bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 5669: Design and synthesis of membrane type matrix metalloproteinase (MT-MMP) targeted anti-tumor agents.
Authors: Falconer Robert A. , Youssef Ahmed M. , Gimenez Warren Javier , Morais Goreti R. , Mitchell Andrew , Shnyder Steve D. , Gill Jason H. , Patterson Laurence H. , Loadman Paul M. 
Published: August 2014

Abstract
Design and synthesis of membrane type matrix metalloproteinase (MT-MMP) targeted anti-tumor agents
Membrane-type matrix metalloproteinases (MT-MMPs) are highly active in tumors, but absent or inactive in normal tissues. MT-MMPs are known to be elevated in the majority of human tumors and to be central to tumor invasion and angiogenesis. Our objective has been to design inactive prodrugs that are converted to a potent drug by selected MMPs within the tumor microenvironment.
We report the design and synthesis of a series of peptide-based conjugates of azademethylcolchicine (a potent colchicine analogue) designed to be selectively cleaved by MT-MMPs in the tumor microenvironment. Azademethylcolchicine was attached to the peptide C-terminus, while the N-terminus is protected from non-specific cleavage by exopeptidases through a masking group. A series of N-terminal masking groups, including unnatural amino acids, substituted aromatic groups, alkyl spacers and more complex endcaps was employed. Insights have been gained into the MT-MMP peptide recognition sequence and the relative importance of individual amino acids with regards MMP-selectivity. The P2’ position in particular has been extensively studied through substitution by both natural amino acid and unnatural amino acids.
We have investigated the efficiency of hydrolytic cleavage of these conjugates to release the active agent in both tumor and normal tissues. Results indicate significant effects of P2’ amino acid substitution upon stability and conversely activation in tumor and normal tissues (liver, kidney, lung, plasma), with half-lives of hydrolysis ranging from 2-60 min in tumor and 3-300 min in normal tissues.
In conclusion, a series of peptide-based prodrug conjugates of azademethylcolchicine was synthesized. Hydrolytic activation of these prodrugs in tumor tissue was rapid compared to liver and other normal tissues. From this screen, ICT-2588, which includes tyrosine at the P2’ position, emerged as the agent with a hydrolytic cleavage rate most suited for further evaluation as a tumour activated peptide-based conjugate.
Citation Format: Robert A. Falconer, Ahmed M. Youssef, Javier Gimenez Warren, Goreti R. Morais, Andrew Mitchell, Steve D. Shnyder, Jason H. Gill, Laurence H. Patterson, Paul M. Loadman. Design and synthesis of membrane type matrix metalloproteinase (MT-MMP) targeted anti-tumor agents. [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 5669. doi:10.1158/1538-7445.AM2013-5669
Abstract 567: Dual functions of Mad1 in mitosis and DNA damage response.
Authors: Yang Chunying , Hao Jianwei , Kong Dejuan , Xu Bo 
Published: August 2014

Abstract
The spindle assembly checkpoint (SAC) and the DNA damage checkpoint are two evolutionarily conserved mechanisms by which the fidelity of chromosome segregation in response to various DNA lesions is protected. These checkpoints are believed to function independently. However, there is growing evidence showing that proteins involved in the two systems have overlapping functions. Here we show that the mitotic arrest-deficient protein 1 (Mad1), a critical component of the SAC, is also required for the DNA damage response (DDR). We found that depletion of Mad1 led to cellular hypersensitivity to ionizing radiation (IR) and prolonged persistence of the H2AX foci. Interestingly, we observed Mad1 to be hyperphosphorylated both in mitosis and in response to DNA damage induced by IR in an ATM (Ataxia Telangiectasia Mutated) dependent manner. ATM is an essential DDR kinase which is also activated in mitosis and required for the SAC. We found that ATM phosphorylated Mad1 on Serine 214 both in vitro and in-cell. We further demonstrated that ATM-mediated Mad1 Serine 214 phosphorylation was required for both SAC and optimal DDR. Collectively, these findings reveal the dual function of ATM-mediated Mad1 phosphorylation in mitosis and DDR.
Citation Format: Chunying Yang, Jianwei Hao, Dejuan Kong, Bo Xu. Dual functions of Mad1 in mitosis and DNA damage response. [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 567. doi:10.1158/1538-7445.AM2013-567
Abstract 5680: Identification and characterization of a novel class of ATX inhibitors.
Authors: Fells James , Lee Sue Chin , Norman Derek , Fujiwara Yuko , Tsukahara Ryoko , Liu Jianxiong , Kirby Jason , Nelson Sandra , Tigyi Gabor 
Published: August 2014

Abstract
The lysophospholipase D (autotaxin, ATX) plays an important role in cancer invasion and metastasis. A High-throughput screen of over 10,000 compounds from the University of Cincinnati Drug Discovery Center, identified several small-molecule inhibitors with IC50 values ranging from nanomolar to low micromolar. The pharmacology of the two most potent compounds, 966791(1) and 918103(2), were further characterized in enzyme, cellular, and whole animal systems. Both of these compounds, significantly reduced cell invasion in melanoma cancer cell lines without any apparent cytotoxicity. Compound (1) was shown to be a competitive inhibitor of ATX for both FS-3 and Pnp-TMP substrates, while compound (2) was competitive only for FS-3. This suggest that compound (2) targets the hydrophobic pocket not the active site of ATX, which was supported by docking of compounds 1 and 2, along with mutagenesis data. The potency of the compounds was comparable to each other in each of the assays. Current ATX inhibitors reported in literature target the active site in the catalytic domain. In our search for ATX inhibitors we identified compounds able to inhibit both the active site and hydrophobic pocket. We conclude that these data suggest compounds solely inhibiting the hydrophobic pocket are sufficient to disrupt the ATX-LPA signaling axis can serve as specific small-molecule modulators for mechanistic studies of ATX as well as a potential leads for the development of anti-cancer drugs.
Citation Format: James Fells, Sue Chin Lee, Derek Norman, Yuko Fujiwara, Ryoko Tsukahara, Jianxiong Liu, Jason Kirby, Sandra Nelson, Gabor Tigyi. Identification and characterization of a novel class of ATX 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 5680. doi:10.1158/1538-7445.AM2013-5680
Abstract 5681: Modulation of Wnt/β-catenin signaling by niclosamide and related derivatives.
Authors: Mook Robert A. , Chen Minyong , Lu Jiuyi , Barak Larry S. , Lyerly H. Kim , Chen Wei 
Published: August 2014

Abstract
The Wnt signal transduction pathway is dysregulated in many cancers, including colorectal cancer (CRC) where activating mutations in this pathway occur in over 80% of sporadic colorectal cancers. As a result, drugs that inhibit the pathway are highly sought-after as the basis of a new generation of innovative therapeutic agents. Unfortunately, a gap exists in the ability to target the pathway with small, drug-like molecules, a gap that is the barrier to discovering drugs targeting defects in this pathway. Recently, we reported the FDA-approved anthelmintic drug niclosamide inhibits Wnt/β-catenin signaling via a novel mechanism that internalizes Frizzled receptors and leads to decreases in Dishevelled and β-Catenin proteins, even in cells harboring mutations in APC and β-catenin. The biological target driving inhibition of Wnt signaling by niclosamide is unknown. To support efforts to translate these findings in clinical trials and assist target identification efforts, we interrogated the mechanism and structure-activity relationships. We will present our findings indicating inhibition of Wnt signaling by niclosamide appears unique among the structurally-related anthelmintic agents tested and that Wnt/β-catenin activity was dependent on small changes in the chemical structure of niclosamide - including the ability to convert inhibition to activation. Overall, the findings support efforts to identify the target of niclosamide inhibition of Wnt/β-catenin signaling and the discovery of novel inhibitors of Wnt/β-catenin signaling to treat cancer, and thus accelerate the translational application of niclosamide and its derivatives to improve patient survival from cancer.
Citation Format: Robert A. Mook, Minyong Chen, Jiuyi Lu, Larry S. Barak, H. Kim Lyerly, Wei Chen. Modulation of Wnt/β-catenin signaling by niclosamide and related derivatives. [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 5681. doi:10.1158/1538-7445.AM2013-5681
Abstract 5682: Design and preclinical evaluation of single agents with combination chemotherapy potential.
Authors: Gangjee Aleem , Pavana Roheeth K. , Ihnat Michael A. , Thorpe Jessica E. , Disch Bryan C. , Bastian Anja , Bailey-Downs Lora C. , Hamel Ernest , Bai Rouli 
Published: August 2014

Abstract
Antiangiogenic agents target tumor mechanisms involved in blood vessel formation vital for tumor growth and metastases. However, these agents are mainly cytostatic and usually not tumoricidal. Several combinations of antiangiogenic and cytotoxic agents have shown significant promise in the clinic, and several clinical trials are in progress. Single agents with both antiangiogenic activities and cytotoxicity would afford agents that would circumvent pharmacokinetic problems of multiple agents, avoid drug-drug interactions, could be used at lower doses to alleviate toxicity, be devoid of overlapping toxicities, and could delay or prevent tumor cell resistance. We designed, synthesized and evaluated a novel compound AG119 that inhibits both vascular endothelial growth factor receptor-2 (VEGFR-2) affording antiangiogenic effects and tubulin for cytotoxic effects in a single agent. Structural modifications of AG119 afforded AG321 that inhibited platelet derived growth factor receptor-β (PDGFR-β) and epidermal growth factor receptor (EGFR) in addition to VEGFR-2 and tubulin. The novel compounds AG119 and AG321 were potent inhibitors (activity comparable to that of combretastatin A-4) of bovine brain tubulin assembly and of [3H]colchicine binding to tubulin, indicating that these compounds bind at the colchicine site on tubulin. Both compounds have potency comparable to those of sunitinib and semaxinib in tumor cell lines overexpressing VEGFR-2. AG321 has potency comparable to that of erlotinib in tumor cell lines overexpressing EGFR and potency comparable to those of erlotinib, DMBI and PD153035 in cell lines overexpressing PDGFR-β. Both AG119 and AG321 also inhibited angiogenesis in the chorioallantoic membrane (CAM) assay. AG321 is a unique compound with four separate mechanisms of action in a single agent including inhibition of tubulin. This is unprecedented and to our knowledge, is the first of its kind. In mice, AG119 reduced tumor size and vascularity in two flank xenograft models [the BLBC MDA-MB-435 model and U251 glioma model] and in a 4T1 triple negative breast orthotopic allograft model. In these in vivo models, the activity of AG119 was superior to those of temozolomide (U251), docetaxel and sunitinib (MDA-MB-435 and 4T1) without overt toxicity to the animals.
Citation Format: Aleem Gangjee, Roheeth K. Pavana, Michael A. Ihnat, Jessica E. Thorpe, Bryan C. Disch, Anja Bastian, Lora C. Bailey-Downs, Ernest Hamel, Rouli Bai. Design and preclinical evaluation of single agents with combination chemotherapy potential. [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 5682. doi:10.1158/1538-7445.AM2013-5682
Abstract 571: Overactive Cdk2 permits polyploidy by overwhelming the tetraploidy checkpoint.
Authors: Jahn Stephan , Corsino Patrick , Law Mary , Davis Brad , Law Brian 
Published: August 2014

Abstract
The p53-dependent tetraploidy checkpoint serves to block the proliferation of cells that double their genome without dividing. Oftentimes, cancers will contain a tetraploid sub-population, indicating either an ability to bypass this checkpoint or that the checkpoint is no longer functional. In studying the chromosomal instability of tumor cell lines from mice with mammary expression of a constitutively active Cyclin D1-Cdk2 fusion protein (D1K2), we noticed an increased rate of polyploidization in the presence of the spindle-poison paclitaxel. This was recapitulated in an MCF10A cell line model, and it was discovered that this is due to the inability of the tetraploidy checkpoint to completely stop DNA replication in tetraploid cells with constitutively active Cdk2. Biochemical analysis shows that tetraploid cells expressing D1K2 maintain Rb phosphorylation longer than tetraploid control cells, matching the phenotype seen in cells that have p53 stably knocked down. Further DNA replication, yielding octaploid cells, appears to further intensify the tetraploidy checkpoint, arresting the cells. Due to the fact that approximately 50% of all breast cancers overexpress Cyclin D, these observations raise intriguing questions about the treatment of tumors with overactive Cdk2. While it appears these tetraploid MCF10A cells are unviable, we can not account for other mutations that may exist in vivo and allow the proliferation of a chromosomally unstable tetraploid tumor population.
Citation Format: Stephan Jahn, Patrick Corsino, Mary Law, Brad Davis, Brian Law. Overactive Cdk2 permits polyploidy by overwhelming the tetraploidy checkpoint. [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 571. doi:10.1158/1538-7445.AM2013-571
Abstract 581: Surfactant-free PLGA encapsulation facilitates delivery of LY294002 to endoplasmic reticulum and enhances its cytotoxicity.
Authors: Hou Chia-Cheng 
Published: August 2014

Abstract
LY294002 (LY) is a potent inhibitor of phosphatidylinositol 3-kinases (PI3Ks); however, bio-applications of LY are limited by its poor solubility and pharmacokinetic profile. Poly(lactic-co-glycolic acid) (PLGA) is a biodegradable nanomaterial that can be used as a carrier for drug delivery. Although LY-loaded polyvinyl alcohol (PVA)-containing PLGA nanoparticles (PVA-LY NPs) have been developed to improve LY solubility, the ratio of NP internalization is unsatisfactory and the cytotoxicity of PVA-LY NPs is inferior to that of free LY. LY-loaded surfactant-free PLGA nanoparticles (SF-LY NPs) were developed to improve the therapeutic efficacy of LY. The size of SF-LY NPs was in the range of 80-100 nm, the shape was spherical and the NPs were monodispersed. The loading capacity of LY in SF NPs was 7.4μg/mg with a sustained-released pattern. In four lung cancer cell lines, SF-LY NPs showed a stronger growth inhibitory effect, sustained suppression of the serine/threonine kinase AKT activation, and increased intracellular uptake of LY compared with PVA-LY NPs or free LY. In addition, it was observed that SF NPs tend to accumulate in the endoplasmic reticulum (ER) and subsequently induce pronounced ER stress. After injection into tumors, SF-LY NPs exhibited a stronger antitumor effect than free LY. These findings indicated that the surfactant-free formulation of PLGA is an ideal vector to carry LY and that SF-LY NPs possess promising anticancer activity.
Citation Format: Chia-Cheng Hou. Surfactant-free PLGA encapsulation facilitates delivery of LY294002 to endoplasmic reticulum and enhances its cytotoxicity. [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 581. doi:10.1158/1538-7445.AM2013-581
Abstract 586: Genomic and functional characterizations of phosphodiesterase 4Din human cancers.
Authors: Lin Dechen , Xu Liang , Ding Ling-Wen , Sharma Arjun , Liu Li-Zhen , Yang Henry , Tan Patrick , Vadgama Jay , Karlan Beth , Lester Jenny , Urban Nicole , Schummer Michèl , Doan Ngan , Said Jonathan , Walsh Martin , Patel Paresma , Thomas Craig , Chan Daniel , Koeffler Phillip 
Published: August 2014

Abstract
Background
Phosphodiesterase 4D (PDE4D) degrades the secondary messenger adenosine 3’, 5’-cyclic monophosphate (cAMP). PDE4D recently was implicated in cancer cell proliferation, but alterations in its genome and function in tumors are unclear.
Methods
PDE4D gene copy number determined by SNP-CHIP was comprehensively analyzed in a large number of solid tumor specimens from diverse origins (n=5,569). Expression of PDE4D gene transcripts were examined in 971 primary tumors, as well as established cancer cell lines. PDE4D protein expression in 11 different types of cancers were evaluated by immunohistochemistry (n=165). Endogenous PDE4D in multiple types of tumor cell lines was suppressed by both shRNAs and compound 26B, a novel inhibitor of PDE4D, and the effects on apoptosis and proliferation were examined. We further investigated the molecular mechanisms involved. Effect of ectopic expression of PDE4D on tumor growth was assessed both in vitro and in vivo.
Results
Homozygous deletion of PDE4D occurred in 198 cases out of 5,569 primary solid tumors (3.56%), with most of them being internal microdeletions. Unexpectedly, these internal microdeletions did not result in loss of its gene products, as the expression of PDE4D mRNA and protein was not compromised in the PDE4D-microdeleted samples. Immunohistochemistry staining revealed that PDE4D protein levels were up-regulated in several types of tumors. Importantly, genetic and pharmacological suppression of endogenous PDE4D caused apoptosis and growth inhibition preferentially in a variety of cancer cells but not in non-malignant epithelial cells. We further showed that anti-tumor events triggered by PDE4D-suppression were lineage-dependently associated with induction of BIM and down-regulation of MITF. Moreover, ectopic expression of the PDE4D short isoform (PDE4D2) enhanced the proliferation of melanoma both in vitro and in vivo.
Conclusions
We show for the first time that although targeted by genomic homozygous microdeletions, alternatively spliced PDE4D can function as a tumor-promoting factor. PDE4D represents a novel, targetable enzyme of cancer cells.
Citation Format: Dechen Lin, Liang Xu, Ling-Wen Ding, Arjun Sharma, Li-Zhen Liu, Henry Yang, Patrick Tan, Jay Vadgama, Beth Karlan, Jenny Lester, Nicole Urban, Michèl Schummer, Ngan Doan, Jonathan Said, Martin Walsh, Paresma Patel, Craig Thomas, Daniel Chan, Phillip Koeffler. Genomic and functional characterizations of phosphodiesterase 4Din human 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 586. doi:10.1158/1538-7445.AM2013-586
Abstract 587: A novel non-COX-inhibitory sulindac derivative induces autophagic cell death by inhibiting Akt signaling in lung cancer cells.
Authors: Gurpinar Evrim , Grizzle William E. , Shacka John J. , Li Nan , Keeton Adam B. , Piazza Gary A. 
Published: August 2014

Abstract
Nonsteroidal anti-inflammatory drugs (NSAIDs) such as sulindac sulfide (SS) have shown promising antineoplastic activity in multiple tumor types, but toxicities resulting from cyclooxygenase (COX) inhibition limit their chronic use for chemoprevention. We recently described a N,N-dimethylethyl amine derivative of SS referred to as sulindac sulfide amide (SSA) that does not inhibit COX-1 or -2, yet displays potent tumor cell growth inhibitory activity. Here, we studied the basis for the growth inhibitory effects of SSA on human lung adenocarcinoma cell lines. SSA potently inhibited the growth of lung tumor cells with IC50 values of 2-5 μM compared with 44-52 μM for SS. SSA also suppressed DNA synthesis and caused a G0/G1 cell cycle arrest more potently than SS. SSA-induced cell death was associated with characteristics of autophagy, including an increase in acidic vesicular organelle content, elevation of the levels of LC3-II, and an increase in autophagic flux. siRNA knockdown of Atg7 attenuated SSA-induced autophagy and cell death. Surface exposure of phosphatidylserine, cleavage of caspases 3 and 7, as well as PARP were detectable with SSA treatment, although the pan-caspase inhibitor, ZVAD was not able to rescue viability. SSA treatment also inhibited Akt/mTOR signaling and the expression of downstream proteins that are regulated by this pathway. Overexpression of a constitutively active form of Akt was able to reduce autophagy markers and confer resistance to SSA-induced cell death. Our findings provide evidence that SSA induces autophagic cell death in lung cancer cell lines by suppressing Akt/mTOR signaling. This unique mechanism of action along with its increased potency and lack of cyclooxygenase inhibition support the development of SSA or related analogs for the prevention and/or treatment of lung cancer. Funding provided by NIH/NCI grants CA131378 and CA148817.
Citation Format: Evrim Gurpinar, William E. Grizzle, John J. Shacka, Nan Li, Adam B. Keeton, Gary A. Piazza. A novel non-COX-inhibitory sulindac derivative induces autophagic cell death by inhibiting Akt signaling in lung 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 587. doi:10.1158/1538-7445.AM2013-587