bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract B55: Antitumor activity of the MDM2 antagonist RG7388.
Authors: Higgins Brian , Tovar Christian , Glenn Kelli , Walz Antje , Filipovic Zoran , Zhang Yu-E , Dangl Markus , Graves Bradford , Vassilev Lyubomir , Packman Kathryn 
Published: August 2014

Abstract
The p53 tumor suppressor is a transcription factor that inhibits tumor development by inducing cell cycle arrest or apoptosis in response to diverse stresses. In normal cells, p53 levels are tightly controlled by MDM2 which binds p53 and negatively regulates its activity and stability. MDM2 is overproduced in many human cancers, thereby impairing p53 function. Antagonists of p53-MDM2 interaction can reactivate p53 and offer a novel approach to cancer therapy. The first potent and selective small-molecule inhibitors of p53-MDM2 binding, the nutlins, provided preclinical proof-of-concept for MDM2 antagonists as therapeutics for patients with tumors expressing wild-type p53. Subsequently, a member of the nutlin family, RG7112, was the first small molecule inhibitor of MDM2 to be tested clinically. Here we describe, RG7388, a highly optimized agent with analogous mechanism of action representing an entirely new branch of the nutlin family of MDM2 antagonists. Like RG7112, RG7388 binds selectively to the p53 site on the surface of the MDM2 molecule, effectively displacing p53 from MDM2, and leading to p53 stabilization and activation of the p53 pathway. However, RG7388 is derived from a distinct chemical series that binds with higher potency and selectivity to the MDM2 protein. RG7388 has substantially improved pharmacological properties, resulting in superior preclinical efficacy at lower doses and exposures as compared with its predecessor, RG7112. RG7388 elicits growth arrest and apoptosis at approximately 10-fold lower concentrations in vitro and in vivo, has an improved CYP inhibition profile, and a 2.5- to 20-fold lower projected human efficacious dose as compared with RG7112. Tumors with functional p53 signaling and MDM2 over-expression or amplification are likely to be the most sensitive to RG7388, however preclinical studies indicate that tumors with normal MDM2 levels may also respond to this novel therapeutic strategy. Results from preclinical safety and toxicology studies support further exploration of this compound in cancer patients. RG7388 is a promising agent that may offer a new therapeutic option and is currently in clinical testing in both solid and hematologic malignancies.
Citation Information: Mol Cancer Ther 2013;12(11 Suppl):B55.
Citation Format: Brian Higgins, Christian Tovar, Kelli Glenn, Antje Walz, Zoran Filipovic, Yu-E Zhang, Markus Dangl, Bradford Graves, Lyubomir Vassilev, Kathryn Packman. Antitumor activity of the MDM2 antagonist RG7388. [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2013 Oct 19-23; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2013;12(11 Suppl):Abstract nr B55.
Abstract C120: Genomic landscape in advanced metaplastic breast cancer and outcomes with mTOR targeted therapy.
Authors: Janku Filip , Kurzrock Razelle , Helgason Thorunn , Valero Vicente , Esteva Francisco , Wheler Jennifer J. , Karp Daniel D. , Meric-Bernstam Funda , Moulder Stacy L. 
Published: August 2014

Abstract
Background: Metaplastic breast cancer (BC) is a treatment-refractory rare type of BC with characteristics similar to claudin-low tumors. Understanding the genomic landscape of metaplastic BC can lead to identification of new therapies.
Methods: Patients with metastatic metaplastic BC referred for experimental therapies, who had adequate archival tumor tissue for DNA extraction, had targeted next-generation sequencing (NGS) for 3,769 exons of 236 cancer-related genes and 47 introns from 19 genes to an average depth of 1000X using the Illumina HiSeq 2000 platform (Foundation One, Foundation Medicine, MA).
Results: NGS results were obtained for 10 women with metaplastic BC (median age 60 years [39-73], median prior therapies for metastatic BC 0 [0-1]). NGS revealed a total of 41 aberrations in 25 genes and all 10 patients had at least 1 molecular aberration (range 1-7, median 4). Of 41 detected molecular aberrations, 17 (41%) included putative activation of the PI3K/mTOR and/or MAPK pathways (PIK3CA [6], PTEN [3], PIK3R1 [1], NF1 [1], EGFR [1], EPHB1 [1], FGF23 [1], FGFR2 [1], HRAS [1], PTPN11 [1]), 13 (32%) loss of cell cycle control (CCND2 [1], CCND3 [1], CCNE1 [1], CDK2 [1], CDKN2A [2], MYC [6], RB1 [1]), 6 (15%) loss of apoptosis (MCL1 [1], NFKBIA [1], TP53 [4]), 2 (5%) aberrant DNA repair (BRCA2 [1], FANCA [1]), 2 (5%) aberrant methylation (KDM6A [1], MLL2 [1]) and 1 (2.5%) aberrant SWI/SNF chromatin remodeling (ARID1A [1]). Of the 10 patients, 9 (90%) received an experimental mTOR targeting therapy combination with temsirolimus, bevacizumab, and liposomal doxorubicin and at the median follow up of 5.8 months, 2 (22%) patients attained a partial response and 3 (33%) had stable disease &gt;/= 4 months. The median progression-free survival was 6.2 months (95% confidence Interval 3.4 - 9.0)
Conclusion: Genomic alterations putatively activating PI3K/mTOR and MAPK pathways are common in metastatic metaplastic BC. A combination therapy targeting mTOR demonstrated encouraging activity.
Citation Information: Mol Cancer Ther 2013;12(11 Suppl):C120.
Citation Format: Filip Janku, Razelle Kurzrock, Thorunn Helgason, Vicente Valero, Francisco Esteva, Jennifer J. Wheler, Daniel D. Karp, Funda Meric-Bernstam, Stacy L. Moulder. Genomic landscape in advanced metaplastic breast cancer and outcomes with mTOR targeted therapy. [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2013 Oct 19-23; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2013;12(11 Suppl):Abstract nr C120.
Abstract C125: Development of gene signature profile predicting nodal metastasis in squamous cell carcinoma of tongue.
Authors: Nair Sudhir V. , Upadhyay Pawan , D'Cruz Anil , Dutt Amit 
Published: August 2014

Abstract
Background: In India, oral cancer is the leading cancer type among men and third most common cancer among women. While 70% of patients in T1 (&lt; 2cm) and 30% in T4 primary tumor stage are clinically node negative (N0), at the time of treatment, studies carried out at Tata Memorial Center suggest that 27% of these N0 patients had microscopic nodal metastatic disease (occult metastasis). Metastases are missed because they are not detectable with the currently available techniques. Hence all patients with oral cancers have to undergo a selective neck dissection as a diagnostic and therapeutic tool. Whole transcriptome Sequencing and simultaneous miRNA expression profiling of primary tumor will be an effective molecular tool to detect occult nodal metastasis.
Material and Methods: Whole Transcriptome Sequencing and miRNA expression profiling on total RNA extracted from 100 primary tumors and normal samples collected prospectively from patients with squamous carcinoma of the tongue with a clinical stage of T1 or T2 with N0 or N+ histopathology is underway. The raw reads obtained are aligned to the genome using TopHat, which uses Bowtie aligner for the mapping of the raw reads. The Bam/Sam output files generated by Tophat is used as an input files for cufflinks to assemble transcripts and estimate their abundance. The GTF files generated by Cufflinks are used to run Cuffdiff to find significant changes in the transcript expression and splicing between N0 and N+ samples.
Results: The literature suggests clinical and histological parameters of the primary tumor can predict lymphatic metastasis with an accuracy of 60%, however molecular profiling has a predictive accuracy of 86% to 90% and if used in clinics, may reduce the requirement for unnecessary neck dissections in a number of patients significantly. 10 whole transcriptome sequencing and 15 miRNA profiling studies from N0 and N+ tumor and normal tissues have been completed so far in this study. Early analysis reveals encouraging molecular profiles to identify subtypes based on the nodal infiltration status of the tumors. Data from these samples and additional ongoing experiments will be presented.
Conclusion: This is the first ongoing study from India to allow identify molecular signature that can prognosticate and stratify tongue cancer patients with potential to inform designing of clinical trials.
Citation Information: Mol Cancer Ther 2013;12(11 Suppl):C125.
Citation Format: Sudhir V. Nair, Pawan Upadhyay, Anil D'Cruz, Amit Dutt. Development of gene signature profile predicting nodal metastasis in squamous cell carcinoma of tongue. [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2013 Oct 19-23; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2013;12(11 Suppl):Abstract nr C125.
Abstract C130: The Hsp90 inhibitor ganetespib promotes the degradation of FGFR3 in bladder cancer models and induces regression in tumors harboring oncogenic FGFR3 fusions.
Authors: Acquaviva Jaime L. , Zhang Chaohua , He Suqin , Jimenez John-Paul , Nagai Masa , Sang Jim , Sequeira Manuel , Smith Donald L. , Knowles Margaret A. , Proia David A. 
Published: August 2014

Abstract
Background: Fibroblast growth factor receptor 3 (FGFR3) is activated by point mutation, chromosomal rearrangement, and/or receptor overexpression in a high percentage of bladder cancers, making FGFR3 an attractive therapeutic target for bladder cancer. Heat shock protein 90 (Hsp90) is a molecular chaperone required for the stability of FGFR3 and hundreds of other kinases and oncoproteins (termed “client proteins”), many of which are known to support tumorigenesis. Ganetespib is a selective inhibitor of Hsp90 currently being evaluated in several clinical trials, including a pivotal Phase 3 study. Here, we investigated the preclinical activity of ganetespib in bladder cancer models expressing FGFR3, as monotherapy or in combination with an FGFR inhibitor.
Results: Ganetespib displayed strong anticancer activity across a panel of 20 bladder cancer cell lines with diverse genetic backgrounds (mean EC50 = 38 nM), including those overexpressing wt FGFR3 or FGFR3 fusions. Notably, ganetespib was 10 times more potent than the selective FGFR3 inhibitor BGJ398 in bladder cancer cells with activating mutations in FGFR3. At the molecular level, ganetespib induced the rapid destabilization of full-length FGFR3 and the FGFR3-TACC3 fusion protein within 4 hours suggesting that FGFR3 is a highly sensitive Hsp90 client. Consequently, MAPK and AKT/mTOR signaling were suppressed, resulting in apoptosis evident by decreased levels of P-BAD and an increase in BIM, cleaved Caspase-3, and PARP expression. In vivo, ganetespib treatment led to tumor regression in RT112 xenografts coordinate with the deactivation of FGFR3-TACC3, as well as numerous other client proteins and their downstream effectors, as determined by phosphoprotein array. Combining ganetespib with BGJ398 increased tumor regression 3-fold compared to monotherapy.
Conclusions: The Hsp90 inhibitor ganetespib elicits the rapid degradation of FGFR3 mutants and fusion proteins in bladder cancer cells resulting in tumor regression in animal models, which could be further enhanced by combination with an FGFR inhibitor. These results may provide a framework for the future treatment of FGFR3-dependent bladder cancer.
Citation Information: Mol Cancer Ther 2013;12(11 Suppl):C130.
Citation Format: Jaime L. Acquaviva, Chaohua Zhang, Suqin He, John-Paul Jimenez, Masa Nagai, Jim Sang, Manuel Sequeira, Donald L. Smith, Margaret A. Knowles, David A. Proia. The Hsp90 inhibitor ganetespib promotes the degradation of FGFR3 in bladder cancer models and induces regression in tumors harboring oncogenic FGFR3 fusions. [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2013 Oct 19-23; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2013;12(11 Suppl):Abstract nr C130.
Abstract C14: Squamous non-small cell lung cancer (NSCLC-SCC) patient-derived xenografts (PDX) from Asian patients have high response rate (RR) to cetuximab than those of adenocarcinoma.
Authors: Yang Mengmeng , Cai Jie , Guo Sheng , Huang Xuesong , Yang Jie , Song Xiaoming , Chen Dawei , Zhang Likun , Jiang Jiahua , Wery Jean-Pierre , Li Henry 
Published: August 2014

Abstract
Cetuximab was approved for advanced colorectal carcinoma (CRC), but yet for NSCLC, although some trials [e.g. FLEX (1) and BMS099 (2)] demonstrated benefit in subsets of patients. Recent retrospective study on Caucasian patients among the FLEX study cohort revealed that high EGFR expressors, uniquely defined by high-IHC score, are likely to benefit from the treatment (3). In particular, this was confirmed in a 50-patient derived xenografts model trial, mouse clinical trial (MCT or “Patient Avatar Trial”), in a similar format of FLEX, first time demonstrating relevance of human trial and MCT. The goal of the present study is identify the subset of Asian NSCLC patients that respond to cetuximab in a MCT. We have established a large panel of PDXs from NSCLC Asian patients of different histology (4): squamous cell carcinoma (SCC), adenocarcinoma (ADC), pleiomorphic carcinoma (PLC), and large cell carcinoma (LCC). We tested cetuximab activity in a randomly selected 32 PDX in a MCT. While NSCLC had overall engraftment rate of 25%, SCC interestingly, had higher rate of ∼31%, near-double ∼17% of ADC, which may have metastasis and prognosis implications. A subset of PDXs were found to respond to cetuximab (10/32) (31%, defined by %ΔT/ΔC &lt; 25%). Surprisingly, all 10 responders exclusively belong to SCC and PLC (9/10 and 1/10 respectively), contrasting none to ADC (0/10). Non-/poor-responders (%ΔT/ΔC &gt; 25%) include ADC (7/22), LCC (2/22) and SCC (12/22). Among the 12 non-/poor-responsive SCC, one has KRAS-G12D mutation, one has ALK-EML4 fusion and one has c-MET gene amplification. Among the SCC responders are ones with activating EGFR mutations. SCC has strikingly higher cetuximab response rate (RR) than ADC, with possible positive factors of EGFR mutation and negative factors of KRAS mutation, ALK fusion and c-met amplification. If proven true clinically, cetuximab could become a new therapy for NSCLC-SCC.
Citation Information: Mol Cancer Ther 2013;12(11 Suppl):C14.
Citation Format: Mengmeng Yang, Jie Cai, Sheng Guo, Xuesong Huang, Jie Yang, Xiaoming Song, Dawei Chen, Likun Zhang, Jiahua Jiang, Jean-Pierre Wery, Henry Li. Squamous non-small cell lung cancer (NSCLC-SCC) patient-derived xenografts (PDX) from Asian patients have high response rate (RR) to cetuximab than those of adenocarcinoma. [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2013 Oct 19-23; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2013;12(11 Suppl):Abstract nr C14.
Abstract C167: Establishment of a cancer-specific anti-podoplanin antibody not reacting with lymphatic endothelial cells.
Authors: Kato Yukinari , Kaneko Mika K. 
Published: August 2014

Abstract
Podoplanin is a mucin-like sialoglycoprotein that is highly expressed in brain tumors, mesotheliomas, testicular tumors, and several squamous cell cancers. Podoplanin has been reported to be a novel marker to enrich tumor-initiating cells, which are thought to resist conventional therapies and to be responsible for cancer relapse. We previously established a neutralizing monoclonal antibody (mAb; NZ-1) and its human chimeric mAb (NZ-8), which inhibit the association between podoplanin and CLEC-2, block the podoplanin-induced tumor metastasis, and possess extremely high antibody-dependent cellular cytotoxicity (ADCC) and complement-dependent cytotoxicity (CDC). However, those mAbs also react with normal cells including type I alveolar cells, podocytes, and lymphatic endothelial cells. Herein, we established the platform to produce cancer-specific mAbs (CasMabs) by combining glycobiology and cell engineering technologies, and successfully produced cancer-specific anti-podoplanin mAbs, which react with tumor cells but not with lymphatic endothelial cells in flow cytometry and immunohistochemistry. Both peptides and glycans of podoplanin were included in the epitopes of those mAbs. The CasMab-producing platform could lead to establishment of the side effect-reducing mAbs.
Citation Information: Mol Cancer Ther 2013;12(11 Suppl):C167.
Citation Format: Yukinari Kato, Mika K. Kaneko. Establishment of a cancer-specific anti-podoplanin antibody not reacting with lymphatic endothelial cells. [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2013 Oct 19-23; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2013;12(11 Suppl):Abstract nr C167.
Abstract C195: CD98hc (SLC3A2) is a central regulator of renal cancer cell behavior.
Authors: Prager Gerald W. , Poettler Marina , Unseld Matthias , Zielinski Christoph 
Published: August 2014

Abstract
CD98, a heterodimeric transmembrane protein, physically associates with certain integrin β subunit cytoplasmic domains via its heavy chain, CD98hc (SLC3A2). Thereby CD98hc regulates adhesion-induced intracellular signal transduction via integrins, thus, affecting cell proliferation and clonal expansion. Disruption of CD98hc led to embryonic lethality in mice (E3.5 and E 9.5) and CD98hc -/- embryonic stem cell transplantation failed to form teratomas, while over-expression of CD98hc in somatic cells resulted in anchorage-independent growth. Although, we and others identified CD98hc to be highly overexpressed in various cancer types, a functional role of CD98hc in tumor cell behavior is so far unknown. Here we demosntarte that the disruption of CD98hc interaction with integrins in clear cell renal cell cancer (ccRCC) leads to impaired tumor cell behavior such as cell spreading, migration, proliferation and survival in vitro and of tumor growth in vivo. CD98hc/integrin interaction was required for adhesion-induced sustained FAK phosphorylation and activation of the major downstream signaling pathways PI3k/Akt and MEK/ERK, while overexpression of a constitutive active form of FAK rescued for the CD98hc deficiency. Thus, we have identified the cell surface protein CD98hc as a critical mediator of integrin-dependent tumor cell functions. These studies suggest that interference with CD98hc might lead to a novel therapeutic strategy in renal cell cancer.
Citation Information: Mol Cancer Ther 2013;12(11 Suppl):C195.
Citation Format: Gerald W. Prager, Marina Poettler, Matthias Unseld, Christoph Zielinski. CD98hc (SLC3A2) is a central regulator of renal cancer cell behavior. [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2013 Oct 19-23; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2013;12(11 Suppl):Abstract nr C195.
Abstract C7: Inhibitory effects of flavonoid Apigenin by oral administration on angiogenesis of ovarian cancer through decrease VEGF expression in mouse model.
Authors: Alipour Majid 
Published: August 2014

Abstract
Diet can play a vital role in cancer prevention. Studies have shown that a diet high in fruits and vegetables is associated with a reduced risk of cancer. Apigenin is a non-toxic and non-mutagenic natural flavonoid. Our previous studies demonstrated the effects of apigenin on angiogenesis in CAM model is by two distintic parallel PI3K/AKT and jak/STAT pathways. Vascular endothelial growth factor (VEGF) is one of the most important of all known inducers of angiogenesis and in many cancers this protein is over-expressed. Studies confirm Apigenin efficient on reduction VEGF expression. In this study, as first time, effect of Apigenin is evaluated by oral administration on angiogenesis decreasing and VEGF expression levels were measured in creatures. After infection of mice's ovarian by A2780 cancer cell line, Apigenin (75/mg/kg/day) were fed once a day for 30 days to the animals and angiogenesis measured in vivo. Histological methods were used for counting blood vessels, ELISA analysis was used to measurement of VEGF protein in infected tissues. to confirm the effect of oral administration of Apigenin on VEGF expression, A2780 cells were infected by VEGF promoter reporter vectors then injected to the mice. Studies have shown that taking these orally, Apigenin reduced VEGF expression and ultimately leads to reduced angiogenesis.
Citation Information: Mol Cancer Ther 2013;12(11 Suppl):C7.
Citation Format: Majid Alipour. Inhibitory effects of flavonoid Apigenin by oral administration on angiogenesis of ovarian cancer through decrease VEGF expression in mouse model. [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2013 Oct 19-23; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2013;12(11 Suppl):Abstract nr C7.
Abstract C79: TDP1 repairs nuclear and mitochondrial DNA damage induced by chain-terminating anticancer and antiviral nucleoside analogs.
Authors: Huang Shar-Yin N. , Murai Junko , Dalla Rosa Ilaria , Dexheimer Thomas S. , Gmeiner William H. , Pommier Yves 
Published: August 2014

Abstract
Nucleoside analogs (NAs) that cause stalling or premature termination of DNA replication forks are widely used as anticancer and antiviral drugs. However, it is not well understood how cells repair the DNA damage induced by these chain-terminating NAs. Here we reveal the importance of tyrosyl-DNA phosphodiesterase 1 (TDP1) in the repair of nuclear and mitochondrial DNA damage induced by chain-terminating NAs. Upon investigating the effects of four NAs: acyclovir (ACV), cytarabine (Ara-C), zidovudine (AZT) and zalcitabine (ddC), we show that TDP1 is capable of removing the covalently-linked corresponding NAs from DNA 3’-ends. We also show that Tdp1–/– cells are hypersensitive and accumulate more DNA damage when treated with ACV and Ara-C, implicating TDP1 in repairing NA-induced DNA damage. Since AZT and ddC are known to cause mitochondrial dysfunction, we examined whether TDP1 repairs the mitochondrial DNA damage they induced. We found that AZT and ddC treatment leads to greater depletion of mitochondrial DNA in Tdp1–/– cells. Thus, TDP1 appears critical for repairing nuclear and mitochondrial DNA damage caused by chain-terminating NAs.
Citation Information: Mol Cancer Ther 2013;12(11 Suppl):C79.
Citation Format: Shar-Yin N. Huang, Junko Murai, Ilaria Dalla Rosa, Thomas S. Dexheimer, William H. Gmeiner, Yves Pommier. TDP1 repairs nuclear and mitochondrial DNA damage induced by chain-terminating anticancer and antiviral nucleoside analogs. [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2013 Oct 19-23; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2013;12(11 Suppl):Abstract nr C79.