bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 4447: Nanoformulation of lapatinib for HER2-positive breast cancer patients with brain metastasis
Authors: Lee Joyce S. , Luo Juntao , Desai Sonal , Lam Kit S. , Li Tianhong 
Published: June 2012

Abstract
Despite HER2-targeting agents having a reduced risk of distant relapse in early-stage breast cancer and improved systemic control in metastatic breast cancer, relapse or progression in the brain is a common and serious concern for mortality and morbidity in these HER2-positive breast cancer patients. Currently, radiation is the only effective therapy for these patients with various clinical outcomes. Thus, there is a significant unmet need to develop new therapeutic modalities to improve treatment efficacy for these patients, especially for patients who have failed radiation therapy. The objective of this project is to develop a novel nanoformulation of lapatinib for the treatment of HER2-positive breast cancer patients with brain metastasis. Lapatinib is the only FDA-approved small molecule tyrosine kinase inhibitor targeting both HER2 and epidermal growth factor receptor (EGFR). Lapatinib anecdotally induces objective response in HER2-positive breast cancer patients with brain metastasis. Current preclinical and clinic data suggest that lapatinib has limited and variable penetration through the blood-brain barrier, which is also affected by large inter-patient variations in the bioavailability of oral formulation of lapatinib. Dr. Lam's laboratory has developed a novel nanoparticle technology using oligocholic acid based micelles (telodendrimers) to load a high dose of hydrophobic drugs for cancer treatment. We have generated a stable nanoformulation of lapatinib with drug loading up to 10 mg per mL. The average particle size is less than 20 nm in diameter, which is desirable for tumor targeting due to the preferential drug accumulation at the tumor site via the enhanced permeation and retention (EPR) effect. We are currently optimizing and characterizing the physicochemical properties of several lapatinib-loaded nanoformulations. The most stable and efficacious nanoformulation of lapatinib will be selected for further preclinical testing using in vitro and in vivo models of HER2+ breast cancer. This nanoformulation of lapatinoib will be suitable for intrathecal injection as it is not affected by individual variations in oral bioavailability and penetration through the blood brain barrier. If successful, we would design a phase I/II clinical study to determine the safety and efficacy of this new nanoformulation of lapatinib for HER2+ breast cancer patients with refractory brain metastasis or meningeal disease.
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 4447. doi:10.1158/1538-7445.AM2011-4447
Abstract 445: Fibroblast-recruited, tumor-infiltrating CD4+ T cells stimulate mammary cancer metastasis through RANKL-RANK signaling
Authors: Strasner Amy 
Published: June 2012

Abstract
Inflammatory mechanisms influence tumor development and metastatic progression. Of interest is the role of such mechanisms in metastatic spread of tumors whose etiology does not involve pre-existing inflammation or infection, such as breast and prostate cancers. We found that prostate cancer metastasis is associated with lymphocyte infiltration into advanced tumors and elevated expression of the tumor necrosis factor (TNF) family members receptor activator of NF-κB (RANK) ligand (RANKL) and lymphotoxin (LT). But the source of RANKL and its role in metastasis were not established. RANKL and its receptor RANK control proliferation of mammary lobuloalveolar cells during pregnancy through activation of IκB kinase α(IKKα), a protein kinase that is required for self-renewal of mammary cancer progenitors and prostate cancer metastasis. We therefore examined whether RANKL, RANK and IKKα are also involved in mammary/breast cancer metastasis. Indeed, RANK signaling in mammary carcinoma cells that overexpress the ErbB2 (c-Neu) proto-oncogene, which is frequently amplified in metastatic human breast cancers, was important for pulmonary metastasis. Metastatic spread of ErbB2-transformed carcinoma cells was also dependent on CD4+CD25+ T cells, whose major pro-metastatic function appeared to be RANKL production. RANKL-producing T cells were mainly FoxP3+ and found in close proximity to smooth muscle actin (SMA)-positive stromal cells in mouse and human breast cancers. The T cell-dependence of pulmonary metastasis was replaced by administration of exogenous RANKL, a procedure that also stimulated pulmonary metastasis of RANK-positive human breast carcinoma cells. These results are consistent with the adverse prognostic impact of tumor-infiltrating CD4+ or FoxP3+ T cells on human breast cancer, and suggest that targeting of RANKL-RANK signaling can be used in conjunction with other therapies to prevent subsequent metastatic disease.
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 445. doi:10.1158/1538-7445.AM2011-445
Abstract 4453: Development of a crosslinked, daunorubicin-loaded micelle with superior pharmacokinetics compared to free daunorubicin and with tunable stability
Authors: Rios-Doria Jonathan , Costich Tara L. , Carie Adam , Sill Kevin 
Published: June 2012

Abstract
Chemotherapeutic drugs are widely used for the treatment of cancer; however, use of these drugs is often associated with patient toxicity and poor delivery to the tumor. Poor delivery to the tumor can be attributed, in part, to rapid elimination of the drug by the reticuloendothelial system (RES), resulting in short circulation times. Nanoscopic drug carriers offer a promising approach to achieving improved delivery of chemotherapeutic drugs to tumors due to their size and ability to avoid RES uptake, but conventional nanoparticles are not stable in complex biological environments. This instability has resulted in little clinical success of conventional nanoparticles to date. Intezyne's IVECTTM Method, which utilizes triblock copolymers to form micelles that are stabilized to dilution in complex media, was used to encapsulate daunorubicin. The resulting daunorubicin loaded micelle's size was determined to be 60 nm by dynamic light scattering analysis. To generate stable micelles, iron (II) chloride was used to form pH-reversible iron-acetate crosslinking bonds in the outer core of the micelle. Release of daunorubicin from stabilized micelles was shown to be pH-dependent through the use of drug-release dialysis assays. Cytotoxicity studies in cancer cell lines revealed that the IC50 values of daunorubicin micelles were similar to free daunorubicin. In vivo, the AUC of daunorubicin released from stabilized daunorubicin micelles was up to 60-fold higher compared to free daunorubicin. Furthermore, the pharmacokinetic parameters were proportional to the iron (II) concentrations used for crosslinking. Repeated injections of daunorubicin micelles in rats showed little to no change in the pharmacokinetic parameters and did not exhibit accelerated blood clearance based on rat IgM ELISA measurements. These data report the development of a stabilized daunorubicin micelle that exhibits pH-dependent release and superior pharmacokinetics based on tunable crosslinking chemistry.
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 4453. doi:10.1158/1538-7445.AM2011-4453
Abstract 4469: Carbamoylating activity associated with the antitumor prodrug Laromustine inhibits angiogenesis in vitro by inducing ASK1-dependent endothelial cell death
Authors: Ghazvinian Roxanne , Praggastis V. Alexandra , Li Xianghong , Zhang Wei , Klinkerch Edmund J. , Coleman Cassandra J. , Boches Alexendar T. , Bellairs Joseph A. , Min Wang , Rice Kevin P. 
Published: June 2012

Abstract
The prodrug Laromustine (1,2-bis[methylsulfonyl]-1-[2-chloroethyl]-2-[(methylamino) carbonyl] hydrazine; Cloretazine; VNP40101M) yields methyl isocyanate and a chloroethylating species (90CE) upon decomposition in situ. Laromustine's cytotoxicity is principally attributed to 90CE via a proposed mechanism that involves interstrand DNA cross-linking. However, the role of methyl isocyanate in the antineoplastic function has not been fully defined. A derivative of Laromustine that generates only methyl isocyanate and not the chloroethylating species, 1,2-bis[methylsulfonyl]-1-[(methylamino) carbonyl] hydrazine (101MDCE), is reported here to induce endothelial cell (EC) death through a non-apoptotic pathway at both relatively low (50 μM) and relatively high (200 μM) concentrations. 90CE, which lacks carbamoylating activity, did not induce this cell fate. 101MDCE, but not 90CE, also inhibited EC tube formation in vitro, a process involved in angiogenesis, which is critical for tumor growth and metastases. To understand the molecular mechanism for 101MDCE-induced EC death, we examined signaling pathways activated by 101DMCE in ECs. We found that 101DMCE, but not 90CE, activated JNK/p38 pathways and their upstream apoptosis activator signal-regulating kinase 1 (ASK1) using Western blot analyses. In resting ECs, ASK1 forms a complex with the reduced form of thioredoxin (Trx). The single cysteine residue in ASK1 (C250) and C32 or C35 in Trx are critical for this interaction. 101MDCE effected ASK1 dissociation from Trx, but not from the phosphoserine-binding inhibitor 14-3-3, in vitro and in vivo, consistent with the known reactivity of methyl isocyanate with the sulfhydryl groups of cysteine residues. We previously reported that the carbamoylating activity of Laromustine inhibits the enzyme Trx reductase from leukemia cell extracts. We conclude that carbamoylating agents induce ASK1-dependent EC death through dissociation of ASK1 from Trx either directly by targeting the critical Cys groups in the ASK1-Trx complex or indirectly by inhibiting Trx reductase.
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 4469. doi:10.1158/1538-7445.AM2011-4469
Abstract 4475: Inhibition of aminoacid biosynthetic pathways lead to increase sensitivity to anthracyclines in Saccharomyces cerevisiae
Authors: Flores-Rozas Hernan , Mazu Tryphon 
Published: June 2012

Abstract
Anthracycline antibiotics are commonly used antineoplastic agents that provide significant therapeutic efficacy in the treatment of both solid tumors and hematological cancers. Although there is a dose-dependent response in the use of these agents, there is also a dose related toxicity associated to them. The most serious toxicity of the use of anthracyclines is chronic cardiotoxicity. To increase our knowledge of the pathways that protect cells from the cytotoxic effects of anthracyclines, we carried out a genetic screening in the eukaryotic model organism S. cerevisiae, to identify gene defects that generate cells hypersensitive to doxorubicin. Our findings indicate that inactivation of some aminoacid biosynthetic pathways hypersensitize cells to doxorubicin. Defects in the biosynthesis of threonine lead to an increase sensitivity to doxorubicin up to 1000-fold higher than wild type cells, while inactivation of serine and tryptophan pathways lead to an increase of up to 100-fold higher than wild type cells. We present evidence that accumulation of intermediate metabolites in the pathway are responsible for the hypersensitivity to doxorubicin and discuss the potential use of these compounds as chemotherapeutic enhancing agents.
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 4475. doi:10.1158/1538-7445.AM2011-4475
Abstract 4484: The dual PI3K/mTOR inhibitor, PI-103, demonstrates therapeutic efficacy in undifferentiated pleomorphic sarcoma
Authors: Zhu Quansheng , Xie Xianbiao , Nguyen Theresa , Bolshakov Svetlana , Pollock Raphael E. , Lev Dina Chelouche 
Published: June 2012

Abstract
The lack of effective systemic therapy is the major unresolved clinical problem in undifferentiated pleomorphic sarcoma (UPS)/malignant fibrohistocytoma (MFH). Novel effective therapeutic approaches are crucially needed. Given the heterogeneity of UPS/MFH, identifying common molecular deregulations amenable to therapeutic targeting would be of major importance. PI3K/AKT/mTOR pathway has been implicated in cancer progression and metastasis, and is highly activated in soft tissue sarcoma (STS). However, not much is known about this pathway in UPS/MFH specifically. We sought to assess AKT/mTOR pathway expression and activation in human UPS/MFH specimens and to evaluate whether combined inhibition of this pathway affects the proliferation and survival of UPS/MFH cells. Materials and methods: A UPS/MFH tissue microarray (TMA) consisting of 180 primary UPS/MFH samples from patients who underwent complete surgical resection has been used to detect the expression of phospho-AKT. Human UPS/MFH primary cell strains/cell lines and murine undifferentiated pleomorphic sarcoma cell lines have been established to determine the pro-tumorigenic effects of PI3K/AKT/mTOR intracellular signaling and to evaluate the efficacy of dual PI3K/mTOR inhibitor PI-103 on cell growth and survival. Results: Phospho-AKT was found to be commonly expressed in UPS/MFH. Enhanced pAKT expression levels inversely correlated with shorter 5-yr disease specific survival (DSS). Phosphorylation of AKT, p70S6K and 4E-BP1 were observed in a panel of human UPS/MFH primary cell strains/cell lines and murine UPS cell lines. PI-103 inhibited PI3/AKT/mTOR pathway signaling in UPS/MFH as observed by WB analysis resulting in marked decrease in tumor cell proliferation, enhanced G1 phase cell cycle arrest, and abrogated migration and invasion. Interestingly, PI103 treatment resulted in decreased expression and activation of the tyrosine kinase receptors EGFR and c-MET. This novel finding suggests that a feedback loop may exist between AKT/mTOR and tyrosine kinase receptor expression. Conclusions: PI3K/AKT/mTOR pathway is a common molecular deregulation in the heterogeneous group of UPS/MFH. The Dual PI3K/mTOR inhibitor, PI-103, should be further be investigated for its anti-UPS/MFH effects.
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 4484. doi:10.1158/1538-7445.AM2011-4484
Abstract 4488: Everolimus (RAD001) activity in renal and hepatocellular carcinoma cells resistant to sunitinib and sorafenib
Authors: Serova Maria , Riveiro Maria Eugenia , Dokmak Safi , Faivre Sandrine , Raymond Eric 
Published: June 2012

Abstract
Background. Acquired resistance to multikinase inhibitors stands as a major clinical challenge. The aim of present study was to evaluate the effects of everolimus in cancer cells that developed resistance to sunitinib and sorafenib.
Materials and Methods: SK-HEP1 (hepatocarcinoma), CAKI1 and 786-0 (renal carcinoma) cells were exposed to stepwise increasing doses of sunitinib or sorafenib for &gt;6 months. Antiproliferative effects of RAD001 were assessed using MTT assay. mRNA levels of selected genes were evaluated using q-RT-PCR. Protein phoshorylation (p) was assessed by western-blot analysis.
Results. CAKI-suni, 786-suni cells and SK-suni were 2-fold more resistant to sunitinib than parental cells. CAKI-sora, 786-sora, and SK-sora were also 2-fold more resistant than parental counterparts. Several changes in gene expressions were detected in cell acquiring resistance to sunitinib. For instance, protracted exposure to sunitinib led to a &gt;3-fold increase mRNA expression of CXCR4, CXCL12, MIF, PDGFRα, RET, IGF1R, VEGFR3, CDH1 in SK-suni as compared to parental SK-HEP1 cells. In hepatocarcinoma models, we showed that the CXCL12/CXCR4 axis was over expressed and functional in resistant tumor. Resistance to sunitinib and/or sorafenib was frequently associated with AKT activation. Interestingly, no cross-resistance between sunitinib (or sorafenib) and everolimus was observed at everolimus concentrations ranging 1-20µM in our models. At concentrations ranging 0.1-10µM everolimus still inhibited 20-70% cell proliferation in sunitinib- and sorafenib-resistant cells. Everolimus (0.1µM) also reduced migration of SK-suni cells. Consistent with mTOR inhibition, 0.05-0.1µM everolimus completely inhibited p-S6 activation in sensitive and sunitinib-resistant 786-suni, CAKI-suni, and SK-suni cells. Interestingly, protracted exposure to everolimus also reduced p-AKT(Ser473) activation and in a lower extent p-PKCα, an antiapoptotic factor downstream to AKT, in resistant cancer cells. Mouse experiments assessing the effects of everolimus and TKIs using those resistant models are ongoing.
Conclusions. Everolimus retains potent antiproliferative effects in hepato- and/or renal carcinoma cells developing resistance to sunitinib/sorafenib. The activated AKT/mTOR signalling observed in sunitinib/sorafenib-resistant models was inhibited by everolimus at clinically relevant concentrations. Altogether, our data suggest that everolimus is an attractive drug to counteract acquired resistance to sunitinib and sorafenib in renal and hepatocellular carcinomas.
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 4488. doi:10.1158/1538-7445.AM2011-4488
Abstract 4512: A novel orally-bioavailable salicylic acid-based small molecular Stat3 inhibitor suppress growth of human breast tumor xenografts
Authors: Zhang Xiaolei , Page Brent D.G. , Yue Peibin , Fletcher Steven , Zhao Wei , Gunning Patrick , Turkson James 
Published: June 2012

Abstract
With the critical role of aberrantly active Signal Transducer and Activator of Transcription (Stat) 3 protein in many human cancers, selective small molecular inhibitors targeting the dimerization event would be valuable as therapeutic agents and as chemical probes to clarify the complex biological functions of Stat3. By computational and structural analyses of the interaction between Stat3 and the lead dimerization disruptor, S3I-201.1066, we have designed a diverse set of analogs. We present evidence from in vitro studies that BP-1-102, a structural analog of S3I-201.1066, directly interacts with Stat3, with an affinity (KD) of 504 nM, inhibits in vitro Stat3 DNA-binding activity, with IC50 of 6.8 μM, and selectively inhibits Stat3 activity in human and mouse tumor cell lines that harbor constitutively-active Stat3. By contrast, BP-1-102 has little or no effect on pShc, pJak, pSrc, and pErk levels. Furthermore, BP-1-102 significantly and specifically suppressed the viability, proliferation, and survival of same malignant cell lines harboring aberrant Stat3 at low concentration, with little or no effect on normal NIH3T3 mouse fibroblasts or the mouse thymus epithelial stromal cells (TE-71) that do not harbor aberrant Stat3 activity. Furthermore, treatment of malignant cells harboring aberrant Stat3 activity with BP-1-102 down-regulated the expression of c-Myc, Cyclin D1, Bcl-xL, Survivin, and VEGF, which are known Stat3-regulated genes. These results together strongly suggest the anti-tumor cell effects of BP-1-102 is largely dependent on the inhibition of aberrant Stat3 activity. Significantly, BP-1-102 induced strong antitumor response in mouse xenografts of human breast cancer when administered via intravenous or oral gavage. Our studies identify a novel small-molecule that binds with a high affinity to Stat3 and that blocks Stat3 activation and function, and thereby induces antitumor response in human breast tumor xenografts harboring aberrant Stat3.
Key Words: Stat3 inhibitor, antitumor, xenograft, BP-1-102, S3I-201.1066
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 4512. doi:10.1158/1538-7445.AM2011-4512
Abstract 4519: In vitro cell and in vivo animal studies of the demethylating agent in treating HER2-amplified breast cancer
Authors: Lo Pang-Kuo , Kanojia Deepak , Chen Hexin 
Published: June 2012

Abstract
PURPOSE: The recent evidence shows that HER2-amplified breast cancers exhibit more frequent CpG island methylation than other types of breast cancers, suggesting epigenetic alterations are involved in HER2-mediated tumorigenesis. In this study, we addressed the possibility of the use of the demethylating agent (5-aza-2’-deoxycytidine, decitabine) for treatment of HER2-overexpressing breast cancer.
EXPERIMENTAL DESIGN: Two cell model systems were used in this study: murine primary Her2-overexpressing tumor cell line (A6O5, derived from the tumor naturally developed in HER2/neu transgenic mice) and human HER2-overexpressing luminal breast cancer cell line MCF7-HER2-18. Cells were cultured in regular cell culture dishes with the serum-containing medium (adhesive culture) or in ultra-low attachment dishes with the serum-free sphere culture medium (tumorsphere culture) for drug testing. Tumors developed from A6O5 cells injected into mammary glands of HER2/neu transgenic mice were used as the xenograft model. The early spontaneous mammary tumors naturally developed in HER2/neu transgenic mice (size &lt; 5 mm) were used for drug treatment.
RESULTS: The in vitro growth of A6O5 was more significantly inhibited by decitabine than that of non-tumorigenic murine mammary epithelial cells. Consistently, MCF7-HER2-18 cells were more sensitive to decitabine-induced growth suppression than its control vector-transfected cell line MCF7-Neo. These results suggest that HER2 overexpression renders cancer cells more sensitive to the effect of decitabine. Surprisingly, the tumorsphere formation of A6O5 and MCF7-HER2-18 was dramatically abrogated by decitabine, suggesting that self-renewal of cancer stem cells in these two cell lines was annihilated by decitabine. Importantly, decitabine inhibited the in vivo growth of A6O5 xenograft tumors. For proof-in-principle of this study, we treated the HER2/neu transgenic mice bearing early developing mammary tumors with decitabine. Indeed, decitabine effectively suppressed the in vivo tumor growth of the decitabine-treated group compared to that of the vehicle-treated group.
CONCLUSIONS: This study for the first time explores the potential of the demethylating agent in the treatment of HER2-amplified breast cancers using in vitro cell and in vivo animal models. These findings shed light on the translational application of epigenetic modifiers with the HER2-signaling blockers to treatment of HER2-amplified breast cancer 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 4519. doi:10.1158/1538-7445.AM2011-4519