras translocation and modulating breast cancer cell sensitivity to chemotherapeutic drug and irradiation
Authors: Zhao Baofeng , Liu Zhong , Kumar Suresh , Miao Robert Q. 
Published: March 2013

Abstract
Ras, a critical oncogene, is one of small GTPase family members. It is active when bound to GTP and inactive when bound to GDP. The activation process needs membrane translocation of Ras because its activators are recruited by membrane receptors, such as EGF receptors. In addition, appropriate localization of activated Ras also is critical for interacting with the downstream effectors. Therefore, regulation of Ras membrane translocation is very important for Ras function.
Nogo-B receptor (NgBR) is a type I receptor with a single transmembrane domain. Our previous work has shown that axon guidance gene family Nogo-B and its receptor (NgBR) are essential for chemotaxis and morphogenesis of endothelial cells in vitro and blood vessel formation in Zebrafish. Here, we demonstrate that NgBR can bind and recruit farnesylated Ras to plasma membrane, which results in the activation of PI3K-Akt and Raf-MEK-ERK signaling pathways in human breast cancer cells. Direct interaction between NgBR and farnesylated Ras has been demonstrated by co-immunoprecipitation of MBP-NgBR from incubation of purified recombinant farnesylated Ras and MBP-NgBR protein. Knockdown of NgBR in MDA-MB-231 human breast cancer cells remarkably reduces the amount of membrane-associated Ras. These results suggest that NgBR is a potential modulator for Ras translocation. Knockdown of NgBR expression in MDA-MB-231 breast cancer cells decreases cancer cell colony formation, and abolishes EGF-stimulated Ras activation and phosphorylation of Akt in MDA-MB-231 cells. In addition, overexpression of NgBR caused the transformation of NIH-3T3 cells via increasing Ras plasma membrane translocation and enhancing EGF-stimulated Ras signaling. Knockdown of NgBR decreases the survival and colony formation of MDA-MB-231 cells after irradiation and increases the cisplatin-induced apoptosis and Caspase-3 activity of MDA-MB-231 Cells. These results suggest that NgBR can increase MDA-MB-231 breast cancer cell sensitivity to chemotherapeutic drug and irradiation. Consequently, our preliminary results further demonstrated that inducible knockdown of NgBR in tumor xenograft of MDA-MB-231 cells in nude mice significantly retards tumor growth. Thus, these data demonstrate that NgBR is a unique receptor that recruits farnesylated Ras to the plasma membrane via its hydrophobic cytoplasmic domain and then activates both PI3K-Akt and Raf-MEK-ERK pathways in human breast cancer cells. Collectively, it is the first study to demonstrate that NgBR is a potential therapeutic target for inhibiting Ras-dependent growth of breast cancer and decreasing the sensitivity of breast cancer cells to chemotherapeutic drug and irradiation.
Abstract A32: Notch signaling regulates recurrence in a model of HER2 targeted therapy
Authors: Abravanel Daniel L. , Sterner Christopher J. , Pan Tien-chi , Belka George K. , Chodosh Lewis A. 
Published: March 2013

Abstract
Breast cancer is the leading cause of cancer-related deaths among women worldwide. While mortality rates have improved over the past thirty years, physicians still lack effective tools for the prevention or treatment of breast cancer recurrence. An essential first step in designing such therapies will be to elucidate the pathways that contribute to therapeutic resistance, dormancy, and recurrence.
Our laboratory has developed a series of mouse models that permit the conditional activation of oncogenes in the mammary glands of mice and can be used to recapitulate key features of breast cancer progression including dormancy and recurrence after targeted therapy. In the MMTV-rtTA;TetO-neu (MTB/TAN) model, treatment with doxycycline (dox) permits mammary specific activation of HER2/neu and drives primary tumor formation. Upon removal of dox and resultant down-regulation of HER2/neu, primary tumors regress as a consequence of oncogene addiction. However, a small population of tumor cells persists in a histologically identifiable residual lesion. After a period of cellular dormancy, residual tumor cells reenter the cell cycle in a stochastic manner and give rise to recurrent tumors, independent of HER2/neu signaling.
Recent evidence suggests that Notch signaling may play a role in breast cancer recurrence. For example, elevated Notch signaling in ductal carcinoma in situ lesions has been found to be associated with early recurrence after surgery. To build on these data, we analyzed microarray datasets from breast cancer patients and found that NOTCH1 expression levels are correlated with recurrence risk, suggesting that this pathway may play a role in human disease. Furthermore, in our mouse model system, we have found that Notch signaling is activated following HER2/neu downregulation. To assess the functional significance of this phenomenon, we performed in vitro clonogenic assays and in vivo recurrence assays. Activation of Notch signaling accelerated colony formation and recurrence, whereas Notch repression inhibited colony formation and recurrence. These data suggest that Notch signaling is both necessary and sufficient to promote recurrence following HER2/neu downregulation.
Taken together, our data support a model in which the Notch signaling pathway provides a mechanism by which HER2/neu driven tumors can escape therapy and cause recurrent disease. As gamma secretase inhibitors are currently in late-stage clinical trials for the treatment of breast cancer, work to determine whether Notch signaling contributes to the survival and recurrence of breast cancer cells could have a significant clinical impact. The observation that Notch signaling is required for recurrence would raise the possibility that these drugs could be used to target residual tumor cells and prevent breast cancer recurrence.
Abstract A42: Sensitivity and resistance to a p-AKT inhibitor in an erlotinib-sensitive model for lung cancer
Authors: El Meskini Rajaa , Martin Philip L. , Gumprecht Michelle , Kulaga Alan , Guerin Theresa , Baran Maureen , Iacovelli Anthony J. , Van Dyke Terry , Weaver Zoe 
Published: March 2013

Abstract
Activating mutations in EGFR, such as the L858R mutation, are effective predictors of response to EGFR tyrosine kinase inhibitor (TKI) therapy. While most patients initially respond to EGFR TKIs, the majority relapse within 6-12 months, underscoring the importance of identifying therapies that enhance and prolong EGFR TKI activity in patients. Agents targeting additional nodes in the EGFR pathway have the potential to overcome such resistance but single-agent activity must be understood first. We utilized mice engineered to develop erlotinib-sensitive lung adenocarcinomas driven by the human EGFR L858R mutation to evaluate the efficacy of a p-AKT inhibitor, MK-2206, currently in clinical trials for a variety of solid tumor malignancies. MK-2206 concentration and target activity were assessed in short-term PK/PD studies in both the lungs and blood of tumor-bearing mice. MK-2206 was then evaluated in an efficacy study using a twice-weekly dosing regimen, both as a single agent and in combination with other TKIs. MK-2206 alone resulted in tumor regression or tumor growth inhibition in ∼50% of the mice, but exhibited greater efficacy in combination with other upstream pathway inhibitors. Temporal evaluation of tumor growth inhibition indicated that MK-2206 was most effective at early time points and did not produce a sustained pathway and growth response as treatment continued. Analysis of gene expression changes in mice treated with MK-2006 alone vs. MK-2206 in combination with EGFR TKIs highlighted the pathways perturbed by both drugs.
Abstract A7: A novel class of selective estrogen receptors degraders regresses tumors in pre-clinical models of endocrine-resistant breast cancer
Authors: Darimont Beatrice , Govek Steven , Lu Nihn , Nagasawa Johnny , Prudente Rene , Qian Jing , Sensintaffar John , Shao Gang , Heyman Richard , Rix Peter , Smith Nicholas , Hager Jeffrey , Joseph James , Grillot Katherine , Aparicio Anna , Bischoff Eric , Kahraman Mehmet , Kaufman Josh , Lai Andiliy , Lee Kyoung-Jin 
Published: March 2013

Abstract
Eighty percent of all breast cancers express the estrogen receptor alpha (ERα) and thus are treated with antihormonal therapies that directly block ERα function (e.g., tamoxifen) or hormone synthesis (aromatase inhibitors). While these therapies are initially effective, acquired resistance invariably emerges and disease progression ensues. Importantly, the majority of these tumors continue to depend on ERα for growth and survival via both ligand-dependent and ligand-independent pathways. The emerging evidence that ERα can signal in the absence of estrogens supports the development of agents that are not only competitive ERα antagonists but also reduce steady state levels of the receptor and thus limit both ligand dependent and independent signaling.
We have identified novel, nonsteroidal ERα antagonists that induce degradation of ERα at picomolar concentrations resulting in significant reduction in steady state ERα protein levels in breast cancer cell lines. Using peptide-based conformational profiling, we show that these ligands induce estrogen receptor conformations that are distinct from both fulvestrant and tamoxifen indicating novel mechanism of action. Importantly, these compounds yield tumor regression in both tamoxifen-sensitive and -resistant models of breast cancer in vivo. Based on their unique in vitro profile, and good pharmacokinetics following oral dosing, these compounds represent a novel class of selective estrogen receptor degraders (SERDs) that hold promise as a next-generation therapy for the treatment of ER+ breast cancer as monotherapy, as well as in combination with agents that target other pathways involved in both intrinsic and acquired endocrine resistance.