bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 5051: MYC-driven models of primitive neuroectodermal tumor are sensitive to inhibitors of glutamine metabolism.
Authors: Ahsan Sama F. , Hanaford Allison , Weingart Melanie , Taylor Isabella , Eberhart Charles , Raabe Eric 
Published: August 2014

Abstract
Brain tumors are a diverse group of cancers in which alterations in growth regulation pathways drive tumorigenicity. Histologically similar tumors may have significant differences in underlying molecular pathways and this in turn may have significant implications for the development of targeted treatment. The MYC family of proteins promotes proliferation and an aggressive phenotype in diverse cancers. Primitive Neuroectodermal Tumors (PNETs) are high grade tumors that can arise throughout the neuro-axis. One subset of PNETs is MYC amplified, and some PNETs are known to express LIN28A, a key regulator of MYC. MYC expression in tumors leads to increased reliance on glutamine metabolism (i.e. the Warburg effect). We hypothesized that MYC-driven PNET tumors would up regulate glutamine metabolism and that glutaminase inhibitors would selectively target MYC-driven tumors. We tested this hypothesis using the MYC-positive PNET cell line PFSK as well as MYC-transformed human neural stem cells. The glutamine methabolic inhibitors DON (6-Diazo-5-oxo-L-norleucine) and acivicin were used to disrupt glutamine metabolism in these cells. Using Tetrazolium dye reduction (MTT assay) and Bromodeoxyuridine assays (BrdU) as indicators for cell growth and replication, we found that PFSK growth is inhibited by acivicin at 10 micromolar concentration (MTT activity reduced by 88%, p&lt;0.05, t-test acivicin treated compared to untreated) MYC-negative UW228 cells were resistant to DON and acivicin treatment. Similarly, DON or acivicin inhibited the proliferation of MYC-transformed human neural stem cells. We observed a 75% reduction in BrdU incorporation in MYC transformed cortex neural stem cells using acivicin, (p&lt;0.001, t-test acivicin treated compared to vehicle treated), 60% reduction in cortex MYC cells using DON (p&lt;0.05), and a 48% reduction in hindbrain MYC cells using DON (p&lt;0.01). The growth of control MYC-negative cells was not significantly inhibited by either drug. This data shows that glutaminase inhibition limits cell replication in tissue culture models of MYC-driven PNET. We are currently investigating the mechanism of growth inhibition (e.g. apoptosis versus cell cycle arrest) caused by glutaminase inhibitors. Murine orthotopic xenograft experiments investigating the efficacy of DON and acivicin treatment in MYC-driven PNET are currently underway in our laboratory.
Citation Format: Sama F. Ahsan, Allison Hanaford, Melanie Weingart, Isabella Taylor, Charles Eberhart, Eric Raabe. MYC-driven models of primitive neuroectodermal tumor are sensitive to inhibitors of glutamine metabolism. [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 5051. doi:10.1158/1538-7445.AM2013-5051
Abstract 5054: The role of neurofibromin in stem cell differentiation.
Authors: Farbaniec Michelle , Chakraborty Adri , Coleman Natalia 
Published: August 2014

Abstract
Neurofibromin is a product of the tumor suppressor gene Nf1 which is responsible for neurofibromatosis type 1 (NF1). When NF1 is mutated, Ras is constitutively active, enabling affected cells to proliferate extensively. This proliferation can result in tumor formation, particularly in neural crest-derived cells in the peripheral nervous system. NF1 patients can also exhibit cognitive deficits and develop other symptoms unrelated to cancer. While it is common knowledge that neurofibromin is involved in tumor formation, little is known about its function in neural stem cell proliferation and differentiation in normal and pathological settings. In addition to Ras-GAP function, recent studies have demonstrated that neurofibromin has a novel role on neuronal differentiation via its GAP-related domain. Thus we have speculated that abnormal regulation of NF1-GAP in neuronal cells may be implicated in NF1-related learning and memory disorders. The aim of the present work is to evaluate the role of neurofibromin in neuronal cell differentiation using stem cells (SCs) expressing different levels of neurofibromin. We have developed a new system to differentiate mouse SCs via formation of an embryoid body, a floating cell cluster which, by markers and function, mimicks adult neural stem cells. We have shown that the mouse embryonic ESs of all NF1 genotypes in our possession retain their pluripotency and can be differentiated into neuronal cells. This systematic study of complex molecular events in signaling pathways that occur in mouse embryonic SCs that have one (Nf1+/-), both (Nf1+/+) or neither (Nf1-/-) functional allele during in vitro differentiation is critical for a better understanding of the biology of neurofibromatosis and identification of potential targets.
Citation Format: Michelle Farbaniec, Adri Chakraborty, Natalia Coleman. The role of neurofibromin in stem cell differentiation. [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 5054. doi:10.1158/1538-7445.AM2013-5054
Abstract 5055: Efficacy of cabazitaxel in mouse models of pediatric brain tumors.
Authors: Olson James M. , Girard Emily , Ditzler Sally , Richards Andrew , Lee Doonhoon , Vrignaud Patricia 
Published: August 2014

Abstract
Successful treatment of pediatric brain tumors is limited by significant long-term toxicities associated with surgery and radiation therapy on the developing central nervous system There is an unmet need for chemotherapy with improved efficacy in difficult to treat tumors, such as supratentorial primitive neuroectodermal tumors (sPNET) and atypical teratoid/rhabdoid tumors (ATRT), as well as diagnoses that currently have good long-term survival, such as medulloblastoma. Overcoming the blood brain barrier is a large hurdle in effectively treating brain tumors, particularly when there is a need, as with very young patients, to avoid radiation therapy. Cabazitaxel is a promising taxane derivative shown to effectively kill tumor cells in pre-clinical in vitro and in vivo experiments. Similar to docetaxel, cabazitaxel has favorable drug properties and a manageable safety profile in patients with advanced solid tumors, with the advantage of being able to cross the blood brain barrier. Additionally, cabazitaxel has shown efficacy in docetaxel resistant tumors. The experiments presented here, tested the relative efficacy of cabazitaxel and docetaxel in mouse models of pediatric brain tumors. A spontaneous mouse model of medulloblastoma driven by Smo activation was evaluated by magnetic resonance imaging for tumor growth and blood brain barrier integrity before and after treatment with cabazitaxel or docetaxel. Efficacy of cabazitaxel and docetaxel against patient-derived pediatric brain tumors was tested in flank and orthotopic xenograft models of medulloblastoma, sPNET, ATRT, and ependymoma. We observed regression in some flank xenograft tumors after treatment with cabazitaxel or docetaxel, with evidence of superior action of cabazitaxel. These data support further testing of cabazitaxel as a therapy to treat human pediatric brain tumors.
This work has been funded by Sanofi Inc.
Citation Format: James M. Olson, Emily Girard, Sally Ditzler, Andrew Richards, Doonhoon Lee, Patricia Vrignaud. Efficacy of cabazitaxel in mouse models of pediatric brain tumors. [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 5055. doi:10.1158/1538-7445.AM2013-5055
Abstract 5061: Roles for matrix metalloproteinase-3 (MMP-3) in the prostate tumor-bone microenvironment.
Authors: Frieling Jeremy S. , Atomi Pamen Lizzie , Cook Leah M. , Yang Shengyu , Lynch Conor C. 
Published: August 2014

Abstract
Prostate cancer commonly metastasizes to bone, resulting in lesions hallmarked by a mixture of osteolysis and osteogenesis. The “vicious cycle” is the paradigm describing tumor-bone interaction, and MMPs have been implicated in regulating the bioavailability and activity of growth factors that control the cycle. We have found that MMP-3, also known as stromelysin-1 and typically generated by host/stromal cells, is differentially expressed in the prostate tumor-bone microenvironment. Based on our initial observations, we hypothesize that host derived MMP-3 expression contributes to prostate tumor growth in bone.
Using an in vivo intratibial model of prostate to bone metastases (PaIII), we found that that tumor growth and tumor induced bone remodeling were significantly mitigated (p&lt;0.05) in MMP-3 null animals compared to wild type controls. Using a candidate approach to examine potential mechanisms, we focused on parathyroid hormone related protein (PTHrP), a powerful regulator of osteoblast behavior in the vicious cycle. We identified that MMP-3 processes mature PTHrP1-36 to yield PTHrP1-16, PTHrP17-26, and PTHrP27-36 fragments in vitro. The fragments did not impact osteoblast proliferation (MTT assay) or differentiation (Alizarin red staining), however, we observed a significant increase in migration of osteoblasts and osteoblast precursors in response to 10nM PTHrP1-16. The stimulation of migration by PTHrP1-16 was significantly greater than that induced by mature PTHrP1-36. Further analysis via confocal microscopy revealed a reduction in actin stress fibers as well as variations in lamellipodia and vinculin organization of osteoblasts treated with PTHrP1-16. In addition, western blots show a reduction of myosin light chain phosphorylation suggesting that PTHrP1-16 may mediate osteoblast migration by modulating Rho-associated protein kinase (ROCK) activity.
Our data demonstrate that host MMP-3 contributes to prostate tumor growth and tumor induced changes in bone remodeling in vivo. Further, we have identified that mature PTHrP1-36 is subject to cleavage by MMP-3 resulting in PTHrP1-16, PTHrP17-26, and PTHrP27-36 fragments of which PTHrP1-16 significantly stimulates migration of osteoblasts and osteoblast precursors. Collectively, these data indicate that specific inhibition of MMP-3 and/or targeting MMP generated neo-epitopes would be efficacious for the treatment of prostate to bone metastases.
Citation Format: Jeremy S. Frieling, Lizzie Atomi Pamen, Leah M. Cook, Shengyu Yang, Conor C. Lynch. Roles for matrix metalloproteinase-3 (MMP-3) in the prostate tumor-bone microenvironment. [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 5061. doi:10.1158/1538-7445.AM2013-5061
Abstract 5063: Matrilysin cleavage of perlecan produces bioactive fragments acting as a molecular switch to alter prostate cancer cell behavior.
Authors: Grindel Brian J. 
Published: August 2014

Abstract
Perlecan/HSPG2[PLN], a large heparan sulfate (HS) proteoglycan, is expressed in the basement membrane (BM) underlying epithelial and endothelial cells. During prostate cancer (PCa) cell invasion, a variety of proteolytic enzymes are expressed that digest BM components including PLN. After proteolysis, fragments of PLN can be released into circulation. A sandwich ELISA with antibodies generated across PLN detected fragments of PLN from IG-repeat domain IV in PCa patient serum. An enzyme upregulated in invasive PCa cells, matrilysin/matrix metalloproteinase-7 (MMP-7), was examined as a candidate for PLN proteolysis both in silico and in vitro. Purified PLN showed high sensitivity to MMP-7 digestion even when fully decorated with HS or when embedded with other BM proteins. MMP-7 fragments of PLN were detected as limit peptides by western blot. While not predicted in silico, MMP-7 cleaved every subpart of recombinantly generated PLN domain IV. The resultant MMP-7 generated PLN Dm IV fragments were identified by mass spectrometry (LC-MS/MS and MALDI) and Edman degradation N-terminal sequencing. Other PCa relevant enzymes had limited ability to cleave PLN including prostate specific antigen, hepsin and fibroblast activation protein. To determine if PLN digestion affects metastatic PCa cells, C4-2B cells were seeded on plates coated with different forms of PLN. Cells on intact PLN formed large clusters of poorly adherent cells, while those on PLN digested with MMP-7 or heparitinase to remove the HS chains attached and spread within 30 minutes. Immunohistochemistry of PCa patient tissue indicates MMP-7 and PLN are in direct contact at interfaces in the stroma. We conclude that enzymatic processing of PLN in the BM and stroma as occurs in the tumor microenvironment can alter PCa cell behavior and favor cell dispersion and invasiveness.
Citation Format: Brian J. Grindel. Matrilysin cleavage of perlecan produces bioactive fragments acting as a molecular switch to alter prostate cancer cell behavior. [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 5063. doi:10.1158/1538-7445.AM2013-5063
Abstract 5071: KGP94, a small-molecule cathepsin L inhibitor with antitumor activity.
Authors: Wittenborn Thomas , Trawick Mary Lynn , Pinney Kevin G. , Chaplin David J. , Siemann Dietmar W. , Horsman Michael R. 
Published: August 2014

Abstract
Purpose: Cathepsins are a class of proteolytic enzymes recognized to play an important role in tumour progression, invasion and angiogenesis. The present study evaluated the anti-tumour activity of the small-molecule cathepsin L inhibitor KGP94 in a murine breast tumour model.
Materials and Methods: Male CDF1 mice were inoculated on the right rear foot with a C3H mammary carcinoma. A solution of KGP94 was prepared each day by dissolving in a mixture of 10% Tween 80 and 90% HEPES-buffer. It was intraperitoneally injected at 0.01ml/g mouse bodyweight. Various doses (5-20mg/kg) were administered between 5-20 days, starting either from the day of tumour implant or when tumours had reached a volume of 200mm3. Tumour response was assessed by determining the tumour growth time, which was either the time in days to reach a volume of 500mm3 (TGT500) for animals treated from the day of tumour implant, or 1000mm3 (TGT1000) for animals treated when tumours were at a volume of 200mm3. Results are listed as Mean (± Standard Error). One-way ANOVA with a posthoc Student-Newman-Keuls comparison of group means was performed, and a P&lt;0.05 was considered significant.
Results: The TGT500 for control animals was 18.3 days (± 0.4). Treating tumours with 10mg/kg for 5 days significantly increased the TGT500 to 21.9 days (± 0.7). When the time of treatment with this dose was increased to 10 or 20 days, no additional growth inhibition was observed. Varying the drug dose for this 5 days treatment period showed that the TGT500 with 5mg/kg and 20mg/kg were 23.5 days (± 1.9) and 23.4 days (± 1.1), respectively. For experiments in which treatments were started when tumours had already reached 200mm3 an effect on TGT1000 was only observed with the highest drug dose at 20mg/kg; the respective TGT1000 being 5.9 days (± 0.2) for controls and 8.3 days (± 0.7) for KGP94.
Conclusion: This synthetic, small-molecule cathepsin L inhibitor significantly delayed tumour growth, but the effect was primarily on the early phase following tumour inoculation. Such an effect suggests that KGP94 may have a role to play in inhibiting metastatic development rather than influencing the growth of established tumours.
Supported by The Danish Cancer Society, The Danish Council for Independent Research: Medical Sciences, and OXiGENE Inc.
Citation Format: Thomas Wittenborn, Mary Lynn Trawick, Kevin G. Pinney, David J. Chaplin, Dietmar W. Siemann, Michael R. Horsman. KGP94, a small-molecule cathepsin L inhibitor with antitumor activity. [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 5071. doi:10.1158/1538-7445.AM2013-5071
Abstract 5075: Targeting TSP1 and inhibiting angiogenesis in UV-induced skin cancer by apigenin.
Authors: Tong Xin , Bridgeman Bryan B. , Mirzoeva Salida , Crawford Susan E. , Volpert Olga V. , Pelling Jill C. 
Published: August 2014

Abstract
Non-melanoma skin cancer (NMSC) is a major health problem in the United States, with over two million new cases diagnosed yearly. Among many genetic and environmental factors contributed to NMSC, ultraviolet B (UVB) radiation is the major carcinogen. As with all solid tumors, angiogenesis is a necessary prerequisite for the progression and metastasis of NMSC. Thrombospondin-1 (TSP1) is the first endogenous inhibitor of angiogenesis to be identified, and its expression is markedly downregulated in epidermis following UVB irradiation and throughout distinct steps of skin carcinogenesis. Apigenin (4’, 5, 7-trihydroxyflavone), a nonmutagenic plant flavonoid, inhibits UV-induced NMSC in mice. However, the molecular mechanisms of apigenin's chemopreventive function remain elusive. For the first time, we found that apigenin restores normal TSP1 levels in UVB-irradiated skin keratinocytes in vitro and in vivo. The regulation of TSP1 expression in UVB/apigenin-treated keratinocytes occurs post-transcriptionally and is mediated by RNA-binding protein Human antigen R (HuR). Importantly, HuR has recently been demonstrated to play an important role in translation of TSP1 mRNA, and we showed that apigenin promotes cytoplasmic localization of HuR, where polyribosomal translation of TSP1 occurs. In addition, knockdown of HuR by siRNA abrogates the ability of apigenin to maintain normal TSP1 levels in UVB-irradiated keratinocytes. Furthermore, apigenin inhibits microvascular density (MVD) in superficial dermis that occurs in response to UVB irradiation. Taken together, our results demonstrate that apigenin promotes TSP1 expression in UVB-irradiated epidermis via HuR leading to inhibition of angiogenesis. Identifying TSP1 as a key target of apigenin and demonstrating its important role in chemoprevention by apigenin will provide a compelling rationale to use apigenin for maintaining the expression of protective TSP1 in the skin as a novel strategy for NMSC prevention and treatment.
Citation Format: Xin Tong, Bryan B. Bridgeman, Salida Mirzoeva, Susan E. Crawford, Olga V. Volpert, Jill C. Pelling. Targeting TSP1 and inhibiting angiogenesis in UV-induced skin cancer by apigenin. [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 5075. doi:10.1158/1538-7445.AM2013-5075
Abstract 5077: Anti-angiogenesis and anti-cancer activities of ZK002, a C-type lectin-like protein isolated from snake venom.
Authors: Yu Shan , Dai Xiangrong , Tai William C.S. , Choi Roy C.Y. , Liang Chaofan , Li Benjamin X.y. , Tsim Karl W.K. , Hsiao Wendy W.L. 
Published: August 2014

Abstract
Snake venoms contain various biologically active proteins including C-type lectins and -like proteins (CTLs), phospholipases, proteinases and metalloproteinases, that could target diverse cellular processes. Among these active components, CTLs have demonstrated antithrombotic effects through their platelet agglutination and coagulation activities. In our study, we have detected anti-angiogenesis activity from the venom of Deinagkistrodon acutus snake. The partial purified fraction of snake venom with anti-angiogenesis activity was isolated through a stepwise separation in anion-exchange and cation-exchange chromatography. At the same time, the monoclonal antibody was generated and used for further protein purification by affinity chromatography. This highly purified protein was named as ZK002. By MALDI-TOF mass spectrometry determination, the mass of ZK002 is about 30KD. By LC-MS/MS analysis, protein sequence of highly purified ZK002 was determined and compared with the Deinagkistrodon acutus snake protein database. ZK002 is a heterodimer of CTLs consisting of alpha and beta peptide chains. Using In vitro chicken embryo chorioallantoic membrane assay and human umbilical vein endothelial cell (HUVEC) tube formation assay, it showed that ZK002 exhibited an anti-angiogenesis effect. Moreover, ZK002 also demonstrated an anti-cancer effect as shown in the ApcMin/+ mouse model for colorectal cancer. Administration of ZK002 significantly suppressed the total number and the size of tumors and showed no observable adverse effect. To further elucidate the anti-angiogenesis functions of ZK002, we deduced the coding DNA sequences from the peptide sequences of the alpha- and beta-chains, then subcloned individual gene sequence into yeast and mammalian expression vectors. Results showed that the recombinant vectors express secreted peptides with the expected molecular weight. Transient transfection of the alpha- and beta-recombinant vectors individually or in combination inhibit tube formation in HUVEC cells, suggesting that both alpha- and beta-chains possess anti-angiogenesis activity. The success of cloning and expression of recombinant ZK002 would greatly facilitate the future development of ZK002 as anti-angiogenesis and anti-cancer drugs.
(This work is supported by the Innovation and Technology Fund (UIM208) of Hong Kong Government)
Citation Format: Shan Yu, Xiangrong Dai, William C.S. Tai, Roy C.Y. Choi, Chaofan Liang, Benjamin X.y. Li, Karl W.K. Tsim, Wendy W.L. Hsiao. Anti-angiogenesis and anti-cancer activities of ZK002, a C-type lectin-like protein isolated from snake venom. [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 5077. doi:10.1158/1538-7445.AM2013-5077