bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 2763: Combination therapy of an acid-sensitive albumin-binding prodrug of doxorubicin (INNO-206) and an albumin-binding prodrug of methotrexate (AW054) that is cleaved by cathepsin B and plasmin induces complete remissions against pancreatic cancer in vivo (MiaPaca-2)
Authors: Kratz Felix , Azab Samar S E E A , Zeisig Rainer , Fichtner Iduna , Warnecke Andre 
Published: August 2012

Abstract
Pancreatic cancer is the fourth most common cause of cancer death across the globe. Pancreatic cancer has a poor prognosis. For locally advanced and for metastatic disease, which collectively represent over 80 % of individuals, median survival is approximately 10 and 6 months, respectively. Gemcitabine and 5-fluorouracil that have been approved for this indication have a poor response rate with a benefit in overall survival for a small population of treated patients of up to 2 months on average. Thus there is an unmet medical need for treating this tumor indication more effectively. INNO-206, the (6-maleimidocaproyl)hydrazone of doxorubicin (DOXO-EMCH) is an albumin-binding prodrug of doxorubicin with acid-sensitive properties that has shown objective responses in a phase I study, and phase II studies are scheduled in sarcoma for 2011/2012 (see www.cytrx.com). For treating essentially chemoresistant pancreatic cancer, we preclinically investigated a combination of two albumin-binding prodrugs, i.e. the albumin-binding prodrug INNO-206 and an albumin-binding prodrug of methotrexate, AW054, that is cleaved by two proteases that are over-expressed in solid tumors, cathepsin B and plasmin. In the pancreatic carcinoma xenograft model MiaPaca-2 both INNO-206 and AW054 were administered simultaneously (i.v.) in a three weekly schedule at half the maximum tolerated dose (MTD) of the respective prodrug, i.e. 3 x 12 mg/kg for INNO-206 (doxorubicin equivalents) and 3 x 10 mg/kg (methotrexate equivalents). Compared to doxorubicin (dosed at the MTD of 3 x 6 mg/kg) or methotrexate (dosed at the MTD of 3 x 125 mg/kg) or the combination of the two free drugs (3 x 3 mg/kg for doxorubicin and 3 x 62.5 mg/kg for doxorubicin) which only showed moderate antitumor effects over control animals treated with saline, the combination of the two albumin-binding prodrugs produced complete remissions and an acceptable body weight loss of −13 %. Immunohistochemical staining with CD31 that makes up a large portion of endothelial cell intercellular junctions was moderate to good in control tumors indicating a sufficient vascularity for the albumin-bound forms of the prodrugs to accumulate in the tumor via the EPR effect. This encouraging in vivo result is an impetus for investigating further combinations of albumin-binding prodrugs with other anticancer agents.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 2763. doi:1538-7445.AM2012-2763
Abstract 2765: Combination strategies for management of ovarian cancer using doxorubicin and withaferin A
Authors: Kakar Sham S. , Gupta Ramesh C. , Fong Miranda Y. 
Published: August 2012

Abstract
Ovarian cancer is the 5th cause of cancer death in women with a mortality rate of 70%. Main treatment options include cytoreductive surgery with platinum-based therapy. However, 70% of patients relapse due to the carcinomas becoming platinum-resistant. As an alternative method, doxorubicin (Dox) is used for the treatment of several cancers, including ovarian. However, due to severe side effects, Dox is used as a second-line treatment strategy despite better patient response rates. To overcome this problem, we developed a novel treatment strategy that combines Dox with Withaferin A (WFA). WFA has been used as an anti-inflammatory and anti-bacterial compound in traditional Indian medicine. More recently, it has gained attention as an anti-cancer compound to prevent tumor growth, angiogenesis, and metastasis. We propose that combination of Dox with WFA will enhance the therapeutic effect of Dox so a lower dose of Dox can be used and many side-effects avoided. We used epithelial ovarian cancer cell line A2780 as our in vitro model. Based on our results, combination of Dox with WFA increased cell death over Dox or WFA alone measured by MTT assays. In particular, combination of Dox 200nM with WFA 2μM resulted in 90-95% cell death after 48 hr of treatment. Early apoptosis marker Annexin V-FITC was used to confirm these results as well as TUNEL assay for DNA damage. In addition, we have studied the signaling mechanism responsible for cell death through the inactivation of pro-survival Akt pathway. We demonstrated that down regulation of mTOR/p70S6K leads to autophagy and confirmed this with transmission electron microscopy, autophagy marker LC3B, and cleaved caspase 3. We have also validated this combination therapy in vivo using a xenograft model of ovarian cancer and showed reduction in tumor growth and weight as well as reduced Ki67 and CD31 staining. Mice tolerated receiving low dose of Dox (1 mg/kg) and combination Dox (1mg/kg) + WFA (2 mg/kg), whereas mice receiving high dose of Dox (9 mg/kg) did not tolerate treatment and died within 6 six days of treatment. Three dimensional tumor growth studies showed that treatment of tumors with Dox and WFA suppressed tumors growth by 80% within 3 days of treatment compared to untreated tumors. This work was supported by a grant from NCI CA124630 (SSK).Three dimensional tumor growth studies were performed in association with Vivo Biosciences Inc., Birmingham, AL.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 2765. doi:1538-7445.AM2012-2765
Abstract 2898: Intracellular dissociation of polymer coating from nanoparticles
Authors: Chen Hongwei , Zou Peng , Paholak Hayley , Sun Duxin 
Published: August 2012

Abstract
Polymer-coated nanoparticles are widely used for drug delivery in cancer therapy. However, it is not known whether the polymer coating will be disrupted in the lipid bilayer or intracellular space. Our current work suggests that the polymer coating of inorganic nanoparticles is disrupted after internalization by cancer cells. Single dispersed red quantum dots (QDs) labeled with 5-FAM (green) (D = 28 nm) were incubated with cancer cells (PC-3) and imaged via fluorescence microscopy. Initially the 5-FAM-labeled polymer coating was attached to the QDs and its green fluorescence was quenched when the nanoparticles were internalized from 2 to 4 hrs, but 5-FAM-labeled polymer became separated from the QDs once they are inside lysosome of cells and its fluorescence suddenly visible from 8 hrs. The fluorescence ratio (5-FAM/QDs) were increased by 29-fold after 8 h incubation compared to 2 h. The fluorescence quenching effect was compared to free PEG-5-FAM mixed with QDs, which only exhibited a 44% decrease in 5-FAM quenching. In addition, the intracellular dissociation of polymer coating from QD loaded micelles (D = 300 nm) was also observed. Furthermore, when labeled amphiphilic polymeric micelles encapsulate hydrophobic iron oxide nanoparticles (IONPs) with the hydrophobic dye BODIPY-TMR (red), double quenching was observed by encapsulated nanoparticles and the hydrophobic region inside the micelles by 8-fold fluorescence reduction. The BODIPY-TMR-labeled nanoparticles also showed polymer dissociation inside of cancer cells after 24 h incubation. These results suggest that polymer coating is stable in the lipid bilayer and it is dissociated from nanoparticles in the lysosome of cancer cells. These data will provide guidance for intracellular drug delivery using polymer coated nanoparticles.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 2898. doi:1538-7445.AM2012-2898
Abstract 2899: Doxorubicin-mitomycin co-loaded polymer lipid nanoparticle enhanced efficacy against breast tumor and decreased toxicity as compared to Doxil
Authors: Prasad Preethy , Shuhendler Adam , Cai Ping , Sun Mei , Liu Peter , Bistrow Rob , Rauth Andrew , Wu Xiao 
Published: August 2012

Abstract
Background: Multidrug resistance acquired by cancer cells and the dose-limiting toxicity of anti-cancer drugs are contributing factors to the failure of cancer chemotherapy. Doxorubicin (Dox) -Mitomycin C (MMC) co-loaded stealth polymer lipid hybrid nanoparticles (DMsPLN) was developed to overcome these problems and demonstrated anti-cancer synergy in vitro. The purpose of the study is to evaluate in vivo efficacy and safety of DMsPLN in a breast cancer model. Method: The efficacy and systemic toxicity of DMsPLN were evaluated against clinically used Doxil in mice bearing murine or human mammary carcinomas. DMsPLN were administered intravenously at 50 mg/m2 doxorubicin single dose or once every 4 days for 4 cycles. Tumor size was measured as function of time to determine therapeutic efficacy of the treatment and systemic toxicity was monitored by repeated measurement of body weight. Results: Significant difference in the efficacy of DMsPLN relative to Doxil was observed in both sensitive and resistant tumor models. A clear enhancement of tumor growth delay (TLD) was evident with both single and 4 times doses of DMs PLN. In single dose and 4x dose DMsPLN groups, the TGD were significantly improved to 100% and 300% in the sensitive tumor model. In the resistant tumor model, the TGD ranged from 30%-130% for the single dose and the 4x dose DMsPLN, respectively. 10% of the mice showed complete tumor disappearance in DMs PLN and 25% complete tumor disappearance was observed in DMs PLN 4x group in the sensitive tumor model. 11% of the mice showed complete tumor disappearance in both DMs PLN and in DMs PLN 4x group in the resistant tumor model. In addition to enhanced efficacy, none of the toxicity associated with Doxil treatment were observed in single or 4x DMsPLN treatment. Conclusions: DMsPLN demonstrated enhanced efficacy and reduced toxicity over Doxil in aggressive mouse models of sensitive and resistant breast cancers. Therefore, DMsPLN may provide clinically relevant, more aggressive anti-cancer interventions.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 2899. doi:1538-7445.AM2012-2899
Abstract 2912: Development of potent SHP2 inhibitors for in vivo studies
Authors: Ge Yiyu , Lawrence Harshani R. , Chen Liwei , Scott Latanya M. , Sebti Said M. , Lawrence Nicholas J. , Wu Jie 
Published: August 2012

Abstract
The Src homology-2 domain-containing protein tyrosine phosphatase-2 (SHP2) is a positive transducer of growth factor, cytokine, integrin, and hormone signaling pathways which regulates processes such as cell proliferation, differentiation, adhesion, migration, and apoptosis and plays a pivotal role in growth factor and cytokine signaling. Gain-of-function SHP2 mutations are associated with various kinds of leukemia, and solid tumors. This makes SHP2 an attractive target for anticancer therapy. We are developing SHP2 inhibitors as novel anticancer drugs. Previously, we have reported on SPI-112 and its methyl ester prodrug SPI-112Me. However, the poor solubility of SPI-112Me has become an obstacle for in vivo studies. In ongoing study, we generate SPI-112 analogs to further improve physicochemical properties of these SHP2 inhibitors, such as solubility and cell permeability. To this aim, we synthesized SPI-112 derivatives containing various phosphotyrosine mimics and their prodrugs. SPI-112 derivatives of SHP2 inhibitors having improved properties have been obtained in this effort.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 2912. doi:1538-7445.AM2012-2912
Abstract 294: Sox2 remodels the tumor microenvironment via recruitment of Tregs
Authors: Xu Yingxi , Mou Wenjun , Chen Yanan , Wang Lina , Xiang Rong , Li Na 
Published: August 2012

Abstract
Recent study showed that Sox2 gene, a key stem cell gene that maintains the pluripotency properties of embryonic stem cell (ESC) and cancer stem cell (CSC) plays an important role in the tumorigenesis and metastasis process of various types of tumor, however its regulatory effect on tumor microenvironment (TME) is still elusive. In this study, we established a BALB/c mice model xenografted with a mice breast cancer cell line-4T1 with down-regulation of Sox2 gene (4T1-shRNA-Sox2). We found that down-regulation of Sox2 inhibits the growth of tumors with a modulated immunomicroenvironment, which was reflected by the increased number of CD3+CD8+ T cells and expression level of Th1 cytokines, such as TFN-γ and decreased number of Foxp3+ Tregs and expression level of Th2 cytokines such as IL4, IL6 and IL10. In addition, the reduced expression level of vascular endothelial cell marker CD31 and lymphatic vessel marker Lyve-1 was also revealed in the 4T1-shRNA-Sox2 xenografted tumors. We further demonstrated that Sox2 modulates the TME by recruiting Tregs. By using real-time RT-PCR, we found the cytokines contributing to recruitment of Tregs, such as CCL1, CCL22, CCL28 and Cxcl12 reduced after Sox2 downregulation. In addition, the mRNA expression level of transcriptional factor NF-κB and its co-transcriptional factor RelA which controlled the expression of CCL1, CCL22 and CCL28 were also reduced. Consequently, our study revealed the functional interaction between tumor cells and the immunocytes in TME by demonstrated that Sox2 gene in tumor cells recruited Tregs to influence the tumor microenvironment thus promotes the growth of tumor.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 294. doi:1538-7445.AM2012-294
Abstract 2941: Inhibition of proteasome deubiquitinating activity as a novel cancer therapy
Authors: D'Arcy1 Pádraig , Brnjic1 Slavica , Olofsson Maria H. , Fryknas Marten , Larsson Rolf , Linder Stig T. 
Published: August 2012

Abstract
Tumor cells display enhanced sensitivity to disruptions in the ubiquitin-proteasome system making this an attractive target for the development of anti-cancer therapies. Ubiquitin-tagged substrates are degraded by the 26S proteasome; a multisubunit complex comprising a proteolytic 20S core particle (20S CP) capped by 19S regulatory particles (19S RP). The 20S CP has evolved as an important target for anti-cancer drug development, resulting in the approval of bortezomib (Velcade®) for the treatment of multiple myeloma. We have identified the small molecule b-AP15 as a novel class of proteasome inhibitor that functions by abrogating the deubiquitinating (DUB) activity of the 19S RP (D'Arcy, Brnjic et al., Nature Medicine Epub Nov 6 2011). b-AP15 inhibits the activity of two 19S RP-associated DUBs, UCHL5 and USP14. Consistent with DUB inhibition, treatment with b-AP15 caused the accumulation of polyubiquitinated proteins with higher molecular weight compared to bortezomib treatment and induced a stronger proteotoxic response. Short exposures were sufficient for induction of apoptosis by the compound. Importantly, apoptosis induction by b-AP15 differed from that of bortezomib by being insensitive to disruptions of the p53 tumor suppressor and insensitive to overexpression of the intrinsic apoptotic suppressor Bcl-2. b-AP15 shows strongest activity on colon and glioma tumor cell lines and is less active on non-transformed cells. Treatment with b-AP15 inhibited tumor progression in human and mouse tumor in vivo models of breast, lung, colon, head & neck carcinoma and inhibited organ infiltration in an acute myeloid leukemia (AML) model. Our results suggest that inhibiting the DUB activity of the 19S RP may be a novel target for the treatment of cancer.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 2941. doi:1538-7445.AM2012-2941
Abstract 297: Effect of hypoxia on the expression of the T cell co-inhibitory ligands B7-H3 and B7-H1 in cancer
Authors: Smallwood Chelsea A. , Barsoum Ivraym B. , Graham Charles H. 
Published: August 2012

Abstract
Escape from adaptive immunity is important for malignant progression. B7-H3 and B7-H1 ligands provide co-inhibitory signals to T cells resulting in T cell anergy or apoptosis. Their expression has been shown to increase in cancer cells and to correlate with disease progression. Tumour hypoxia is a major contributor to the spread of cancer and resistance to radiation and chemotherapy. We proposed that hypoxia results in the up-regulation of the B7 molecules B7-H3 and B7-H1, thus contributing to immune escape. Using breast and prostate cancer cell lines, we investigated whether hypoxia increases the expression of these ligands and, if so, whether the transcription factor hypoxia-inducible factor-1 (HIF-1) is required for this hypoxic effect. We incubated MDA-MB-231 breast cancer cells and DU145 prostate cancer cells in standard culture conditions (20% O2, 37°C, 5% CO2), hypoxic conditions (0.5% O2, 37°C, 5% CO2), or with 100μM CoCl2 (known to stabilize HIF-1α) for 24 hours. Our findings revealed that B7-H3 expression is not increased in hypoxia. However, hypoxia and exposure to CoCl2 increased B7-H1 expression, which correlated with the levels of HIF-1α accumulation. Furthermore, HIF-1α knockdown attenuated B7-H1 mRNA levels. These results indicate a role for hypoxia in the up-regulation of B7-H1 on cancer cells, thus potentially contributing to immune escape of cancer cells.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 297. doi:1538-7445.AM2012-297
Abstract 2973: Adhesion of tumor cells to ECM microarrays identifies novel ECM interactions in metastasis
Authors: Reticker-Flynn Nathan E. , Malta David F. Braga , Winslow Monte M. , Xu Mary J. , Lamar John M. , Hynes Richard O. , Jacks Tyler E. , Bhatia Sangeeta N. 
Published: August 2012

Abstract
Extracellular Matrix (ECM) interactions play an essential role in all phases of tumorigenesis and metastasis. Here, we report a novel ECM microarray platform for investigating the combinatorial effects of ECM adhesion on cancer metastasis. This platform is composed of micropatterned spots of nearly 800 unique ECM combinations, and can be used to measure cellular adhesion, proliferation, marker expression, or any other phenotypic responses that can be queried by microscopy. Using a genetic model of lung adenocarcinoma (KrasLSL-G12D/+;p53flox/flox), we tested the adhesion of cell lines derived from tumors throughout the stages of tumor progression. We found that the adhesion profiles of primary tumors and their metastases could be distinguished by Euclidian clustering whereas gene expression profiles of the same cells could not. In particular, we identified combinations of ECM molecules that exhibited preferential adhesion to either the metastatic or primary tumor cell lines. Histological examination of tissues from mice bearing the autochthonous tumors confirmed that the primary tumor-associated molecules are present in the lungs but not the sites of metastases. Conversely, metastasis-associated ECM molecules were not present in the primary tumors, but were expressed at the metastatic sites. From the known integrin-ECM interactions, we then identified several integrins as playing a functional role in ECM interactions during lung cancer metastasis. Flow cytometry confirmed higher expression of these candidates on the cell surface of the metastatic lines than the primary lines. Knockdown of integrin expression in the metastatic cells by shRNAs reduced the adhesion of the cells to the cognate ECM molecules in vitro, confirming a functional role in our phenotypic assay. Additionally, abrogation of cell-ECM interactions through inhibition of contact between the metastasis-associated molecules and the receptors on the metastatic cells prevented metastases from seeding in vivo. Thus, ECM microarrays offer a novel platform for the phenotypic characterization of tumor cells from different stages of tumor progression, identification of key ECM interactions, and the identification of potential therapeutic targets in cancer metastasis. In the future, we will apply the ECM Microarrays for the stratification of patients to assist in diagnostics and treatment guidance.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 2973. doi:1538-7445.AM2012-2973
Abstract 2975: Transgenic mouse model of Twist1-induced metastasis reveals genes highly prognostic for human hepatocellular carcinoma
Authors: Bellovin David I. , Tran Phuoc T. , Adam Stacey J. , Gentles Andrew J. , Wang Xin W. , Felsher Dean W. 
Published: August 2012

Abstract
Hepatocellular carcinoma (HCC) is a top global cancer health concern due to its high rate of mortality and increasing incidence. HCC lethality is largely attributable to its poor response to existing therapy and frequent diagnosis at late stage of disease, consequently resulting in HCC that progresses to local invasion and distant metastasis. Expression of Twist1 has been correlated with cancer invasion and metastasis, but a causal role has yet to be established for autochthonous tumors. Here, we report a new conditional transgenic mouse model of Twist1- and MYC-induced primary hepatocellular carcinoma (HCC). Expression of MYC alone produced primary tumors, but failed to induce metastasis, while Twist1 co-expression with MYC caused extra-hepatic metastases to the lymph nodes, spleen, peritoneum, and lungs. Moreover, Twist1 expression caused an increase in circulating tumor cells (CTCs). Combined Twist1 and MYC inactivation resulted in sustained regression of both primary and metastatic HCC as shown by X-ray computed tomography (micro-CT) and bioluminescence imaging (BLI) and the suppression of metastasis as measured by a loss of CTCs. Importantly, gene expression profiling illustrated that our mouse model of Twist1/MYC-induced liver cancer was representative of human HCC. Moreover, we exploited the Twist1-induced progression to identify a gene signature in Twist1/MYC tumors that is highly predictive of metastasis in human HCC patients, as well as prognostic for overall survival. Hence, we show that Twist1 expression can causally induce stepwise disease progression to metastasis in primary HCC, allowing for the identification of a gene signature that is highly predictive of clinical outcome in human liver cancer.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 2975. doi:1538-7445.AM2012-2975