bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract DDT02-03: Discovery of GDC-0994, a potent and selective ERK1/2 inhibitor in early clinical development
Authors: Robarge Kirk , Schwarz Jacob , Blake Jim , Burkard Michael , Chan Jocelyn , Chen Huifen , Chou Kang-Jye , Diaz Dolores , Gaudino John , Gould Stephen , Grina Jonas , Linghu Xin , Liu Lichuan , Martinson Matthew , Moreno David A. , Orr Christine , Pacheco Patricia , Qin Ann , Rasor Kevin , Ren Li , Shahidi-Latham Sheerin , Stults Jeffrey , Sullivan Francis , Wang Weiru , Yin Peter , Zhou Aihe , Belvin Marcia , Merchant Mark , Moffat John G. 
Published: May 2015

Abstract
The extracellular-signal-regulated kinases (ERK1 and ERK2) represent an essential node within the RAS/RAF/MEK/ERK signaling cascade that commonly is activated by oncogenic mutations in BRAF or RAS or by upstream oncogenic signaling, such as receptor tyrosine kinase (RTK) activation. While targeting upstream nodes with RAF and MEK inhibitors has proven effective clinically, resistance frequently develops through reactivation of the pathway. Simultaneous targeting of multiple nodes in the pathway, such as MEK and ERK, offers the prospect of enhanced efficacy as well as reduced potential for acquired resistance. Here, we present the discovery and characterization of GDC-0994, an orally bioavailable, small molecule inhibitor of ERK kinase activity. GDC-0994 is highly selective for ERK1 and ERK2, with biochemical potency of 1.1 nM and 0.3 nM, respectively. Daily, oral dosing of GDC-0994 results in significant single-agent activity in multiple in vivo cancer models, including KRAS-mutant and BRAF-mutant human xenograft tumors in mice. PD biomarker inhibition of phospho-p90RSK in these tumors correlates with potency in vitro and in vivo. In contrast to other published ERK inhibitors, GDC-0994 neither increases nor decreases phospho-ERK, suggesting that different ERK inhibitors have alternative mechanisms of action with respect to feedback signaling. Furthermore, we demonstrate a novel approach for targeting the oncogenic signaling through the RAS pathway by combining ERK and MEK inhibitors. GDC-0994 is currently in Phase I clinical development.
Citation Format: Kirk Robarge, Jacob Schwarz, Jim Blake, Michael Burkard, Jocelyn Chan, Huifen Chen, Kang-Jye Chou, Dolores Diaz, John Gaudino, Stephen Gould, Jonas Grina, Xin Linghu, Lichuan Liu, Matthew Martinson, David A. Moreno, Christine Orr, Patricia Pacheco, Ann Qin, Kevin Rasor, Li Ren, Sheerin Shahidi-Latham, Jeffrey Stults, Francis Sullivan, Weiru Wang, Peter Yin, Aihe Zhou, Marcia Belvin, Mark Merchant, John G. Moffat. Discovery of GDC-0994, a potent and selective ERK1/2 inhibitor in early clinical development. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr DDT02-03. doi:10.1158/1538-7445.AM2014-DDT02-03
Abstract LB-101: The antiandrogen drug dutasteride sensitizes triple negative breast cancer cells to chemotherapy via HIF-1α / VEGF-signaling
Authors: Wahlde Marie-Kristin von , Huelsewig Carolin , Ruckert Christian , Götte Martin , Kiesel Ludwig , Liedtke Cornelia , Bernemann Christof 
Published: May 2015

Abstract
Background: Triple negative breast cancer is characterized by a lack of expression of both estrogen and progesterone receptor as well as lack of amplification of HER2. Patients with triple negative breast cancer carry an unfavorable prognosis compared to other breast cancer subtypes given that endocrine or HER-2 targeted therapies are not effective, rendering chemotherapy the sole effective treatment option to date.
In a previous work by Liedtke et al. ((Liedtke et al., Cancer Res 2009) we generated a list of genes, which showed higher expression in triple negative breast cancer and, in addition, are known to encode targets for known non-oncologic drugs. These gene products might represent targets for future therapies of triple negative breast cancer.
Results: We could identify SRD5A1, which encodes the type-1 isoform of the steroid-5-alpha-reductase, showing a higher expression in triple negative breast cancer both in vivo and in vitro. Dutasteride is a dual blocker of both the type-1 and type-2 isoform of SRD5A1 and is indicated in the treatment of benign prostate hyperplasia. Treatment of triple negative breast cancer cell lines with dutasteride was associated with a dose-dependent decrease in cell viability, altered protein expression of VEGF and HIF-1α and increased chemosensitivity.
Conclusion: Our results demonstrate that firstly, using differential gene expression analysis in clinically relevant breast cancer subtypes, potential new drug targets can be generated. Secondly, we identified the SRD5A1-corresponding anti androgenic drug dutasteride as a combinatorial therapeutic option besides standard chemotherapy in highly aggressive triple negative breast cancer.
Citation Format: Marie-Kristin von Wahlde, Carolin Huelsewig, Christian Ruckert, Martin Götte, Ludwig Kiesel, Cornelia Liedtke, Christof Bernemann. The antiandrogen drug dutasteride sensitizes triple negative breast cancer cells to chemotherapy via HIF-1α / VEGF-signaling. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr LB-101. doi:10.1158/1538-7445.AM2014-LB-101
Abstract LB-103: L1CAM-targeted delivery of siRNA using elastin-like polypeptide (ELP) nanoparticles inhibits the growth of human tumors implanted in mice
Authors: Primiano Thomas , Chang Bey-Dih , Heidel Jeremy D. 
Published: May 2015

Abstract
Small interfering RNA (siRNA) drugs provide ideal means for perturbing intracellular oncogenic targets. However, specific delivery of siRNA to tumors has proven to be difficult. An ELP was engineered with an N-terminal region that binds to L1 cell adhesion molecule (L1CAM), and a C-terminal region that binds siRNA. Upon binding of siRNA, the L1CAM targeted ELP (ELP-L) spontaneously assembled into a spherical nanocomplex with the siRNA protected within, and the CAM-binding region protruding from the surface. These nanoparticles were used to deliver siRNA to SKOV3 tumors formed following surgical implantation of the cells into the left ovary of mice. Two weeks after implantation, mice were dosed with vehicle, ELP-L-complexed control siRNA (siCON), or ELP-L-complexed siEVI1, an siRNA to the oncogenic transcription factor EVI1, that is known to enable cell proliferation and inhibits apoptosis in ovarian tumor cells. To initially assess biodistribution, a single dose of ELP-L-DY800-labeled siEVI1 (10 mg/kg, ip) localized into ovarian tumors as early as 4 h, and remained for 72 h, as measured by co-registration of near infrared fluorescence with tumor bioluminescence in live mice. The ELP-L-DY800-siEVI1 was eliminated via kidney and did not accumulate in heart, lung, spleen or liver showing specific localization to tumors. To evaluate efficacy, the mean flux of bioluminescence from ovarian tumors of ten mice receiving 14 doses of 10 mg/kg siEVI1 in ELP-L over 28 days decreased by 92% with respect to mice dosed with 5% dextrose. Immunoblot and qPCR results showed EVI1 protein and mRNA levels decreased more than 50% in mice dosed with siEVI1 compared to siCON or vehicle. There were no observable adverse effects in the mice throughout the dosing period. These results are consistent with an RNA interference mechanism and suggest that ELP-L effectively delivers siEVI1 to tumors with limited toxicity. Furthermore, EVI1 appears to be a good target for ovarian cancer therapy and silencing by siRNAs is an effective means of triggering the death of ovarian tumor cells.
Citation Format: Thomas Primiano, Bey-Dih Chang, Jeremy D. Heidel. L1CAM-targeted delivery of siRNA using elastin-like polypeptide (ELP) nanoparticles inhibits the growth of human tumors implanted in mice. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr LB-103. doi:10.1158/1538-7445.AM2014-LB-103
Abstract LB-112: Highly potent and selective interleukin-1 receptor-associated kinase 4 inhibitors for the therapy of lymphoid malignancies
Authors: Kelly Priscilla N. , Chaudhary Divya , Young Ryan M. , Shaffer Art , Robinson Shaughnessy , Romero Donna L. , Kapeller Rosana , Staudt Louis M. 
Published: May 2015

Abstract
Pathologic activation of the Toll-like receptor (TLR) pathway underlies various human disorders such as autoimmune diseases, chronic inflammatory diseases and lymphoid malignancies. Current therapy of these diseases relies on immunosuppressive or chemotherapeutic agents, but more effective therapies tailored to disease-causing mechanisms are required. The IL-1 receptor-associated kinase 4 (IRAK4), is critical to TLR signaling and is recruited to TLRs by the adapter protein MyD88. Gain-of-function MYD88 mutations are activated by IRAK4 kinase in several mature B cell malignancies, including activated B-cell-like diffuse large B cell lymphoma (ABC DLBCL).
Development of selective IRAK4 kinase inhibitors has been confounded by the challenging structure of IRAK4 catalytic domain. Using structure-based drug design methodologies, we identified potent and selective IRAK4 kinase inhibitors. ABC DLBCL cell lines that specifically harbor activating MYD88 mutations are killed by these inhibitors, both in vitro and in mouse xenograft models. Gene expression profiling revealed that IRAK4 kinase inhibitors downregulated prosurvival NF-κB signatures, and cytokine analysis showed a decrease in the production of inflammatory cytokines IL-6 and IL-10. Our findings open new possibilities for the therapy of malignant diseases that rely upon IRAK4 kinase.
Citation Format: Priscilla N. Kelly, Divya Chaudhary, Ryan M. Young, Art Shaffer, Shaughnessy Robinson, Donna L. Romero, Rosana Kapeller, Louis M. Staudt. Highly potent and selective interleukin-1 receptor-associated kinase 4 inhibitors for the therapy of lymphoid malignancies. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr LB-112. doi:10.1158/1538-7445.AM2014-LB-112
Abstract LB-114: The long noncoding RNA HOTAIR promotes glioblastoma cell proliferation
Authors: Pastori Chiara , Penas Clara , Kapranov Philipp , St.Laurent Georges , Zhang Ming , Ayad Nagi , Wahlestedt Claes 
Published: May 2015

Abstract
Glioblastoma (GBM) is the most common and aggressive primary brain malignancy in adults. The standard treatment consists of surgery followed by radiotherapy and chemotherapy, although this only modestly affects patient survival. Partial tumor resection and poor drug delivery to the brain impede effective treatment options. The development of high-throughput sequencing technology has allowed the cancer research community to identify hundreds of genetic alterations such as amplification, deletion, mutation, and changes in gene expression. However, all this information still needs to be translated into new therapeutic approaches.
These novel therapies may come from understanding long non-coding RNAs (lncRNAs). lncRNAs modulate transcription, regulate post-transcriptional RNA processing, translation, DNA methylation, and chromatin architecture through local (cis) and long distance (trans) mechanisms. Although relatively few lncRNAs have been functionally characterized, fewer are reported to have oncogenic or tumor suppressor properties. Recently, small signatures of 6 long-noncoding RNAs with altered expression have been reported for glioblastoma and these lncRNAs have shown correlation to overall survival.
Using the Helicos Next Generation Sequencing platform 12 GBM samples and 8 controls were sequenced. Our lab identified hundreds of lncRNAs potentially dysregulated in GBM. Among these there was the well-known lncRNA HOTAIR, which was found to be massively upregulated in GBM. This observation correlated with what has been observed in other cancers. However, increased expression of HOTAIR has been linked to poor prognosis due to metastatic events. Here we show that in glioblastoma HOTAIR does not promote metastasis, but instead sustains the ability of these cells to proliferate. We demonstrate that HOTAIR knockdown in GBM strongly impairs the proliferation of cells and induces apoptosis in vitro and in vivo experiments. To identify the direct gene targets of HOTAIR we employed the chirp technique (chromatin isolation by RNA precipitation), which allowed us to explain how this lncRNA affects gene transcription involved in proliferation/apoptosis and shed light on the cellular pathways regulated by HOTAIR. In addition to cell cycle regulation mediated by HOTAIR we find that certain epigenetic enzyme inhibitors potently downregulate HOTAIR expression. These exciting studies define a novel mechanism through which these enzymes control cell proliferation via lncRNA expression.
Citation Format: Chiara Pastori, Clara Penas, Philipp Kapranov, Georges St.Laurent, Ming Zhang, Nagi Ayad, Claes Wahlestedt. The long noncoding RNA HOTAIR promotes glioblastoma cell proliferation. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr LB-114. doi:10.1158/1538-7445.AM2014-LB-114
Abstract LB-115: Ultrasensitive detection of cancer mutations in metastatic colorectal cancer FFPE and cell-free DNA samples using multiplexed droplet digital PCR
Authors: Yang Wei , Shelton Dawne N. , Cooper Samantha , Berman Jennifer , Tzonev Svilen , Hefner Eli , Regan John F. 
Published: May 2015

Abstract
Targeted therapies in many forms of cancer today have allowed unprecedented progress in the treatment of disease. Despite these advances, routine implementation of genomic testing is still limited by: 1) methods to detect, with confidence, mutational loads below 10%, 2) limited amounts of sample (pg-ng range) per biological specimen, 3) diagnostic turnaround time, and 4) cost. In metastatic colorectal cancer (mCRC), anti-epidermal growth factor receptor antibodies (αEGFR) are used to target the wild-type EGFR receptor. However, KRAS is mutated in approximately 40% of colorectal cancers and is indicative of a negative response to αEGFR therapy. BRAF and PIK3CA mutations are also associated with poor response in the remaining patients with KRAS wild-type genotype. To optimize therapy strategies for personalized care, it is therefore critical to rapidly screen patient samples during the course of disease for the presence of multiple mutations.
The low abundance of mutants and limited amount and quality of available clinical samples (FFPE and cfDNA) render it difficult to reliably detect multiple mutations with current platforms and methods. We have developed a multiplexing strategy for screening clinically-actionable KRAS, BRAF, and PIK3CA mutations in mCRC clinical samples using digital PCR. No pre-amplification step was required. This sensitive and inexpensive method reduces the risk of contamination and can be easily implemented in molecular diagnostic laboratories for rapid, routine screening and monitoring of residual disease in cancer patients.
Citation Format: Wei Yang, Dawne N. Shelton, Samantha Cooper, Jennifer Berman, Svilen Tzonev, Eli Hefner, John F. Regan. Ultrasensitive detection of cancer mutations in metastatic colorectal cancer FFPE and cell-free DNA samples using multiplexed droplet digital PCR. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr LB-115. doi:10.1158/1538-7445.AM2014-LB-115
Abstract LB-12: EphA2 as a diagnostic imaging target in glioblastoma: A PET/MRI study
Authors: Puttick Simon , Stringer Brett W. , Day Bryan W. , Mardon Karine , Cowin Gary J. , Fay Michael , Thurecht Kristofer J. , Whittaker Andrew K. , Boyd Andrew W. , Rose Stephen 
Published: May 2015

Abstract
Neuroimaging has evolved from being a purely anatomical tool to a discipline that can offer anatomical, functional, hemodynamic, metabolic and molecular information. From the perspective of patients with glioblastoma multiforme (GBM), the use of neuroimaging techniques is an essential stage in diagnosis and classification of the tumour and to assess patient response following treatment.[1]
The Eph receptor tyrosine kinases (RTKs) and their Eph-interacting ligands (ephrins) are the largest family of RTKs consisting of 16 Eph receptors and 9 ephrin ligands.[2] From the discovery of the first Eph RTK evidence has been presented to implicate the Eph family in tumour development and progression, a body of work which continues to grow. The complex bidirectional signaling mechanisms between Eph RTKs and ephrin ligands have been shown to influence cell morphology, adhesion, migration, invasion, cell proliferation and survival.[2-4] Recently, many studies have linked Eph and ephrin expression levels with tumour progression and metastatic spread and, as a consequence, patient survival. In the specific case of EphA2, an increasing number of studies have shown a correlation between EphA2 overexpression and poor patient prognosis.[5,6] As such, EphA2 represents an attractive target for highly specific PET imaging using a labeled monoclonal antibody (mAb).
In this study we present simultaneous PET/MRI of a 64Cu labeled mAb specific to the human form of EphA2. We show efficient targeting of the tumour in three intracranial mouse models of GBM. In addition, we show that non-specific binding can be significantly reduced by blocking removal of the mAb from the blood pool via Fc receptor binding. In all cases we compare the ability of the mAb to delineate tumour boundaries with the current clinical imaging techniques of 18F-FDOPA PET imaging and gadolinium (Gd) contrast enhanced MRI.
[1] Henson, J. W.; Gonzalez, R. G. Expert review of neurotherapeutics 2004, 4.
[2] Pasquale, E. B. Nature Reviews Cancer 2010, 10, 165.
[3] Pasquale, E. B. Cell 2008, 133, 38.
[4] Pasquale, E. B. Nat Rev Mol Cell Bio 2005, 6, 462.
[5] Lackmann, M.; Boyd, A. W. Science Signaling 2008, 1.
[6] Zhuang, G. L. et al. Cancer Res 2010, 70, 299.
Citation Format: Simon Puttick, Brett W. Stringer, Bryan W. Day, Karine Mardon, Gary J. Cowin, Michael Fay, Kristofer J. Thurecht, Andrew K. Whittaker, Andrew W. Boyd, Stephen Rose. EphA2 as a diagnostic imaging target in glioblastoma: A PET/MRI study. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr LB-12. doi:10.1158/1538-7445.AM2014-LB-12
Abstract LB-123: Novel function of STAT1 pathway as a modulator of tumor progression in serous papillary endometrial cancer
Authors: Kharma Budiman , Baba Tsukasa , Matsumura Noriomi , Kang Hyun Sook , Murakami Ryusuke , Yamaguchi Ken , Hamanishi Junzo , Mandai Masaki , Murphy Susan K , Konishi Ikuo 
Published: May 2015

Abstract
Serous papillary endometrial cancers (SPEC) are highly progressive with poor prognosis, and its oncogenic profile is known different from endometrioid endometrial cancers. It, however, still remains unclear that which pathway promotes tumor progression. The IFN-γ transcription factor signal transducer and activator of transcription 1 (STAT1) has been considered as a tumor suppressor with transcription-dependent and transcription-independent mechanisms, but recent studies showed STAT1 was associated with poor prognosis in some cancers with unclear mechanisms.
In this study, we performed a genome-wide analysis by microarray analysis of 63 human endometrial cancers which revealed STAT1 pathway was constitutively up-regulated in SPEC, and its expression was confirmed significantly higher in SPECs tissue cancer by immunohistochemical staining (p&lt;0.001). Immunohistochemical staining also exhibited co-localization of ICAM-1 and PD-L1 at tumor frontier with CD8-T cells (p&lt;0.001) as well as STAT1 expression in SPECs. Using a SPEC cell line, SPAC-1L, it was confirmed that IFN-γ induced STAT1 expression not only to promote cellular proliferation (p&lt;0.05), adhesion (p&lt;0.0001), and invasion (p=0.0002), but to induce expression of cMyc, ICAM-1 and PD-L1 (p&lt;0.05). In contrast, suppression of STAT1 attenuated induction of these genes (p&lt;0.05) and inhibited xenograft tumor growth on NOD-SCID mice (p&lt;0.0001).
These results indicate that STAT1 pathway modulates the micro-environment of SPECs in driving its downstream genes to promote tumor progression. Furthermore, it could be developed as a novel potential target for molecular therapy in SPEC.
Citation Format: Budiman Kharma, Tsukasa Baba, Noriomi Matsumura, Hyun Sook Kang, Ryusuke Murakami, Ken Yamaguchi, Junzo Hamanishi, Masaki Mandai, Susan K Murphy, Ikuo Konishi. Novel function of STAT1 pathway as a modulator of tumor progression in serous papillary endometrial cancer. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr LB-123. doi:10.1158/1538-7445.AM2014-LB-123