bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 1280: The intersection of the PI3K/mTOR and HIPPO pathways: a potential therapeutic target for medulloblastoma
Authors: Ronecker Jennifer S. , Lee Paul , Sridhara Sudeepta , LaBagnara Michael , Murali Raj , Jhanwar-Uniyal Meena 
Published: July 2016

Abstract
Medulloblastoma (MB) is the most common malignant pediatric brain tumor; it is genetically defined into 4 subgroups which defines the clinical course of the disease. Despite current treatment modalities such as surgical resection, radiation, and chemotherapy, there are still significant morbidities and adverse side-effects. Recently defined genetic pathways could possibly offer a better management and treatment of patients with MB. The HIPPO signaling pathway has recently been shown to intersect with PI3K and Sonic Hedgehog (SHH) pathways to modulate mechanistic target of rapamycin (mTOR), an important regulator in cell growth and migration. The aim of this study is to elucidate the interaction of Hippo and Akt/mTOR signaling pathways with SHH pathways in MB, and define the potential downstream targets of therapy by using combined inhibitors. In order to achieve our goals, we evaluated the expression of activated AKT/mTOR in MB tumors using immunohistochemistry (IHC), along with the expression of transcriptional co-activators yes-associated protein (YAP), a down-stream effector of the HIPPO pathway. Scratch and chemotactic migration were used to assess the motility of MB cells following treatment with inhibitors of the aforementioned pathways. Cell cycle analysis and proliferation were measured using EdU and MTT techniques, respectively. YAP-SiRNA treatment was used to inhibit HIPPO pathway. MicroRNA-29, which mediates the mTOR pathway by modulating PTEN levels, was investigated. Results demonstrated: 1. A significant number of MBs expressed activated pAKTSer473 and pmTORSer2448, along with YAP, the downstream effector of the HIPPO pathway; 2. Treatment with inhibitors of PI3K/AKT (LY294002) and mTOR (rapamycin), given with EGF, significantly reduced cellular motility; 3. SHH inhibitor cyclopamine given with LY294002 or rapamycin significantly reduced cellular motility; 4. Cell proliferation was suppressed by inhibition of the HIPPO pathway using 3 unique 27mer duplexes of YAP1 siRNA treatments; 5. Combined treatment of cyclopamine with either LY294002 or rapamycin caused maximum suppression of cellular growth. In conclusion, these results demonstrate that the Hippo and PI3K/Akt/mTOR pathways are over-expressed in MB, and that the combined targeting of mTOR/HIPPO pathway with SHH inhibitor may provide alternative strategies for the treatment of MB, and offers a targeted therapy for improved prognosis.
Citation Format: Jennifer S. Ronecker, Paul Lee, Sudeepta Sridhara, Michael LaBagnara, Raj Murali, Meena Jhanwar-Uniyal. The intersection of the PI3K/mTOR and HIPPO pathways: a potential therapeutic target for medulloblastoma. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 1280.
Abstract 1302: A comprehensive approach to delineate FGFR2 targeted therapy response in diffuse gastric cancer
Authors: Chen Jiamin , Lee Hojoon , Ji Hanlee 
Published: July 2016

Abstract
Dysregulation of fibroblast growth factor receptors (FGFRs) signaling has been associated with tumorigenesis and progression in various cancers. Preclinical models have shown that FGFR2 signaling activation due to FGFR2 amplification is essential driver for specific gastric cancers. Cancer cell lines or patient-derived gastric cancer xenograft models with FGFR2 amplification are highly sensitive to AZD4547, which is a small-molecule tyrosine kinase (TRK) inhibitor that selectively targets FGFR1-3. However, recent clinical trial studies failed to demonstrate the therapeutic potential of AZD4547 in patients with FGFR2 amplification. For this study, we identified critical genetic and molecular features that determine the response to FGFR2 inhibitors in gastric cancer.
To systematically delineate the pathways that modulate response to FGFR2 inhibitors, we identified CRISPR-library-based gene knockouts that result in resistance to AZD4547 in Kato III cells, a gastric cancer cell line with high sensitivity to this drug. Although majority of transduced Kato III cells undergo cell senescence upon AZD4547 treatment, a small population of resistant cells rendered by CRISPR knockout is enriched. Subsequent sequencing and pathway analysis reveal the alternative activated pathways that contribute to the cell growth in lieu of FGFR2 inhibition.
Furthermore, we applied the elastic-net regression analysis to identify genetic features associated with the drug sensitivity to FGFR2 inhibition in cancer cell lines. The cell line drug response data are derived from the Cancer Therapeutic Response Portal (CTRP v2) and the Cancer Cell Line Encyclopedia (CCLE). Notably, few cancer cell lines have high FGFR2 copy numbers (CN&gt;4). The elastic-net algorithm simultaneously integrates mutation, copy number, gene expression data, and forms multiple linear regression to learn the coefficient weights associated with FGFR2 inhibitor sensitivity. Using the method, we identify the whole spectrum of genetic and molecular features that are potential drug response markers.
In summary, our study provides new insight into genetic and molecular features that implicate in the cellular response to FGFR2 inhibitors, which can facilitate the development of more effective strategies to treat patients with FGFR2 amplification.
Citation Format: Jiamin Chen, Hojoon Lee, Hanlee Ji. A comprehensive approach to delineate FGFR2 targeted therapy response in diffuse gastric cancer. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 1302.
Abstract 1311: High order drug combinations are required to effectively kill colorectal cancer cells
Authors: Horn Thomas , Ferretti Stephane , Ebel Nicolas , Tam Angela , Ho Samuel , Harbinski Fred , Farsidjani Ali , Zubrowski Matt , Sellers William R. , Schlegel Robert , Porter Dale , Morris Erick , Wuerthner Jens , Jeay Sebastien , Greshock Joel , Halilovic Ensar , Garraway Levi A. , Caponigro Giordano , Lehar Joseph 
Published: July 2016

Abstract
Tumors are complex biological systems that often retain proliferative capacity even when challenged with drug treatment. Given this resiliency, drug combinations may provide greater therapeutic benefit, however, which molecules to combine and how many to include in combinations for effective responses is not clear yet. Using image-based proliferation and apoptosis assays in colorectal cancer cell lines we systematically investigated combinations that ranged in number from two to six drugs and targeted critical oncogenic pathways. Drug pairs targeting key signaling pathways resulted in synergies across a broad spectrum of genetic backgrounds, but often yielded only cytostatic responses. Enhanced cytotoxicity was observed when additional processes including apoptosis and cell cycle were targeted as part of the combination. In many cases, where cell lines were resistant to two- and three-way drug combinations, increased expression of anti-apoptotic proteins was observed and induction of cytotoxic responses required up to fourth-order combinations. Our results demonstrate that high-order drug combinations might be needed to kill cancers and show how systematic drug combination screening together with a molecular understanding of drug responses can guide their identification.
Citation Format: Thomas Horn, Stephane Ferretti, Nicolas Ebel, Angela Tam, Samuel Ho, Fred Harbinski, Ali Farsidjani, Matt Zubrowski, William R. Sellers, Robert Schlegel, Dale Porter, Erick Morris, Jens Wuerthner, Sebastien Jeay, Joel Greshock, Ensar Halilovic, Levi A. Garraway, Giordano Caponigro, Joseph Lehar. High order drug combinations are required to effectively kill colorectal cancer cells. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 1311.
Abstract 1314: Evaluating payload delivery to the CNS from surface-modified nanoparticles
Authors: Householder Kyle T. , DiPerna Danielle , Ghaffari Layla , Sirianni Rachael 
Published: July 2016

Abstract
The blood-brain barrier (BBB) remains a major obstacle to treatment of intracranial tumors. Most drugs are poorly bioavailable in the brain, and peripheral toxicity can severely limit administerable dose. Drug loaded nanoparticles are capable of accumulating preferentially in the core of angiogenic tumors by a mechanisms known as the enhanced permeation and retention (EPR) effect, which can improve therapeutic efficacy of encapsulated molecules compared to free form. However, to achieve complete tumor kill, chemotherapy must target both the leaky tumor core and cells that reside behind an intact blood-brain barrier.
The goal of this work was to evaluate payload delivery to the CNS from nanoparticles modified with one of four targeting ligands: TAT, antennapedia (AP), angiopep2 (Ang2) or Tet-1. Poly(lactic acid)-co- poly(ethylene glycol) nanoparticles (NPs) encapsulating Nile Red, a small fluorescent dye, were produced by solvent-evaporation technique. Peptides were covalently attached to the nanoparticle surface by a maliemide-thiol reaction. The effect of targeting ligands on NP payload delivery to healthy brain and spinal cord compared to unmodified NPs was evaluated in mice at 2 and 6 hours post injection. Mice were perfused with saline, and the brains and spinal cord were removed, homogenized and payload delivery quantified by fluorescence.
All targeting ligands evaluated significantly increased payload delivery to the brain at both 2 and 6 hours, with the cell-penetrating peptides, TAT and AP, producing the greatest effect of a 4-fold increase over control. Additionally, the cell-penetrating peptides significantly increased payload delivery to the spinal cord at 2 hours but had no significant effect on delivery at 6 hours. Interestingly, the receptor-mediated peptides, Ang2 and Tet-1, did not significantly change spinal cord delivery at 2 hours but significantly increased payload concentration at 6 hours. These data suggest both receptor and nonspecific targeting ligands affect payload delivery and kinetics in a regionally specific manner. Future work is focused on evaluating additional ligands to better understand how the type of cell-nanoparticle interactions affects payload distribution.
Citation Format: Kyle T. Householder, Danielle DiPerna, Layla Ghaffari, Rachael Sirianni. Evaluating payload delivery to the CNS from surface-modified nanoparticles. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 1314.
Abstract 1353: Validation and implementation of screens for partial agonists and antagonists of the ErbB4/HER4 receptor tyrosine kinase: Targeted melanona drug discovery
Authors: Cullum Richard , David Allan , Riese David J. 
Published: July 2016

Abstract
Introduction: Gain-of-function mutations in the gene encoding the ErbB4 (HER4) receptor tyrosine kinase have been detected in melanoma cell lines and these cell lines are dependent on ErbB4 expression for proliferation. Consequently, ErbB4 antagonists hold promise as targeted melanoma therapeutics and we have sought to identify small molecule ErbB4 antagonists. Our approach is based on the observation that the Q43L mutant of the ErbB4 peptide growth factor agonist Neuregulin 2beta (NRG2b) functions as a partial agonist at ErbB4; NRG2b/Q43L stimulates ErbB4 tyrosine phosphorylation, fails to stimulate ErbB4 coupling to cell proliferation, antagonizes stimulation of cell proliferation by ErbB4 full agonists, and causes ErbB4 down-regulation.
Experimental procedures: We have developed a high-throughput screening (HTS) strategy that can be used to identify ErbB4 antagonists. The primary screen identifies molecules that stimulate ErbB4 tyrosine phosphorylation. The secondary screen distinguishes between molecules that stimulate and fail to stimulate ErbB4-dependent proliferation. The tertiary screen identifies molecules that antagonize agonist stimulation of ErbB4-dependent proliferation.
Results: An phospho-ErbB4 sandwich ELISA assay identifies molecules that stimulate ErbB4 tyrosine phosphorylation with high sensitivity and fidelity (Z’ &gt;0.5). MTT assays using a cell line that displays ErbB4-dependent proliferation distinguish between molecules that stimulate and fail to stimulate ErbB4-dependent proliferation (Z’&gt;0.5) and identify molecules that antagonize agonist stimulation of ErbB4 dependent proliferation (Z’&gt;0.5). These assays have been used to identify small molecules that stimulate ErbB4 tyrosine phosphorylation. Efforts to determine whether these hits function as ErbB4 full agonists or partial agonists (antagonists) are underway and will be reported. Structures of these small molecule ErbB4 full and partial agonists may be reported, pending submission of a provisional patent application.
Conclusions: We have validated an HTS strategy for identifying ErbB4 partial agonists that function as ErbB4 antagonists and deployment of that strategy has led to the identification of several hits. Such molecules may hold promise as targeted therapeutics for melanoma and other ErbB4-dependent tumors.
Citation Format: Richard Cullum, Allan David, David J. Riese. Validation and implementation of screens for partial agonists and antagonists of the ErbB4/HER4 receptor tyrosine kinase: Targeted melanona drug discovery. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 1353.
Abstract 1355: A novel derivative of benzoxazole enhances radiosensitivity of human colon cancer cells through p53-mediated G2/M arrest and mitochondrial apoptotic pathway
Authors: Ryu Hwani , Seo Bitna , Kim Jooyoung , Jung In-Sung , Song Jie-Young , Ahn Jiyeon 
Published: July 2016

Abstract
The tumor suppressor p53 plays a critical role in cell cycle regulation and apoptotic cell death, and its activation can sensitize cancer cells to radio- or chemotherapy. To identify small molecules that induce apoptotic cell death via increasing p53 transcriptional activity, we designed and synthesized 44 benzoxazole derivative small molecule compounds. Using a cell-based screening with p53-responsive luciferase reporter assay system of benzoxazole derivatives, we found AU14022, which significantly increased p53 transcriptional activity in a concentration dependent manner. Treatment of AU14022 increased p53 protein expression, its phosphorylation on serine 15 and its target p21 gene/protein expression and induced apoptotic cell death measured by FACS analysis using Annexin V/PI double staining in wild-type p53 HCT116 human colon cancer cells but not in p53 knockout HCT116 cells. Furthermore, treatment of HCT116 cells with AU14022 exhibited mitochondrial dysfunction including bcl-2 family modulation and cytochrome c release. Combination treatment of AU14022 and ionizing radiation (IR) synergistically induced apoptotic cell death, compared to IR or AU14022 alone. Further investigation demonstrated that cell cycles are significantly arrested at G2/M phase, and marked inductions of p21 protein expression and phosphorylation of Chk1 protein and a decrease of cyclin B1 protein expression were observed by treatment of AU14022 alone and combination treatment with AU14022 and IR. Our findings indicate that AU14022 induced apoptosis through p53-mediated cell cycle arrest with mitochondrial dysfunction, leading to enhanced radiosensitivity of colon cancer cells. These results provide a basis for the further investigations required for its assessment as a promising anticancer agent.
Citation Format: Hwani Ryu, Bitna Seo, Jooyoung Kim, In-Sung Jung, Jie-Young Song, Jiyeon Ahn. A novel derivative of benzoxazole enhances radiosensitivity of human colon cancer cells through p53-mediated G2/M arrest and mitochondrial apoptotic pathway. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 1355.
Abstract 1360: Genistein-AR antagonist conjugate potently induce growth arrest in both androgen dependent and independent prostate cancer cell lines
Authors: Raji Idris O. , George Alex , Kucuk Omer , Oyelere Adegboyega K. 
Published: July 2016

Abstract
The ability of prostate cancer to transition from androgen dependent- to androgen independent state (castration resistant), during androgen deprivation therapy, requires that new chemotherapeutic agents be introduced that will retain activity in the two prostate cancer types. Though described as androgen independent, castration resistant prostate cancer (CRPC) still relies heavily on androgen receptor (AR) signaling for survival. Enzalutamide, an AR antagonist, is probably that most effective drug used in androgen deprivation therapy for CRPC and AR dependent prostate cancer. Despite its clinical success, there is the fear of resistant to enzalutamide due to mutation in the ligand binding domain of AR. This poses a challenge that requires developing new agents devoid of resistance, in the event of mutation. One of the approaches being proposed is to develop new agents that can selectively induce AR degradation, an approach that was successfully used to develop the selective estrogen receptor degrader, fulvestrant.
In our study, we incorporate genistein, a soy isoflavone known to perturb multiple biochemical pathways relevant for cancer survival, into an AR binding template to give AG-1-33. AG-1-33 was evaluated for growth inhibitory activity in LNCaP (AR dependent) and DU-145 (AR independent) prostate cancer cell lines. This compound retained its AR antagonist activity and also showed low micromolar anti-proliferation activity in the two prostate cancer cell lines. We also evaluated the effect of AG-1-33 on AR expression, as well as its ability to act as a selective AR degrader in LNCaP.
Citation Format: Idris O. Raji, Alex George, Omer Kucuk, Adegboyega K. Oyelere. Genistein-AR antagonist conjugate potently induce growth arrest in both androgen dependent and independent prostate cancer cell lines. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 1360.
Abstract 1370: A new RAS G12D specific rabbit polyclonal antibody for immunohistochemical FFPE application
Authors: Chen. Chi-Kuan 
Published: July 2016

Abstract
Background: Determining RAS mutation status is considered as prognostic factor for colorectal cancer patients in anti-epidermal growth factor receptor (EGFR) antibody therapy. Because genetic testing remains costly and time-consuming, it is necessary to develop mutation specific antibody for immunological analysis. However RAS G12D mutation antibody for immunohistochemical (IHC) staining is not available.
Results: Here we report a novel RAS G12D rabbit polyclonal antibody (GTX132407) for immunochemistry (IHC) testing, which was developed by cooperating with GeneTex In. Based on analyzing 15 clinical colorectal cancer specimens, the result of IHC staining using RAS G12D mutation specific antibody (GTX132407) was correlated with genetic testing of RAS G12D mutation using ultra-sensitive total RAS mutation screen kit [Hong Jing Biotechnology Inc. (FemtoPath)].
Conclusion: In summary, the result showed that IHC testing with RAS G12D specific mutation antibody could be a reliable tool for predicting RAS genetic mutation status.
Citation Format: Chi-Kuan Chen. A new RAS G12D specific rabbit polyclonal antibody for immunohistochemical FFPE application. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 1370.
Abstract 1395: Development and validation of NGS-based clinical cancer panels for precision medicine in Asian and Caucasian adult cancers
Authors: Kuo Winston Patrick , Wang Amy , Cheng Tak , Du Pan , Jia Shidong 
Published: July 2016

Abstract
In the new era of precision medicine, comprehensive cancer panels are needed to identify actionable cancer genes and match patients to personalized therapies. Here, we report a Pan-Cancer NGS Panel designed by leaders in the field that comprises of all exon coding and selected hotspots of critical cancer genes in the most common cancer types for both Asian and Caucasian cohorts, including but not limited to lung, colon, breast and prostate cancer. The panel allows detection of known and novel variants in indication-specific signaling pathways, disease biology, DNA repair, and in particular drug resistance, to advance research into personalized cancer treatment and for use in clinical trials to help the development of new targeted therapies. Technical validation was performed to characterize point mutations, indels, copy number variations and fusions across clinically relevant, actionable cancer genes in both liquid biopsies and formalin-fixed paraffin-embedded (FFPE) clinical specimens. Assay sensitivity, specificity and accuracy were tested using reference samples with known genetic profiling and further validated on a variety of orthogonal platforms such as digital PCR, allele-specific PCR and Sanger sequencing. To the best of our knowledge, this is the first ethnic-specific NGS diagnostic test designed specifically for Asian and Caucasian adult cancer patients.
Citation Format: Winston Patrick Kuo, Amy Wang, Tak Cheng, Pan Du, Shidong Jia. Development and validation of NGS-based clinical cancer panels for precision medicine in Asian and Caucasian adult cancers. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 1395.