bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 2524: Targeting microtubule-associated protein 4 with novel small molecule CH4938056 confers antitumor activity under quasi in vivo conditions and in xenograft models
Authors: Kondoh Osamu , Saito Hidemi , Nakanishi Yoshito , Tsukaguchi Toshiyuki , Nagano Kohji , Inomata Noriyuki , Sakata Kiyoaki , Fujii Toshihiko , Satoh Yasuko , Hattori Kazuo , Niizuma Satoshi , Koyama Kohei , Okada Takehiro , Minoshima Yukinori , Kawashima Toshiyuki , Kitamura Toshio , Tsukuda Takuo , Nobuo Shimma , Arisawa Mikio , Ishii Nobuya , Aoki Yuko 
Published: June 2012

Abstract
Tumor microenvironment is a major factor influencing treatment resistance to conventional anticancer therapies. Indeed, under “quasi in vivo” conditions, with low oxygen (1%), low pH (6.5) and low glucose concentration (0.01%) to mimic the environments in grafted tumors in mice or in clinical tumors, anti-proliferative activities of some conventional anticancer agents were diminished. Here, we describe the small molecule CH4938056, which has a novel chemical structure and was identified through cell-based screening under the “quasi in vivo” conditions followed by chemical modification.
Our initial phenotypic profiling revealed that CH4938056 specifically arrests cells at the M phase and that it overcomes multiple resistance mechanisms to conventional anticancer agents including over-expression of MDR1 and BCRP. Then, after designing and identifying a water-soluble phosphate prodrug which successfully converts to CH4938056 after injection, we demonstrated antitumor efficacy of CH4938056 in a HCT116 xenograft model and a MDR1-overexpressing cancer model.
Chemo-proteomic studies and consequent biochemical analysis revealed that CH4938056 binds to microtubule-associated protein 4 (MAP4). Moreover, CH4938056 inhibited MAP4-dependent microtubule assembly in a cell free system. siRNA-mediated knockdown of MAP4 induced chromosomal misalignment in metaphase cells, which closely resembles the primary phenotype of the CH4938056-treated cells. Under the “quasi in vivo” conditions, MAP4 expression turned out to be down-regulated (since MAP4 transcription is known to be negatively regulated by p53 which is up-regulated under these conditions) and when we knocked down MAP4 with siRNA, cancer cells became sensitive to CH4938056, which altogether is consistent with the fact that CH4935056 has antitumor activity even under the “quasi in vivo” conditions. From these observations, we conclude that CH4938056 inhibits proliferation of cancer cells by targeting MAP4. Targeting MAP4 with CH4938056 offers a novel approach for the treatment of cancer, especially for patients resistant to conventional anticancer therapies.
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 2524. doi:10.1158/1538-7445.AM2011-2524
Abstract 2550: Combination of the KSP inhibitor ARRY-520 with bortezomib causes sustained tumor regressions and significantly increased time to regrowth in bortezomib sensitive and resistant models of multiple myeloma
Authors: Woessner Richard , Tunquist Brian , Walker Duncan , Rana Sumeet , Orlowski Robert , Kuhn Deborah 
Published: June 2012

Abstract
The allosteric kinesin spindle protein (KSP) inhibitor ARRY-520 has potent antitumor activity as a single agent in xenograft models of multiple myeloma, with complete response rates as high as 100%. It has shown promising signs of activity in a phase 1 trial in patients with advanced / refractory multiple myeloma, and a phase 2 study in this patient population is in progress. We report here on the striking activity of ARRY-520 in combination with bortezomib in multiple myeloma xenograft models.
We investigated the activity of the combination of ARRY-520 with bortezomib in several xenograft models of multiple myeloma that are sensitive (Kas-6, ANBL-6, and H929) and resistant (RPMI8226, JJN3, a subline of ANBL-6 made resistant to bortezomib by in vitro treatment, and a subline of RPMI8226 that acquired a PI3K activating mutation) to bortezomib. The combination of ARRY-520 with bortezomib showed additive or superadditive activity, compared to either drug alone, in 6 of the 7 models tested. Complete responses and cures were observed in several models. The Kas-6 model was particularly sensitive, with a 100% cure rate (complete response through day 100). Since previous work from our lab (Mol. Cancer Ther. 9(7), 2046, 2010) implicates MCL1 status as a predictor of response to ARRY-520 in multiple myeloma cell lines, we evaluated the effect of the ARRY-520 + bortezomib combination on MCL1 and other markers of apoptosis. Treatment with the combination resulted in elevation of the cleaved / full length PARP ratio (up to 15X), compared to tumors treated with the single agents, along with a decline in MCL1 levels that coincided with elevation of the level of a 28kd fragment of MCL1 (up to 17X). This shortened form of MCL1 has been reported to be pro-apoptotic. Thus, the cleavage of MCL1 to a proapoptotic form, leading to a decrease in survival signaling and an increase in apoptotic signaling, may play a role in the activity of the ARRY-520 + bortezomib combination. The observation that the combination remained highly active even in models that were poorly responsive to single agent bortezomib suggests that the mechanisms underlying resistance to bortezomib may be distinct from those that contribute to activity of the combination.
These results support ARRY-520 + bortezomib as a rational combination for clinical evaluation, including in patients with bortezomib-refractory disease. A phase 1 trial to evaluate the combination of ARRY-520 + bortezomib + dexamethasone is in progress.
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 2550. doi:10.1158/1538-7445.AM2011-2550
Abstract 2552: Synergistic antitumor effects of FGFR2 inhibitor with 5-fluorouracil on diffuse-type gastric carcinoma
Authors: Yashiro Masakazu , Shinto Osamu , Nakamura Kazunori , Tendo Masashige , Matsuoka Tasuku , Matsuzaki Taro , Kaizaki Ryoji , Miwa Atsushi , Hirakawa Kosei 
Published: June 2012

Abstract
Purpose: Diffuse-type gastric carcinoma carries the highest mortality because of a frequent metastasis to lymph node. S1, a 5-fluorouracil (5-FU) analog, is clinically available for gastric cancer at advanced stage. Fibroblast growth factor receptor 2 (FGFR2) is required for the proliferation of diffuse-type gastric carcinoma. The objective of this study is to clarify the benefit of a combination of S1 and kinase inhibitors including FGFR2 inhibitor Ki23057 in gastric cancer.
Experimental Design: OCUM-2MLN and KATO-III were derived from diffuse-type gastric carcinoma. MKN-7 and MKN-74 were derived from intestinal-type gastric carcinoma. MTT assay was used to examine the growth-inhibitory activity of 5 small-synthetic molecules including Ki23057, Sunitinib, Glivec, Lapatinib, or SU11274, in cells cultured with 5-FU. Combination effects of 5-FU with Ki23057 on proliferation, apoptosis, and mRNA expression were examined. S1 and/or Ki23057 were administered to murine models of diffuse-type gastric carcinoma created by the orthotopic inoculation of OCUM-2MLN cells.
Results: Ki23057 at 100 nM significantly (p&lt;0.01) inhibited the proliferation, and decreased the phosphorylation of FGFR2 in diffuse-type gastric carcinoma cells, but not in intestinal-type gastric carcinoma. Ki23057 showed synergistic anti-tumor effects for diffuse-type gastric carcinoma cells in combination with 5-FU using CalcuSyn analysis, but Sunitinib, Glivec, Lapatinib, and SU11274 did not. The combination of Ki23057 and 5-FU decreased DPD expression, and increased apoptosis rates, and p21 expression level of diffuse-type gastric carcinoma cells. The combined administration of S1 and Ki23057 significantly (p&lt;0.05) decreased orthotopic tumors as well as lymph node metastasis more effectively than S1 alone.
Conclusion: The combined treatment with 5-FU and Ki23057 produced synergistic anti-tumor effects, and is a therapeutically promising for diffuse-type gastric carcinoma treatment.
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 2552. doi:10.1158/1538-7445.AM2011-2552
Abstract 2573: Combinations of QBI-139, a clinical stage ribonuclease drug
Authors: Strong Laura E. , Kink John A. , Pensinger Daniel , Mei Baigen , Shahan Mark N. , Raines Ronald T. 
Published: June 2012

Abstract
RNA has been recognized as a drug target for cancer therapy, as evidenced by the ongoing clinical trials of RNAi and antisense therapies. An alternative approach that circumvents the delivery and stability issues of RNAi and antisense is to harness the activity of naturally occurring enzymes that degrade RNA. The ribonuclease approach is partially validated by objective clinical responses seen in clinical trials of ribonuclease (RNase) discovered in frog eggs. Our research has focused on creating variants of human RNases with the ability of frog RNase to evade the human RNase inhibitor. Diminished binding of mammalian RNases to the inhibitor have been shown to endow the RNase with the ability to kill cancer cells.
One of the RNase variants, called QBI-139, demonstrated particularly strong anti-cancer activity against a variety of tumor types in in vivo models. QBI-139 is differentiated from the frog RNase because QBI-139 is 95 % identical to a native human RNase, while the frog RNase is only 20% similar. This difference may be what has led to a significantly improved tolerability profile for QBI-139 across species. QBI-139 was selected for clinical development and is now in a Phase I trial of solid tumors.
In charting the clinical development path for QBI-139, the ability of the RNase to work in combination with a variety of standard of care agents had to be evaluated. Based in the single agent activity of QBI-139 in colon, non-small cell lung, ovarian and pancreatic cancers, the potency of QBI-139 in combination with the standard of care agents for these indications was explored.
In in vitro screening, QBI-139 has demonstrated additive and synergistic activity in combination with cisplatin, 5-FU and docetaxel. The treatments were evaluated using fixed ratios of QBI-139 and the combination drug based on their EC50 values. The Combination Index (CI) was determined using median effect analysis. A CI of 1 indicates additive effects, whereas a CI &lt; 1 indicates synergy. Synergy was demonstrated with QBI-139 in combination with cisplatin against solid tumors of non-small cell lung cancer (A549 and H1975) and an additive effect in ovarian (Ovcar-3) cancer. 5-FU and docetaxel also were synergistic with QBI-139 against solid tumors of colon (HCT-116) and ovarian (SK-OV-3) cancer, respectively.The goal of this project is development of an innovative, differentiated therapy, QBI-139, to provide clinical benefit to patients with colon, non-small cell lung and ovarian cancer, which are among the seven deadliest forms of cancer in the United States. In addition to being serious diseases, effective treatment of these cancers also represent unmet medical needs.
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 2573. doi:10.1158/1538-7445.AM2011-2573
Abstract 2576: Mechanism of action of a novel Stat3 inhibitor for cancer therapy
Authors: Buettner Ralf R. , Corzano Renzo , Lin Jianping , Vaidehi Nagarajan , Yip Richard , Chen Yuan , Jove Richard , Horne David , Williams John 
Published: June 2012

Abstract
Stat3 is a latent transcription factor that promotes cell survival and proliferation and is often constitutively active in multiple cancers. Inhibition of Stat3 signaling pathways suppresses cell survival signals and leads to apoptosis in cancer cells, suggesting direct inhibition of Stat3 function is a viable therapeutic approach. Herein, we identify a small molecule, C48, as a selective Stat3-family member inhibitor. To determine its mechanism of action, we used site-directed mutagenesis and multiple biochemical techniques to show that C48 alkylates Cys468 in Stat3, a residue at the DNA-binding interface. We further demonstrate that C48 blocks accumulation of activated Stat3 in the nucleus in tumor cell lines that over-express active Stat3 leading to impressive inhibition of tumor growth in mouse models. Collectively, these findings suggest Cys468 in Stat3 represents a novel site for therapeutic intervention and demonstrates the promise of alkylation as a potentially effective chemical approach for Stat3-dependent cancers.
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 2576. doi:10.1158/1538-7445.AM2011-2576
Abstract 2579: YK5, a small molecule inhibitor of Hsp70 and Hsc70, reveals a multifaceted role for the Hsp70 chaperones in regulating oncogenic and non-oncogenic addiction of tumors
Authors: Rodina Anna , Kang Yanlong , Taldone Tony , Patel Hardik , Patel Pallav , Caldas-Lopes Eloisi , Erdjument-Bromage Hediye , Guzman Monica , Young Jason C. , Melnick Ari , Chiosis Gabriela 
Published: June 2012

Abstract
Background. The cancerous phenotype evolves through accumulation of a large repertoire of elements that allow for increased proliferative potential, self-sufficiency in growth signals and resistance to apoptotic and antiproliferative signals. While much is now gained in understanding the many factors that lead to a malignant phenotype, little remains known on how cancer cells are able to accumulate and to survive with such complexity and high load of aberrant processes.
Study design. Here we use the novel dual Hsp70 and Hsc70 inhibitor, YK5, and its biotinylated derivative, YK55, to investigate the interactome of cytosolic Hsp70s.
Results. We show that heat shock protein 70 family members (Hsp70s) keep active conformations of key oncoproteins and inhibit the function of tumor suppressors. Hsp70s also buffer levels of activated molecules by maintaining them in a conformation that alters their dephosphorylation by phosphatases. Pharmacologic inhibition of Hsp70s by YK5 impairs oncoprotein stability and function, restores tumor suppressor activity, affects major cancer hallmarks and is selectively lethal to cancer cells. We show that enhanced affinity of YK5 for cancer cell-Hsp70s species is an essential mechanism for providing selective tumor lethality.
Conclusion. By demonstrating that pharmacologic dual inhibitors of Hsp70 and Hsc70, such as YK5, confer specific and broad tumor lethality, and interact selectively with tumor Hsp70s species, this work proposes Hsp70s inhibitors as potential anti-cancer therapeutics with a large spectrum of activity.
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 2579. doi:10.1158/1538-7445.AM2011-2579
Abstract 2591: Folate receptor alpha: A promoter of cancer cell proliferation that is independent of folate
Authors: Rybinski Katherine A. , Tomkowicz Brian E. , Kamen Barton A. , Grasso Luigi , Nicolaides Nicholas , Sass Philip , Zhou Yuhong 
Published: June 2012

Abstract
Folate receptor alpha (FRα) is over-expressed in malignant tumors of epithelial origin, particularly in ovarian cancer, but largely absent in normal tissue. High levels of protein expression in tumor cells are associated with increased proliferative capacity and enhanced chemo-resistance to Cisplatinum (CP). However, the underlying mechanism remains unclear. We sought to evaluate the biological function of FRα in CP-resistant cancer and hypothesized that alterations of FRα expression levels in drug CP-resistant cancers would result in the re-sensitization of tumor cells to CP. We first developed a human ovarian cancer cell line, IGROV-1, with increased CP resistance and found that these cells also showed an increase in FRα expression over parental IGROV-1 cells. Then, we used FOLR1 specific siRNA to completely knock-down FRα expression. Surprisingly, ablation of FRα expression did not restore sensitivity to CP but had a substantial negative impact on proliferation in both parental and CP-resistant cells. Similar phenomena were also observed when FRα was knocked-down in 786-0 cells, a human renal carcinoma line that expresses robust levels of FRα. In contrast, when we applied FRα knock-down to the normal human kidney cells HK-2 (FRα+), we observed no impairment on proliferation. One explanation of these results is that removal of FRα in cancer cells impairs the ability of these cells to uptake reduced folates, a requirement for nucleic acid synthesis and other methylation reactions. However, even pharmacological concentrations of 5-methyltetrahydrofolate, provided only partial restoration of proliferation in these cells. Taken together, these results suggest that FRα plays an essential role in the proliferation of tumor cells, but not in normal cells via a yet undefined pathway.
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 2591. doi:10.1158/1538-7445.AM2011-2591
Abstract 2595: KML001 displays vascular-disrupting properties and irinotecan-combined antitumor activities against a murine tumor model
Authors: Min Young Joo , Lee Ho Yong , Moon Chang Hoon , Cha Seung Joo , Lee Hee-Soon , Cha Hee Jeong 
Published: June 2012

Abstract
Purpose: KML001 (sodium metaarsenite) is an orally available arsenic compound that has entered phase II clinical trials in solid tumors. The aim of this study is to assess vascular-disrupting properties of KML001 and to investigate whether KML001 as VDA (vascular-disrupting agent) augments anti-tumor effects of irinotecan in a murine model of colon cancer.
Experimental Design: Female BALBc mice bearing subcutaneos CT26 colon carcinoma cells were injected intraperitoneally with KML001(10 mg/kg) or irinotecan alone, or coadministered weekly for 4 weeks. Moreover, we assessed cytoskeletal changes of HUVEC cells when treated with KML001.
Results: We observed massive necrosis in the central part of the tumor by 24 h after treated with KML001 alone and the regrowth was seen from the periphery of the tumor after 2 days. Otherwise, we observed the significant tumor growth delay when KML001 was administered either 24 hr or 72hr after irinotecan. In addition, we found that KML001 degraded tubulin in HUVEC cells, which might be related with vascular disrupting properties of KML001. Evidence of proteosome-mediated degradation was obtained by demonstrating that adding a proteosome inhibitor.
Conclusions: These results suggest that KML001 is a novel VDA, which can increase anti-tumor activities of irinotecan.
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 2595. doi:10.1158/1538-7445.AM2011-2595
Abstract 2598: RHAMM- A potential predictor of metastasis and therapeutic target in kidney cancer
Authors: Benitez Anaid , Yates Travis , Chi Andrew , Gahan Jeffrey , Bird Vincent , Lokeshwar Vinata 
Published: June 2012

Abstract
Up to 25% of patients with renal cell carcinoma (RCC) have metastasis at initial diagnosis. Current targeted therapies (e.g., Sorafenib) are not curative and the 5-year survival of these patients is &lt;10%. Molecular determinants of RCC growth and metastasis may be accurate prognostic markers for metastasis and could be targeted for therapy. We evaluated the expression of 5 genes (and their splice variants) as prognostic indicators. We also tested the therapeutic efficacy of the combination of 4-methylumbelliferone (4-MU), a non-toxic, orally bioavailable hyaluronic acid (HA) synthesis inhibitor and Sorafenib (Soraf). Tumor specimens were collected from RCC patients undergoing nephrectomy (n=81; T1, 40; T2+, 41; Grade 1, 5; Grade 2, 32; Grade 3, 25; Grade 4, 19). Nine patients developed metastasis within 24 months. Tissue-RNA was subjected to Q-PCR for HA receptors (CD44, RHAMM), chemokine receptors (CXCR4, CXCR7); and chemokines (SDF1-α,β,γ). mRNA levels were correlated with metastasis by logistic regression. Effect of 4-MU, Soraf and 4-MU+Soraf on cell proliferation, cell cycle and apoptosis was examined in RCC cells (HTB46, 786-O, ACHN, 769-P, A498) by cell counting, flow cytometry and Cell Death ELISA. Boyden chamber was used for motility assay. Effect on cell cycle, apoptosis, and HA receptor levels were evaluated by immunoblotting and Q-PCR. RHAMM expression (157±124) was 8-fold elevated in tumors which later metastasized when compared to those which did not (20.1±31.5; P=0.005). In univariate analysis age, grade, stage and RHAMM levels significantly correlated with metastasis. In multivariate analysis, only RHAMM significantly correlated with metastasis (P=0.03; chi-sq = 4.6; sensitivity 88.9%; specificity 90%). Combination of 4-MU (0.2 mM) and Soraf (2.5 or 5 μM), at non-cytotoxic doses caused 60-90% inhibition in proliferation after 48-72 h treatment and motility in RCC cells. Inhibition of cell proliferation could not be reversed by HA addition. Only the combination induced cycle arrest in late S- and G2-M phases (1.5-2.5-fold) and induced apoptosis (3-4-fold). Cell cycle arrest and apoptosis were confirmed by increased phospho-Chk1 and PARP levels. 4-MU+Soraf combination down regulated CD44 and RHAMM mRNA levels by 2- and 68-fold, respectively. RHAMM expression in RCC tissues is potentially an independent prognostic indicator for metastasis. 4-MU+Soraf combination which targets RHAMM expression inhibits RCC cell growth and motility.
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 2598. doi:10.1158/1538-7445.AM2011-2598