bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract A80: Metronomic cyclophosphamide induces macrophage recruitment in regressing human and rat gliosarcoma xenografts
Authors: Doloff Joshua C. , Waxman David J. 
Published: June 2012

Abstract
Metronomic chemotherapy has shown improved therapeutic activity over conventional schedules, both in preclinical studies and in initial clinical trials for several malignancies. Metronomic cyclophosphamide treatment (140 mg/kg BW every 6 days) induces dramatic, near-complete regression of established xenografts of human U251 and rat 9L gliosarcoma in s.c. scid mouse models, whereas maximum tolerated dose cyclophosphamide effects moderate tumor growth delay without sustained regression. Metronomic cyclophosphamide-induced regression of 9L tumors is accompanied by a reduction in microvessel density, suppression of CD31 expression, induction of the anti-angiogenic factor thrombospondin-1 (TSP1), and impaired drug uptake. These findings are consistent with the high intrinsic sensitivity of proliferating endothelial cells to metronomic chemotherapy shown by others, and with the prevailing view that anti-angiogenesis is a major factor in the therapeutic effectiveness of metronomic chemotherapy. However, VEGF receptor inhibition induces substantially greater anti-angiogenesis in these tumor models, yet does not induce major tumor regression. Presently, we investigate whether non-anti-angiogenic mechanisms may contribute to the observed regression of U251 and 9L gliosarcomas, and demonstrate metronomic cyclophosphamide-induced host macrophage recruitment. This recruitment is associated with induction of the mouse (host) factors PEDF (pigment epithelium-derived factor; Serpinf1) and PAI-1 (plasminogen activation inhibitor-1; Serpine1), with the levels of PEDF RNA being strongly correlated (r=0.89) with TSP1 RNA in large sets of 9L and U251 tumors isolated various times after initiation of metronomic cyclophosphamide therapy. Notably, PAI-1 and TSP1 are both expressed by tumor-associated macrophages. Metronomic cyclophosphamide also induced Fas, which stimulates macrophage recruitment during inflammation, and the macrophage marker CD68, supporting the involvement of tumor-associated macrophages in the response to metronomic chemotherapy. These findings highlight the ability of metronomic chemotherapy to induce macrophage recruitment, thereby activating innate immunity leading to regression of established gliosarcomas and potentially other tumor types. Supported in part by NIH grant CA49248 (to DJW).
Citation Information: Mol Cancer Ther 2009;8(12 Suppl):A80.
Abstract A82: HHER2-positive breast cancer cells resistant to trastuzumab and lapatinib lose reliance upon HER2 and become sensitive to the multitargeted kinase inhibitor sorafenib
Authors: Capellero Sonia , Valabrega Giorgio , Cavalloni Giuliana , Zaccarello Gianluca , Petrelli Annalisa , Migliardi Giorgia , Milani Andrea , Neia Caterina Peraldo , Gammaitoni Loretta , Favero Francesco , Moggio Aldo , Giordano Silvia , Aglietta Massimo , Montemurro Filippo 
Published: June 2012

Abstract
HER2 targeting with trastuzumab has changed the prognosis of breast cancer patients carrying amplification and/or overexpression of this oncogene. Despite this progress, however, resistance to trastuzumab occurs in the vast majority of patients. Newer anti-HER2 therapies, like the dual tyrosine-kinase inhibitor (TKI) lapatinib, show antitumor activity in a limited proportion of patients, indicating that HER2 can be still exploited as a target after trastuzumab failure. However, due to the high proportion of patients that fail to respond to these alternative strategies, it is reasonable to assume that cells escaping HER2 targeting may rely on alternative pathways not involving HER2 to sustain their growth. Their knowledge is relevant for exploiting new therapies. To investigate this hypothesis we generated a human HER2 overexpressing breast cancer cell line resistant to trastuzumab and lapatinib (T100) and we have characterized it genetically and molecularly.
In T100 cells, the previously proposed mechanisms of resistance to HER2 inhibitors did not explain cell escape. Notably, silencing HER2 by shRNA did not affect the growth of T100 cells, suggesting loss of reliance upon HER2. Among the alternative pathways that we explored, altered levels of the antiapoptoptic proteins Mcl-1 and Survivin were observed. This suggested the possibility of targeting resistant cells with the multitarget inhibitor sorafenib. Moreover, sorafenib, nearly inactive in parental cells, strongly inhibited the in vitro growth of T100 cells.
In conclusion, we provide a new model where the activation of HER2 independent mechanisms sustains the growth of tumor cells, significantly increasing the sensitivity to sorafenib.
Citation Information: Mol Cancer Ther 2009;8(12 Suppl):A82.
Abstract A83: Liposomal doxorubicin induces Golgi-dependent apoptosis in hormone-refractory prostate cancer cell lines (HRPC)
Authors: Fabbri Francesco , Carloni Silvia , Brigliadori Giovanni , Ulivi Paola , Tesei Anna , Montanari Marco , Amadori Dino , Silvestrini Rosella , Zoli Wainer 
Published: June 2012

Abstract
Purpose: The current efficacy of HRPC therapy is disappointing and new agents and therapeutic modalities are urgently required. The aims of the present work were to examine the mechanisms of action and the in vitro activity of liposomal doxorubicin in HRPC cell lines.
Methods: Doxorubicin (Doxo) and liposomal Doxo (Myocet®) activity was assessed by SRB test, and apoptosis by TdT assay, in DU145 and DU145-R HRPC cell lines. Intracellular drug incorporation and localization was analyzed by fluorescence image microscopy, CD95 and GD3 expression by cytofluorimetry, and protein marker alterations by Western blot.
Results: Myocet® showed a higher cytotoxic activity than Doxo in both cell lines, particularly in docetaxel-resistant DU145-R cells after a 72-h exposure, with 70% of apoptotic cells at 1/10 of the plasma peak concentration. In addition, cytofluorimetry and fluorescence microscopy revealed that Myocet® achieved higher intracellular concentrations than Doxo. The liposomal anthracycline formulation was found to concentrate primarily in the Golgi apparatus and induced a significant increase in the expression of CD95 death receptor, GD3 ganglioside, and caspase-2 and -3 in both cell lines. Interestingly, Myocet® also induced a stronger Mcl-1 downregulation than Doxo, although this was more pronounced in the parental DU145 cell line.
Conclusions: Myocet® demonstrates a remarkable activity in HRPC cells, particularly in those previously resistant to Doxo, probably due to its high intracellular drug concentration and Golgi localization. Myocet® appears to have two mechanisms of action: a conventional anthracycline-induced DNA damage-dependent apoptosis, and a Golgi-dependent cell death pathway, confirmed by the increase in CD95, GD3 and caspase-2 and -3 expression. Our results strengthen the hypotheses that the Golgi apparatus may act as a stress sensor, and that organelles other than mitochondria may trigger cell death, further proof that combinatorial targeting of diverse cell death pathways may improve the efficacy of anti-cancer strategies. In conclusion, our data advocate further evaluations of Myocet® as a second line treatment for advanced HRPC.
Citation Information: Mol Cancer Ther 2009;8(12 Suppl):A83.
Abstract A85: Discovery of highly potent and selective B-Raf Kinase inhibitors
Authors: Wang Xiaolun , Berger Dan M. , Salaski Edward J. , Torres Nancy , Hu Yongbo , Jeremy Levin I. , Powell Dennis , Wojciechowicz Donald , Collins Karen , Frommer Eileen 
Published: June 2012

Abstract
B-Raf kinase, a serine/threonine protein kinase, is a component of RAS-Raf-MEK-ERK signaling pathway and plays a central role in cell growth and survival. B-Raf mutations have been found in about 8% of all cancers with the highest incidence in melanomas (66%). Thus a potent Raf inhibitor could have a significant impact in treating cancers that are dependent on this pathway for survival and proliferation signaling. As part of our program to prepare potent and structurally novel B-Raf kinase inhibitors, we designed a series of substituted pyrazolo[1,5- ]pyrimidines. Molecular modeling studies were utilized to validate the preparation of this series, as well as to optimize analogs to ultimately provide B-Raf inhibitors with subnanomolar IC50s. The modeling result also suggested these compounds bind to the active conformation of B-Raf. These pyrazolo[1,5- ]pyrimidine derivatives have moderate selectivity for B-Raf vs. C-Raf. Selected examples were screened for inhibition of a panel of 24 kinases and found to be highly selective. In addition to their enzymatic potency, the cell antiproliferative activities of these inhibitor were evaluated in B-Raf mutant cell lines (A375,WM266-4) and a cell line with wild type B-Raf (Caco-2). Selective inhibition of the B-Raf mutant cell lines with IC50 values less than 10 nM was observed for the most potent compounds. Finally, protein immunoblot analyses confirmed the inhibition of this MAPK signaling pathway by these analogs.
Citation Information: Mol Cancer Ther 2009;8(12 Suppl):A85.
Abstract A86: Design, synthesis, and SAR of focal adhesion kinase (FAK) inhibitors
Authors: Roberts Walter Gregory , Berliner Martin , Coleman Kevin , Emerson Erling , Griffor Matt , Hulford Catherine , Jani Jitesh , Kath John , LaGreca Susan , Lin Jing , Lorenzen Marianne J. , Marr Eric , Martinez-Alsina Luis , Patel Nandini , Richter Daniel , Roberts Erika , Autry Christopher , Ung Ethan , Felix Vajdos , Vetelino Beth , Wessel Matthew , Whalen Pamela , Xu Huiping , Yao Lili 
Published: June 2012

Abstract
Focal adhesion kinase (FAK) is a non-tyrosine kinase that localizes to focal adhesion plaques. It is activated in response to intergin binding to cellular ligands and when phosphorylated inhibits anoikis allowing for anchorage independent cell growth. Recent studies have shown increased FAK expression and phosphorylation status in many types of invasive and aggressive human tumors strongly suggesting FAK is a possible target for anticancer chemotherapy. Literature, in house HTS and de novo studies identified 2, 4-diaminopyrimidines as potent FAK inhibitors. Early SAR efforts quickly determined that smaller substituents, particularly CF3, were optimal in the C5 position. Parallel medicinal chemistry strategies were executed for the C2 and C4 positions. These studies suggested that substituted aryl and fused heteroaryl groups at the C2 position in conjunction with substituted phenyl and heterocycles at the C4 position imparted optimum activity and metabolic stability. Inhibitor-FAK co-crystal structures were utilized to guide in the SAR strategy around the 2, 4-diaminopyrimidine template which afforded several lead compounds. The team's effort culminated in the advancement of PF-562,271 as a potent and reversible inhibitor of FAK (kinase IC50 of 2 nM and cell IC50 of 5 nM) that is &gt; 100x selective against a long list of non-target kinases. In summary, detailed SAR studies were executed on the 2, 4-diaminopyrimidine templates that produced potent inhibitors of FAK with improved ADME properties, and identified a novel and potent series of FAK inhibitors that are selective against most other kinases and have shown activity in clinical trials. This poster will present design, synthesis, challenging chemistry, optimization, and complete inhibitor chemical structures of lead analogs.
Citation Information: Mol Cancer Ther 2009;8(12 Suppl):A86.
Abstract A92: Chemoprevention of small cell lung carcinomas in mice by the retinoid X receptor agonist bexarotene
Authors: Wang Yian , Wen Weidong , Yi Yijun , Zhang Zhongqiu , Lubet Ronald A. , You Ming 
Published: June 2012

Abstract
In the present study, we examined the effect of bexarotene (Targretin) and budesonide in chemoprevention of small cell lung carcinoma (mSCLC) using a lung specific knockout model of Rb1 and p53. Upon treatment with bexarotene, tumor incidence, number, and load were significantly reduced (p &lt; 0.05). Budesonide treatment trended to inhibition, but the effect was not statistically significant (p &gt; 0.05). Immunohistochemical staining indicated that bexarotene treatment decreased cell proliferation and increased apoptosis in tumors. The Rb1/p53 gene targeted mouse appears to be a valuable model for chemopreventive studies on human small cell lung cancer (hSCLC). Our results indicate that the retinoid X receptor (RXR) agonist bexarotene may be a potent chemopreventive agent in this cancer type.
Citation Information: Mol Cancer Ther 2009;8(12 Suppl):A92.
Abstract A93: Topical ISC-4 for the prevention of melanoma
Authors: Sharma Arati , Nguyen Natalie , Nguyen Nhung , Sharma Arun , Desai Dhimant , Huh Sung Jin , Amin Shantu , Robertson Gavin P. 
Published: June 2012

Abstract
New strategies are urgently needed to prevent development of melanoma. Currently, surgical excision is the mainstay for eliminating early melanocytic lesions or preventing development of more aggressive cancer. However, use of sunscreen or body lotions containing topical agents with chemopreventive efficacy could be potentially useful for preventing cancer development. Therefore, novel topical chemopreventive agents with negligible systemic toxicity to prevent melanocytic lesion development would be a highly significant. In order to meet this unmet medical need, potent anti-melanoma agents called isoselenocyanates (ISC) have been developed from naturally occurring isothiocyanates (ITC), which are derived from plants. In these agents, sulfur has been replaced with selenium and the alkyl side chain has been lengthened from 1 or 2 to 4 or 6. The chemopreventive efficacy of ISC-4 for preventing melanoma development was evaluated in a human skin melanoma model containing early or advanced stage melanocytic lesion cell lines. Cumulative topical application of ISC-4 resulted in a &gt;75% reduction in melanoma nodule developed in 3-D human skin reconstructs. Histological examination of drug treated skin reconstructs confirmed the chemopreventive efficacy without any obvious damage to skin cells. Furthermore, topical application of ISC-4 also effectively prevented melanoma tumor development in animals by ∼70% at 3. 83 mM with negligible toxicity compared to vehicle control. Mechanistically, ISC-4 decreased melanoma tumorigenesis causing an 3-fold increase in apoptosis by reducing pAkt3 and pPRAS40 levels and triggered caspase-3/7 activity. Furthermore, ISC-4 treatment reduced G0–G1 phase cells (30–40% decrease), and increased G2-M population by 50–60%. A 15-fold increase in the sub-G0–G1 cell population was also observed upon ISC-4 treatment compared to vehicle control treated cells. Thus, ISC-4 is a potent selenium-containing topical chemopreventive agent with significant potential to prevent melanocytic lesion development.
Citation Information: Mol Cancer Ther 2009;8(12 Suppl):A93.
Abstract B100: The expression of thioredoxin-interacting protein (Txnip): Modulators, mechanisms and functions
Authors: Yu Faxing , Luo Yan 
Published: June 2012

Abstract
Thioredoxin interacting protein (Txnip) is a multifunctional protein involved in regulation of cell cycle events and cellular metabolism; the expression of the Txnip gene is down-regulated in a large range of cancer cells and up-regulated in diabetic and pre-diabetic patients. Therefore, Txnip might be a link between metabolism and cancer development, and the study of regulatory mechanism(s) that governs Txnip expression has important clinical relevance.
The expression of Txnip is induced by glucose, which is mediated by an earlier defined carbohydrate response element (ChoRE) on Txnip promoter and its associated transcription factors, MondoA (or its homolog, ChREBP) and Max-like protein X (MLX). Here, we show that the transcription of the Txnip gene is induced by an array of adenosine-containing molecules, of which an intact adenosine moiety is necessary and sufficient. When cells are treated with adenosine-containing molecules, the glucose uptake is inhibited and cell cycle progression is retarded, probably attributed to enhanced Txnip expression. The induction of Txnip expression by adenosine-containing molecules is in a glucose-dependent manner, and MondoA and MLX are known to convey stimulatory signals from extracellular molecules to the Txnip promoter. Therefore, the regulatory role of adenosine-containing molecules is exerted via amplifying glucose signaling, hence suggesting that these molecules may modulate the kinetics of glucose homeostasis. To gain more knowledge about the regulation of Txnip expression, we have also studied the underlying regulatory mechanisms of glucose and adenosine-containing molecules on Txnip expression in details. An additional ChoRE on the promoter of Txnip gene has been identified, and this ChoRE is able to recruit MondoA and MLX in a similar fashion as the previously identified ChoRE in vitro and in vivo. Both ChoREs function cooperatively to mediate optimal Txnip expression under glucose or adenosine-containing molecules treatment. However, these two ChoREs are not sufficient to mediate the induction of Txnip expression by glucose or adenosine-containing molecules, and two CCAAT boxes, both can recruit nuclear factor Y (NF-Y) to the Txnip promoter, are also required for the induction. We also found that the function of ChoREs and associated factors is contingent on tandem CCAAT boxes, in that the occupancy of the Txnip promoter by the CCAAT box-associated NF-Y is a prerequisite for efficacious recruitment of MondoA/MLX to ChoREs under glucose stimulation. Such a strategy suggests a synergy between NF-Y and MondoA/MLX in enhancing Txnip expression, which leads us to propose a model for the glucose-dependent Txnip expression mediated by dynamic chromatin changes in response to diverse physiological inducers.
Citation Information: Mol Cancer Ther 2009;8(12 Suppl):B100.
Abstract B105: Axl is an essential epithelial-to-mesenchymal transition-induced regulator of breast cancer metastasis and patient survival
Authors: Gjerdrum Christine , Tiron Crina , Høiby Torill , Stefansson Ingunn , Haugen Hallvard , Sandal Tone , Collet Karin , Li Shan , McCormack Emmet , Gjertsen Bjørn Tore , Micklem David , Akslen Lars , Glackin Carlotta , Lorens James 
Published: June 2012

Abstract
Metastasis underlies the majority of cancer-related deaths. Hence, furthering our understanding of the molecular mechanisms that enable tumor cell dissemination is a vital health issue. Epithelial-to-mesenchymal transitions (EMT) endow carcinoma cells with enhanced migratory and survival attributes that facilitate malignant progression. Characterization of EMT effectors is likely to yield new insights into metastasis and novel avenues for treatment. We show that the presence of the receptor tyrosine kinase Axl in mammography-detected primary breast cancers independently predicts strongly reduced overall patient survival, and matched patient metastatic lesions show enhanced Axl expression. We demonstrate that Axl is strongly induced by epithelial-to-mesenchymal transition in pre-malignant mammary epithelial cells that establishes an autocrine signaling loop with its ligand, Gas6. Using epi-allelic RNA interference analysis in metastatic breast cancer cells we delineated a distinct threshold of Axl expression for mesenchymal-like in vitro cell invasiveness, and to form tumors in foreign and tissue engineered microenvironments in vivo. Importantly, Axl knockdown completely prevented the spread of highly metastatic breast carcinoma cells from the mammary gland to lymph nodes and several major organs, and increased overall survival, in two different optical imaging-based experimental breast cancer models. Thus, Axl represents a novel downstream effector of tumor cell EMT that is required for breast cancer metastasis. The detection and targeted treatment of Axl-expressing tumors represents an important new therapeutic strategy for breast cancer.
Citation Information: Mol Cancer Ther 2009;8(12 Suppl):B105.
Abstract B117: Expression of c-MET and related oncogenic signals in formalin-fixed paraffin-embedded human tumors
Authors: Cousens Laura , Waghorne Carol , Rodig Scott J. , Gu Xiubin , Zhao Xiaolan , Yu Yi , Chang Edward , Chan Thomas C.K. 
Published: June 2012

Abstract
Background: Hepatocyte growth factor (HGF) and its receptor tyrosine kinase c-MET are often dysregulated in cancer. Stimulation of the HGF/MET signaling pathway can lead to increased cell migration, proliferation, and angiogenesis and is associated with highly invasive malignant cancers. Oncogenic activation of the c-MET pathway occurs by gene amplification, mutation, or autocrine/paracrine stimulation.
Methods: We have examined the expression of total c-MET and the active, phosphorylated forms of MET and associated cellular signals in a panel of solid human tumors by immunohistochemistry (IHC).
Results: Total c-MET is expressed in a wide variety of human tumors including breast, lung, colorectal, pancreatic, liver, glial and testicular cancers. Phospho-MET (p-c-MET) and phospho-focal adhesion kinase (pFAK, a downstream signal of MET) are expressed in a subset of c-MET expressing tumors. Table 1 includes preliminary results.
Conclusions: Detection of p-c-MET and p-FAK in archival formalin fixed paraffin embedded tumors by IHC staining is possible, and we have identified a subset of tumors where HGF/MET activation is evident. These tumors would be an important indication for c-MET targeted antitumor therapies.
Table 1 Percentage of human tumors that express c-MET biomarkers Positive IHC Staining Tumors Total Tumor Type c-MET (N) p-c-MET (N) p-FAK (N) breast 96% (23) 61% (23) 65% (23) lung (NSCLC) 75% (36) 50% (36) 61% (36) colorectal 85% (20) 50% (20) ND pancreas 85% (55) 64% (53) 58% (55) Liver 91% (22) 14% (22) 18% (22) glioma 83% (18) 39% (18) 39% (18) Testis 65% (30) 23% (30) 45% (28) ND = not done
Citation Information: Mol Cancer Ther 2009;8(12 Suppl):B117.