bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract LB-1: PKR promotes genetic instability and evolution of MDS to acute leukemia in mice by negatively regulating DDR and DNA repair in a novel mechanism
Authors: Cheng Xiaodong , Byrne Michael , Bennett Richard Lynn , May Stratford William 
Published: May 2015

Abstract
The interferon-inducible, dsRNA-dependent protein kinase, PKR, is reported to be involved in diverse cytoplasmic functions. However, PKR has recently been reported to be expressed in the nucleus of high-risk MDS and leukemia patients but its nuclear function is not known.
We confirm that increased nuclear activated PKR does occur in AML cell lines compared to normal MEF and bone marrow stem/progenitor cells. Increased nuclear PKR is associated with impaired DNA damage response (DDR) and double strand break (DSB) repair following ionizing irradiation (IR). Knock-down and pharmacological inhibition of PKR reveals that activated nuclear PKR may function to suppress the γ-H2AX response characteristic of DDR following IR. Mechanistically, we find that nuclear PKR binds and co-immunoprecipitates with ATM in a mechanism that inhibits ATM phosphorylation. This leads to inefficient initiation of DDR (as measured by retarded γ-H2AX response) as well as inhibition of interaction between ATM, γ-H2AX, and MRN as part of the DDR complex. As a result, activated nuclear PKR retards DDR and leads to insufficient DSB repair as detected by prolonged Olive Tail Moment in a neutral Comet assay. However, since DNA repair can be restored by inhibiting PKR (by either knock-down or treatment with a PKR inhibitor), this supports a negative regulatory role for PKR in DDR and DSB repair Additional studies further demonstrate that PKR may block DDR by inhibiting ATM activity indirectly by binding with and activating PP2A, a known ATM protein phosphatase. Furthermore, in support of PKR inhibiting DSB repair, in vivo studies reveal that age-related or IR-induced genetic instability is more prevalent in PKR Tg vs WT mice and markedly lower in PKR knock-out mice as measured by the loss of GPI-linked CD24 on reticulocytes (a measure of increased somatic mutation rates due to loss of X-linked GPI activity). Interestingly, an increased somatic mutation rate and a more rapid evolution from MDS to acute leukemia is observed for double transgenic TgPKR/NHD13 vs Wt/NHD13 mice, which is significantly higher than evolution observed in PKRnull/NHD13 mice. Collectively, these data identify a novel function for PKR in suppressing DDR and DSB repair, which may enhance genetic instability and play a fundamental role in the evolution of MDS to acute leukemia.
Citation Format: Xiaodong Cheng, Michael Byrne, Richard Lynn Bennett, Stratford William May. PKR promotes genetic instability and evolution of MDS to acute leukemia in mice by negatively regulating DDR and DNA repair in a novel mechanism. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr LB-1. doi:10.1158/1538-7445.AM2014-LB-1
Abstract LB-100: Discovery of HM61713 as an orally available and mutant EGFR selective inhibitor
Authors: Lee Kwang-Ok , Cha Mi Young , Kim Mira , Song Ji Yeon , Lee Jae-Ho , Kim Young Hoon , Lee Young-Mi , Suh Kwee Hyun , Son Jeewoong 
Published: May 2015

Abstract
Introduction: Activating mutations of EGFR are well known as oncogenic driver mutations in lung adenocarcinoma. Currently, EGFR TKIs including Gefitinib and Erlotinib are used as the first line therapy in NSCLC patients harboring EGFR activating mutations. However, drug resistance caused by T790M mutation limits the efficacy of these 1st generation EGFR TKIs. Currently, some of the next generation EGFR TKIs are under investigation for the treatment of lung cancer patients having T790M mutation. In our current presentation, to obtain HM61713, an EGFR mutant selective inhibitor, as a clinical candidate and the evaluation of HM61713 for mutant EGFR cancer model will be introduced.
Method: Novel analogues were designed and synthesized to find active compounds for the T790M mutation as well as EGFR activating mutations with good selectivity over wild- type EGFR. Finally, HM61713 was selected as a clinical candidate through multi-optimization processes including both in vitro and in vivo pharmacologcal studies.
Results: HM61713 was designed as an irreversible kinase inhibitor having a Michael acceptor, which covalently binds to a cysteine residue near the kinase domain of mutant the EGFR. In a cell wash out test, HM61713 inhibited phospho-EGFR for a long duration with a half-life of over 24 hours. From in vitro study, HM61713 showed potent activities for H1975 (L858-T790M) and HCC827 (exon 19 del.) with GI50 values of 9.2 nM and 10 nM, respectively. Instead, it showed low potency for H358 (wild type EGFR NSCLC) with GI50 of 2,225 nM. In xenograft studies using H1975 and HCC827, HM61713 resulted in good efficacy without showing any side effects.
Conclusion: HM61713 showed excellent in vitro and in vivo activities for H1975 harboring L858R-T790M mutation as well as HCC827 having exon 19 deletion mutation with selectivity over wild-type EGFR. Currently, HM61713 is undergoing phase I study (NCT01588145) for NSCLC patients after the failure of 1st generation EGFR TKIs in Korea.
Citation Format: Kwang-Ok Lee, Mi Young Cha, Mira Kim, Ji Yeon Song, Jae-Ho Lee, Young Hoon Kim, Young-Mi Lee, Kwee Hyun Suh, Jeewoong Son. Discovery of HM61713 as an orally available and mutant EGFR selective inhibitor. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr LB-100. doi:10.1158/1538-7445.AM2014-LB-100
Abstract LB-102: A tumor-specific tissue penetrating peptide inhibits metastasis
Authors: Sugahara Kazuki N. , Braun Gary B. , Mendoza Tatiana H. de , Kotamraju Venkata R. , Teesalu Tambet , Ruoslahti Erkki , French Randall P. , Lowy Andrew M. 
Published: May 2015

Abstract
Neuropilin-binding tumor-penetrating peptides increase vascular and tissue permeability in tumors, allowing drugs conjugated to the peptide and even free drugs co-injected with the peptide to widely distribute within the tumor tissue (Sugahara KN et al, Cancer Cell 16:510, 2009; Science 328:1031, 2010). Thus, the peptides provide an elegant way to enhance therapeutic index of anti-cancer drugs. However, the ability of the peptides to increase vascular permeability has raised concerns that the peptides might enhance metastasis by promoting cell seeding from the primary tumor. Here, we show a recent unexpected finding that a prototypic tumor-penetrating peptide, iRGD (amino acid sequence: CRGDK/RGPD/EC), is a potent metastasis inhibitor. iRGD did not cause systemic tumor cell dissemination or metastasis in mice bearing breast tumors with low metastatic potential. iRGD treatment of mice bearing aggressive orthotopic pancreatic tumors resulted in significant decrease in spontaneous metastasis formation. Primary tumor growth was not affected by the treatment. Another tumor-penetrating peptide, iNGR, also inhibited metastasis, while conventional RGD peptides or a scrambled iRGD peptide that lack neuropilin affinity failed to do. These results indicate that the anti-metastatic effect of iRGD was dependent on its neuropilin-binding peptide motif. In vitro migration assays demonstrated that iRGD potently inhibits tumor cell migration and serves as a chemorepellent of tumor cells in a neuropilin-dependent manner. Chemorepulsion assays based on live cell imaging confirmed the findings, and further demonstrated that iRGD dramatically collapses tumor cell protrusions leading to an instantaneous retraction of tumor cells from iRGD-bound surfaces.
Our finding refutes the hypothesis that iRGD may cause enhanced metastasis. The mechanism of the anti-metastatic effect may involve neuropilin-mediated chemorepulsion of tumor cells. Collectively, iRGD may simultaneously achieve tumor-specific drug delivery and metastasis inhibition when utilized for cancer treatment.
Citation Format: Kazuki N. Sugahara, Gary B. Braun, Tatiana H. de Mendoza, Venkata R. Kotamraju, Tambet Teesalu, Erkki Ruoslahti, Randall P. French, Andrew M. Lowy. A tumor-specific tissue penetrating peptide inhibits metastasis. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr LB-102. doi:10.1158/1538-7445.AM2014-LB-102
Abstract LB-11: Discovery, synthesis, and structure-activity relationship of N-benzyl-2-phenylpyrimidin-4-amine derivatives as potent USP1/UAF1 deubiquitinase inhibitors with anticancer activity against non-small cell lung cancer
Authors: Dexheimer Thomas S. , Rosenthal Andrew S. , Luci Diane , Liang Qin , Villamil Mark A. , Jadhav Ajit , Simeonov Anton , Zhuang Zhihao , Maloney David J. 
Published: May 2015

Abstract
Protein ubiquitination is a dynamic and reversible post-translational modification that has been linked to many essential cellular processes in eukaryotes. In addition, deregulation of ubiquitin conjugation or deconjugation has been implicated in the pathogenesis of many human diseases, including cancer. For example, the deubiquitinating enzyme USP1 (ubiquitin-specific protease 1) in association with its WD40-repeat protein binding partner, UAF1 (USP1-associated factor 1), is a known regulator of DNA damage tolerance and repair and has been proposed as a promising target for anticancer therapy. To further evaluate the USP1/UAF1 complex as a therapeutic target, we conducted a quantitative high throughput screen of &gt;400,000 compounds and subsequent medicinal chemistry optimization in pursuit of small molecules that inhibit the deubiquitinating activity of USP1/UAF1. These efforts lead to the identification of ML323 and a series of N-benzyl-2-phenylpyrimidin-4-amine derivatives, which possess nanomolar USP1/UAF1 inhibition and exhibit excellent selectivity over related proteases. Moreover, we demonstrate a strong correlation between compound IC50 values for USP1/UAF1 inhibition in vitro and activity in non-small cell lung cancer cells, specifically increasing the level of ubiquitinated-PCNA and decreasing cell survival. Taken together, our results establish the druggability of the USP1/UAF1 deubiquitinase complex and its potential as molecular target for anticancer therapies.
Citation Format: Thomas S. Dexheimer, Andrew S. Rosenthal, Diane Luci, Qin Liang, Mark A. Villamil, Ajit Jadhav, Anton Simeonov, Zhihao Zhuang, David J. Maloney. Discovery, synthesis, and structure-activity relationship of N-benzyl-2-phenylpyrimidin-4-amine derivatives as potent USP1/UAF1 deubiquitinase inhibitors with anticancer activity against non-small cell lung cancer. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr LB-11. doi:10.1158/1538-7445.AM2014-LB-11
Abstract LB-116: Cep55, a master regulator of cytokinesis in breast cancer pathogenesis
Authors: Kalimutho Murugan , Simmons Jacinta , Fernando Winnie , Saunus Jodi , Spring Kevin , Lakhani Sunil , Al-Ejeh Fares , Khanna Kum Kum 
Published: May 2015

Abstract
Defects in the number, structure, and function of centrosomes can generate mono- or multipolar mitotic spindles and cytokinesis failure resulting in aneuploidy and chromosome instability, which are common characteristics of tumour cells. Centrosomal proteins thus play central roles in the execution of proper cell division. Cep55 is a centrosomal protein required for proper segregation of two daughter cells during cytokinesis. It often elevated in wide range of cancer types including breast cancer. To ascertain the functional role of Cep55 in breast cancer pathogenesis, we performed publically available data mining as well as IHC staining in a cohort of breast cancer patients and found that elevated levels of Cep55 is significantly associated with p53 mutation, basal like subtype, relapse free and distant-metastasis free survival. Immunoblot analysis of non-malignant and breast cancer cell lines revealed higher expression of Cep55 protein in basal like subtype. RNAi mediated Cep55 depletion in cultured human breast cancer cells resulted in decreased cell proliferation, induction of apoptosis in-vitro and failure to establish xenografts in-vivo. Moreover, these cells failed to establish lung colonisation due to less proliferative, migrative and invasive capacity in experimental metastasis models. In an initial effort to identify causal effective of Cep55 mediated breast cancer pathogenesis, we found that Cep55-depleted cells that survive following long term culture have restored their ploidy compared with aneuploid cells that have constitutively high levels of Cep55. Moreover, these non-tumorigenic cells also have defect in major signalling networks assessed by Kinexus proteomic array. In line with this finding, we found that constitutive overexpression of Cep55 in non-transformed mammary epithelial cells, MCF-10a induced ERK1/2 and STAT3 signalling possibly due to increase in chromosome instability. Taken together, these results indicate that Cep55 promotes breast cancer initiation, progression and lung colonisation through pleiotropic effect and genomic instability that likely contribute to aneuploidy state of breast cancer tumours
Citation Format: Murugan Kalimutho, Jacinta Simmons, Winnie Fernando, Jodi Saunus, Kevin Spring, Sunil Lakhani, Fares Al-Ejeh, Kum Kum Khanna. Cep55, a master regulator of cytokinesis in breast cancer pathogenesis. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr LB-116. doi:10.1158/1538-7445.AM2014-LB-116
Abstract LB-124: Histone deacetylase 5 stabilizes HIF-1α through Hsp70 deacetylation in cytosol
Authors: Chen Shuyang , Yin Chengqian , Lao Taotao , Liang Dongming , Sang Nianli 
Published: May 2015

Abstract
Hypoxia is frequently associated with solid tumors and ischemic disorders, which are the top two leading causes of mortality in the world. Hypoxia-inducible factor 1 is a major regulator of angiogenesis and cellular adaptation to hypoxia. Accordingly HIF-1 function has been considered a therapeutic target for multiple diseases. Histone deacetylase (HDAC) activity has been involved in regulating HIF function and some HDAC inhibitors (HDACIs) have been documented to repress HIF-1 function. However, histone deacetylases encompass multiple members, each has different cellular functions. HDACIs in clinical application or under development generally inhibit more than one HDAC. It is unclear which specific member of the HDAC family is required for HIF-1 function. We present data here to show that histone deacetylase 5 (HDAC5) is required for HIF-1α protein stability. Knockdown of HDAC5 impaired hypoxic accumulation of HIF-1α and HIF-1 function. Furthermore, overexpression of HDAC5 enhanced HIF-1α stability and nuclear accumulation. Specifically, HDAC5 mutant exclusively localized at cytosol is sufficient for this function, stabilizing HIF-1α more efficiently than wild-type HDAC5. We further demonstrate that heat shock 70 kD protein (Hsp70) is a cytosolic substrate of HDAC5; and acetylation of Hsp70 promotes its association with HIF-1α and HIF-1α degradation. Taken together, our data suggest that deacetylation of Hsp70 catalyzed by HDAC5 facilitates the stabilization and hypoxic accumulation of HIF-1α. These findings also suggest that HDAC5 could be a potential target for therapies based on modulating HIF-1 function.
Citation Format: Shuyang Chen, Chengqian Yin, Taotao Lao, Dongming Liang, Nianli Sang. Histone deacetylase 5 stabilizes HIF-1α through Hsp70 deacetylation in cytosol. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr LB-124. doi:10.1158/1538-7445.AM2014-LB-124
Abstract LB-13: Hyaluronic acid-based CD44 targeted nanoparticle delivery of combination MDR1 siRNA/paclitaxel to overcome drug resistance in ovarian cancer
Authors: Yang Xiaoqian , lyer Arun , hornicek Francis , Amiji Mansoor , Duan Zhenfeng 
Published: May 2015

Abstract
A major obstacle in the success of chemotherapy in ovarian cancer is the emergence of multidrug resistance (MDR). Overexpression of the MDR1 gene and corresponding P-glycoprotein (Pgp) efflux pumps is one of the best characterized MDR mechanisms. Although MDR1 siRNA based strategies are emerging as highly promising approaches to reverse MDR, the systemic delivery still remains a great challenge. In the present study, CD44 targeting hyaluronic acid (HA) based self-assembling nanoparticle systems were designed with MDR1 siRNA to evaluate its delivery efficiency and combination anticancer therapeutic efficacy with paclitaxel in vitro and in vivo. The results showed that HA-poly(ethyleneimine)/HA-poly(ethylene glycol) (HA-PEI/HA-PEG) nanoparticle successfully delivered MDR1 siRNA into MDR ovarian cancer cell lines, SKOV-3TR and OVCAR8TR. Western blot analysis, calcein AM retention assay, and MTT assay further demonstrated that HA-PEI/HA-PEG nanoparticles loaded with MDR1 siRNA efficiently down-regulated the expression of MDR1 and inhibited the functional activity of Pgp, and subsequently increase cell sensitivity to paclitaxel. HA-PEI/HA-PEG/MDR1 siRNA nanoparticle therapy followed by paclitaxel treatment produced a significant inhibitory effect on the drug-resistant tumor growth as compared with control groups in MDR ovarian cancer xenograft mouse models. These results indicated CD44-targeted HA-PEI/HA-PEG nanoparticle platform is an effective siRNA delivery system for potential siRNA-based anticancer therapeutics in ovarian cancer.
Citation Format: Xiaoqian Yang, Arun lyer, Francis hornicek, Mansoor Amiji, Zhenfeng Duan. Hyaluronic acid-based CD44 targeted nanoparticle delivery of combination MDR1 siRNA/paclitaxel to overcome drug resistance in ovarian cancer. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr LB-13. doi:10.1158/1538-7445.AM2014-LB-13
Abstract LB-14: Polyisoprenylated cysteinyl amides as targeted small molecule anti-Ras therapies
Authors: Lamango Nazarius S. , Aguilar Byron J. , Nkembo Augustine T. , Duverna Randolph , Amissah Felix , Poku Rosemary A. , Ablordeppey Seth Y. 
Published: May 2015

Abstract
Pancreatic cancer harbors the highest reported rates of K-Ras mutations, lacks effective therapies and is the most challenging to treat. It is thus the most deadly neoplasm with a 5-year survival rate of only 6%. We reveal here that polyisoprenylated methylated protein methyl esterase (PMPMEase) is overexpressed in 93% of pancreatic duct adenocarcinoma. We further present novel compounds with the potential to serve as effective targeted therapies for pancreatic and other cancers with hyperactive growth signaling pathways mediated by Ras and related G-proteins. The design and synthesis of the polyisoprenylated cysteinyl amide inhibitors (PCAIs) of PMPMEase incorporate three key elements to obtain compounds to selectively disrupt polyisoprenylation-mediated protein-protein interactions; the farnesyl group for high affinity interactions, a substituted amide bioisostere of the scissile ester bond of the endogenous substrates and an ionizable appendage group designed to mitigate the excessive hydrophobicity of the farnesyl cysteinyl amide that constitutes the pharmacophore. The PCAIs inhibited PMPMEase with Ki values ranging from 3.7 to 20 μM. The 48 h EC50 values for pancreatic cancer Mia PaCa-2 and BxPC-3 cell lines were as low as 1.9 μM while Salirasib (farnesylthiosalicylic acid, FTS) and farnesylthiosalicylamide were not effective even at 20 μM. The PCAIs thus have the potential to serve as a novel class of targeted therapies for cancers with hyperactive G-proteins and the growth factor receptors whose signals they transmit.
Citation Format: Nazarius S. Lamango, Byron J. Aguilar, Augustine T. Nkembo, Randolph Duverna, Felix Amissah, Rosemary A. Poku, Seth Y. Ablordeppey. Polyisoprenylated cysteinyl amides as targeted small molecule anti-Ras therapies. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr LB-14. doi:10.1158/1538-7445.AM2014-LB-14
Abstract LB-152: Macrophage control of cancer cell stemness and tumor metastasis
Authors: Gorjestani Sara 
Published: May 2015

Abstract
A characteristic feature of cancer is the presence of an abundant inflammatory infiltrate, which includes tumor-associated macrophages. In response to diverse tumor-derived chemoattractants, macrophages invade the tumor microenvironment, promoting angiogenesis, growth, immunosuppression and metastasis. Because they stimulate tumor progression and metastasis, it is possible that tumor-associated macrophages enhance cancer initiating cell populations leading to increased tumorigenicity and metastasis. In the tumor microenvironment, macrophages are characterized into having two phenotypes, classical (M1) or alternative (M2). M2 macrophages suppress T-cell activation and promote angiogenesis and tumor progression, while M1 macrophages produce immunostimulatory cytokines and stimulate T cell mediated anti-tumor immunity. Whether and how macrophages affect cancer cell stemness and metastasis is not well understood. Recently our lab showed that suppression of PI3Kinase-gamma signaling in myeloid cells leads to a reduction in tumor growth, angiogenesis, and metastasis. Genetic or pharmaceutical blockade of PI3Kinase-gamma or its target alpha4beta1 integrin inhibits the trafficking of monocytes to tumors and blocks expression of M2 macrophage factors, such as TGF-beta, Arginase and IL-6. To discover how PI3Kinase-gamma regulates the macrophage phenotype we performed RNA sequencing (RNA-seq) of classical and alternative polarization conditions in PI3Kinase-gamma-deficient and WT macrophages. Using this approach, we identified gene clusters associated with tumor immunity and metastasis that are regulated by PI3Kinase-gamma. Furthermore, we observed that macrophages polarized to the M2 phenotype enhanced the colony formation of breast and lung cancer cell lines in an anchorage independent tumor spheroid outgrowth assay whereas M1 polarization inhibited colony formation. Taken together, our data support the hypotheses that PI3Kinase-gamma expressing M2 macrophages promote cancer cell stemness and tumor metastasis. These studies could lead to new approaches for cancer therapy by encouraging the use of PI3Kinase-gamma antagonists as adjuvants for immunotherapy of human cancer.
Citation Format: Sara Gorjestani. Macrophage control of cancer cell stemness and tumor metastasis. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr LB-152. doi:10.1158/1538-7445.AM2014-LB-152