bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 5437: The histone deacetylase (HDAC) inhibitor SNDX-275 enhances the antitumor effect of interleukin 2 (IL-2) by suppressing regulatory T cell gene expression and function
Authors: Shen Li , Pili Roberto 
Published: February 2011

Abstract
In our previous studies we have reported that the combination of IL-2 and the HDAC inhibitor SNDX-275 had an in vivo synergistic antitumor effect in an immuno-competent murine model of renal cell carcinoma (RENCA). The antitumor effect was associated with a decreased number of T regulatory cells (Tregs). In this study we observed that SNDX-275 treatment affects Tregs function by modulating the transcriptional factor Foxp3, a key regulator of Treg function. We assessed the levels of CD4+Foxp3+ cells (Tregs) by fluorescence-activated cell sorting analysis (FACS) and evaluated mRNA level of Foxp3 by QRT-PCR. Both in vitro and in vivo treatment of SNDX-275 reduced Foxp3 protein level and mRNA level in Tregs. Moreover, in the RENCA tumor mouse model, by testing peripheral blood lymphocytes, we found that the antitumor activity of SNDX-275 was associated with reduced Foxp3 protein level in Treg cells. In addition, Tregs were purified from splenocytes of SNDX-275 treated or vehicle-treated mice. Regulatory T cell functional assay showed that Tregs from SNDX-275 (5mg/kg) treated mice had a significantly reduced inhibitory activity on proliferating T effector cells as compared to Tregs from vehicle-treated mice. While 20mg/kg dose of SNDX-275 had a dramatic inhibitory effect on T effector cells, lower dose SNDX-275 (5mg/kg) had either none or moderate negative effect on T effectors. Taken together, these results indicate that SNDX-275 inhibits Foxp3 gene and protein expression, which leads to inhibition of Tregs function, in a dose dependent fashion. Tregs-suppressing features of the HDAC inhibitor SNDX-275 provides the rationale to include this agent in combinational strategies involving immuno-modulatory therapies such as IL-2 to further improve antitumor immune response.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 5437.
Abstract 5444: Polyamine-based HAT inhibitors as therapy sensitizers
Authors: Bandyopadhyay Keya , Banères Jean-Louis , Martin Aimée , Blonski Casimir , Parello Joseph , Gjerset Ruth A. 
Published: February 2011

Abstract
Histone acetylation plays an important role in regulating chromatin structure and is tightly controlled through the actions of histone acetyltransferases (HAT) and histone deacetylases (HDAC). Deregulation of either HAT or HDAC activity can affect chromatin remodeling needed to carry out its functions and contribute to cancer. While HATs are potential targets for anticancer therapeutics, the development of effective HAT inhibitors has been slow. We have examined the cellular effects of an S-substituted coenzyme A (CoA) inhibitor of histone acetylation, consisting of spermidine (Spd) linked to the S-terminus of CoA through a thioglycolic acid linkage (adduct abbreviated as Spd-CoA), as well as the effects of a truncated Spd-CoA derivative lacking the negatively charged portion of the CoA moiety. While exposure of cancer cells to Spd-CoA has little effect on cell viability, it causes a rapid inhibition of specific acetylated lysines, H3-K9 and H3-K56. That inhibition correlates with a transient arrest of DNA synthesis, a transient delay in S-phase progression, and an inhibition of nucleotide excision repair and DNA double strand break repair. Furthermore, Spd-CoA synergizes with a variety of commonly used DNA damaging chemotherapeutic agents, cisplatin (PlatinolTM) and 5-fluorouracil, camptothecin, as well as UV-C radiation to induce cancer cell killing. This suggests that a common mechanism, relevant to DNA damage, underlies the ability of histone acetylation inhibition to synergize with drugs and radiation. Normal human fibroblasts and epithelial cells are not sensitized to DNA damage by Spd-CoA due to a barrier to uptake, indicating that this differential uptake can be exploited to achieve cancer cell-specific sensitization. Furthermore, therapy sensitization occurs in both p53-null cancer cells and in cancer cells expressing wild-type p53, indicating that p53-mediated apoptosis is not required. The truncated Spd-CoA derivative displays similar but enhanced chemosensitization effects, suggesting that this class of inhibitors may be amenable to further refinement and have considerable clinical potential as a novel class of potent therapy sensitizers applicable to a broad range of conventional cancer treatments, particularly to reduce therapy toxicity and reverse therapy resistance.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 5444.
Abstract 5449: Histone deacetylase inhibitor treatment in B-cell non-Hodgkin's lymphoma - effect of ex vivo treatment on primary patient samples
Authors: Nielsen Torsten H. , Petruccelli Luca A. , Dobocan Monica C. , Petterson Filippa , Haliotis Tina P. , Assouline Sarit , Mann Koren K. , Miller Wilson H. 
Published: February 2011

Abstract
The use of histone deacetylase inhibitors (HDACis) is approved in cutaneous T-cell lymphoma, but the efficacy in other lymphomas, particularly B-cell Non-Hodgkin's lymphoma (B-NHL), remains to be established. To investigate the hypothesis that HDACis have anti-neoplastic effects in B-NHL, we have tested a series of primary B-NHL patient samples for response to the two HDACis Vorinostat (SAHA) and Panobinostat (LBH589).
Lymph node biopsies from patients with B-NHL were obtained with patient consent. A single-cell suspension was prepared and mononuclear cells isolated by Ficoll gradient separation. Lymphocytes were treated with clinically achievable doses of SAHA (2.5 μM, 5 μM and 7 μM) and LBH589 (10 nM, 25 nM and 50 nM) ex vivo for 48 hours. Treatment effect was evaluated by assays of cell viability (trypan blue staining and Cell TiterGlo luminescence assay) and cell death (propidium iodide staining analyzed by flow cytometric quantification of the sub-G0 cell population). Expression of acetylated histone H4, Bcl-2 and BCL6 was evaluated by western blot.
To date, 16 patient samples, covering a wide variety of B-NHL, have been analyzed. Diagnoses include: follicular lymphoma (n=7), diffuse large B-cell lymphoma (n=5), mantle cell lymphoma (n=1), nodal marginal zone lymphoma (n=1), hairy cell leukemia (n=1) and small lymphocytic lymphoma/chronic lymphocytic leukemia (n=1). Fifteen out of 16 patient samples analyzed showed moderate to high sensitivity to one or both HDACis tested at the given concentrations. Overall, the effects of SAHA and LBH589 were comparable. Western blots of lymphocytes treated with both types of HDACi showed increased acetylation of histone H4 compared to untreated cells. No change in Bcl-2 expression was seen (n=2) and no expression of BCL6 was detected in the samples tested for this (n=2).
Based on the data outlined herein, B-NHL is sensitive to the growth inhibitory effects of HDACis at clinically achievable doses. Building upon this pilot study, we are developing cell line models of B-NHL in order to characterize the mechanism of action of HDACis in B-NHL, including combination therapy with currently used agents such as Rituximab. A phase 2 clinical trial of LBH589 in diffuse large B-cell lymphoma, including an arm evaluating combination therapy with Rituximab, is also planned.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 5449.
Abstract 5453: Inhibition of lactate dehydrogenase A induces oxidative stress and inhibits tumor progression
Authors: Le Anne , Cooper Charles R. , Gouw Arvin , Maitra Anirban , Dinavahi Ramani , Deck Lorraine , Royer Robert , Jagt David Vander , Semenza Gregg , Dang Chi Van 
Published: February 2011

Abstract
As the result of genetic alterations and tumor hypoxia, many cancer cells avidly take up glucose and generate lactate through lactate dehydrogenase A (LDHA), which is encoded by a target gene of c-Myc and HIF-1. Previous studies with reduction of LDHA expression indicate that LDHA is involved in tumor initiation, but its role in tumor maintenance and progression has not been established. Furthermore, how reduction of LDHA expression by interference or antisense RNA inhibits tumorigenesis is not well understood. Here, we report that reduction of LDHA by siRNA or its inhibition by a small molecule inhibitor (FX11) reduced ATP levels and induced significant oxidative stress and cell death that could be partially reversed by the antioxidant N-acetylcysteine. Furthermore, we document that FX11 inhibited the progression of sizable human lymphoma and pancreatic cancer xenografts. When used in combination with the NAD+ synthesis inhibitor FK866, FX11 induced lymphoma regression. Hence, inhibition of LDHA with FX11 is an achievable and tolerable treatment for LDHA-dependent tumors. Our studies document a therapeutic approach to the Warburg effect and demonstrate that oxidative stress and metabolic phenotyping of cancers are critical aspects of cancer biology to consider for the therapeutic targeting of cancer energy metabolism.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 5453.
Abstract 5454: Novel STAT3:STAT3 small-molecule inhibitors as potential anticancer agents
Authors: Haque Mohammad R. , Zinzalla Giovanna , Kaye Samantha L. , Haider Shozeb , Basu B. Piku , Anderson John , Rahman Khondaker M. , Antonow Dyeison , Essex Samantha , Palmer Jonathan , Nkansah Edwin , Hasan Fyeza , Morgenstern Daniel , Wilderspin Andrew F. , Neidle Stephen , Thurston David E. 
Published: February 2011

Abstract
Transcription factors are important targets for cancer therapy. The inhibition of protein-protein interactions (PPIs) within signalling pathways known to be key regulators of transcriptional activity is a viable approach to novel chemotherapeutic strategies. Proof-of-concept studies in cell-culture and animal models have validated the potential of small-molecule inhibitors of STAT3 signalling in cancer therapy. In particular, the protein-protein interaction between two STAT3 monomers (i.e., the dimerisation event in the signalling cascade) has been identified as a valid target to inhibit DNA-binding and the resultant transcriptional activation. Of the approximately 20 small-molecule STAT3 inhibitors reported in the literature to date, only three are described as potential STAT3:STAT3 dimerisation inhibitors, and these have IC50 values in STAT3-expressing cell lines of between 10-90 μM.
Using in silico and medicinal chemistry-based approaches based on a published X-Ray structure of STAT3 (PDB: ID-1BG1) to identify “hit” inhibitors, a focussed library (approx. 50 members) was designed around one such “hit” and synthesized employing an efficient 4-step linear approach. Library members were then entered into a screening cascade involving initial evaluation of their ability to inhibit STAT3:STAT3 interaction in a Fluorescent Polarisation (FP)-based primary PPI binding assay. “Hit” molecules from this primary assay were then studied in two cell-based assays designed to test for STAT3 selectivity. The first was a comparative MTS assay between STAT3-expressing MDA MB231 breast cancer cells and STAT3-null colon A4 cells. The second was a luciferase reporter assay designed to measure transcription inhibition in STAT3-Luc-transformed Hela cells compared to SV40-Luc-transformed Hela control cells. A potential “lead” molecule, RH06, emerged from this screening cascade with potentially selective STAT3 inhibitory activity in the low micromolar (i.e., ∼1 µM) region. RH06 is currently being studied for its effect on STAT3 and pSTAT3 signal activation, and its potentially differential effect on upstream and downstream mediators (i.e., JAK2, Bcl-xl, Cyclin D1 and pSTAT1).
Note: This abstract was not presented at the AACR 101st Annual Meeting 2010 because the presenter was unable to attend.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 5454.
Abstract 5455: Antitumor activity of death receptor agonists for prostate cancer therapy
Authors: Shankar Sharmila , Marsh Luke , Jackman Chris , Srivastava Rakesh K. 
Published: February 2011

Abstract
Clinical trials on TRAIL and death receptor (TRAIL-R1 and TRAIL-R2) agonist antibodies are being carried out through out the world. Until today, there are no small organic molecules that bind to TRAIL-death receptors, and induce apoptosis mainly in cancer cells. Through molecular and biological approaches, we have identified novel death receptor agonists (small molecular weight organic compounds). Death receptor agonists termed as “DRAs” inhibited cell viability and colony formation, and induced apoptosis in androgen-dependent (LNCaP) and -independent (PC-3) human prostate cancer cell lines, but had no effect on human normal prostate epithelial cells and hepatocytes. The combinations of DRAs with TRAIL had additive effects on apoptosis in prostate cancer cells. Commonly used anticancer drugs further enhanced the apoptosis-inducing potential of DRAs. DRAs recruited FADD and activated caspase-8, and thus formed active TRAIL-DISC (death-inducing signaling complex) similar to that of TRAIL. DRAs inhibited the growth of PC-3 and LNCaP xenografts in nude mice, and prostate cancer growth in TRAMP mice. In vivo, DRAs inhibited tumor cells proliferation (Ki67 staining) and induced caspase-3 activity and apoptosis (TUNEL staining). Pharmacokinetics data demonstrate that DRA is stable, possesses a long terminal half-life, and meats the criteria of clinical trials. Our data suggest, for the first time, that DRAs are specific activators of death receptor pathway of apoptosis, and can be used to treat human prostate cancer. Further studies are underway to assess their clinical significance for the treatment of prostate cancer.
(Funding Support: Department of Defense, US Army)
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 5455.
Abstract 5457: High levels of fatty acid synthase expression in esophageal cancers represent a potential target for therapy
Authors: Orita Hajime , Coulter Jonathan , Tully Ellen , Montgomery Elizabeth , Abe Masaaki , Maekawa Hiroshi , Sato Kouichi , Tsurumaru Masahiko , Hino Okio , Gabrielson Edward 
Published: February 2011

Abstract
Fatty acid synthase (FAS) is overexpressed in many human cancers and is considered to be a promising target for therapy. To investigate the expression of this candidate target in esophageal cancer, we evaluated expression of FAS protein in - cases of esophageal squamous cancer, - cases of esophageal adenocarcinoma, and - cases of Barrett's esophagus with dysplasia - a lesion thought to represent a pre-invasive precursor to esophageal cancer. Using immunohistochemistry, we found significantly higher levels of FAS expression in -% of the squamous cancers and -% of the adenocarcinomas compared to normal esophageal epithelium. To evaluate the potential for inhibiting this enzyme as a treatment of esophageal cancer, we treated mice bearing xenografts of the Colo680N (squamous carcinoma) and Bic1 (adenocarcinoma) cell lines using C93, a rationally designed molecule that inhibits FAS activity. In these experiments, C93 significantly inhibited the growth of orthotopic xenograft tumors from without causing anorexia and weight loss in the treated animals. We conclude that, similar to several other common types of human cancer, FAS is expressed at very high levels in esophageal cancer, and growth of these cancers can be inhibited by pharmacological agents that target this enzyme. Moreover, this high expression of FAS is also seen in pre-invasive lesions of the esophagus, leading us to propose considering of FAS-inhibitors for purposes of esophageal cancer chemoprevention.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 5457.
Abstract 5458: Clinical and biological significance of CCR9-CCL25 axis in prostate cancer
Authors: Sharma Praveen K. , Singh Rajesh , Grizzle William E. , Singh Shailesh 
Published: February 2011

Abstract
Bone metastasis is major cause of prostate cancer (PCa) associated deaths and handful treatment alternatives are available to treat this condition. Therefore, better understating of metastatic process and identification of molecular signature on metastatic cells are urgently needed to develop therapeutic for metastatic PCa. We have shown that CCR9, a CC chemokine receptor is highly expressed by the PCa tissue and cells and play an important role in regulating the metastatic process under the influence of its natural ligand CCL25. CCL25 is also known as a thymus-expressed chemokine (TECK) and primarily expressed by the thymus, which involutes with age. Interestingly, we have observed higher serum CCL25 in PCa patients in comparison to normal healthy donors. For the first time, we show secretion of CCL25 within the primary prostate cancer tissue in a paracrine manner. Interestingly, CCL25 was highly produced by the bone marrow cells isolated from tumor bearing mice in comparison to non-tumor bearing mice. Furthermore, inhibition of CCR9-CCL25 interaction in vivo using CCL25 neutralization antibodies, showed significant inhibition of bone metastasis after intra-cardiac injection of PC3 cells and tumor establishment after intra-tibial injection. These results provide clinical and biological significance of CCR9-CCL25 axis in prostate cancer progression and metastasis. We have also demonstrated that CCR9-CCL25 axis plays an important role in lowering the chemotherapeutic efficacy by supporting anti-apoptotic and survival signals in prostate cancer cells. Interestingly, significant inhibition in tumor burden was observed, when etoposide was given in combination CCL25 neutralization antibody in comparison to both as a single agent. Our data show strong clinical and biological significance of CCR9-CCL25 axis in prostate cancer. Furthermore, these results also show that activation of CCR9-CCL25 axis may be the possible cause behind low apoptosis rate in prostate cancer cells and could be a possible cause for unsatisfactory chemotherapeutic outcomes. Therefore, developing CCR9-CCL25 directed therapies, may improve the therapeutic outcome of prostate cancer either as a single agent or in combination with other therapeutic modalities.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 5458.
Abstract 5460: Identification of c-Src as a potential therapeutic target for gastric cancer and of MET activation as a cause of resistance to c-Src inhibition
Authors: Okamoto Wataru , Okamoto Isamu , Yoshida Takeshi , Hatashita Erina , Yamada Yuki , Kuwata Kiyoko , Arao Tokuzo , Yanagihara Kazuyoshi , Nishio Kazuto , Fukuoka Masahiro , Nakagawa Kazuhiko 
Published: February 2011

Abstract
Therapeutic strategies that target c-Src hold promise for a wide variety of cancers. We have now investigated both the effects of dasatinib, which inhibits the activity of c-Src and several other kinases, on cell growth as well as the mechanism of dasatinib resistance in human gastric cancer cell lines. Immunoblot analysis revealed activation of c-Src at various levels in most gastric cancer cell lines examined. Dasatinib inhibited phosphorylation of extracellular signal-regulated kinase (ERK) and induced G1 arrest, as revealed by flow cytometry, in a subset of responsive cell lines. In other responsive cell lines, dasatinib inhibited both ERK and AKT phosphorylation and induced apoptosis, as revealed by an increase in caspase-3 activity and cleavage of poly(ADP-ribose) polymerase. Depletion of c-Src by RNA interference also induced G1 arrest or apoptosis in dasatinib-responsive cell lines, indicating that the antiproliferative effect of dasatinib is attributable to c-Src inhibition. Gastric cancer cell lines positive for activation of MET were resistant to dasatinib. Dasatinib had no effect on ERK or AKT signaling, whereas the MET inhibitor PHA-665752 induced apoptosis, in these cells. The subsets of gastric cancer cells defined by a response to c-Src or MET inhibitors were distinct and nonoverlapping. Our results suggest that c-Src is a promising target for treatment of gastric cancer, and that analysis of MET amplification might optimize patient selection for treatment with c-Src inhibitors.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 5460.