bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract LB-197: Hepatocyte Growth Factor Activator (HGFA) Inhibitors of c-MET/RON Kinase Signaling
Authors: Janetka James W. , Agarwal Manjula , Jones Darin E. 
Published: August 2014

Abstract
Continuous advances have been made in the treatment of cancer however 70% of the patients still die of cancer every year strongly correlated to tumor metastasis. The treatment options available at present are rarely able to effectively treat metastatic cancer. Targeting hepatocyte growth factor (HGF) signaling with receptor tyrosine kinase (RTK) inhibitors is a well-developed strategy for metastatic cancer therapy however no studies have explored targets upstream of kinase activation. One such target is hepatocyte growth factor activator (HGFA) which is upregulated in a large number of cancer cell lines and patient samples. HGFA is a trypsin-like serine protease which stimulates both the c-MET and RON signaling pathways by proteolysis of the inactive single-chain zymogen growth factor ligand precursors to activated two-chain HGF and macrophage stimulating protein (MSP) respectively. Increased activation of these pathways has been shown to trigger a number of downstream signaling events necessary for metastasis including cell migration, invasion, proliferation, and angiogenesis. The present study was undertaken to discover inhibitors of HGFA based on the naturally occurring bicyclic peptide, sunflower trypsin inhibitor (SFTI).
Using a combination of solution and solid-phase peptide methods, we have synthesized the natural product SFTI and analogs thereof. The compounds were tested for HGFA activity in a competitive fluorescence resonance energy transfer (FRET) assay of proteolytic cleavage by using a fluorogenic peptide substrate. We have identified several inhibitors of HGFA with low μM activity in the FRET assay. We have also demonstrated one inhibitor effectively prevented the conversion of native pro-HGF to HGF as determined by western blotting in a biochemical assay of HGFA activity. This ground breaking discovery of novel HGFA inhibitors will enable future studies on the role of HGFA and other serine proteases in the regulation of growth factors, cell signaling, and cancer metastasis. Inhibitors of HGFA offer an innovative therapeutic strategy upstream of kinase activation and signaling for the treatment of metastatic cancer.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr LB-197. doi:10.1158/1538-7445.AM2011-LB-197
Abstract LB-205: Using cell-delivered nanoparticles to cause local hyperthermia increases survival in a murine metastatic pancreatic cancer model
Authors: Basel Matthew T. , Balivada Sivasai , Wang Hongwang , Shrestha Tej B. , Seo Gwi Moon , Pyle Marla M. , Abayaweera Gayani , Dani Raj , Chikan Viktor , Bossmann Stefan , Troyer Deryl 
Published: August 2014

Abstract
Hyperthermia has been a method for cancer treatment for several decades now because cancer cells are slightly more susceptible to hyperthermia than healthy cells. Unfortunately, whole body hyperthermia has prohibitive side effects limiting its use or usefulness. Local hyperthermia, directed only to tumor tissue, could alleviate this problem and prove to be a potent cancer treatment. One method of generating local hyperthermia is to deliver magnetic nanoparticles to the tumor site and then generate heat using an alternating magnetic field (AMF). Here we demonstrate a system that uses tumor homing cells to actively carry iron/iron oxide nanoparticles into tumor tissue for AMF treatment. Paramagnetic iron/iron oxide nanoparticles were synthesized that absorb and convert AMF energy into heat very efficiently. These nanoparticles were loaded into Raw264.7 cells (mouse monocyte/macrophage like cells, Mo/Ma), that we have previously shown to be tumor homing cells. Test showed that the nanoparticles loaded at high concentration in the cells with very low toxicity. To test the system, a murine pancreatic cancer model was generated by injection of Pan02 cells i.p. After tumor development, Mo/Ma loaded with iron/iron oxide nanoparticles were injected i.p. and allowed to crawl into the tumor. Three days after injection, mice were exposed to an alternative magnetic field for twenty minutes to cause the cell-delivered nanoparticles to generate heat. This treatment regimen was repeated three times. A survival study demonstrated that this system can significantly increase survival in a murine pancreatic cancer model, with an average post-diagnosis life expectancy increase of 33%. Thus, for the first time, a cell-delivered nanoparticle system for generating localized hyperthermia has been demonstrated that can significantly prolong the life of i.p. pancreatic tumor bearing mice. This system has the potential to become a useful method for specifically and actively delivering nanoparticles for local hyperthermia treatment of cancer.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr LB-205. doi:10.1158/1538-7445.AM2011-LB-205
Abstract LB-306: Pre-treatment sera from NSCLC patients with different outcomes on EGFR-TKI therapy differentially affects sensitivity of lung cancer cell lines to EGFR-TKIs
Authors: Hunsucker Stephen W. , Grigorieva Julia , Helfrich Barbara A. , Allen Jenna , Bunn Paul A. , Roder Heinrich 
Published: August 2014

Abstract
Background: VeriStrat (VS) is a pre-treatment mass spectrometry-based test that correlates with clinical outcome after 2nd line therapy with gefitinib or erlotinib in advanced NSCLC. The blinded validation showed that patients classified as “Good” had significantly better overall survival than those classified as “Poor” (HR = 0.47 P = 0.0094 in one cohort, HR = 0.33 P = 0.0007 in another).(1) Mass spectra from VS Poor patients have relatively high abundance of eight peaks (proteins) and we believe these reflect an elevated host response to the tumor. Based on our clinical data and our understanding of the VeriStrat signature, we hypothesized that serum from VS Poor patients would increase the resistance of tumor cells to gefitinib in vitro.
Methods: The gefitinib sensitive line HCC4006 has an EGFR exon 19 deletion and the resistant line A549 is EGFR wild type. Human sera were from stage IIIB/IV NSCLC patients and characterized as VS Good or Poor. Pools were created by combining sera within each classification and used in growth inhibition assays. Cells were plated (10 replicates/drug concentration; 2,000 cells/well) using two media compositions; RPMI with 10% Good serum or RPMI with 10% Poor serum. After 24 hours, gefitinib was added and the plates were incubated for 6 days. The MTT assay was used to measure growth inhibition.
Conclusion: There was a relative decrease in inhibition of sensitive cells when grown in VS Poor serum, but no significant change in resistant tumor cells. We demonstrate that VS Poor serum has a different biological effect on tumor cells than VS Good serum. These results shed light on the nature of the host-tumor interaction and the relative efficacy of targeted therapies in patient populations. We will have similar data from 6–8 additional cell lines with and without EGFR mutations.
(1) Taguchi et al. J Natl Cancer Inst. 2007 99(11):838–46.

Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr LB-306. doi:10.1158/1538-7445.AM2011-LB-306
Abstract LB-370: Radiation and hypoxia-induced bystander effect in human lung cancer cells
Authors: Tubin Slavisa , Gupta Seema , Ahmed Mansoor M. 
Published: August 2014

Abstract
Purpose: The bystander effects of radiation are well documented. However, it is shown that many cell lines that respire anaerobically do not show cytotoxic bystander effects. There is no existing data on the acute hypoxia-induced bystander effects. The purpose of this study was to investigate the status of radiation-induced bystander effect in normoxic, hypoxic and normoxic-hypoxic mixed conditions that are equivalent to in vivo tumor compartments as well as acute hypoxia-induced bystander effect. Methods: Two lung cancer cell lines, A549 and H460 were used. The cells were exposed either to real hypoxia (&lt; 2 % oxygen) for 3 days or incubated in normoxic conditions and then irradiated (2 or 10Gy) after changing the media. After 24h (irradiated and unirradiated cells were continued to be in the hypoxic or normoxic environment respectively), unirradiated hypoxic (H-CM) or normoxic (N-CM) conditioned media and irradiated hypoxic (H-RCM) or normoxic (N-RCM) conditioned media was collected and cells were incubated with fresh media for another 24h before collecting the second respective CM. Unirradiated normoxic cells were exposed to H-CM, N-CM, H-RCM or N-RCM and cell growth was monitored dynamically in real time using real time cell electronic sensing system (RT-CES). Results: Our preliminary results in A549 cells showed that H-RCM was much more effective in inducing growth delay compared to N-RCM. For all the treatments except for 2Gy N-RCM, which promoted slight cellular growth, RCM induced significant growth delay compared to CM. Further, as expected N-RCM obtained after 10Gy irradiation was more cytotoxic/cytostatic than 2Gy N-RCM.
Interestingly, H-RCM obtained after 2Gy and 10Gy irradiation did not show significant differences in the growth delay of A549 cells. During the first 48h under real hypoxic conditions (24 or 48h H-CM), the H-CM promoted slight increase in cellular growth followed by significant growth delay which were most pronounced at 96h. When, in addition to the bystander factors, the cells were exposed to 2Gy direct irradiation, the growth was severely affected. Currently, we are performing these experiments in more radiosensitive cell line, H460 and also investigating the effects of acute hypoxia and mixed normoxia-hypoxia on generation of bystander effects. Conclusions: The findings from this study demonstrate for the first time that irradiation of hypoxic cells and exposing the cells to acute hypoxia lead to significant bystander effect that has important clinical implications.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr LB-370. doi:10.1158/1538-7445.AM2011-LB-370
Abstract LB-374: IGFBP-6, a novel prognostic biomarker in nasopharyngeal carcinoma (NPC) patients
Authors: Lu Yi , Chen Qiuyan , Qi Weici , Hong Minghuang , Mizokami Atsushi , Keller Evan , Zhang Jian 
Published: August 2014

Abstract
A variety of cancer types, including NPC, that have metastasized to bone, have a dysregulated insulin-like growth factor (IGF) system. This suggests that IGF-IGF receptor axis may contribute to the interaction between host and cancer cells resulting in promotion of skeletal metastases. In this study, IGFBP6 expression levels were first determined by immunohistochemistry in clinical specimens from NPC patients (n=76). IGFBP6 was differentially expressed in malignant epithelia and in non-neoplastic tissues. The 5-year overall survival rate of IGFBP-6 negative and positive group was 27% and 73% (survival analysis P=0.007), respectively and the 5-year distant metastasis-free survival rate was 53% and 89% (P=0.002), respectively. Multivariate analysis in a Cox model showed that IGFBP-6 was an independent and positive prognostic biomarker in NPC patients. Furthermore, we found that in vitro cell proliferation and invasion were inhibited by recombinant IGFBP6 treatment in CNE2 cells but not in HK-1 cells. Finally, CNE2 cells were stably transfected with IGFBP6 short hairpin RNA (shRNA) or scrambled RNA. The cells were inoculated into the tibiae of SCID mice for 3 weeks. The IGFBP6 knockdown significantly enhanced CNE2 tumor growth in bone. These results indicate that IGFBP6 may play key roles in NPC tumor progression. We conclude that, for the first time, IGFBP-6 is a novel prognostic biomarker in NPC patients.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr LB-374. doi:10.1158/1538-7445.AM2011-LB-374
Abstract LB-4: Mechanisms by which the unfolded protein response/α-Basic-crystallin (CRYAB) regulates VEGF signaling of tumor endothelial cells
Authors: Cai Jun , Ruan Qing , Han Song , Chen Zhijuan , Law Brian K. , Jiang Wengou 
Published: August 2014

Abstract
Angiogenesis is an essential component of tumour development and is tightly regulated by a network of pro-angiogenic and anti-angiogenic factors. The tumour cells are known to produce many of the proteins that interact with vascular endothelial cells and drive the angiogenic process. Of the known angiogenic factors, VEGF has been established as a potent inducer of tumor angiogenesis. Like almost all secretory and membrane proteins, VEGF attains its final folded or assembly conformation in ER before making its way to its target organelles or the cell surface. The deleterious tumor microenvironment characterized by progressive hypoxia, nutrient starvation and acidosis results in the ER stress in the tumor vascular endothelial cells, which in turn leads to the unfolded/misfolded VEGF accumulated in the ER.
Molecular chaperon proteins counteract the formation of aberrantly folded VEGF and allow its correct folding. One of molecular chaperons is CRYAB. It has been reported that CRYAB contains interactive sequences for VEGF. The misfolded VEGF interacts with BiP (chaperone immunoglobulin heavy chain-binding protein) causing its release from one or more of the three ER stress sensors [PKR-like ER kinase (PERK), inositol-requiring protein-1 (IRE1) and transcription factor 6 (ATF6)], which leads to activation of the unfolded protein response (UPR) pathway. All three sensor pathways can lead to chaperone induction but the IRE1 and ATF6 pathways are thought to play the major role in up-regulation of CRYAB. Activation of IRE1 generates a mature XBP-1 mRNA by unconventional splicing of XBP-1 pre-mRNA and activated XBP-1 up-regulates CRYAB. Activation of ATF6 results in its translocation to the Golgi apparatus and proteolytic cleavage to yield its cytosolic domain not only for directly up-regulating genes encoding CRYAB and folding catalysts, but also for assisting IRE1-dependent upregulation of CRYAB. An excessively elevated level of CRYAB has been detected in breast carcinomas, correlating with lymph node involvement resulting in metastasis and short term survival. Taken together, it is clear that CRYAB has the potential to a) protect VEGF from intracellular degradation thus maintaining the intracellular pool and b) increase VEGF secretion. Both these actions serve to enhance the autocrine VEGF signaling response which serves as one of strategies adapted by the tumor vasculature to perpetuate aberrant angiogenesis.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr LB-4. doi:10.1158/1538-7445.AM2011-LB-4
Abstract 1006: A novel class I histone deacetylase (HDAC) inhibitor, paragazole, demonstrates antiproliferative and proapoptotic effects in triple-negative breast cancer models.
Authors: Astling David P. , Tentler John J. , Cross Benjamin R. , Newton Timothy P. , Pitts Todd M. , Gunther Eric , Liu Xuedong , Eckhardt S. Gail , Diamond Jennifer R. 
Published: August 2014

Abstract
Introduction: Triple-negative breast cancer (TNBC) is a clinically aggressive breast cancer subtype which lacks estrogen receptor expression. Histone deacetylase (HDAC) inhibitors have previously been shown to induce estrogen receptor expression in TNBC models. Paragazole is a selective class I HDAC inhibitor (HDACs 1, 2, and 3) currently in preclinical development. In this project, we explored the antiproliferative and proapoptotic activity of paragazole and investigated the combination of paragazole and chemotherapy in a panel of breast cancer cell lines.
Methods: Breast cancer cell lines were exposed to varying sub-micromolar concentrations of paragazole alone and in combination with carboplatin, paclitaxel, and gemcitabine. Proliferation was assessed using an SRB assay and analyzed using the Calcusyn program, whereby synergy was defined as a Combination Index of less than 1. Cell cycle analysis was performed using flow cytometry and apoptosis was analyzed using a caspase 3/7 assay. Baseline HDAC expression was measured by RT-PCR and RNA-Seq was used pre- and post-treatment in a subset of 2 sensitive and 2 resistant cell lines.
Results: Exposure to paragazole resulted in a decrease in cell proliferation at submicromolar concentrations with more robust antiproliferative activity observed in the TNBC cell lines compared to the estrogen receptor positive cell lines. An increase in apoptosis that was maximal at 24-48 hours was observed with single agent paragazole in a subset of sensitive TNBC cell lines. The combinations of paragazole with either paclitaxel, gemcitabine, or carboplatin all resulted in additive or synergistic growth inhibition. Expression of HDAC 1 was higher in the sensitive TNBC cell lines than in the resistant lines. Exposure to paragazole led to an increase in CARM1 mediated estrogen receptor expression.
Discussion: These in vitro results demonstrate that paragazole has antiproliferative and proapototic activity against TNBC cell lines and may potentiate the activity of chemotherapy. These data support confirmation of the findings using in vivo models and the investigation of paragazole in combination with anti-estrogen agents such as tamoxifen and fulvestrant.
Citation Format: David P. Astling, John J. Tentler, Benjamin R. Cross, Timothy P. Newton, Todd M. Pitts, Eric Gunther, Xuedong Liu, S. Gail Eckhardt, Jennifer R. Diamond. A novel class I histone deacetylase (HDAC) inhibitor, paragazole, demonstrates antiproliferative and proapoptotic effects in triple-negative breast cancer models. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 1006. doi:10.1158/1538-7445.AM2013-1006
Abstract 1020: VRC2, a novel bortezomib re-sensitizing compound for the treatment of multiple myeloma.
Authors: Lulla Amriti , Stessman Holly , Dicker David , Van Ness Brian , El-Deiry Wafik , Dolloff Nathan G. 
Published: August 2014

Abstract
The development of novel agents including the proteasome inhibitor bortezomib (Btz) has significantly improved treatment outcomes in multiple myeloma (MM). Despite these advances, resistance to therapy invariably emerges and MM remains an incurable disease. The objective of this study was to identify new therapeutic agents and combinations with the ability to overcome resistance to Btz in MM cells. We developed a high throughput drug screening (HTS) assay system to discover small molecules that selectively target Btz resistant MM cells as single agents and/or re-sensitize resistant cells to Btz. For HTS we used isogenic pairs of Btz sensitive (595 P) and resistant (595 VR) cells derived from iMycCα/Bcl-xL transgenic mouse model of MM. Cell viability was the HTS assay read-out, and 3 treatment groups (595 P, 595 VR, and 595 VR + Btz) were included to identify compounds with selective activity against Btz resistant cells as single agents, and compounds that restore Btz sensitivity in the presence of Btz. Our screening of multiple publically-available compound libraries identified several chemical structures with selective activity against Btz resistant cells. One compound in particular showed modest but significant selectivity for Btz resistant cells as a single agent, and most notably, exhibited potent Btz re-sensitizing activity when the 2 drugs were combined. We named this compound Velcade Re-sensitizing Compound 2, or VRC-2 for short. The Btz re-sensitizing activity of VRC-2 was confirmed using multiple human and mouse cell lines that had been selected for Btz resistance in vitro. IC50s for VRC-2 in normal mouse and human fibroblasts were 100-fold higher than that observed in MM cells, suggesting it may have a low toxicity profile in vivo. We are currently evaluating the activity of VRC-2 in animal models of MM, alone and in combination with Btz, and conducting molecular studies to identify its precise mechanism of action. This study establishes the proof-of-principal for our HTS approach and demonstrates the potential of VRC-2 in Btz refractory MM.
Citation Format: Amriti Lulla, Holly Stessman, David Dicker, Brian Van Ness, Wafik El-Deiry, Nathan G. Dolloff. VRC2, a novel bortezomib re-sensitizing compound for the treatment of multiple myeloma. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 1020. doi:10.1158/1538-7445.AM2013-1020