bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 4495: Small molecule approach for targeting tumor-associated macrophages via a functional FRβ
Authors: Wheeler Leroy W. , Lu Yingjuan , Cross Vicky , Lloyd Alex , Parker Nikki , Qi Longwu , Wang Kevin , Wang Ian , Hahn Spencer , Vaughn Jeremy , Vlahov Iontcho P. , Low Philip S. , Leamon Christopher P. 
Published: August 2015

Abstract
Tumor-associated macrophages (TAMs) are considered an attractive target for oncotherapy because of their important role in tumor microenvironment. While TAMs mostly arise from inflammatory blood monocytes, they become quickly programmed to the pro-tumor phenotype. In response to tumor-derived factors, these M2-biased TAMs are essentially tumor helper cells, as both cancer cells and TAMs promote each another through a paracrine signaling loop involving epidermal growth factor and colony stimulating factor-1. This important cellular interaction is critical at all stages of tumor progression including angiogenesis, invasion, growth and metastasis.
In recent years, TAMs (CD68+, CD163+) have been found to express a functional folate receptor-β (FRβ) that displays high-affinity ligand binding and subsequent ligand-initiated endocytosis. FRβ-expressing TAMs are present in various cancer subtypes, the perivascular region, and the tumor invasive front. The abundance of FRβ+ TAMs has been linked to poor patient survival in pancreatic ductal adenocarcinoma. In the present study, we first characterized the phenotype of FRβ+ TAMs ex-vivo from both syngeneic and xenographic tumor models (breast, lung, melanoma, and pancreatic cancers). Using thioglycollate-elicited macrophages as positive controls, we estimated FRβ levels on TAMs with monoclonal antibodies and functional folate ligands. Using a ligand conjugation approach, we focused on targeting FRβ+ TAMs in tumors arising from cancer cells that do not express functional FR themselves. Preliminary proof-of-concept was established in the highly aggressive FR-negative 4T1 mammary tumor with a folate-targeted DNA alkylating agent. In addition, immunohistochemical analysis showed high FRβ expression in human anaplastic thyroid cancer, a TAM-rich disease with very poor prognosis. Collectively, our data suggest that targeting a TAM-rich cancer via FRβ may be a viable therapeutic approach with potential applications in FR-negative tumors.
Citation Format: Leroy W. Wheeler, Yingjuan Lu, Vicky Cross, Alex Lloyd, Nikki Parker, Longwu Qi, Kevin Wang, Ian Wang, Spencer Hahn, Jeremy Vaughn, Iontcho P. Vlahov, Philip S. Low, Christopher P. Leamon. Small molecule approach for targeting tumor-associated macrophages via a functional FRβ. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 4495. doi:10.1158/1538-7445.AM2015-4495
Abstract 450: Suppression of innate and adaptive immune responses in the human lung tumor microenvironment via microRNA-183
Authors: Tejera Melba Marie , Tejera Melba Marie , Donatelli Sarah S. , Zhou Jun-Min , Gilvary Danielle L. , Chen Xianghong , A Erika 
Published: August 2015

Abstract
Innate and adaptive immunity plays a critical role in defense against cancer but can be undermined by the tumor microenvironment. To understand the underlying mechanism, we set out to analyze the molecular and cellular basis for natural killer (NK) and CD8 T cell suppression by human lung tumor cells. We found that transforming growth factor-beta (TGFb), abundantly produced by tumor cells, effectively reduced tumoricidal function in activated NK cells and CD8 T cells by specifically targeting a key adaptor protein, DAP12, which is required for surface anchoring of multiple NK receptors, including NKp44. For proof of the TGFb-miR-183-DAP12 circuit, flow cytometric analysis demonstrated that TGFb reduced surface levels of NKp44 on activated primary human NK and CD8 T cells, but western blot analysis demonstrated their intact presence in the cytoplasm. This was due to loss of DAP12, which is critical for surface expression of NKp44 and for downstream signaling to mobilize lytic granules to kill tumor cells. Mechanistically, TGFb readily induced miR-183 expression in both primary human NK cells and T cells which could bind specifically to the 3′UTR of human DAP12 to inhibit transcription and translation. Only miR-183 but not miR-185 or control (CT) transfection repressed luciferase activity of DAP12 3′UTR luciferase reporter constructs transferred into HELA cells. Moreover, we overexpressed lentiviral miR-183 in either primary NK and T cells and found that such expression effectively reduced DAP12 levels in both cell types. Flow cytometric analysis of these same cells indicated that loss of DAP12 was accompanied by loss of NKp44 surface expression and by loss of cytotoxic function against tumor cells. As further proof, we showed that lentiviral anti-sense miR-183 transfection into NK cells and T cells prevented TGFb from suppressing DAP12 expression. Thus, we have uncovered a seminal TGFb-miR-183-DAP12 pathway utilized by tumor cells to silence infiltrating NK and T cells, constituting the first report of miR control of an adaptor protein to control both NK and T cell immune function.
Citation Format: Melba Marie Tejera, Melba Marie Tejera, Sarah S. Donatelli, Jun-Min Zhou, Danielle L. Gilvary, Xianghong Chen, Erika A.. Suppression of innate and adaptive immune responses in the human lung tumor microenvironment via microRNA-183. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 450. doi:10.1158/1538-7445.AM2015-450
Abstract 4502: Identification of an aspirin-derived small molecule as a potential therapeutic for colorectal cancer
Authors: Karelia Deepkamal , Pandey Manoj , Plano Daniel , Narayan Satya , Jani Jitesh , Sharma Jay , Amin Shantu , Sharma Arun K. 
Published: August 2015

Abstract
In the US, colorectal cancer (CRC) remains the second leading cause of cancer-related death. The 5-year survival rate for patients with CRC is 64%, although for patients who present with distant metastases at diagnosis the 5 year survival is only 12%. Currently used standard care for CRC can only marginally extend the survival of patients and is associated with numerous adverse events. Hence, there remains an urgent need for more effective and less toxic treatments, which can increase CRC patient survival with better quality of life. Non-steroidal anti-inflammatory drugs (NSAIDs) (e.g. Aspirin, Ibuprofen, Naproxen), which are widely used for their anti-inflammatory and analgesic effects, have also been shown to be effective in reducing colon cancer incidences and are proposed to be effective chemopreventive agents. However, these NSAIDs are not potent enough to be used as cancer therapeutics and also carry a liability of gastrointestinal bleeding mainly associated with COX inhibition. Through extensive structure activity relationship (SAR) studies based on newly synthesized NSAID-analogs, we have identified a novel aspirin analog, ASD-49, as the most effective small molecule that showed efficacy in different cancer cell lines, including CRC cells with an EC50 ranging between 1 to 2.5 μM at 48 h treatment in culture. This unique compound selectively killed cancer cells and is &gt;50-times more potent than the current therapy for CRC and &gt;100-times more potent than the parent compound, aspirin. Our preliminary results show that ASD-49 induces G1 and G2 cell cycle arrest in HT29 cells. In addition, ASD-49 induced apoptosis as indicated by PARP cleavage in HCT116 and RKO cells. Furthermore, we observed down-regulation of anti-apoptotic protein Bcl-2 in a dose-dependent manner in both HCT116 and RKO cell lines. Unlike aspirin, the novel analog did not alter COX-2 protein expression, suggesting that ASD-49 may not possess adverse effects related to COX-2 inhibition. In addition, &gt;100-times lower dose requirement as compared to aspirin is expected to further minimize side effects associated with aspirin structure. Taken together, our results suggest that ASD-49 may be a promising agent for CRC treatment. Detailed results regarding the efficacy and mechanism of action of ASD-49 will be presented.
Citation Format: Deepkamal Karelia, Manoj Pandey, Daniel Plano, Satya Narayan, Jitesh Jani, Jay Sharma, Shantu Amin, Arun K. Sharma. Identification of an aspirin-derived small molecule as a potential therapeutic for colorectal cancer. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 4502. doi:10.1158/1538-7445.AM2015-4502
Abstract 4507: Intra-tumoral pharmacokinetic profiling for doxorubicin within solid tumor micromilieu using multicellular layers culture in-vitro
Authors: Al-Abd Ahmed M. , Al-Abbasi Fahad A. , Khedr Alaa , Atteiah Salah G. 
Published: August 2015

Abstract
In contrast to plasma pharmacokinetics, intratumoral pharmacokinetics of DOX determines its spatial anti-tumoral activity. Three dimensional multicellular layers (MCL) model for solid tumors present optimum experimental platform for studying the intratumoral pharmacokinetics of DOX. This might imply new insights for understanding intratumoral pharmacokinetic parameters with realistic clinical implications. Herein, we are presenting simplified method for the spatial in-situ concentration assessment of DOX within the avascular simulating MCL solid tumor model of DLD-1 and HT-29 cell lines. DLD-1 and HT-29 formed viable well structured MCL model abundant in extracellular matrix component (fibronectin). DOX (100 μM) showed stronger anti-proliferative effect against MCL of DLD-1 compared to HT-29 MCL (38.8% and 27.9%, respectively). The differential potencies of DOX closely correlate to the intratumoral pharmacokinetics within MCL's of both cell lines. DOX penetrated faster and washed out slower through the MCL of DLD-1 compared to HT-29 MCL. Distribution of DOX within MCL of DLD-1 was more homogenous compared to HT-29 MCL. Tissue concentration of DOX within MCL of DLD-1 was significantly higher than HT-29 MCL's after 96 h exposure (0.7 and 0.4 μmole/gm tissue, respectively). Concentration of DOX within MCL of both cell lines exceeded the IC50 under monolayer conditions (2.3±0.6 μM and 0.6±0.1 μM, respectively). In addition, DOX was extensively metabolized to less active metabolites (doxorubicinol and doxorubicinone) during traversing the thickness of both MCL’s. In conclusion, Intratumoral pharmacokinetic barriers to DOX might be key determinant in drug resistance on the tissue level, despite cellular and molecular events.
Citation Format: Ahmed M. Al-Abd, Fahad A. Al-Abbasi, Alaa Khedr, Salah G. Atteiah. Intra-tumoral pharmacokinetic profiling for doxorubicin within solid tumor micromilieu using multicellular layers culture in-vitro. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 4507. doi:10.1158/1538-7445.AM2015-4507
Abstract 4534: Cyclooxygenase inhibitors as delivery vehicles for histone deacetylase inhibitors
Authors: Raji Idris Olawale , Janeira Emily , Yadudu Fatima , Shaghayegh Fathi , Kornacki James , Mrksich Milan , Oyelere Adegboyega 
Published: August 2015

Abstract
Reversible acetylation state of histones determines the existence of the chromatin in either the euchromatin state or the heterochromatin state, which in turn control the accessibility of transcription factors to promoter regions of genes on the chromatin. This reversible acetylation state is regulated by two enzymes: histone deacetylases (HDAC) and histone acetyl transferases (HAT). Imbalance in the expression of these enzymes is associated with many diseases, with equilibrium tilted towards HDAC in tumors. Reversal of the HDAC enzymes to their basal expression level, by small molecule inhibition, has been shown to significantly reduce the growth of tumors and/or completely eliminate them. Currently, there are three (3) FDA approved HDAC inhibitors in the market: vorinostat, FK228 and belinostat (all approved by the FDA for treatment of cutaneous T-cell lymphoma). Although highly effective, these compounds suffer drawbacks such as lack of activity against solid tumors, off-target toxicities, short half-life, and lack of HDAC isoform selectivity. To address some of these challenges, we chose to incorporate a targeting moiety to the head group in the classical vorinostat pharmacophoric model (comprising head group, linker and zinc binding group (ZBG)). We envisaged that selective toxicity towards tumors (hence, reduction in off-target toxicities), may be achieved if the HDAC inhibitor is selectively delivered to tumor cells expressing cyclooxygenase 2 (COX-2) enzyme. COX-2, which catalyzes the conversion of arachidonic acid to prostaglandins, is ubiquitously expressed in a wide range of cancer types and has been exploited to selectively image cancer cells in the past. To achieve this, we designed and synthesized series of hydroxamic acid-based compounds having either celecoxib or indomethacin (COX-2 inhibitors) as the targeting moiety. In addition to these compounds, we made compounds having “biaryl group” as ZBG. Compounds based on this ZBG have been reported to selectively inhibit HDAC isoforms 1&2, both culprits in a wide range of cancer types.
Consistent with the reported HDAC isoform selectivity, our “biaryl” ZBG compounds potently and selectively inhibited HDACs 1& 2. Also, our hydroxamic acid-based compounds were better than vorinostat in cell-free assay and showed potent activity in MCF-7, A549 and HCT-116 cancer cell lines. Effort is underway to evaluate the in vivo activity of our lead compounds in animal models.
Citation Format: Idris Olawale Raji, Emily Janeira, Fatima Yadudu, Fathi Shaghayegh, James Kornacki, Milan Mrksich, Adegboyega Oyelere. Cyclooxygenase inhibitors as delivery vehicles for histone deacetylase inhibitors. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 4534. doi:10.1158/1538-7445.AM2015-4534
Abstract 4550: Antiproliferative activity of 8-methoxypsoralen without UV light irradiation: A new perspective for cancer therapy
Authors: de Oliveira Diêgo M. , Lima Rute M F , Velozo Eudes S. , Amorim Ilza A. , Mota Tales H A , Costa Silvia L. , Silva Fabio P. , El-Bachá Ramon S. 
Published: August 2015

Abstract
The furanocoumarin-derivative 8-methoxypsoralen (8-MOP) is commonly used combined with UV light irradiation for treatment of skin diseases. We have recently demonstrated that 8-MOP inhibits GST-P1 in tumor cells and acts as chemosensitizer. These new data show direct antitumor activity of this compound without photoactivation in an in vitro model of glioma, the most common and lethal primary malignant brain tumor. Rat glioma C6 cells and human glioblastoma GL-15 cells were submitted to treatment with 8-MOP, as well as primary rat astrocytes cultures for comparison. Cell viability was measured by MTT assay; phase contrast microscopy and quantification of total protein content were also performed. The trypan blue dye exclusion assay and colony formation test were used to analyze cell proliferation. Flow cytometry was used for cell cycle analyses. Morphological changes were accessed by electron microscopy and proteins expression was studied by using immunolabeling techniques. As main results, 8-MOP reduced cell viability and cellularity, time- and dose-dependently, more efficiently in tumor than in normal cells. The compound also showed considerable antiproliferative effect against tumor cells and induced cell death by apoptosis when used at high concentration. However, 8-MOP did not promote cell cycle arrest and also did not increase labeling of markers associated to bad prognostic. Additional tests with cell lines from other tumors (breast cancer, colorectal cancer and lymphoma) showed that they respond differently to 8-MOP treatment, pointing to a pathway-specificity of its action. A qualitative structure-activity relationship study was also performed using coumarin derivatives structurally related to 8-MOP, from these experiments it was possible to suggest the relevance of each part of 8-MOP molecular structure for antiproliferative action. These results point furanocoumarin derivatives as a possible new class of anticancer agents.
Note: This abstract was not presented at the meeting.
Citation Format: Diêgo M. de Oliveira, Rute M F Lima, Eudes S. Velozo, Ilza A. Amorim, Tales H A Mota, Silvia L. Costa, Fabio P. Silva, Ramon S. El-Bachá. Antiproliferative activity of 8-methoxypsoralen without UV light irradiation: A new perspective for cancer therapy. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 4550. doi:10.1158/1538-7445.AM2015-4550
Abstract 4551: Impairment of c-kit expression in human cancer cell lines by a novel pharmacophoric unit selected for the recognition of the proto-oncogene KIT promotorial region
Authors: Sissi Claudia , Da Ros Silvia , Zorzan Eleonora , Musetti Caterina , Shahidian Lara Zorro , Palumbo Manlio , Giantin Mery , Dacasto Mauro 
Published: August 2015

Abstract
G-quadruplex structures at telomeric region and in oncogene promotorial sequences represent promising chemotherapeutic targets. Among these latter ones, an interesting site of intervention is represented by the promotorial sequence of KIT, a proto-oncogene whose overexpression or mutations characterize several human cancers. This region contains two G-rich sequences, kit1 and kit2, whose G-quadruplex structures have been extensively studied by using X-ray crystallography and NMR. The stabilization of these secondary structures by small molecules has been shown to result in a suppression of gene transcription. The peculiarity of these G-quadruplex structures rest in the presence of unprecedented structural domains which foresees the possibility to design small molecules able to recognize them, with a higher selectivity in comparison to other nucleic acid tetra-helixes.
In order to identify novel ligands for these sequences, we started a screening program by using an available “in house” library of compounds. Each member was previously confirmed to provide a basal level of nucleic acid recognition. Ligand selection was performed by applying two validated different screening assays (FRET and FID); they were properly designed to identify the best binders and to preliminary exclude compounds with low selectivity among different G-quadruplexes.
For selected compounds, the DNA binding properties were fully characterized in terms of binding affinity, binding mode and ability to convert unfolded sequences into a G-quadruplex structure. On parallel, the ligands cellular effects were explored in two human cancer cell lines (MCF7 and HCG27). At first, we evaluated their cytotoxic potential; then, we examined the extent of potential c-kit down-regulation following the exposure to candidates at both mRNA and protein level.
By merging these results we were able to highlight the relevance of one pharmacophore as potential selective KIT targeting agent.
Citation Format: Claudia Sissi, Silvia Da Ros, Eleonora Zorzan, Caterina Musetti, Lara Zorro Shahidian, Manlio Palumbo, Mery Giantin, Mauro Dacasto. Impairment of c-kit expression in human cancer cell lines by a novel pharmacophoric unit selected for the recognition of the proto-oncogene KIT promotorial region. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 4551. doi:10.1158/1538-7445.AM2015-4551
Abstract 4553: Substituted monocyclic pyrimidines as potent tubulin inhibitors that circumvent P-glycoprotein mediated resistance
Authors: Mohan Rishabh , Gangjee Aleem , Bai Ruoli , Hamel Ernest 
Published: August 2015

Abstract
Tubulin is involved in several critical cellular functions, including cell division, cell motility and development and maintenance of cell shape. Although microtubule disrupting agents like paclitaxel are highly successful chemotherapeutic agents, these compounds are easily recognized by P-glycoprotein (Pgp) and are pumped out of cancer cells, resulting in resistance to the agent. Thus, these compounds have major limitations against multidrug resistant tumors. Recently, we reported simple, monocyclic pyrimidines with the N-methyl-4′-methoxyaniline moiety at the 4-position. These compounds circumvent some of the important limitations of paclitaxel while preserving its antimitotic activity. To further evaluate the SAR at the 4-position of the pyrimidine scaffold, a series of compounds were designed and synthesized that involved replacing the chloro moiety of the 5-amino-4,6-dichloro-2-methylpyrimidine with various anilines. The replacement of the N-methyl-4′-methoxyaniline moiety of the lead molecule with a conformationally restricted 6′-methoxy-tetrahydroquinoline moiety resulted in potent tubulin assembly inhibition (IC50 = 3.0 ± 0.03 μM) comparable to that observed with combretastatin A-4 (CSA4, IC50 = 1.1 ± 0.1 μM), of which the phosphorylated derivative is currently in clinical trials. It is a potent inhibitor of [3H]colchicine binding (65% at 5 μM concentration) indicating that it binds at the colchicine binding site on tubulin similar to CSA4. Similarly, the monocyclic pyrimidine with a conformationally restricted 4-N-methyl 2′,3′-dihydrobenzofuran moiety was also a potent inhibitor of bovine tubulin assembly. Replacement of the 4′-methoxy of the lead with a 4′-thiomethyl retained potency against tubulin assembly (IC50 = 2.6 ± 0.1 μM). In Pgp overexpressing NCI/ADR-RES cell line, three of the newly synthesized compounds were found to be 1.5-5-fold more potent (IC50 = 170-630 nM) than in the wild type OVCAR-8 cell line, thus, overcoming an important mechanism associated with clinical resistance to paclitaxel. These attributes of the 4-N-substituted monocyclic pyrimidines provide the impetus for further preclinical development of these compounds.
Citation Format: Rishabh Mohan, Aleem Gangjee, Ruoli Bai, Ernest Hamel. Substituted monocyclic pyrimidines as potent tubulin inhibitors that circumvent P-glycoprotein mediated resistance. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 4553. doi:10.1158/1538-7445.AM2015-4553