bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 319: Cholesterol inhibition reduces Hh mediated chondrosarcoma
Authors: Wei Qingxia , Ramu Eyal , AL-Jazrawe Mushriq , Poon Raymond , Wunder Jay , Alman Benjamin 
Published: July 2017

Abstract
Constitutive activation of Hh signaling is a common occurrence in chondrosarcoma(CSA). Gene profiling analysis showed that Gli transcription regulates genes that govern cholesterol homeostasis, which alters cholesterol accumulation in chondrocytes; a higher level of Gli-mediated transcription results in accumulation of intracellular cholesterol. Here we determined if targeting cholesterol-processing genes downstream of Hh signalling could be used as a novel treatment approach. With institutional review board approval, human CSA samples were obtained fresh from surgery. For in vitro studies, CSA explants of 2mmx2mm x2 mm cubic in size establihed as organ cultures. For in vivo studies, one million CSA cells were subcutanously injected into NSG mice. Cells from five CSAs were treated both in vitro and in vivo with a hedgehog inhibitor, Cur61414, a cholesterol inhibitor, Lovastatin, or both. In vitro, CSA explants were treated for 48 hrs at concentration of 20 μM of each drug. In vivo, mice were treated with 4.5mg/kg/day of Cur61414, Lovastatin, or both by intraperitoneal injection for 4 wks. At the end of treatment, the explants or xenografts were harvested and processed for further analysis. RT-PCR was used to meausre the expression of Hh and cholesterol target genes. Tumor size was meausred from the xenografts. Blockade of Hh signaling significantly decreased Gli1 gene expression by 30%, increased 3-hydroxy-3-methylglutaryl-CoA reductase (HMGCR) expression for more than 300% indicating decreased intracellular cholesterol. Treatment with the cholesterol inhibitor Lovastatin increased expression of HMGCR for more than 500%. The combination of Hh and cholesterol blockage resulted in increased expression of HMGCR for more than 3400%. Analysis of chondrosarcoma xenografts in vivo showed a significnat decrease in tumor size with Lovastatin (32% decline), 3 folds reducation of Brdu(+) cells, and 2.4 fold increase of Caspase-3 + cells, treatment with Cur 61414 reduced the tumor growth by 5% with no significant reduction of Brdu(+) cells but 2.6 fold increase of Caspase-3 (+) cells . The combination treatment of lovastatin and Cur61414 on xenografts resulted in a significnat decrease in tumor size (32% decline), 3 fold reduction of Brdu (+) cells, but no significant changes of Caspase-3 (+) cells . These data suggest that cholesterol functions downstream of Hh signaling pathway in CSA. The more effective reduction in tumor growth with cholesterol inhibition compared to Hh blockade suggests cholesterol blockade is an effective therapeutic approach.
Citation Format: Qingxia Wei, Eyal Ramu, Mushriq AL-Jazrawe, Raymond Poon, Jay Wunder, Benjamin Alman. Cholesterol inhibition reduces Hh mediated chondrosarcoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 319. doi:10.1158/1538-7445.AM2017-319
Abstract 3201: Therapeutic potential of anti-angiogenic multimodal biomimetic peptide in hepatocellular carcinoma
Authors: Barbhuiya Mustafa A. , Mirando Adam C. , Simons Brian W. , Lemtiri-Chlieh Ghali , Green Jordan J. , Popel Aleksander S. , Pandey Niranjan B. , Tran Phuoc T. 
Published: July 2017

Abstract
Hepatocellular carcinoma (HCC) related mortality ranks second worldwide and stands one step behind lung cancer. Due to the asymptomatic nature of the cancer, early diagnosis is a major problem. Currently only liver transplantation is curative for early stage hepatocellular cancer. There are other multidisciplinary treatment options like radiation and chemotherapy available for advanced patients. However, chemotherapy resistance is a common problem in the treatment of liver cancer. Newer therapeutics are needed for better management of advanced HCC. Angiogenesis and lymphangiogenesis are processes that are vital for tumorigenesis and metastasis. HCC is known to be a hypervascular tumor and many pro-angiogenic proteins are found significantly overexpressed in HCC. We explored the therapeutic potential of the anti-angiogenic and anti-lymphangiogenic, biomimetic peptide SP2043 developed by our group in HCC. Hepatocellular carcinoma cell lines HuH-7, Hep3b and HepG2 showed significant disruption of cell adhesion and migration following treatment. Furthermore, SP2043 was found to impair microvascular endothelial cell (MEC) tube formation induced by HepG2 tumor conditioned media and to significantly inhibit HepG2 tumor xenograft growth compared to untreated controls. The peptide drug was also found to improve the survival of autochthonous Myc induced HCC in a transgenic mouse model from two weeks to four weeks. We discovered the peptide to be a multi-modal anti-angiogenic drug that also inhibits IGF1R and MET signaling pathways in HCC cell lines. We also found that SP2043 treatment reduced the microvascular density in both subcutaneous and autochthonous liver tumors with reduced tumor cell proliferation and increased apoptosis. This study shows the therapeutic potential of SP2043 in the treatment of hepatocellular carcinoma.
Note: This abstract was not presented at the meeting.
Citation Format: Mustafa A. Barbhuiya, Adam C. Mirando, Brian W. Simons, Ghali Lemtiri-Chlieh, Jordan J. Green, Aleksander S. Popel, Niranjan B. Pandey, Phuoc T. Tran. Therapeutic potential of anti-angiogenic multimodal biomimetic peptide in hepatocellular carcinoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 3201. doi:10.1158/1538-7445.AM2017-3201
Abstract 3207: Targetting proteasome function by inhibition of the proteasome deubiquitinase USP14
Authors: Linder Stig T. , D'Arcy Padraig , Zhang Xiaonan 
Published: July 2017

Abstract
The 20S proteasome core particle has evolved as an important target for anti-cancer drug development. We previously identified the small molecule b-AP15 as a novel class of proteasome inhibitors that function by abrogating the deubiquitinating (DUB) activity of the 19S regulatory particle. An optimised lead of b-AP15 (VLX1570) has been approved by the FDA for clinical studies and is currently in clinical trials for relapsed multiple myeloma. VLX1570 has also shown promising activity in Ewings sarcoma and paediatric leukemias. b-AP15 and VLX1570 bind to the proteasome DUB ubiquitin-specific protease-14 (USP14) in vitro and in exposed cells (CETSA). Binding and inhibition of enzymatic activity is believed to be due to targeting Cys114 in the active site. The cell death response to b-AP15/VLX1570 is distinct from that of 20S proteasome inhibitors. Thus, the sensitivity to these compounds is unaffected by overexpression of BCL2-family proteins and unaffected by p53 status. We here show that b-AP15 induces direct effects on mitochondria, possible explaining this phenomenon. We also provide additional understanding of drug-target interactions using a series of compounds identified by screening. Our findings demonstrate promising antiproliferative activities of USP14 inhibitors in vitro and in vivo.
Citation Format: Stig T. Linder, Padraig D'Arcy, Xiaonan Zhang. Targetting proteasome function by inhibition of the proteasome deubiquitinase USP14 [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 3207. doi:10.1158/1538-7445.AM2017-3207
Abstract 3208: AZD1775 modulates kinetochore component Wee1-CDC2 and NF-κB signaling as potential therapeutic targets in head and neck squamous cell carcinoma
Authors: Hu Zhengbo , Saleh Anthony , Chen Jianghong , Sophie Carlson , An Yi , Paul Clavijo , Wang Ru , Cornelius Shaleeka , Chen Zhong , Waes Carter Van 
Published: July 2017

Abstract
Recent findings in The Cancer Genome Atlas (TCGA) analysis of head and neck squamous cell carcinomas (HNSCC) revealed frequent alterations affecting the cell cycle and NF-κB pathway, which are critically involved in cancer cell proliferation and survival. We hypothesized that common mechanism(s) could coordinate cell cycle and NF-κB cell survival signaling in HNSCC. Recently, we established an NF-κB β−lactamase reporter UM-SCC-1 cell line and performed genome-wide RNAi screening to explore this hypothesis. We identified genes involved in the cell cycle and related to components of the kinetochore that co-modulate NF-κB activity. Among these targets, WEE1 kinase is currently under investigation as a therapeutic target of inhibitor AZD1775 in HNSCC. We found that WEE1-CDC2 axis protein levels were higher in a panel of HNSCC lines than in normal human oral keratinocytes (HOK). To further investigate the potential cross-talk between WEE1 cell cycle regulation and NF-κB activation, we showed that treatment of HNSCC cells with AZD1775 decreased NF-κB transcriptional activation and decreased TNFα-induced phosphorylation of IKKs and RELA subunit. Furthermore, AZD1775 inhibited NF-κB regulated proteins modulating the cell cycle and survival, including p21, CyclinD1, BCL2 and BCL-XL. These changes also correlate with alteration in cell cycle and survival detected by flow cytometry, as tumor cells treated by AZD1775 exhibited increased G2/M phase and sub-G0 fragmented DNA, and decease in G1/S phases. WEE1 inhibitor AZD1775 inhibited tumor cell proliferation and colony formation in a dose-dependent manner, and exhibited combinatory effects with cisplatin chemotherapy in tumor xenografts. Thus, we identified the novel cross-talk between WEE1-CDC2 and NF-κB signaling, potentially implicating decreased NF-κB prosurvival signaling in the anti-tumor activity of Wee1 inhibitors. (Supported by NIDCD/NIH intramural projects ZIA-DC-000016, 73, and 74; NIDCD core facility: advanced imaging, ZIC DC000081).
Citation Format: Zhengbo Hu, Anthony Saleh, Jianghong Chen, Carlson Sophie, Yi An, Clavijo Paul, Ru Wang, Shaleeka Cornelius, Zhong Chen, Carter Van Waes. AZD1775 modulates kinetochore component Wee1-CDC2 and NF-κB signaling as potential therapeutic targets in head and neck squamous cell carcinoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 3208. doi:10.1158/1538-7445.AM2017-3208
Abstract 3218: Molecular function of PARP inhibition in glioblastoma
Authors: Aldrighetti Christopher , Huebert Barbara , Quenet Delphine 
Published: July 2017

Abstract
Glioblastoma (GBM) is the most common primary malignant brain tumor, whose major biomarkers are the DNA methylation status of the promoter for O6-methylguanine-DNA-methyltransferase (MGMT) and the loss/mutation of the tumor suppressor phosphatase and tensin homolog (PTEN). Despite treatment combining surgery, radiotherapy and chemotherapy with the alkylating agent temozolomide (TMZ), patient survival remains poor and recurrence is virtually inevitable, due to TMZ resistance. Poly(ADP-ribose)polymerase-1 (PARP-1) is a nuclear protein involved in multiple facets of DNA repair and transcriptional regulation. This enzyme catalyses the transfer and polymerization of ADP ribose units from NAD+ to form branched polymers of ADP-ribose, called poly(ADP-ribose) (PAR), covalently attached to heterologous acceptor proteins or PARP-1 itself. There is a growing interest in PARP inhibitors (PARPi) for their clinical potential in cancer treatment. Because of the importance of PARP-1 activity in the maintenance of genomic integrity and DNA repair, treatment with PARPi as adjuvant to TMZ chemotherapy can be beneficial in GBM. PARPi are currently in clinical trials for patients with GBM (NCT02152982, NCT01390571, NCT01514201), and one of them is a phase II/III study of the PARPi veliparib for patients with newly-diagnosed GBM (NCT02152982). However, the molecular role of PARP-1 and its activity in GBM remains elusive. Using cellular and molecular approach, we are assessing the effectiveness of the PARPi veliparib compared to standard treatment with TMZ in PTEN-mutated GBM and TMZ-resistant GBM cell lines. By understanding the biology of PARP inhibition in GBM, we will establish a specific molecular signature that predicts the efficacy of PARPi treatment in patients diagnosed with GBM.
Citation Format: Christopher Aldrighetti, Barbara Huebert, Delphine Quenet. Molecular function of PARP inhibition in glioblastoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 3218. doi:10.1158/1538-7445.AM2017-3218
Abstract 3231: Identifying high quality, potent and selective pyrimidinylthienopyrrolone inhibitors of ERK1/2 kinase: LY3214996
Authors: Zhao Gaiying , McMillen William T. , Cai Shufen , Zhao Baohui , Whitesell Matthew , Wu Wenjuan , Huss Karen , Anderson Bryan , Yuan Xiu-Juan , Jaken Susan , Kindler Lisa , Flack Robert S. , McCann Denis , Mathes Brian , Dropsey Andrew J. , Walgren Jennie , Yuen Eunice , Manro Jason , Gong Xueqian , Cortez Guillermo , McLean Johnathan , Rodriguez Michael J. , Tiu Ramon V. , Bhagwat Shripad V. , Joseph Sajan 
Published: July 2017

Abstract
The ERK/MAPK pathway plays a central role in the regulation of critical cellular processes and is activated in more than 30% of human cancers. While targeting upstream nodes with RAF and MEK inhibitors has proven effective clinically, resistance frequently develops through reactivation of the pathway. ERK inhibitors have the potential to address resistance caused by ERK reactivation. Herein, a potent, selective small molecule ERK1/2 inhibitor is described. LY3214996 possesses an optimal balance of potency (hERK1 IC50 5 nM, hERK2 IC50 5nM, pRSK IC50 0.43 µM), solubility (FaSSIF solubility at pH 6.5 0.133 µM), PK properties (dog, AUCoral 23800 nM*hr, CL 12.1 mL/min/kg, bioavailability 75.4%), IVTI (TED50 =16 mg/kg pRSK1) and demonstrated significant in vivo efficacy in several human cancer xenograft models. LY3214996 is currently undergoing early clinical evaluation.
Citation Format: Gaiying Zhao, William T. McMillen, Shufen Cai, Baohui Zhao, Matthew Whitesell, Wenjuan Wu, Karen Huss, Bryan Anderson, Xiu-Juan Yuan, Susan Jaken, Lisa Kindler, Robert S. Flack, Denis McCann, Brian Mathes, Andrew J. Dropsey, Jennie Walgren, Eunice Yuen, Jason Manro, Xueqian Gong, Guillermo Cortez, Johnathan McLean, Michael J. Rodriguez, Ramon V. Tiu, Shripad V. Bhagwat, Sajan Joseph. Identifying high quality, potent and selective pyrimidinylthienopyrrolone inhibitors of ERK1/2 kinase: LY3214996 [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 3231. doi:10.1158/1538-7445.AM2017-3231
Abstract 3236: Delivering selective and cell-active inhibitors of V804M mutant RET kinase through structure-guided drug discovery
Authors: Jordan Allan M. , Newton Rebecca , Waszkowycz Bohdan , Bayliss Richard , Begum Habiba , Burschowsky Daniel , Echalier Aude , Hitchin Samantha , Hutton Colin , Johns Shaun , Jones Stuart , Lin Li-Ying , Richards Mark , Seewooruthun Chitra , Stowell Alex , Waddell Ian , Watson Mandy , Ogilvie Donald 
Published: July 2017

Abstract
Activating gene fusions in the RET receptor tyrosine kinase have been found to drive 1-2% of lung adenocarcinomas and therefore offer an attractive target for targeted therapy. Whilst non-selective tyrosine kinase inhibitors with RET activity are efficacious in this setting, their use is generally limited by dose limiting toxicity associated with their more potent activity versus other targets, specifically KDR (VEGFR2) in the case of cabozantinib and vandetanib. Given this limitation, there is considerable interest in developing more selective inhibitors of RET kinase. Tyrosine kinase inhibitors are prone to early clinical failure due to mutations in the kinase ATPase binding domain, which render the kinase catalytically active but no longer sensitive to drug treatment. Such mutations often occur in the so-called “gatekeeper” region and in this specific case, resistance is predicted to arise from a Val-Met or Val-Leu mutation at residue 804. Through a combination of computational methods, structural biology and drug design, we have identified and further optimized a series of inhibitors of the V804M mutant RET kinase which show sub-micromolar cellular activity in cells driven by V804M RET. Moreover, these agents show excellent selectivity against the wtRET kinase and KDR. As such, these agents may offer valuable start-points for second-generation RET inhibitors for use in patents who relapse after treatment with first generation selective RET inhibitors.
Citation Format: Allan M. Jordan, Rebecca Newton, Bohdan Waszkowycz, Richard Bayliss, Habiba Begum, Daniel Burschowsky, Aude Echalier, Samantha Hitchin, Colin Hutton, Shaun Johns, Stuart Jones, Li-Ying Lin, Mark Richards, Chitra Seewooruthun, Alex Stowell, Ian Waddell, Mandy Watson, Donald Ogilvie. Delivering selective and cell-active inhibitors of V804M mutant RET kinase through structure-guided drug discovery [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 3236. doi:10.1158/1538-7445.AM2017-3236
Abstract 3237: Development of direct inhibitors of KRAS mutants for the treatment of cancer
Authors: Tian Xiaohong , Geng Guoyan , Wu Jian Hui 
Published: July 2017

Abstract
Oncogenic KRAS mutations occur in ~ 30% of all human cancer. All attempts to develop inhibitors of oncogenic KRAS have failed to reach the clinic for decades and promote the perception of ‘undruggable’ KRAS proteins. Given the recent advances in understanding of mechanism of oncogenic KRAS, there is renewed enthusiasm toward development of direct inhibitors of KRAS. In a recent breakthrough, Shokat et al. discovered a “pocket," where they designed a series of mutant-specific small molecular inhibitors that are covalently binding to the mutant Cys 12 in KRAS protein (KRAS G12C). In human cancer, G12C, G12D and G12V are the predominant KRAS mutants. The G12C mutation accounts for 29,700 new diagnoses annually (lung, colon and pancreatic). The G12D and G12V, annually account for 53,700 and 39,100 new cancer diagnoses, respectively, occurring most frequently in Pancreatic ductal adenocarcinoma (PDAC) (51% G12D and 30% G12V) and colorectal cancer (45% G12D and 27% G12V). Thus, there is an urgent need to develop direct inhibitor of KRAS 12D and 12V mutants. By computer-aided drug design techniques, we have discovered a series of novel chemical inhibitors that potently inhibit KRAS G12D mutant in reporter assays using HEK293 cells and in Western blot analysis using PANC10.05 and SNU-C2B cells, which express endogenous KRAS G12D mutant. The direct binding of our compounds with KRAS G12D mutant was confirmed by Surface Plasmon Resonance (SPR) analysis. Our compounds also inhibit KRAS G12V mutant. Chemical optimization of these initial hits as direct inhibitors of multiple KRAS mutants is in progress.
Citation Format: Xiaohong Tian, Guoyan Geng, Jian Hui Wu. Development of direct inhibitors of KRAS mutants for the treatment of cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 3237. doi:10.1158/1538-7445.AM2017-3237
Abstract 3245: Preclinical evaluation of the imipridone family of small molecules, including analogues of clinical-stage anti-cancer small molecule ONC201, reveals potent anti-cancer effects of ONC212
Authors: Wagner Jessica , Kline C. Leah , Olson Gary , Nallaganchu Bhaskara , Pottorf Richard , Prabhu Varun , Stogniew Martin , Allen Joshua , El-Deiry Wafik 
Published: July 2017

Abstract
We previously identified a novel, potent anti-cancer small molecule ONC201, which upregulates the integrated stress response (ISR) through ATF4/CHOP/DR5 and acts as a dual inactivator of Akt and ERK, leading to TRAIL gene activation. After completing a first-in-human phase I clinical trial that revealed exceptional safety, therapeutic pharmacokinetic (PK) profile and tumor engagement, ONC201 is under investigation in several advanced cancer Phase I/II trials. Given the unique imipridone core chemical structure of ONC201, we synthesized a family of analogues in an effort to identify additional chemical family members with distinct therapeutic properties. Based on in vitro potency improvements in human cancer cell lines and therapeutic window approximations with normal human fibroblasts, select analogues were investigated in animals for toxicity, maximum tolerated dose (MTD), and antitumor efficacy. ONC212 is one of the most promising new imipridones that was further evaluated to establish the PK profile, oral bioavailability, and efficacy in tumor types that are less sensitive to ONC201. Compared to ONC201, we noted distinct and more rapid kinetics of activity as well as improved potency in multiple human cancer cell lines in vitro. ONC212 has a broad therapeutic window, an acceptable PK profile, and is orally well-tolerated in mice. With no evidence of toxicity at efficacious doses in both colon and triple negative breast cancer, we have begun further evaluation of antitumor efficacy studies in ONC201-resistant tumor types. Efficacy studies with ONC212 are ongoing in melanoma models that are sensitive to ONC212 but less sensitive to ONC201 in vitro. Preliminary data indicates potent tumor growth reduction by ONC212 in vivo in ONC201-resistant melanoma xenografts. With a wide safety margin, potent antitumor activity in ONC201-insenstive tumors, and drug-like characteristics, ONC212 is being further developed as a drug candidate from the new imipridone class of compounds that complements the spectrum of activity of ONC201.
Citation Format: Jessica Wagner, C. Leah Kline, Gary Olson, Bhaskara Nallaganchu, Richard Pottorf, Varun Prabhu, Martin Stogniew, Joshua Allen, Wafik El-Deiry. Preclinical evaluation of the imipridone family of small molecules, including analogues of clinical-stage anti-cancer small molecule ONC201, reveals potent anti-cancer effects of ONC212 [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 3245. doi:10.1158/1538-7445.AM2017-3245