bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 5567: Development of a novel magnetic anti-cancer drug for hyperthermic therapy.
Authors: Umemura Masanari , Fukumura Hidenobu , Sato Itaru , Feng Xianfeng , Eguchi Haruki , Ishikawa Yoshihiro 
Published: August 2014

Abstract
Background: Hyperthermic therapy is a type of cancer treatment in which body tissue is exposed to high temperature (up to 113°F). Despite of its effectiveness, it has not been widely used. One reason is that it is technically difficult to increase high temperature only in a target cancer site. To address this issue, we have developed a novel nano-magnetic particle, i.e., EI236. EI236 exhibits not only anti-cancer effect, but also ferromagnetic property. Because of its magnetism, this drug can generate heat by itself when it is exposed to an alternating current magnetic field (ACMF).
Method: We established a rabbit model of VX2 cells (rabbit osteosarcoma) grafted on legs to examine the anti-cancer and hyperthermal effects of EI236 in vivo. Rabbits were divided into five groups; 1) no treatment group 2) intra-venous (iv.) EI236 injection group 3) intra-arterial (ia.) EI236 group 4) ia. Methotrexate (MTX) injection group, and 5) ia. EI236+ACMF group. The volume of tumor was measured daily, and then the samples were harvested and evaluated histologically by HE, Ki67, and TUNEL staining.
Results: The effect of EI236 was similar to that of MTX when EI236 was injected via intra-arterial infusion. Via intra-arterial infusion was more effective than iva intra-venous infusion. When EI236 was injected and the tumor was exposed to ACMF for simultaneous chemotherapeutic and hyperthermal effects, it showed the greatest regression of tumor among all the groups examined. EI236 significantly increased necrosis as determined by HE staining, and further increased it by ACMF. Similarly, EI236 decreased cell proliferation as determined by Ki67, and further decreased it by ACMF. Moreover EI236 increased apoptosis as determined by TUNEL staining, and further increased it by ACMF. These results demonstrated that the exposure of ACMF greatly enhanced the anti-cancer effect of EI236. Taken together, EI236 exhibited simultaneous effects of anti-cancer and thyperthermia.
Conclusion: These results demonstrate that EI236 can provide us in developing a new strategy of simultaneous hyperthermo-chemotherapy in the future.
Citation Format: Masanari Umemura, Hidenobu Fukumura, Itaru Sato, Xianfeng Feng, Haruki Eguchi, Yoshihiro Ishikawa. Development of a novel magnetic anti-cancer drug for hyperthermic therapy. [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 5567. doi:10.1158/1538-7445.AM2013-5567
Abstract 5573: Discovery of potent oridonin derivatives for the treatment of breast cancer.
Authors: Zhang Yusong , Ding Chunyong , Yang Zhengduo , Chen Haijun , Chu Lili , Zhou Jia , Shen Qiang 
Published: August 2014

Abstract
Oridonin, a diterpenoid derived from the herbal Rabdosia rubescens, has been reported to have antitumor effects on various types of cancer cells. However, its relatively low aqueous solubility and bioavailability have limited its development into clinical applications. Herein, we chemically modified oridonin and generated a series of novel analogues. We then employed MTT assay to detect their effects on cell growth and a number of new and potent molecules have been identified. Among them, compounds CYD-6-86 and CYD-6-92 significantly inhibited the proliferation of human breast cancer MDA-MB-231 and MCF-7 cells. Furthermore, both compounds induced enhanced apoptosis in a dose- and time-dependent fashion when compared with oridonin. Cell cycle analysis indicated that both CYD-6-86 and CYD-6-92 induced S phase arrest in MDA-MB-231 cells and G0/G1 phase arrest in MCF-7 cells, while oridonin induced G2/M phase arrest in MDA-MB-231 and MCF-7 cells. Consistent with oridonin, Western blot analysis showed that CYD-6-86 and CYD-6-92 inhibited the expression of NF-κB and Bcl-2, and increased expression of Bax and cleaved PARP. Intriguingly, compounds CYD-6-86 and CYD-6-92 have demonstrated to suppress the growth of adriamycin-resistant MCF-7 clone, while at the same dosage oridonin displayed no effect on these cells. Our findings suggest that these new analogues may be superior to the natural product oridonin to overcome the chemo-resistance, and have great potential to be developed as novel therapeutics for the treatment of breast cancer.
Citation Format: Yusong Zhang, Chunyong Ding, Zhengduo Yang, Haijun Chen, Lili Chu, Jia Zhou, Qiang Shen. Discovery of potent oridonin derivatives for the treatment of breast cancer. [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 5573. doi:10.1158/1538-7445.AM2013-5573
Abstract 5576: Pharmacologic targeting of CtBP by established and newly designed inhibitors.
Authors: Byun Jung S. , Gardner Kevin L. 
Published: August 2014

Abstract
Breast cancer is not one single entity but a collection of multiple diseases that affect different populations with varying incidence, morbidity and mortality. Thus finding a unified marker and associated biological processes that provide an overall indication of prognosis with clear insights into therapy opportunities is critically needed. Previous our studies showed that CtBP drives invasion and metastasis by governing a mode of gene regulation that is not only reversible and strongly influenced by environmental factors, like metabolic status, but can be stably passed on to expanding clones of tumor cells. Recent studies indicate that this form of “epigenetic regulation” plays a critical role in tumor progression. Our most recent finding that CtBP expression can function as a single predictor of overall poor survival from breast cancer, independent of current criteria such as hormone receptor status, suggests that inhibiting CtBP and the pathways it controls may provide a unifying concept for improving breast cancer diagnosis and treatment.
Using Computer Assisted Drug Design (CADD), we have identified multiple potential CtBP inhibitors from a panel of library of commercially available compounds. To validate the efficacy of these inhibitors, we have used targeted assessment by quantitative gene expression and ChIP analysis of established CtBP targets. We then scored compounds that disrupt CtBP controlled processes including EMT and genome instability at a low micromolar range. We found that some compounds were able to displace CtBP from endogenous genes and reactivate repressed gene expression. A smaller subset of these was able to inhibit cellular reprogramming associated with EMT and the wound healing response.
These findings suggest that CtBP may be an effective target of pharmacological inhibition to impair tumor invasion and metastasis, and offers a proof-of-principle that will provide a foundation for more effective treatment strategies against aggressive forms of breast cancer.
Citation Format: Jung S. Byun, Kevin L. Gardner. Pharmacologic targeting of CtBP by established and newly designed inhibitors. [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 5576. doi:10.1158/1538-7445.AM2013-5576
Abstract 5591: Clinical significance of EML4-ALK fusion gene and association with EGFR and KRAS gene mutations in 208 Chinese patients with non-small cell lung cancer.
Authors: Chen Jun , Liu Hongyu , Li Ying , Li Yongwen , Yang Tong , Wei Sen , Wang Jing , Zhou Qinghua 
Published: August 2014

Abstract
EML4-ALK fusion gene has been recently identified in a small subset of non-small cell lung cancer (NSCLC) patients who respond positively to ALK inhibitors. The characteristics of EML4-ALK fusion gene in Chinese patients with NSCLC are poorly understood. Here, we report on the prevalence of EML4-ALK, EGFR status and KRAS mutations in 208 Chinese patients with NSCLC. EGFR mutations were found in 24.5% (51/208) of patients. In concordance with previous reports, these mutations were identified at high frequencies in females (47.5% vs 15.0% in males; P &gt; 0.05); never-smokers (42.3% vs 13.9% in smokers; P &lt; 0.05), and adenocarcinoma patients (44.2% vs 8.0% in non-adenocarcinoma patients; P &lt; 0.05). There were only 2.88% (6/208) patients with KRAS mutations in our study group. We identified 7 patients who harbored the EML4-ALK fusion gene (3.37%, 7/208), including 4 cases with variant 3 (57.1%), 2 with variant 1, and 1 with variant 2. All positive cases corresponded to female patients (11.5%, 7/61). Six of the positive cases were non-smokers (7.69%, 6/78). The incidence of EML4-ALK translocation in female, non-smoking adenocarcinoma patients was as high as 15.2% (5/33). No EGFR/KRAS mutations were detected among the EML4-ALK positive patients. Pathological analysis showed no difference between solid signet-ring cell pattern (4/7) and mucinous cribriform pattern (3/7) in ALK-positive patients. Immunostaining showed intratumor heterogeneity of ALK rearrangement in primary carcinomas and 50% (3/6) of metastatic tumors with ALK-negative staining. Meta-analysis demonstrated that EML4-ALK translocation occurred in 4.84% (125/2580) of unselected patients with NSCLC, and was also predominant in non-smoking patients with adenocarcinoma. Taken together, EML4-ALK translocations were infrequent in the entire NSCLC patient population, but were frequent in the NSCLC subgroup of female, non-smoker, adenocarcinoma patients. There was intratumor heterogeneity of ALK rearrangement in primary carcinomas and at metastatic sites.
Citation Format: Jun Chen, Hongyu Liu, Ying Li, Yongwen Li, Tong Yang, Sen Wei, Jing Wang, Qinghua Zhou. Clinical significance of EML4-ALK fusion gene and association with EGFR and KRAS gene mutations in 208 Chinese patients with non-small cell lung cancer. [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 5591. doi:10.1158/1538-7445.AM2013-5591
Abstract 5598: A comprehensive study to analyze tumor sensitivity to HSP90 inhibition therapy.
Authors: Riolo Matthew , Modi Shanu , Corben Adriana , Hudis Clifford , Alpaugh Mary , Chiosis Gabriela 
Published: August 2014

Abstract
There have been great advances in receptor-targeted breast cancer therapeutics. However, limited sensitivity and tumor resistance remain significant problems for many patients. To overcome these obstacles our laboratory has focused on targeting HSP90, a global mediator of oncogenic pathways involved in nearly all cancer types. Our laboratory has developed PU-H71 which selectively inhibits oncogenic HSP90 and is one of the first targeted therapies to show preclinical potent activity in the treatment of triple negative breast cancers. Here, we investigate how the complex biology of different types of breast tumors influences response to HSP90 inhibition. Our preliminary data indicate that sensitivity to PU-H71 goes beyond a tumor's receptor status and is highly driven by its intracellular protein composition. Our objective is to identify specific pharmacodynamic changes in select HSP90 onco-client proteins and regulators of apoptosis associated with HSP90 inhibition as a tool to monitor therapeutic response. Using several different breast cancer cell lines we evaluate how alterations in specific onco-client phosphorylated species as well as the induction of pro-apoptotic protein cleavage correlates to a tumor's sensitivity to HSP90 inhibition. In addition to testing cell lines, we have developed a system to investigate PU-H71 on primary tumors by treating surgery specimens ‘ex vivo’ (fresh tissue sectioning) to determine response and pharmacodynamic alterations in patient samples. Our long term goal is to establish specific pharmacodynamic changes (PD markers) that correlate to tumor sensitivity allowing us to better predict those patients more likely to benefit from HSP90 inhibition i.e. PU-H71 therapy.
Citation Format: Matthew Riolo, Shanu Modi, Adriana Corben, Clifford Hudis, Mary Alpaugh, Gabriela Chiosis. A comprehensive study to analyze tumor sensitivity to HSP90 inhibition therapy. [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 5598. doi:10.1158/1538-7445.AM2013-5598
Abstract 5625: Targeting different LRP receptors and sulfated proteoglycan by branched neurotensin provide high cancer selectivity.
Authors: Bracci Luisa , Falciani Chiara , Brunetti Jlenia , Lelli Barbara , Ravenni Niccolò , Lozzi Luisa , Depau Lorenzo , Pini Alessandro 
Published: August 2014

Abstract
In previous paper we reported on the much higher selectivity toward cancer cells and tissues of tetra-branched neurotensin peptides (NT4) compared to monomeric NT peptide. We also demonstrated that NT4 can be coupled to many different functional units for cancer cell tracing and drug delivery and can induce tumor growth reduction in animal studies. We then proposed NT4 as promising cancer selective theranostics for different human cancers, including CRC, pancreas adenocarcinoma and urinary bladder cancer. Nonetheless, multimeric binding of tetrabranched peptides, together with the chemical modification produced by coupling to the branched core, might have modified receptor selectivity of NT4 with respect to native monomeric NT and actually we had no conclusive indication on which receptor our branched NT4 peptides were binding to.
Data reported in the present paper demonstrate that synthesis of neurotensin sequence in a tetra-branched form induce a switching of receptor selectivity, by decreasing affinity to the NT high affinity receptor NTR1 and contemporarily acquiring binding to additional receptors, which produces a much higher cancer cell selectivity of NT4 with respect to monomeric NT peptides. We demonstrate here that NT4 binds sortilin and SorLa and also acquire the ability to bind different receptors belonging to the Low Density Lipoprotein Receptor Related Protein (LRP) family as well as heparin and other Heparan Sulfate Proteoglycans (HSPG).
The much higher binding of NT4 in respect to native NT to either cancel cell lines or human cancer surgical samples, as well as the higher selectivity toward human cancer tissues of NT4 is due to binding to different membrane receptors, which are very selectively expressed by many different human cancers. Moreover, our results confirm that sulfated proteoglycan can mimic the ligand binding site of different LRP receptors and indicate that targeting of multiple LRP receptors together with sulfated proteoglycans produce an extremely high selectivity towards many different human cancers.
Citation Format: Luisa Bracci, Chiara Falciani, Jlenia Brunetti, Barbara Lelli, Niccolò Ravenni, Luisa Lozzi, Lorenzo Depau, Alessandro Pini. Targeting different LRP receptors and sulfated proteoglycan by branched neurotensin provide high cancer selectivity. [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 5625. doi:10.1158/1538-7445.AM2013-5625
Abstract 5629: Prolyl isomerase Pin1 negatively regulates CDK10 stability to induce tamoxifen resistance in breast cancer.
Authors: Kharam Prem , Choi Hong Seok 
Published: August 2014

Abstract
Endocrine therapies that inhibit estrogen receptor (ER)-α signaling are the most common and effective treatment for ER-α-positive breast cancer. However, the use of these agents is limited by the frequent development of resistance. The aim of this study was to elucidate the mechanisms by which downregulation of CDK10 expression confers resistance to tamoxifen in breast cancer. Here, we show that peptidyl-prolyl isomerase Pin1 downregulates CDK10 protein as a result of its interaction with and ubiquitination of CDK10, thereby affecting CDK10-dependent Raf-1 phosphorylation (S338). Pin1-/- mouse embryonic fibroblasts (MEFs) show higher CDK10 expression than Pin1+/+ MEFs, whereas CDK10 protein was downregulated in the rescued Pin1-/- MEFs after reexpression of Pin1. Pin1 silencing in SKBR-3 and MCF7 cells increased the CDK10 expression. In human tamoxifen-resistant breast cancer and tamoxifen-resistant MCF7 cells, immunohistochemical staining and immunoblotting analysis shows an inverse correlation between the expression of CDK10 and the degree of tamoxifen resistance. There was also a positive correlation between the high level of P-Raf-1 (Ser338) and Pin1 in human tamoxifen-resistant breast cancer and tamoxifen-resistant MCF7 (TAMR-MCF7) cells. Importantly, 4-OH tamoxifen (4-OHT), when used in combination with overexpressed CDK10 or Raf-1 inhibitor, increased cleaved PARP and DNA fragmentation to inhibit cologenic growth of MCF7 cells and tamoxifen-resistant MCF7 cells, respectively. On the basis of these findings, we suggest that the Pin1-mediated CDK10 ubiquitination is a major regulator of tamoxifen-resistant breast cancer cell growth and survival.
Citation Format: Prem Kharam, Hong Seok Choi. Prolyl isomerase Pin1 negatively regulates CDK10 stability to induce tamoxifen resistance in breast cancer. [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 5629. doi:10.1158/1538-7445.AM2013-5629
Note: This abstract was not presented at the AACR Annual Meeting 2013 because the presenter was unable to attend.
Abstract 5660: Cell-free generation and characterization of ErbB2-nanoparticle conjugates.
Authors: He Wei , Saldana Matthew , Scharadin Tiffany , Gellner Candice , Li Yuanpei , Lam Kit , Carraway Kermit , Henderson Paul , Coleman Matthew 
Published: August 2014

Abstract
We have developed a rapid process for cell-free production of full-length ErbB2, a receptor tyrosine kinase that contributes to the onset and progression of breast and other tumor types. The receptor is solubilized and stabilized via incorporation into nanolipoprotein particles (NLPs). NLPs are discoidal structures, approximately 20 nm in diameter, that arise from the self-assembly of apolipoproteins around a phospholipid bilayer that acts as a mimic of the cell membrane. The ErbB2-NLP complex was soluble and could be recognized by antibodies, such as Trastuzumab, that indicate the presence of correctly folded ErbB2 extracellular domains. Kinase function was confirmed using Lapatinib, which inhibited tyrosine autophosphorylation during cell-free synthesis. The cell-free synthesis and biochemical characterization data support the potential use of ErbB2-NLPs and related variants for novel biochemistry and drug screening studies.
Citation Format: Wei He, Matthew Saldana, Tiffany Scharadin, Candice Gellner, Yuanpei Li, Kit Lam, Kermit Carraway, Paul Henderson, Matthew Coleman. Cell-free generation and characterization of ErbB2-nanoparticle conjugates. [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 5660. doi:10.1158/1538-7445.AM2013-5660
Abstract 5676: Discovery of novel benzo[b][1,4]oxazin-3(4H)-ones as poly(ADP-Ribose)polymerase inhibitors.
Authors: Gangloff Anthony R. , Brown Jason , De Jong Ron , Erickson Philip , Grimshaw Charles , Hixon Mark , Jennings Andy , Kamran Ruhi , Kiryanov Andre , O'Connell Shawn , Taylor Ewan , Vu Phong 
Published: August 2014

Abstract
Poly(ADP-ribose) polymerase (PARP) is a critical DNA repair enzyme involved in DNA single-strand break repair via the base excision repair pathway. PARP inhibitors sensitize tumors to DNA-damaging agents and also inhibit the growth of cancers with BRCA1/2 loss. The synthesis, enzymatic, cellular & pharmacodynamic activities of a series of PARP-1 inhibitors with a novel 1,4-benzoxazin-3-one scaffold are described. A small screening fragment was elaborated through structure-based drug design, ultimately producing several vectors for optimization including interaction with a hydrophobic shelf and extension into the back pocket. The synthesis of 40 compounds is outlined. Optimization of the screening fragment improved LLE's to &gt; 5.0. Several of the resulting inhibitors displayed greater than 1000-fold enhancement of temozolimide (TMZ)-mediated DNA damage in cellular assays. Pharmacodynamic effects in SW620 tumor bearing nude mice demonstrated inhibition of poly-ADP-ribosylation through 24 hours following a single dose.
PARP-1 Binding Potencies and Efficiency Metrics for Benzoxazinones 2-3CmpdaR1R2R3PARP-1 Kd (uM)PARP-1 LLE2aHHH&gt;500-2dMeHH322.32gMeMeH&gt;500-2bHH6-Formyl1702.02fHH6-Ethyl1002.03aHH6-PhenylNHCH2262.23bHH6-BenzylNHCH2113.53cMeH6-BenzylNHCH25.23.23dHH6- (4-(Me2N)piperidine)CH2153.03eMeH6- (4-(Me2N)piperidine)CH20.0964.63fHH6- (4-(Phenyl)piperidine)CH20.2963.43gMeH6- (4-(Phenyl)piperidine)CH20.0463.73hMeH7- (4-(Phenyl)piperidine)CH2101.43iHH6- (4-(4-chlorophenyl)-1,2,3,6-tetrahydropyridine)CH20.0154.53jMeH6- (4-(4-chlorophenyl)-1,2,3,6-tetrahydropyridine)CH20.0034.93kMeH7- (4-(4-chlorophenyl)-1,2,3,6-tetrahydropyridine)CH21000.23lEtH6- (4-(4-chlorophenyl)-1,2,3,6-tetrahydropyridine)CH21000.1  Enzymatic and Cellular Activity for Benzoxazinones 10CmpdR1R2R3PARP-1 IC50 (nM)Cell EC50 w/TMZ (uM)Cell EC50 w/o TMZ (uM)Cell PF5010aHHMe2915141.010bHHEt2215422.810cHClEt1841002010dMeHMe1711756.810eMeHEt699410.410fMeHcPr3351002010gOMeHMe29272519.310hOmeHEt23161519.410iOMeHcPr30161621010jMeClMe4914453.210kMeClEt8914473.410lMeClcPr760.0143430010mMeMeMe389788.710nMeMeEt569556.110oMeMecPr52181005.610pOmeMeMe360.06100166710qOMeMeEt320.0144440010rOMeMecPr1470.0277385010sOEtMeMe350.0226130010tOEtMeEt550.02100500010uOEtMecPr410.021005000ABT-888---16316056AZD-2281---60.0616660MK-4827---350.2031160
Citation Format: Anthony R. Gangloff, Jason Brown, Ron De Jong, Philip Erickson, Charles Grimshaw, Mark Hixon, Andy Jennings, Ruhi Kamran, Andre Kiryanov, Shawn O'Connell, Ewan Taylor, Phong Vu. Discovery of novel benzo[b][1,4]oxazin-3(4H)-ones as poly(ADP-Ribose)polymerase inhibitors. [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 5676. doi:10.1158/1538-7445.AM2013-5676