bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 4394: Salinomycin downregulates PDGFRβ and c-Myc in human medulloblastoma.
Authors: Wu Erxi 
Published: August 2014

Abstract
Medulloblastoma (MB) is the most common childhood brain tumor and approximately one-third of patients with MB tumors remain incurable. In a goal of search for more effective therapeutic agents to treat MB, we tested the effects of salinomycin, an anti-coccidial drug showing inhibitory effects on breast cancer stem cells with more than 100-fold potency than paclitaxel, in MB cells in vitro. In this study, we first determined the cytotoxicities of salinomycin in MB cells in vitro using cell based assays and demonstrated that salinomycin inhibits cell proliferation, induces cell death and cell cycle arrest in MB cells. We then analyzed the effects of salinomycin on the expression of some key mediators involved in cell death and cell cycle progression and demonstrated that salinomycin up-regulates the expression of cyclin A and down-regulates the expression of Bcl-2 and p21 in MB cells. Finally, we examined the effects of salinomycin on the expression of PDGFRβ and c-Myc, two potential critical therapeutic targets in MB, and found that it suppresses the expression of c-Myc and PDGFRβ in MB cells. Our data suggest that salinomycin may be used as a novel therapeutic agent to treat patients with MB.
Citation Format: Erxi Wu. Salinomycin downregulates PDGFRβ and c-Myc in human medulloblastoma. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 4394. doi:10.1158/1538-7445.AM2013-4394
Abstract 4433: DW-MR imaging as a predictive biomarker of radiosensitization of GBM through targeted inhibition of checkpoint kinases.
Authors: Williams Terence , Galbán Stefanie , Li Fei , Heist Kevin , Galbán Craig , Lawrence Theodore S. , Holland Eric C. , Thomae Tami , Chenevert Thomas , Rehemtulla Alnawaz , Ross Brian D. 
Published: August 2014

Abstract
Purpose: The inherent treatment resistance of glioblastoma (GBM) can involve multiple mechanisms including checkpoint kinase (Chk1/2) mediated increased DNA repair capability which can attenuate the effects of genotoxic chemotherapies and radiation. The goal of this study was to evaluate DW-MRI as a biomarker for Chk1/2 inhibitors in combination with radiation for enhancement of treatment efficacy in GBM.
Experimental Design: We evaluated a specific small molecule inhibitor of Chk1/2, AZD7762, in combination with radiation using in vitro human cell lines and in vivo using a genetically engineered GBM mouse model. Diffusion-weighted and T1-contrast MRI were used to follow treatment effects on intracranial tumor cellularity and growth rates, respectively.
Results: AZD7762 inhibited clonal proliferation in a panel of GBM cell lines and increased radiosensitivity in p53-mutated GBM cell lines to a greater extent compared to p53-wild type cells. In vivo efficacy of AZD7762 demonstrated a dose-dependent inhibitory effect on GBM tumor growth rate and a reduction in tumor cellularity based on DW-MRI scans along with enhancement of radiation efficacy.
Conclusion: DW-MRI was found to be a useful imaging biomarker for the detection of radiosensitization through inhibition of checkpoint kinases. Chk1/2 inhibition resulted in antiproliferative activity, prevention of DNA-damage induced repair, and radiosensitization in preclinical GBM tumor models, both in vitro and in vivo. The effects were found to be maximal in p53-mutated GBM cells. These results provide the rationale for integration of DW-MRI in clinical translation of Chk1/2 inhibition with radiation for the treatment of GBM.
Citation Format: Terence Williams, Stefanie Galbán, Fei Li, Kevin Heist, Craig Galbán, Theodore S. Lawrence, Eric C. Holland, Tami Thomae, Thomas Chenevert, Alnawaz Rehemtulla, Brian D. Ross. DW-MR imaging as a predictive biomarker of radiosensitization of GBM through targeted inhibition of checkpoint kinases. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 4433. doi:10.1158/1538-7445.AM2013-4433
Abstract 4442: Enhancement of radiation response in KRAS mutant non-small cell lung cancer cells with the MEK inhibitor GSK1120212.
Authors: Lin Steven H. , Zhang Jing , Giri Uma , Heymach John V. 
Published: August 2014

Abstract
Biomarkers that can select appropriate patient subsets for optimal treatment will likely improve personalized delivery of cancer treatment. While radiotherapy is a cornerstone for the management of non-metastatic lung cancers, there are no clinically useful biomarkers to help predict for radiation responsiveness and to help select drugs to enhance radiation sensitization in non-small cell lung cancer (NSCLC). KRAS mutations are found in 20%-30% of NSCLC and confer drug resistance. Drugs that target downstream pathways activated in KRAS mutant cells could enhance cytotoxic effects. The purpose of this study is to evaluate if the potent MEK1/2 inhibitor GSK1120212 can selectively enhance radiation response based on the genomic context in lung cancer cell lines. We selected a panel of NSCLC cell lines with or without KRAS mutations and tested their response to combinational treatment with radiation and MEK inhibitor via clonogenic survival assay. We found that GSK1120212 had no radiation enhancement effect in the three KRAS wild type (WT) cell lines tested. In contrast, in three KRAS mutant lung cancer cells, GSK1120212 dramatically reduced clonogenic survival to radiation treatment (radiation enhancement factor 1.2-1.9). We found that GSK1120212 selectively induced G1 cell cycle arrest through regulating the expression of several cell cycle regulation proteins, such as Cyclin B1, Cyclin E1 and RB. GSK1120212 also enhanced the G2/M phase arrest caused by radiation therapy and significantly decreased cell number in S phase. Ultimately, this led to cellular senescence selectively in KRAS mutant but not WT cells. At the dose chosen for this study (IC30), GSK1120212 didn't augment DNA damage or induce cell apoptosis caused by radiation. Taken together, our data suggested that MEK inhibitor GSK1120212 may have some selectivity in enhancing radiation effects in KRAS mutant lung cancer cells. A phase I clinical trial is currently ongoing to test the safety and preliminary efficacy of combining GSK1120212 and chemoradiation in locally advanced NSCLC.
Citation Format: Steven H. Lin, Jing Zhang, Uma Giri, John V. Heymach. Enhancement of radiation response in KRAS mutant non-small cell lung cancer cells with the MEK inhibitor GSK1120212. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 4442. doi:10.1158/1538-7445.AM2013-4442
Abstract 4453: Development and characterisation of AZD-8931-resistant HER-2 positive breast cancer cells.
Authors: Creedon Helen , Muir Morwenna , Hayward Larry , Brunton Valerie 
Published: August 2014

Abstract
The introduction of HER-2 directed therapies has revolutionised the management of both early and advanced HER-2 positive breast cancer. However, despite significant improvements in treatment outcomes, both inherent and acquired resistance are frequently encountered problems. Emerging evidence from early phase neo-adjuvant clinical trials, such as Neo-sphere and Neo-ALTTO, suggests that targeting multiple members of the Human epidermal growth factor receptor (HER) family is more efficacious than single target inhibition. AZD 8931 is a novel equipotent reversible tyrosine kinase inhibitor of EGFR, HER-2 and HER-3 signalling with proven pre-clinical efficacy in breast, head and neck and non-small cell lung cancers {1}.
To investigate potential mechanisms of acquired resistance to AZD-8931, HER-2 amplified SKBR-3 breast cancer cells were rendered resistant by culture with escalating doses of drug. Resistant and parental cell lines were phenotypically distinct with resistance being associated with greater cell spreading and increased cell density. Cross resistance to lapatinib, a reversible dual EGFR/HER 2 tyrosine kinase inhibitor, was demonstrated with an over 50 fold increase in IC50. Signalling changes associated with a resistant phenotype were explored with a combination of Reverse Phase Protein Array (RPPA) and western blotting. Following drug treatment, resistant cells still displayed a dose-dependent reduction in phospho HER-2 (Tyr 1248)/EGFR (Tyr 1173). However, constitutive activation of the HER 3 pathway resulted in persistent downstream signalling via the PI3K/AKT pathway and increased cell survival.
Tumorigenesis in the MMTV-Nic model is driven by mammary-specific expression of a constitutively active HER 2 transgene {2}. This model has been crossed with a strain with a floxed PTEN allele {2} and studies are currently under way to explore the role of PTEN in AZD-8931 resistance.
Citation Format: Helen Creedon, Morwenna Muir, Larry Hayward, Valerie Brunton. Development and characterisation of AZD-8931-resistant HER-2 positive breast cancer cells. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 4453. doi:10.1158/1538-7445.AM2013-4453
Abstract 4462: Resistance to selective kinase inhibitors upon epithelial to mesenchymal transition.
Authors: Wilson Catherine R. , Nicholes Katrina , Bustos Daisy , Lin Eva , Shi Lily , Kirkpatrick Donald , Settleman Jeffrey 
Published: August 2014

Abstract
Epithelial to mesenchymal transition (EMT) is a pivotal mechanism contributing to cancer metastasis and has been associated with resistance to multiple cancer therapies including targeted kinase inhibitors (TKIs). EMT has been associated with an acquired resistance to the EGFR TKI erlotinib independent of known resistance mechanisms such as secondary mutations T790M or MET amplification. RTK-addicted cancer cell lines that are induced to undergo EMT with exogenous TGF-β become resistant to their appropriate TKI. In vitro-based assays determined that the resistance is not due to exogenous TGF-β, drug efflux, or autocrine/paracrine growth factor signaling. To identify potential therapeutic vulnerabilities specifically within the mesenchymal, TKI resistant cells, we performed a small molecule screen of approximately 200 agents using the EGFR mutant non-small cell lung cancer (NSCLC) HCC827 cell line and its corresponding TGF-β-induced mesenchymal derivative line. This screen revealed that the mesenchymal cells are cross-resistant to a variety of small molecules, including TKIs and chemotherapeutic agents. However, a small number of agents showed selective growth inhibitory activity against the mesenchymal cells, with the most potent being the dual Brc-Abl and Src inhibitor, dasatinib. Within the parental HCC827 cell line, we detected a non-proliferating vimentin positive sub-population of cells. Interestingly, when the parental cell line was co-treated with erlotinib and dasatinib the entire cell population was killed and drug-resistant clones failed to emerge after prolonged treatment. To determine the mechanism underlying the resistance observed within the mesenchymal cells a proteomic analysis was undertaken, which demonstrated that the focal adhesion kinase, FAK, is the most abundant differentially phosphorylated protein in the resistant mesenchymal cells that is specifically suppressed by dasatinib. However, specific gene knock-down of FAK was not sufficient to kill the mesenchymal cells or revert their sensitivity to Erlotinib suggesting that FAK alone is not required to maintain resistance upon EMT. These findings identify dasatinib as a potential therapeutic for treatment of erlotinib resistance associated with EMT.
Citation Format: Catherine R. Wilson, Katrina Nicholes, Daisy Bustos, Eva Lin, Lily Shi, Donald Kirkpatrick, Jeffrey Settleman. Resistance to selective kinase inhibitors upon epithelial to mesenchymal transition. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 4462. doi:10.1158/1538-7445.AM2013-4462
Abstract 4467: Targeting both PI3K/mTOR and EGFR pathways leads to synergistic anti-tumor activity in erlotinib resistant non-small-cell lung cancers.
Authors: Mehta Pramod P. , Baxi Sangita M. , Walls Marlena , Chen Stella , Cheng Hengmiao , Li Gang , Smeal Tod , Yin Min-Jean 
Published: August 2014

Abstract
NSCLCs with EGFR mutations, such as a deletion in exon 19 (del E746-A750) or point mutation in exon 21 (L858R), are sensitive to TKI (gefitinib and erlotinib) treatments. However, acquired resistance to TKI therapy occurs in patients after 12-14 months. Approximately 50% of these resistant patients have developed secondary (gatekeeper) T790M mutation in EGFR; many other resistance mechanisms also have been described including a PIK3CA mutation and PTEN deletion. In this study, we characterize a dual PI3K/mTOR inhibitor, PF-4979064, in combination with a pan-ErbB inhibitor, PF-299804 (dacomitinib) in erlotinib resistant NSCLC lines NCI-H1975 (harboring EGFR and PIK3CA mutation) and NCI-H1650 (harboring EGFR and PTEN deletion). As a clinically relevant concentration of PF-299804 only induces moderate anti-tumor activity in both H1975 and H1650 cells, PF-4979064 was added in a variety of cellular and animal studies to determine whether the combination was able to achieve a synergistic induction of anti-tumor activity. Results demonstrate that the combination of PF-4979064 and PF-299804 lead to a synergistic inhibition in cell proliferation and xenograft tumor growth in both the NCI-H1975 and NCI-H1650 models. Our results further suggest that there is a rationale to examine a potential clinical development plan combining the dual PI3K/mTOR inhibitor (PF-4979064) and dacomitinib (PF-299804) in NSCLC patients who have developed resistance to erlotinib and have a concomitant PIK3CA mutation or PTEN deletion.
Citation Format: Pramod P. Mehta, Sangita M. Baxi, Marlena Walls, Stella Chen, Hengmiao Cheng, Gang Li, Tod Smeal, Min-Jean Yin. Targeting both PI3K/mTOR and EGFR pathways leads to synergistic anti-tumor activity in erlotinib resistant non-small-cell lung cancers. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 4467. doi:10.1158/1538-7445.AM2013-4467
Abstract 4475: New water-soluble and stable N-mustard-benzeneconjugates with potent antitumor activity, BO-2094, generated via leadoptimization by bioisostere approach.
Authors: Su Tsann-Long , Tala Satishkumar , Ou Tai-Hsin , Tala Kiranben , Kakadiya Rajesh , Lin Yi-wen , Chen Chi-Wei , Lee Te-Chang 
Published: August 2014

Abstract
The water solubility of drug candidate plays an important determinant of the bioavailability and supports whether a drug candidate can be successfully developed for clinical application. Previously, we have synthesized a series of water-soluble N-mustards, in which the phenyl N-mustard pharmacophore is linked to a benzamide moiety containing a hydrophilic side-chain at the meta- or para-position of the carboxamide function via a urea spacer. Of these derivatives, the water-soluble BO-1055 HCl exhibits a broad spectrum of antitumor activity and potent therapeutic efficacy against various human solid tumor (such as breast MX-1, colon HCT-116, and prostate PC-3) xenografts. To optimize the antitumor activity of BO-1055 via structural modification by bioisostere approach, we synthesized a series of new N-mustard-benzene conjugates, in which the phenyl N-mustard pharmacophore is linked to a benzene moiety via a urea linker, which can reduce the reactivity of the reactive N-mustard moiety. The benzene ring contains a variety of ω-N,N-dialkylaminoalkylamide or ω-cyclicaminoalkylamide side-chains at the meta- or para-position of the ureido linker. The tertiary amino function on the side-chain can be converted into a variety of water-soluble salts with inorganic or organic acids. The newly synthesized conjugates were subject to antitumor studies both in vitro and in tumor xenograft model. The results showed that these water-soluble conjugates exhibit a broad spectrum of antitumor activity against a panel of human leukemia and solid tumor cell growth in culture. Among these derivatives, BO-2094 [N-(4-(3-(4-(bis(2-chloroethyl)amino)phenyl)ureido)phenyl)-2-(diethylamino)acetamide], was revealed to be more cytotoxic than BO-1055 in inhibiting various tumor cell growth in vitro. It also showed that this agent is more potent than BO-1055 against human colon HCT-116, prostate PC3, and lung cancer H460 xenografts in mice. Studies on the mechanism of action revealed that BO-2094 is able to induce DNA cross-linking and cell arrest at G2/M phase. The present investigations conclude that BO-2094, a new water-soluble N-mustard-benzene conjugated with more potent therapeutic effect than BO-1055, has high potential to be selected as a candidate for preclinical antitumor studies.
Citation Format: Tsann-Long Su, Satishkumar Tala, Tai-Hsin Ou, Kiranben Tala, Rajesh Kakadiya, Yi-wen Lin, Chi-Wei Chen, Te-Chang Lee. New water-soluble and stable N-mustard-benzeneconjugates with potent antitumor activity, BO-2094, generated via leadoptimization by bioisostere approach. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 4475. doi:10.1158/1538-7445.AM2013-4475
Abstract 448: Mechanisms involved in the tumor-induced thymic involution.
Authors: Carrio-Jardines Roberto , Iragavarapu-Charyulu Vijaya , Libreros Stephania , García-Areas Ramón A. , Torroella-Kouri Marta , Lopez Diana M. 
Published: August 2014

Abstract
The thymus is a central lymphoid organ critical for the development and maintenance of an effective peripheral T cell repertoire. Most important, it provides a specialized environment for the selection of rearranged clones that will function appropriately in the adaptive immune response. T cell maturation progresses through well-defined stages in which proliferation, differentiation, and apoptosis are central to the selection of a functional TCR repertoire. During mammary tumorigenesis, there is a profound thymus involution associated with a severe depletion of the most abundant subset of thymocytes, CD4+CD8+ double positive (DP) immature cells. Thymic involution has been observed in several model systems; including graft-vs-host disease, aging, and tumor development, however, the precise mechanisms involved in this phenomenon remain poorly defined. Previous results from our laboratory have reported that the severe thymic atrophy and impaired T cell development seen in mammary tumor bearers are associated with a profound decrease in thymus size accompanied by a disrupture of the normal thymic architecture, an arrest in at least two steps of T cell differentiation, and an increase in thymic apoptosis in tumor-bearers. In our studies we have used the murine D1-DMBA-3 mammary tumor model to elucidate the exact mechanisms associated to the tumor-induced impaired T cell development and thymic involution. We have found that the disruption in the thymic architecture of tumor bearers appears to be related to a downregulated expression of hepatocyte growth factor in the medullar zone of the thymus. Moreover, the progressive increase of apoptosis in thymocytes during the tumor development is associated to a downregulation of Bcl-xL and A1, two important molecules that control programmed cell death. Additionally, the impaired T cell development observed during the tumor-induced thymic involution is associated to a profound decrease of IL-7 and IL-15, two crucial cytokines involved in T cell development; a downregulation in the expression of most of the Jak/Stat signaling proteins; and an increased expression of several suppressor of cytokine signaling (SOCS) members. Our data provides the bases for understanding the mechanisms associated to the impaired T cell development and thymic involution present in the thymuses of tumor bearers.
Citation Format: Roberto Carrio-Jardines, Vijaya Iragavarapu-Charyulu, Stephania Libreros, Ramón A. García-Areas, Marta Torroella-Kouri, Diana M. Lopez. Mechanisms involved in the tumor-induced thymic involution. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 448. doi:10.1158/1538-7445.AM2013-448
Abstract 4492: Structure-activity relationship study anti-microtubule agents targeting the colchicine site on tubulin that circumvent drug resistance.
Authors: Gangjee Aleem , Xiang Weiguo , Mooberry Susan L. , Hamel Ernest 
Published: August 2014

Abstract
The vinca alkaloids and taxanes are successful antitumor agents. However, drug resistance limits their clinical utility in cancer chemotherapy. Overexpression of P-glycoprotein (Pgp) and expression of the β-tubulin subtype, β-III tubulin, are two clinically established drug resistance mechanisms that reduce the effectiveness of these agents. In 2010, we reported that the 6-CH3 cyclopenta[d]pyrimidine scaffold affords water soluble antimitotic agents targeting the colchicine site on tubulin. Molecular modeling and docking studies of the parent compound in the X-ray crystal structure of tubulin (PDB: 1SA0) suggested that the N4-CH3 moiety involved in hydrophobic interactions with the side chain C of Lysβ254, Alaβ250 and Leuβ248. However, this binding pocket in tubulin is relatively large. We designed a variety of N4-alkyl substitutions to determine optimal size of the substituent at the N4-position for these hydrophobic interactions. Among the different substitutions at the N4 were n-propyl, i-propyl and cyclopropyl. These compounds inhibited the growth of human breast cancer cell line MDA-MB-435 in culture, with IC50’s 130, 410, and 300nM, respectively. The previously reported methyl substituent at the N4-position is the most potent analog against these cancer cells, with IC50 of 10.6 nM. Thus, increasing the size of the N4-alkyl substituent caused a decrease in the potency of the analogs indicating that groups larger than methyl may be progressively detrimental to potency. This could be due to conformational restriction of various rotatable bonds in the molecule, lack of appropriate hydrophobic interactions with the colchicine site, and/or due to other factors such as transport into the tumor cells. The experiments to distinguish among these possibilities are undergoing.
Citation Format: Aleem Gangjee, Weiguo Xiang, Susan L. Mooberry, Ernest Hamel. Structure-activity relationship study anti-microtubule agents targeting the colchicine site on tubulin that circumvent drug resistance. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 4492. doi:10.1158/1538-7445.AM2013-4492