bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract S1-01: The association between event-free survival and pathological complete response to neoadjuvant lapatinib, trastuzumab or their combination in HER2-positive breast cancer. Survival follow-up analysis of the NeoALTTO study (BIG 1-06)
Authors: Piccart-Gebhart M , Holmes AP , de Azambuja E , Di Cosimo S , Swaby R , Untch M , Jackisch C , Lang I , Smith I , Boyle F , Xu B , Barrios C , Gelber R , Eidtmann H , Baselga J 
Published: August 2014

Abstract
Background: The NeoALTTO study demonstrated a significantly higher breast pathological complete response (pCR) rate (NSABP definition – ypT0/is) with dual HER2 blockade using lapatinib and trastuzumab compared with single HER2 blockade using either lapatinib or trastuzumab (51.3% vs. 24.7% vs. 29.5%, respectively; p&lt; 0.01 for both) in HER2 positive primary breast cancer (BC). A similar pattern was seen for locoregional pCR (ypT0/is ypN0) (Baselga J et al. Lancet 2012).
Material and Methods: From January, 2008, to December, 2009, 455 patients were randomized from 99 participating sites in 23 countries. Patients were randomized to receive either lapatinib 1500 mg/d (154 pts), or trastuzumab 4 mg/kg IV loading dose followed by 2 mg/kg IV weekly (149 pts), or lapatinib 1000 mg/d with trastuzumab for a total of 6 weeks (152 pts). After this biological window, patients continued on the same targeted therapy plus weekly paclitaxel 80 mg/m2 for a further 12 weeks, until definitive surgery (total neoadjuvant therapy duration of 18 weeks). After surgery, patients received 3 cycles of adjuvant FEC followed by the same targeted therapy as in the biological window of the neoadjuvant phase for a further 34 weeks (to complete 52 weeks of anti-HER2 therapy), with on-going follow-up planned until 10 years after last randomised patient.
Secondary objectives included disease-free survival and overall survival (OS). Following current practice and draft FDA recommendations for neoadjuvant trial endpoints, an amendment was made to the protocol secondary objectives (released in May 2013). DFS (from surgery) was replaced by event-free survival (EFS) from randomisation; OS from surgery was correspondingly replaced with OS from randomisation, and examination of the association between these survival endpoints and locoregional pCR (ypT0/is ypN0) was added as a secondary objective. EFS was defined as the time from randomization to first EFS event (breast cancer relapse, second primary malignancy or death without recurrence). OS was defined as the time from randomization to death from any cause.
Results: The clinical cut-off date for the first planned analysis of these secondary objectives was on 26 May 2013, three years after the date of last surgery. Data cleaning is ongoing and analysis will be completed by November 2013. Results for EFS, OS and their association with pCR will be presented at the meeting.
Funding: GlaxoSmithKline is the sponsor of this trial.
Citation Information: Cancer Res 2013;73(24 Suppl): Abstract nr S1-01.
Abstract B08: Triptolide has antitumor effects in lung cancer via Wnt pathway inhibition.
Authors: Li Youqiang , Zheng Li , Shen Binghui , Kim Jae , Raz Dan 
Published: August 2014

Abstract
Introduction: Triptolide is an extract of the herb Tripterygium wilfordii (Tw), which has been used to treat autoimmune disorders in traditional Chinese medicine. It has also been reported to have anti-cancer effects in vitro, although little is known about its mechanism of action. The Wnt/B-catenin pathway has been implicated in regulating cancer stem cells in lung cancer, making this pathway a potential target for novel lung cancer therapies.
Methods: Here we tested the efficacy of triptolide in several lung cancer cell lines. We elucidated a Wnt pathway mechanism for triptolide effect in lung cancer, first by using a Wnt focused cDNA array in vitro. We examined the effect of triptolide on tumor cell death using flow cytomotery and a beta-galactosidase assay. We tested the ability of triptolide to prevent development of lung tumors in the E160D transgenic mouse model of lung cancer, which carries a somatic mutation in the DNA repair enzyme flap endonuclease-1 (FEN-1). Twelve month old mice were fed triptolide 1mg/kg daily for 2 months and were sacrificed at 18 months along with a control group.
Results: Triptolide had more potent therapeutic efficacy in multiple lung cancer cell lines compared with cisplatin and paclitaxel, in vitro. In H460 and A549 cell lines, we found that triptolide resulted in Wnt pathway silencing via overexpression of Wnt inhibitory factor-1 (WIF-1), which occurs due to promoter demethylation. Addition of recombinant Wnt3a, which causes Wnt pathway activation, partially rescues the effect of triptolide on lung cancer cell lines. Triptolide resulted in cellular senescence as demonstrated by beta-galactosidase assay. Finally, in the E160D transgenic mouse model of lung cancer, a two month course of oral triptolide treatment decreased the development of lung tumors from 70% to 30% at 18 months (p=0.01). There were no observed clinical toxicities at the dosage of triptolide used.
Conclusions: Triptolide has potent anti-cancer effects in vitro in lung cancer cell lines, and significantly decreases lung tumor development in a transgenic mouse model. Triptolide suppresses the Wnt pathway by causing upregulation of WIF-1a by promoter demethylation. Future studies are needed to test this promising and novel Wnt-targeting therapy in lung cancer animal models, and to identify biomarkers which may predict sensitivity in particular subgroups of lung cancer patients.
Citation Format: Youqiang Li, Li Zheng, Binghui Shen, Jae Kim, Dan Raz. Triptolide has antitumor effects in lung cancer via Wnt pathway inhibition. [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 B08.
Abstract IA03: Genomic and epigenomic targets in small cell lung cancer.
Authors: Rudin Charles M. 
Published: August 2014

Abstract
Recent comprehensive analyses of the genome, transcriptome, and proteome of small cell lung cancer (SCLC) have provided new insights into the biology of this particularly aggressive cancer type. As has been known for several years, most SCLC demonstrate concomitant loss or inactivation of two key tumor suppressors, p53 and RB; conditional loss of these genes in a mouse model results in lung cancer with many of the properties of human SCLC. Amplification and aberrant expression of MYC family members, including L-MYC and N-MYC, are strongly implicated in SCLC. Other important oncogenes amplified in subsets of SCLC include SOX2, a key developmental transcription factor, and the receptor tyrosine kinase FGFR1. Several key epigenetic control genes are mutated or disregulated in SCLC, including EZH2. Recent analyses of the SCLC methylome suggest that these cancers may be categorized into subsets based on global gene expression and methylation patterns. Taken together with recent proteomic studies highlighting additional potential targets including PARP1, these recent observations are providing a new landscape of investigational therapeutic opportunities for SCLC.
Citation Format: Charles M. Rudin. Genomic and epigenomic targets in 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 IA03.
Synergistic Simvastatin and Metformin Combination Chemotherapy for Osseous Metastatic Castration-Resistant Prostate Cancer
Authors: Babcook Melissa A. , Shukla Sanjeev , Fu Pingfu , Vazquez Edwin J. , Puchowicz Michelle A. , Molter Joseph P. , Oak Christine Z. , MacLennan Gregory T. , Flask Chris A. , Lindner Daniel J. , Parker Yvonne , Daneshgari Firouz , Gupta Sanjay 
Published: August 2014

Abstract
Docetaxel chemotherapy remains a standard of care for metastatic castration-resistant prostate cancer (CRPC). Docetaxel modestly increases survival, yet results in frequent occurrence of side effects and resistant disease. An alternate chemotherapy with greater efficacy and minimal side effects is needed. Acquisition of metabolic aberrations promoting increased survival and metastasis in CRPC cells includes constitutive activation of Akt, loss of adenosine monophosphate-activated protein kinase (AMPK) activity due to Ser-485/491 phosphorylation, and overexpression of 3-hydroxy-3-methylglutaryl–Coenzyme A reductase (HMG-CoAR). We report that combination of simvastatin and metformin, within pharmacologic dose range (500 nmol/L to 4 μmol/L simvastatin and 250 μmol/L to 2 mmol/L metformin), significantly and synergistically reduces C4-2B3/B4 CRPC cell viability and metastatic properties, with minimal adverse effects on normal prostate epithelial cells. Combination of simvastatin and metformin decreased Akt Ser-473 and Thr-308 phosphorylation and AMPKα Ser-485/491 phosphorylation; increased Thr-172 phosphorylation and AMPKα activity, as assessed by increased Ser-79 and Ser-872 phosphorylation of acetyl-CoA carboxylase and HMG-CoAR, respectively; decreased HMG-CoAR activity; and reduced total cellular cholesterol and its synthesis in both cell lines. Studies of C4-2B4 orthotopic NCr-nu/nu mice further demonstrated that combination of simvastatin and metformin (3.5–7.0 μg/g body weight simvastatin and 175–350 μg/g body weight metformin) daily by oral gavage over a 9-week period significantly inhibited primary ventral prostate tumor formation, cachexia, bone metastasis, and biochemical failure more effectively than 24 μg/g body weight docetaxel intraperitoneally injected every 3 weeks, 7.0 μg/g/day simvastatin, or 350 μg/g/day metformin treatment alone, with significantly less toxicity and mortality than docetaxel, establishing combination of simvastatin and metformin as a promising chemotherapeutic alternative for metastatic CRPC. Mol Cancer Ther; 13(10); 2288–302. ©2014 AACR.
Abstract A11: Synthetic lethal screens in zebrafish
Authors: Sidi Samuel 
Published: August 2014

Abstract
This abstract is being presented as a short talk in the scientific program. A full abstract is printed in the Proffered Abstracts section (PR07) of the Conference Proceedings.
Citation Format: Samuel Sidi. Synthetic lethal screens in zebrafish. [abstract]. In: Proceedings of the AACR Precision Medicine Series: Synthetic Lethal Approaches to Cancer Vulnerabilities; May 17-20, 2013; Bellevue, WA. Philadelphia (PA): AACR; Mol Cancer Ther 2013;12(5 Suppl):Abstract nr A11.
Abstract B04: A chemical genetic screen identifies novel ATM/ATR pathway inhibitors that sensitize p53-deficient cells to DNA-damaging agents without affecting ATR kinase catalytic activity
Authors: Kawasumi Masaoki , Bradner James E. , Tolliday Nicola , Thibodeau Renee , Sloan Heather , Brummond Kay M. , Nghiem Paul 
Published: August 2014

Abstract
An important goal in cancer therapy has been to selectively sensitize cancers to existing drugs that typically work by inducing DNA damage. In particular, many cancers are p53-defective and chemoresistant, thus novel approaches to target p53-defective cancers are needed. One promising strategy to sensitize p53-deficient cells has been to inhibit DNA damage response kinases such as ATM/ATR via ATP-competitive kinase inhibitors. To better understand ATM/ATR activation mechanisms and discover novel probes for the ATM/ATR pathway, we performed a phenotype-based screen of 9,195 small-molecule compounds for inhibitors of hydroxyurea-induced phosphorylation of Chk1, a key ATR substrate. After subsequent biological screens, we selected 4 compounds that inhibited ATR and ATM pathways; 3 were known bioactive agents and 1 was a diversity-oriented-synthetic product. These compounds sensitized p53-deficient cells to diverse DNA-damaging agents. Xenograft experiments were performed on one compound, and it showed synergistic suppression of p53-deficient tumor growth with cisplatin. Importantly, these compounds did not suppress ATR kinase catalytic activity in vitro, unlike typical ATM/ATR kinase inhibitors that are ATP-competitive. To identify molecular targets of one compound, “MARPIN” (ATM and ATR pathway inhibitor), we defined its active site through structure-activity relationship analysis, resulting in synthesis of inactive derivatives of MARPIN. Identification of proteins that specifically bind MARPIN, but not its inactive derivatives, is underway. This phenotype-based chemical genetic screen identified novel ATM/ATR pathway inhibitors that are mechanistically distinct from kinase catalytic inhibitors, and these compounds could serve as probes to identify previously unrecognized druggable targets in DNA damage response pathways.
Citation Format: Masaoki Kawasumi, James E. Bradner, Nicola Tolliday, Renee Thibodeau, Heather Sloan, Kay M. Brummond, Paul Nghiem. A chemical genetic screen identifies novel ATM/ATR pathway inhibitors that sensitize p53-deficient cells to DNA-damaging agents without affecting ATR kinase catalytic activity. [abstract]. In: Proceedings of the AACR Precision Medicine Series: Synthetic Lethal Approaches to Cancer Vulnerabilities; May 17-20, 2013; Bellevue, WA. Philadelphia (PA): AACR; Mol Cancer Ther 2013;12(5 Suppl):Abstract nr B04.
Abstract B31: Pak1 and β-catenin inhibition blocks tumor progression in ErbB2-driven breast cancer models
Authors: Arias-Romero Luis E. , Villamar-Cruz Olga , Chernoff Jonathan 
Published: August 2014

Abstract
p21-activated kinase-1 (Pak1) is frequently upregulated in human breast cancer and is required for transformation of mammary epithelial cells by ErbB2. However, its role in tumorigenesis in vivo, and the particular signaling pathways affected, are not defined.
In this work, we examined the distinct roles of Pak1 and Pak2 in cellular and animal models of ErbB2-driven breast cancer. We found that inhibition of Pak1, but not Pak2, impedes transformation by ErbB2 in a 3D cell culture system, but that loss of either Pak1 or Pak2 causes loss of both Erk and Akt activation. A phospho-proteomic screen revealed that Pak1-deficient, but not Pak2-deficient, ErbB2 cells showed almost total loss of β-catenin expression that is accompanied by a significant reduction in almost all known β-catenin target genes. In MMTV-ErbB2 transgenic mice, loss of Pak1 prolonged survival, and mammary tissues of such mice showed loss of β-catenin. Expression of a β-catenin mutant bearing a phospho-mimetic mutation at Ser 675, a specific Pak1 phosphorylation site, restored the ability of ErbB2 to transform Pak1-deficient mammary epithelial cells. Lastly, we showed that small molecule inhibitors of Pak or β-catenin blocked transformation by ErbB2 in 3D culture and tumorigenesis by ErbB2 in mouse xenografts, and combined inhibition by both agents was synergistic. These findings establish Pak1 as a new target in ErbB2-driven breast cancer and define a new mechanism of action primarily through the β-catenin, but not the Erk or Akt, signaling pathways.
Citation Format: Luis E. Arias-Romero, Olga Villamar-Cruz, Jonathan Chernoff. Pak1 and β-catenin inhibition blocks tumor progression in ErbB2-driven breast cancer models. [abstract]. In: Proceedings of the AACR Precision Medicine Series: Synthetic Lethal Approaches to Cancer Vulnerabilities; May 17-20, 2013; Bellevue, WA. Philadelphia (PA): AACR; Mol Cancer Ther 2013;12(5 Suppl):Abstract nr B31.
Abstract B39: MYC, a downstream target of BRD-NUT, is necessary and sufficient for the blockade of differentiation in NUT midline carcinoma
Authors: Walsh Erica M. , Grayson Adlai R. , Cameron Michael J. , Godec Jernej , Ashworth Todd , Aserlind Alexandra B. , Wang Hongfang , Evan Gerard , Kluk Michael J. , Bradner James E. , Aster Jon C. , French Christopher A. 
Published: August 2014

Abstract
NUT midline carcinoma (NMC) is an aggressive type of squamous cell carcinoma that is defined by the presence of BRD-NUT fusion oncogenes, which encode chimeric proteins that block differentiation and maintain tumor growth. BRD-NUT oncoproteins contain two bromodomains whose binding to acetylated histones is required for the blockade of differentiation in NMC, but the mechanisms by which BRD-NUT act remain uncertain. Here we provide evidence that MYC is a key downstream target of BRD4-NUT. Expression profiling of NMCs show that the set of genes whose expression is maintained by BRD4-NUT is highly enriched for MYC upregulated genes, and MYC and BRD4-NUT protein expression is strongly correlated in primary NMCs. More directly, we find that BRD4-NUT associates with the MYC promoter and is displaced by acetyl histone mimetic BET inhibitor, JQ1, which prevents binding of BET bromodomains to acetylated histones. BRD4-NUT is also required to maintain MYC expression in NMC cell lines, as shown by a dramatic decrease in MYC expression upon JQ1 treatment and knockdown of BRD4-NUT with NUT specific siRNAs. Moreover, both siRNA knockdown of MYC and a dominant-negative form of MYC, omomyc, induce differentiation of NMC cells. Conversely, differentiation of NMC cells induced by knockdown of BRD4-NUT is abrogated by enforced expression of MYC. Together, these findings suggest that MYC is a downstream target of BRD4-NUT that is required for maintenance of NMC cells in an undifferentiated, proliferative state. Our findings support a model in which dysregulation of MYC by BRD-NUT fusion proteins has a central role in the pathogenesis of NMC.
Citation Format: Erica M. Walsh, Adlai R. Grayson, Michael J. Cameron, Jernej Godec, Todd Ashworth, Alexandra B. Aserlind, Hongfang Wang, Gerard Evan, Michael J. Kluk, James E. Bradner, Jon C. Aster, Christopher A. French. MYC, a downstream target of BRD-NUT, is necessary and sufficient for the blockade of differentiation in NUT midline carcinoma. [abstract]. In: Proceedings of the AACR Precision Medicine Series: Synthetic Lethal Approaches to Cancer Vulnerabilities; May 17-20, 2013; Bellevue, WA. Philadelphia (PA): AACR; Mol Cancer Ther 2013;12(5 Suppl):Abstract nr B39.
Abstract IA10: Targeting intratumoral genetic heterogeneity through rationally designed combination therapy
Authors: Lauffenburger Douglas A. , Zhao Boyang , Pritchard Justin R. , Hemann Michael T. 
Published: August 2014

Abstract
Deep sequencing of distinct tumor biopsies from a single cancer has revealed dramatic genetic intratumoral heterogeneity in patients. Additionally, sequencing of tumors at multiple time points has led to the characterization of minor tumor subclones prior to treatment that expand to become the predominate tumor subpopulation at relapse. These data suggest an urgent need to directly address the issue of intratumoral heterogeneity in the design of chemotherapeutic regimens. Here we model tumor heterogeneity using RNA interference (RNAi), and show, both in vitro and in vivo, how optimized drug combinations can yield predictable effects on the composition of heterogeneous tumors. The ability to predict population trajectories has allowed us to mathematically optimize combination therapies to minimize the effect of heterogeneity in three-component heterogeneous tumors. We discover that for certain ensembles of tumor cells, knowledge of the predominant subpopulation is insufficient in deriving an optimal drug combination for the heterogeneous tumor. With optimized drug combinations, our in vitro and in vivo validations confirmed that we can control the predicted trajectories of a heterogeneous tumor, with improved survival in mice. Such approaches will enable us to gain a better understanding of the underlying design principles for combination therapy in the context of intratumoral diversity and construct drug regimens that are optimized for more complex tumors.
Citation Format: Douglas A. Lauffenburger, Boyang Zhao, Justin R. Pritchard, Michael T. Hemann. Targeting intratumoral genetic heterogeneity through rationally designed combination therapy. [abstract]. In: Proceedings of the AACR Precision Medicine Series: Synthetic Lethal Approaches to Cancer Vulnerabilities; May 17-20, 2013; Bellevue, WA. Philadelphia (PA): AACR; Mol Cancer Ther 2013;12(5 Suppl):Abstract nr IA10.
Abstract IA18: Gene-drug interaction screens in cancer using isogenic cell models
Authors: Nijman Sebastian 
Published: August 2014

Abstract
With the complete molecular characterization of the major cancer types in sight, it is clear that only a minority of the cancer genes represent readily accessible drug targets. Furthermore, mechanistic biomarkers that predict response to targeted therapies remain scant. To address these challenges, we employ large-scale chemical genetic screens in isogenic cells to systematically uncover gene-drug interactions. For instance, using a panel of engineered cell lines we have recently identified several known and novel breast cancer vulnerabilities and a mechanism of resistance to drugs inhibiting the PI3K/mTOR pathway. We have performed similar screens in an isogenic lung cancer model that attempts to capture some of the higher order gene-drug interactions. In addition, I will present our efforts concerning the generation of a collection of haploid human knockout cells covering the majority of expressed genes that represents a powerful platform empowering haploid genetics in human cells.
Citation Format: Sebastian Nijman. Gene-drug interaction screens in cancer using isogenic cell models. [abstract]. In: Proceedings of the AACR Precision Medicine Series: Synthetic Lethal Approaches to Cancer Vulnerabilities; May 17-20, 2013; Bellevue, WA. Philadelphia (PA): AACR; Mol Cancer Ther 2013;12(5 Suppl):Abstract nr IA18.
Abstract IA20: Framing therapeutic opportunities in tumor-activated gametogenic programs
Authors: Whitehurst Angelique 
Published: August 2014

Abstract
Tumors frequently activate genes whose expression is otherwise restricted to gametogenic tissues. These genes, the Cancer/Testes-antigens (CTA, CT-antigens), were originally identified by virtue of the humoral immune response they invoked in cancer patients. Given their germ line biased expression pattern, CT-antigens may afford the potential for an extraordinary therapeutic window, if they are required for tumor cell proliferation and survival. However, functional roles for CT-antigens in tumorigenesis and any efficacy as therapeutic intervention points have not been extensively investigated. Recently, our group and others have implicated CT-antigens in supporting mitotic fidelity, p53 silencing and retinoic acid signaling to promote tumorigenesis. This data indicates that gametogenic genes anomalously expressed in tumors can functionally buttress neoplastic phenotypes. To generate a more comprehensive understanding of the functional roles of CTAs in the tumorigenic setting, we have employed an unbiased, multi-dimensional, loss of function discovery platform to systematically assess the contribution of CT-antigens to a range of oncogenic signaling pathways and phenotypes. This effort has revealed that distinct CTA's can support many of the hallmarks of cancer, including: 1) enhanced energy production 2) hijacking developmental programs that promote self-renewal and metastases 3) modulation of cell-fate programs that support proliferation 4) adaption to low oxygen conditions inherent in the tumor microenvironment and 5) activation of survival and inflammatory signaling. These findings suggests that reactivation of these primordial genes may impact a broad spectrum of signaling mechanisms and cell biological behaviors that promote tumor growth and survival. Thus, CT-antigens present previously unrecognized tumor-specific vulnerabilities that may be exploited for therapeutic intervention.
Citation Format: Angelique Whitehurst. Framing therapeutic opportunities in tumor-activated gametogenic programs. [abstract]. In: Proceedings of the AACR Precision Medicine Series: Synthetic Lethal Approaches to Cancer Vulnerabilities; May 17-20, 2013; Bellevue, WA. Philadelphia (PA): AACR; Mol Cancer Ther 2013;12(5 Suppl):Abstract nr IA20.