bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract B02: Protein Kinase C iota is required for the maintenance of a tumor-initiating cell phenotype in lung squamous cell carcinoma.
Authors: Justilien Verline , Walsh Michael P. , Ali Syed A. , Thompson E. A. , Fields Alan P. 
Published: August 2014

Abstract
Background: Protein kinase C iota (PKCι) is an oncogene that is frequently targeted for tumor-specific gene amplification in human cancers harboring the 3q26 amplicon including Non-Small Cell Lung Carcinoma (NSCLC). PKCι is required for the maintenance of the transformed phenotype of NSCLC cells in vitro and in vivo. In addition, PKCι is critical for lung tumorigenesis in the LSL-K-rasG12D mouse model of NSCLC. Recently, we demonstrated that genetic disruption of Prkcι/λ; in LSL-K-rasG12D mice blocks K-ras-mediated expansion and morphological transformation of bronchioalveolar stem cells (BASCs), the first identifiable step in K-ras-mediated transformation in this model. These results demonstrate that PKCι plays a requisite role in tumor initiation, and suggest that PKCι may serve a similar role in the tumor-initiating activity of lung cancer stem cells. Our current studies aim to identify and characterize the molecular signaling pathway(s) by which PKCι regulates the biology of human lung squamous cell carcinoma (LSCC) tumor initiating cells (TICs) isolated from LSCC cell lines and primary tumors.
Methods: Cultures enriched in TICs were established from LSCC lines or primary human LSCC tumors that harbor PRKCI amplification. PKCι expression in TIC cultures was inhibited by lentiviral shRNA, and the effect of PKCι knockdown on their stem-like properties was assessed. Whole genome deep sequencing analysis was performed on mRNA from parental, control TIC and PKCι knockdown TIC cultures in order to identify PKCι-regulated targets and signaling pathways in TICs.
Results: LSCC TIC cultures express putative stem cell markers, and exhibit clonal expansion, self-renewal, enhanced anchorage-independent growth and tumorigenic potential in vivo. RNAi-mediated knockdown of PKCι inhibited TIC growth, clonal expansion, transformed growth and tumor initiation. mRNA sequencing revealed that PKCι regulates the expression and function of critical molecules involved in the stem-like phenotype of LSCC TICs. Details of PKCι-mediated signaling in LSCC TICs will be discussed.
Conclusions: PKCι is required for maintenance of a highly tumorigenic stem-like population of cells in human LSCC. Given the prevalence of 3q26 amplification in human cancer, PKCι may regulate the biology of TICs in tumor types other than LSCC. Our results provide a rationale for therapeutic targeting of PKCι in LSCC TICs.
Citation Format: Verline Justilien, Michael P. Walsh, Syed A. Ali, E. A. Thompson, Alan P. Fields. Protein Kinase C iota is required for the maintenance of a tumor-initiating cell phenotype in lung squamous cell carcinoma. [abstract]. In: Proceedings of the AACR-IASLC Joint Conference on Molecular Origins of Lung Cancer; 2014 Jan 6-9; San Diego, CA. Philadelphia (PA): AACR; Clin Cancer Res 2014;20(2Suppl):Abstract nr B02.
Abstract IA18: Early but promising data: PD-1 inhibitors in non-small cell lung cancer.
Authors: Garon Edward B. , Wolf Brian R. , Wong Deborah JL , Goldman Jonathan W. 
Published: August 2014

Abstract
Blockade of the programmed death (PD-1) checkpoint has emerged as a promising approach for immunotherapies in the treatment of non-small cell lung cancer (NSCLC). Immune checkpoints, such as PD-1, an inhibitory T-cell immunoreceptor, and the receptor's ligands, PD-L1 and PD-L2, assist in hindering autoimmunity and protecting peripheral tissues to minimize damage (1). However, in cancers, the interaction between PD-1 and its ligands also can result in the promotion of an immunosuppressive tumor microenvironment (1).
Several agents targeting PD-1 are currently undergoing clinical development. Clinical trials of anti-PD-1 antibodies nivolumab (BMS-936558) and MK-3475 have produced encouraging results in non-small cell lung cancer patients with regards to objective response rates (ORR) and progression free survival (PFS) (2,3). In a pretreated advanced NSCLC population, nivolumab produced durable responses, particularly at 3 and 10 mg/kg doses (2). For 38 previously-treated NSCLC patients, MK-3475, administered at 10 mg/kg every three weeks, led to an ORR of 24 percent based on irRC (21 percent based on RECIST 1.1) (3). Median overall survival was 51 weeks with a PFS, which had not been reached at a time when the minimum PFS would be 62 weeks among the responders (3). ORR was 67% in patients with tumors having PD-L1 expression above a cutpoint versus 4% in those below the cutpoint (3). Based on the favorable response rates relative to historical controls, and the durability of responses in clinical trials, the development of PD-1 inhibitors in lung cancer is proceeding rapidly.
Future trials utilizing anti PD-1 antibodies will explore further biomarkers, and combination with other therapies.
Citation Format: Edward B. Garon, Brian R. Wolf, Deborah JL Wong, Jonathan W. Goldman. Early but promising data: PD-1 inhibitors in non-small cell lung cancer. [abstract]. In: Proceedings of the AACR-IASLC Joint Conference on Molecular Origins of Lung Cancer; 2014 Jan 6-9; San Diego, CA. Philadelphia (PA): AACR; Clin Cancer Res 2014;20(2Suppl):Abstract nr IA18.
Abstract IA41: A new TRacK in lung cancer: NTRK1 gene fusions as a therapeutic target.
Authors: Doebele Robert C. 
Published: August 2014

Abstract
Non-small cell lung cancer (NSCLC) is a heterogeneous disease that can be organized into groups designated by the dominant oncogene or oncogenic ‘driver’. Classification of NSCLC by oncogenes is critical because oral kinase inhibitors or other targeted therapeutic strategies can often effectively inhibit these oncogenes leading to dramatic tumor shrinkage and thus significant clinical benefit for patients. Several of these oncogenes are the result of chromosomal translocations that generate gene fusions in which the kinase domain of a receptor tyrosine kinase is aberrantly expressed and activated by the addition of sequence from an unrelated gene. Recent examples of such gene fusions in NSCLC include those involving the ALK, ROS1, RET and FGFR1/2/3 genes. We have recently discovered previously uncharacterized gene fusions involving the NTRK1 gene in patients with lung adenocarcinoma whose tumors did not harbor other known oncogenes. These novel oncogenes contain the 3 portion of the neurotrophic tyrosine kinase, receptor, type 1 (NTRK1) gene, which encodes the kinase domain of the TRKA receptor. Cloning and ectopic expression of these novels genes in non-tumor cells demonstrate their oncogenic potential. Treatment of cells expressing NTRK1 gene fusions with TRK inhibitors inhibits autophosphorylation of the chimeric TRKA proteins, important downstream signaling pathways, and cellular proliferation. Gene fusions involving NTRK1 (TRKA), NTRK2 (TRKB), and NTRK3 (and TRKC) have now been identified across multiple tumor types. As clinical next generation sequencing becomes increasingly common, cancer patients with these somatic gene abnormalities will be identified and therefore it is critical to understand their biology, utility as a therapeutic target, and mechanisms of intrinsic and acquired drug resistance in order to advance a precision medicine strategy for the treatment of NSCLC.
Citation Format: Robert C. Doebele. A new TRacK in lung cancer: NTRK1 gene fusions as a therapeutic target. [abstract]. In: Proceedings of the AACR-IASLC Joint Conference on Molecular Origins of Lung Cancer; 2014 Jan 6-9; San Diego, CA. Philadelphia (PA): AACR; Clin Cancer Res 2014;20(2Suppl):Abstract nr IA41.
Abstract PR02: Recurrent oncogenic mutations in the small GTPase RIT1 activate PI3K and MEK.
Authors: Berger Alice H. , Duke Fujiko , Imielinski Marcin , Kaplan Nathan , Wala Jeremiah , Shi Geng-Xian , Andres Douglas A. , Meyerson Matthew 
Published: August 2014

Abstract
Recently, we identified somatic mutations in the RAS-family small GTPase gene RIT1 in 2.4% (10/413) of lung adenocarcinoma tumors. Mutation of RIT1 is mutually exclusive with other oncogenic mutations in the receptor tyrosine kinase/RAS pathway, suggesting that RIT1 mutations are rare driver mutations in lung adenocarcinoma. Oncogenic RIT1 mutations cluster in the switch II domain of the protein and are observed not only in lung adenocarcinoma but also in myeloid malignancies, breast carcinoma, cervical carcinoma, and in the germline of Noonan syndrome patients. Here we functionally characterize 26 RIT1 point mutations and in-frame insertions/deletions in murine fibroblasts and human immortalized lung epithelial cells and find that the majority of somatic RIT1 mutations are able to transform cells. Furthermore, we identified a human lung cancer cell line, NCI-H2110, with an endogenous RIT1 p.M90I mutation. Knockdown of RIT1 in NCI-H2110 cells revealed the role of RIT1 in regulation of PI3K and MEK signaling. Consistently, combination PI3K/MEK inhibition could inhibit cellular transformation induced by ectopic expression of mutated RIT1. Furthermore, PI3K inhibition suppressed in vivo growth of NCI-H2110 cells. These data identify RIT1 as an oncogene and nominate combined PI3K and MEK inhibition as a therapeutic strategy in RIT1-mutated cancers.
This abstract is also presented as Poster A04.
Citation Format: Alice H. Berger, Fujiko Duke, Marcin Imielinski, Nathan Kaplan, Jeremiah Wala, Geng-Xian Shi, Douglas A. Andres, Matthew Meyerson. Recurrent oncogenic mutations in the small GTPase RIT1 activate PI3K and MEK. [abstract]. In: Proceedings of the AACR-IASLC Joint Conference on Molecular Origins of Lung Cancer; 2014 Jan 6-9; San Diego, CA. Philadelphia (PA): AACR; Clin Cancer Res 2014;20(2Suppl):Abstract nr PR02.
Functional Kinomics Identifies Candidate Therapeutic Targets in Head and Neck Cancer
Authors: Moser Russell , Xu Chang , Kao Michael , Annis James , Lerma Luisa Angelica , Schaupp Christopher M. , Gurley Kay E. , Jang In Sock , Biktasova Asel , Yarbrough Wendell G. , Margolin Adam A. , Grandori Carla , Kemp Christopher J. , Méndez Eduardo 
Published: August 2014

Abstract
Purpose: To identify novel therapeutic drug targets for p53-mutant head and neck squamous cell carcinoma (HNSCC).
Experimental Design: RNAi kinome viability screens were performed on HNSCC cells, including autologous pairs from primary tumor and recurrent/metastatic lesions, and in parallel on murine squamous cell carcinoma (MSCC) cells derived from tumors of inbred mice bearing germline mutations in Trp53, and p53 regulatory genes: Atm, Prkdc, and p19Arf. Cross-species analysis of cell lines stratified by p53 mutational status and metastatic phenotype was used to select 38 kinase targets. Both primary and secondary RNAi validation assays were performed on additional HNSCC cell lines to credential these kinase targets using multiple phenotypic endpoints. Kinase targets were also examined via chemical inhibition using a panel of kinase inhibitors. A preclinical study was conducted on the WEE1 kinase inhibitor, MK-1775.
Results: Our functional kinomics approach identified novel survival kinases in HNSCC involved in G2–M cell-cycle checkpoint, SFK, PI3K, and FAK pathways. RNAi-mediated knockdown and chemical inhibition of the WEE1 kinase with a specific inhibitor, MK-1775, had a significant effect on both viability and apoptosis. Sensitivity to the MK-1775 kinase inhibitor is in part determined by p53 mutational status, and due to unscheduled mitotic entry. MK-1775 displays single-agent activity and potentiates the efficacy of cisplatin in a p53-mutant HNSCC xenograft model.
Conclusions: WEE1 kinase is a potential therapeutic drug target for HNSCC. This study supports the application of a functional kinomics strategy to identify novel therapeutic targets for cancer. Clin Cancer Res; 20(16); 4274–88. ©2014 AACR.
Abstract A32: Fractalkine receptor, CX3CR1, Can regulate the response of ovarian carcinoma cells to radiation therapy
Authors: Xie Jia , Gurler Hilal , Barbolina Maria 
Published: August 2014

Abstract
Ovarian carcinoma is a leading cause of death from gynecologic malignancies. The current treatment, a combination of chemotherapy and radiation, fails to keep patients in remission. Therefore, mechanistical understanding of the disease and modifications of the therapy could offer benefits to overcome current problems and combat the disease. Fractalkine receptor (CX3CR1) belongs to a chemokine family of G protein-coupled receptors, the most frequently and successfully drug-targeted group of proteins. Previous publications show that interaction of chemokines with their receptors plays an important role in homing distant metastasis, as well as promoting migration, adhesion, and proliferation in many types of cancer. X-Ray radiotherapy is a well-developed method of anti-cancer treatment, however, it is seldom used against ovarian carcinoma due to multiple reasons, including dose-related effects. Hence, strategies for reducing the dose of radiation while keeping its efficiency at a therapeutically effective level could provide rational for developing approaches for a more wide-spread use of this method.
Our data indicate that transient downregulation of CX3CR1 in p53-null cells and p53-mutant cells but not in p53 wild-type ovarian carcinoma cell lines can lead to approximately 50% sensitization to x-ray radiation, as determined by the clonogenic assay. Importantly, our in vivo studies demonstrated that a transient downregulation of CX3CR1 in combination with x-ray radiation led to approximately 50% reduction of tumor weights compared to either downregulation of CX3CR1 or x-ray radiation alone. We are currently characterizing the detailed mechanisms behind the CX3CR1-dependent radiosensitization, including those related to changes in cell cycle progression, involvement of cellular reactive oxygen species accumulation and regulation of DNA single and double strand break repair. Taken together, our date indicate that disruption of the CX3CR1 signaling could sensitize ovarian carcinoma to radiation therapy.
Citation Format: Jia Xie, Hilal Gurler, Maria Barbolina. Fractalkine receptor, CX3CR1, Can regulate the response of ovarian carcinoma cells to radiation therapy. [abstract]. In: Proceedings of the AACR Special Conference on Advances in Ovarian Cancer Research: From Concept to Clinic; Sep 18-21, 2013; Miami, FL. Philadelphia (PA): AACR; Clin Cancer Res 2013;19(19 Suppl):Abstract nr A32.
Abstract A40: New approaches to target mevalonate biosynthesis
Authors: Casella Cinzia , Brodsky Alexander S. 
Published: August 2014

Abstract
To support rapid growth, tumors need to synthesize lipids and cholesterol, and stopping production of these metabolites can inhibit tumors. Statins are among the most prescribed and well-tolerated drugs in the world to treat cardiovascular disease by inhibiting cholesterol synthesis. Statins are known to be toxic to cancer cells and have attracted renewed attention because of the increased appreciation of the importance of the regulation of metabolism in tumors. Statins have not progressed beyond clinical trials because some patients significantly benefit, while others do not in a range of cancers. Our strategy is to improve our understanding of the mechanisms of tumor responses to statins and thereby enhance statin toxicity to cancer cells. We have found that combining statins with oxysterols synergistically enhances statin toxicity by 10-fold. Oxysterols are oxidized cholesterol metabolites that naturally occur during cholesterol synthesis. We hypothesize that oxysterols inhibit the expression of cholesterol synthesis through a master regulator of metabolism, SREBP-2, making cells more sensitive to statins. We find that oxysterols enhance statin induced apoptosis and suppress the expression of SREBP-2 along with SREBP-2 targets including HMGCR. We have tested a number of oxysterols that work with a range of efficacies in seven representative ovarian cancer cell lines. P53 status is not a major factor in mediating oxysterol activity. Oxysterols inhibit expression of SREBP-2 leading to lower expression of the statin target, HMGCR, along with lower expression of most of the mevalonate and cholesterol biosynthesis pathways. These observations suggests that the cell's response to statins and not initial expression levels may be most critical to determine which patients may benefit from statin therapy. Current studies are testing the combination in mouse models and evaluating the function and regulation of SREBP-2 in ovarian cancer. In summary, we have discovered an approach to suppress cancer cell's response to statins leading to greatly improved statin efficacy highlighting the importance of the mevalonate and cholesterol pathways in mediating growth and survival.
Citation Format: Cinzia Casella, Alexander S. Brodsky. New approaches to target mevalonate biosynthesis. [abstract]. In: Proceedings of the AACR Special Conference on Advances in Ovarian Cancer Research: From Concept to Clinic; Sep 18-21, 2013; Miami, FL. Philadelphia (PA): AACR; Clin Cancer Res 2013;19(19 Suppl):Abstract nr A40.
Abstract A53: Biomarkers of chemotherapy resistance in serous epithelial ovarian cancer identified by integrative genomic and transcriptomic analysis
Authors: Koti Madhuri , Gooding Robert J. , Nuin Paulo , Haslehurst Alexandria , Crane Colleen , Weberpals Johanne , Chids Timothy , Bryson Peter , Dharsee Moyez , Evans Kenneth R. , Feilotter Harriet E. , Park Paul C. , Squire Jeremy A. 
Published: August 2014

Abstract
Resistance to platinum-based chemotherapy remains a major impediment in the treatment of serous epithelial ovarian cancer. The objective of this study was to use gene expression and copy number profiling to delineate major deregulated pathways and biomarker networks associated with the development of intrinsic chemotherapy resistance with exposure to standard first-line therapy for ovarian cancer. The study cohort comprised 28 high grade serous ovarian cancer patients divided into two groups based on their varying sensitivity to first-line chemotherapy using progression free survival (PFS) as a surrogate of response. Twelve patient tumors demonstrating relative resistance to platinum based chemotherapy corresponding to shorter PFS (less than 6 months) were compared to 16 tumors from platinum-sensitive patients (PFS more than 18months). Molecular profiling was performed using Affymetrix high-resolution microarray platforms to permit global comparisons of gene expression levels and copy number profiles between tumors from the resistant group with the sensitive group. Microarray data analysis using statistical methods revealed a set of 204 discriminating genes of which expression levels may be influencing differential chemotherapy response between the two groups. Pathway analysis of the differentiating genes showed IGF1 network to be significantly altered between the two groups in addition to PI3K, NFkB, distinguishing the chemotherapy resistant with the sensitive group. Copy number analysis showed differences in the chromosomal regions, 4q31.22, 5q13.2, 9p24.3, 2p23.2, 16q21, 6q14.1, 7p22.3, 12p13 and Xq.
Integrative copy number and gene expression profiling will delineate the drivers of chemotherapy resistance in patients undergoing standard platinum-based treatment of ovarian cancer. Future studies to validate these markers are necessary to apply this knowledge to biomarker-based clinical trials.
Citation Format: Madhuri Koti, Robert J. Gooding, Paulo Nuin, Alexandria Haslehurst, Colleen Crane, Johanne Weberpals, Timothy Chids, Peter Bryson, Moyez Dharsee, Kenneth R. Evans, Harriet E. Feilotter, Paul C. Park, Jeremy A. Squire. Biomarkers of chemotherapy resistance in serous epithelial ovarian cancer identified by integrative genomic and transcriptomic analysis. [abstract]. In: Proceedings of the AACR Special Conference on Advances in Ovarian Cancer Research: From Concept to Clinic; Sep 18-21, 2013; Miami, FL. Philadelphia (PA): AACR; Clin Cancer Res 2013;19(19 Suppl):Abstract nr A53.
Abstract A56: Identification of a micro RNA profile to predict response to therapy and improve patient survival in ovarian cancer
Authors: Rigau Marina , Majem Blanca , Altadill Tatiana , Lanau Lucia , Sánchez-Iglesias José-Luis , Castellví Josep , Pérez-Benavente Assumpció , Cabrera Silvia , García Angel , Xercavins Jordi , Alameda Francesc , Matias-Guiu Xavier , Gil-Moreno Antonio , Campo Josep-Maria Del , Llauradó Marta , Reventós Jaume 
Published: August 2014

Abstract
Introduction & Objectives: Ovarian cancer (OC) is the leading cause of death among gynecological malignancies in developed countries. The standard treatment is surgery plus platinum-paclitaxel (CP/TX) chemotherapy. Nevertheless, 70% of these patients are diagnosed in advanced stages, and, among those, 75% will recur, become resistant to therapies and die. We believe that an improvement in OC survival might be related with an early identification of those patients, since long survival (SV) is related to chemosensitivity. Our aim is to identify an expression profile of micro RNAs (miRNAs) associated with SV of patients with advanced OC.
Material & Methods: Formalin-fixed paraffin-embedded (FFPE) primary tumor tissues from late stage (III/IV) OC patients were collected at the time of surgery for the study. All patients were treated with optimal surgery and standard chemotherapy (CP/TX; after surgery). Samples were divided into two groups; (a) patients with “long SV” (SV&gt;10 years after diagnosis) and (b) patients with “short SV”. The identification of miRNAs associated with each profile of SV was performed using TaqMan Array MicroRNA microfluidic cards in 30 patients.
Results: The identification phase has shown that the majority of the miRNAs appeared to be down-regulated in the group of “short SV” versus the “long SV”. A validation phase in a new group of tumor tissue samples is ready to validate the promising miRNA candidates that seem to be associated with the resistant (short SV) and the sensitive (long SV) profiles.
Conclusions: The ability to identify markers associated with “long SV” in patients with advanced OC could allow transforming the impact of the disease through the reduction of chemotherapy treatments and the reduction of unnecessary health care costs. Moreover, it could permit the generation of knowledge applicable to the future development of new therapies for the “short SV” since they are supposed to be resistant to the therapy.
Citation Format: Marina Rigau, Blanca Majem, Tatiana Altadill, Lucia Lanau, José-Luis Sánchez-Iglesias, Josep Castellví, Assumpció Pérez-Benavente, Silvia Cabrera, Angel García, Jordi Xercavins, Francesc Alameda, Xavier Matias-Guiu, Antonio Gil-Moreno, Josep-Maria Del Campo, Marta Llauradó, Jaume Reventós. Identification of a micro RNA profile to predict response to therapy and improve patient survival in ovarian cancer. [abstract]. In: Proceedings of the AACR Special Conference on Advances in Ovarian Cancer Research: From Concept to Clinic; Sep 18-21, 2013; Miami, FL. Philadelphia (PA): AACR; Clin Cancer Res 2013;19(19 Suppl):Abstract nr A56.