bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 4501: Development of novel Lithocholic acid carboxamides with antiproliferative and pro-apoptotic effects on human cancer cells
Authors: Ramisetti Srinivasa R. , Karelia Deepkamal , Neagley Melanie , Amin Shantu , Sharma Arun K. 
Published: August 2015

Abstract
Bile acids, the products of cholesterol catabolism, are synthesized in the liver and subsequently excreted into the bile canaliculus and the digestive tract as N-acyl conjugates of glycine or taurine. Among all bile acids, Lithocholic acid (LCA) and Ursodeoxycholic acid (UDCA) conjugates have been reported to inhibit the growth of various human cancer cells both in vitro and in vivo. Most importantly LCA has been shown to inhibit growth of different cancer cell lines including prostate and neuroblastoma cells, while sparing normal cells. In addition, a report has shown LCA-amphiphiles to be effective anti-tumor agents in a colon cancer xenograft model. In contrast, there are reports indicating that LCA may promote dimethyl hydrazine (DMH) induced colon carcinogenesis and may also act as a carcinogen itself. This indicates that in spite of having anti-cancer properties, LCA may pose a risk of developing colon cancer. We hypothesized that LCA structure can be optimized to eliminate the carcinogenesis promoting properties, while enhancing its potency to create effective therapeutics against colon, prostate, and other cancers. Therefore, we designed and synthesized a series of novel cyclic and acyclic LCA-carboxamides by blocking the acid functionality of LCA. The cytotoxicity of the novel analogs was evaluated against colon (HT29) and prostate (DU145) cancer cells. Three analogs ASR-320, ASR-322 and ASR-339 inhibited the viability of these cells with an EC50 value of 5-10 μM, while LCA had no effect on cell viability at highest dose used (50 μM). The results suggests that the new analogs are at least 10 times more potent than the parent compound, LCA. One of the agents, induced apoptosis in both prostate (DU145) and colon (HT29) cancer cell lines, as indicated by Caspase 3 activation and PARP degradation. Currently, we are further optimizing the structure based on the initial leads and investigating efficacy and mechanistic studies in prostate and colon cancer models. Detailed results of these investigations will be presented.
Citation Format: Srinivasa R. Ramisetti, Deepkamal Karelia, Melanie Neagley, Shantu Amin, Arun K. Sharma. Development of novel Lithocholic acid carboxamides with antiproliferative and pro-apoptotic effects on human cancer cells. [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 4501. doi:10.1158/1538-7445.AM2015-4501
Abstract 4521: Evaluation of the relationship between serum exposure, receptor (GITR) availability and tumor suppression following administration of the anti-GITR antibody DX400 in mouse syngeneic tumor models
Authors: Ovacik Ayse Meric , Shinsky-Bjorde Natalie , Hodges Douglas , Antonenko Svetlana , Ueda Roanna , Mauze Smita , Gu Danling , Wiswell Derek , Zhang Shuli , Beebe Amy , Tabrizi Mohammad 
Published: August 2015

Abstract
GITR is a type I transmembrane protein of the tumor necrosis factor receptor superfamily which is expressed primarily on T lymphocytes and natural killer cells. Ligation of GITR on activated T cells provides a costimulatory signal that positively modulates antigen-specific T cell responses, leading to enhanced cellular and humoral immunity. The anti-GITR antibody DX400 is a murinized agonistic monoclonal antibody that targets mouse GITR, and has shown tumor growth inhibition in mouse syngeneic tumor models. In this study we examined the pharmacokinetic/pharmacodynamics (PK/PD) properties of DX400. Studies were conducted to examine the potential relationships between anti-GITR antibody serum exposure (PK) and receptor availability (PD) on the relevant T-cell subsets. The concentrations of DX400 in serum were determined using an electrochemiluminescence (ECL) assay, and the availability of receptor (GITR) was determined using flow cytometry. Non-linear PK properties for DX400 were observed over the dose range examined. In line with changes in serum concentration-time profiles for the antibody, a dose dependent effect in receptor availability was also observed. The relationships between receptor availability, serum concentrations of DX400 and tumor suppression were described by a mechanistic PK/PD model. This analysis provided an estimated potency (EC50) value of 4.2 ng/mL for blood receptor engagement on T-cell subsets.
Citation Format: Ayse Meric Ovacik, Natalie Shinsky-Bjorde, Douglas Hodges, Svetlana Antonenko, Roanna Ueda, Smita Mauze, Danling Gu, Derek Wiswell, Shuli Zhang, Amy Beebe, Mohammad Tabrizi. Evaluation of the relationship between serum exposure, receptor (GITR) availability and tumor suppression following administration of the anti-GITR antibody DX400 in mouse syngeneic tumor models. [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 4521. doi:10.1158/1538-7445.AM2015-4521
Abstract 4544: Synthesis and biological evaluation of novel 6-substituted pyrrolo[2,3-d]pyrimidines as targeted antifolates
Authors: Gangjee Aleem , Golani Lalit , Wallaceb Adrianne , Matherly Larry H. 
Published: August 2015

Abstract
Reduced folates are essential cofactors for the biosynthesis of purines and pyrimidines. Since humans do not synthesize folate, it is necessary to obtain these cofactors from dietary sources. In mammals, three specialized systems exist that mediate membrane transport of folates and antifolates across biological membranes. These include the reduced folate carrier (RFC), the primary route for the uptake of folates and antifolates in mammalian cells, folate receptors (FRs) α and β, and the proton-coupled folate transporter (PCFT). Whereas RFC is ubiquitously expressed, FRs and PCFT show a narrower pattern of tissue expression. Toxicity of clinically used antifolates is attributed to their lack of selectivity for tumor cells over normal cells, likely due in part to their RFC transport. Antifolates with tumor-selective FR and/or PCFT drug uptake would circumvent major toxicities of currently used antifolates. We previously described the synthesis and biological activity of AGF23, a 6-substituted pyrrolo[2,3-d]pyrimidine. Against FRα- and PCFT-expressing KB human tumor cells, AGF23 was potently inhibitory (IC50 = 1.9 nM). Two novel isosteres of AGF23, AGF215 and AGF234 with oxygen and nitrogen in place of carbon at C11, respectively, were designed and synthesized. This simple isosteric replacement of carbon with heteroatoms in the bridge affords compounds with different chain lengths, angles, conformations and extra hydrogen bond donors and/or acceptors compared to the parent carbon chain analog. AGF215 and AGF234 were compared to AGF23 as inhibitors of proliferation of engineered Chinese hamster ovary (CHO) cells expressing human PCFT (R2/PCFT4), FRα (RT16), or RFC (PC43-10). AGF215 and AGF234, like AGF23, were inactive toward PC43-10 cells. AGF23 and AGF234 showed low level activity toward R2/PCFT4 cells (IC50∼200 nM), whereas AGF215 was inactive. Toward FRα-expressing RT16 cells, all the analogs were potently active with IC50 values of 1-6 nM. Toward KB tumor cells, AGF215 and AGF234 were highly potent with IC50 values of 3 and 1.3 nM, respectively. AGF215 and AGF234 are potential analogs for further preclinical studies and analog design.
Citation Format: Aleem Gangjee, Lalit Golani, Adrianne Wallaceb, Larry H. Matherly. Synthesis and biological evaluation of novel 6-substituted pyrrolo[2,3-d]pyrimidines as targeted antifolates. [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 4544. doi:10.1158/1538-7445.AM2015-4544
Abstract 4546: Depleting cysteine: A novel approach to tumor therapy
Authors: Hanigan Marie H. , Burgett Anthony W. G. , Wakeham Nancy , Terzyan Simon S. 
Published: August 2015

Abstract
A cure remains elusive for many types of tumors that initially respond to chemotherapy but recur with drug-resistant disease. Cysteine, (or its oxidized form cystine) is an essential amino acid for tumors. Enhanced uptake of cysteine and/or cystine is required for tumors to maintain their intracellular glutathione (GSH) levels and redox balance. In addition, some stem cells within epithelial tumors express CD44v8-10, which stabilizes the cystine transporter, increasing cystine uptake into the cell and enhancing resistance to pro-oxidant therapy. Depleting cysteine during treatment has a profound effect on sensitizing the tumor to therapy. We have a novel strategy that reduces the cysteine (and cystine) concentration in serum and extracellular fluid. The strategy exploits the finding that a severe cysteine deficiency develops in mice lacking the enzyme gamma-glutamyl transpeptidase (GGT). This enzyme reclaims the cysteine from GSH as the blood is filtered through the kidney. Inhibiting GGT activity results in excretion of GSH in the urine and a precipitous drop in the concentration of cysteine and cystine in serum. The inhibitors of GGT that have been evaluated in the clinic are glutamate analogs and are too toxic for clinical use. We have discovered and are developing a new class of GGT inhibitors that are not glutamate analogs. These inhibitors are orders of magnitude less toxic than the glutamate analogs. We have determined the crystal structure of human GGT. In the current study we have co-crystallized human GGT with a series of inhibitors. We report the identification of residues within the active site that are critical for inhibitor binding. We have identified changes in the conformation of the active site upon substrate binding. We have also delineated movement within the active site during substrate cleavage. Site-directed mutagenesis and functional assays have confirmed the role of the key residues identified in the structural studies. These data provide new insights for continued development of a potent, specific, non-toxic inhibitor of GGT that can be used clinically in cancer therapy. Supported by an Institutional Development Award (IDeA) from the National Institutes of Health under grant P20GM103640.
Citation Format: Marie H. Hanigan, Anthony W. G. Burgett, Nancy Wakeham, Simon S. Terzyan. Depleting cysteine: A novel approach to tumor 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 4546. doi:10.1158/1538-7445.AM2015-4546
Abstract 4547: Preparation of peptide-based Shp2 substrates with phosphatase activity-dependent fluorescence
Authors: Gunawan Steven , Luo Yunting , Ren Yuan , Lawrence Harshani R. , Wu Jerry , Lawrence Nicholas J. 
Published: August 2015

Abstract
The Shp2 protein tyrosine phosphatase mediates signal transduction of growth factor receptors and regulates cellular activities critical to tumor growth and metastasis. Shp2-activating mutations are associated with several types of leukemias and solid tumors, making Shp2 an attractive target for anticancer development. While there are reports of Shp2 inhibitors, there is a need for compounds with higher potency and improved selectivity. One approach to the discovery of new Shp2 inhibitors is via high throughput screening (HTS) of small molecule libraries. The small molecule probe 6,8-difluoro-4-methylumbelliferyl phosphate (DiFMUP) is currently a widely used substrate for phosphatases and has been used to assay Shp2 activity. However, DIFMUP binds only the catalytic site of the phosphatase and is unlikely to reveal compounds that are selective for Shp2 in an HTS. There is clearly a need to develop probes that are more sensitive and more specific for a particular phosphatase to identify Shp2 selective inhibitors and to measure Shp2 activity. We have developed a new phosphopeptide-like Shp2 substrate that becomes fluorescent upon enzyme-mediated hydrolysis, based on a phosphopeptide sequence that has high affinity for Shp2. We will report details of the novel Shp2 activity probe and its use as a reagent for HTS and determination of Shp2 inhibitor potency. We will also report on its suitability for HTS and preliminary results from screening and its potential for the discovery of novel Shp2 inhibitors. We will discuss the binding mode of the probe, based on novel co-crystal structures of related peptides with Shp2.
Citation Format: Steven Gunawan, Yunting Luo, Yuan Ren, Harshani R. Lawrence, Jerry Wu, Nicholas J. Lawrence. Preparation of peptide-based Shp2 substrates with phosphatase activity-dependent fluorescence. [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 4547. doi:10.1158/1538-7445.AM2015-4547
Abstract 4549: A comparative efficacy study of Saquinavir in combination with cisplatin or paclitaxel in platinum-resistant ovarian cancer cells
Authors: Waite Terry-Ann E. , Reboe Monique , Levy Arkene , Dhandayuthapani Sivanesan , Rathinavelu Appu 
Published: August 2015

Abstract
Background and Objective: Ovarian cancer is the 7th most common cancer affecting women Worldwide which has a 5-year survival rate of 45%. First line therapy, platinum and taxol compounds, produces 60% to 80% response rates in platinum sensitive ovarian cancer. However, incidence of resistance to this therapy is high resulting in poor prognosis. The present study evaluated the comparative efficacy of Saquinavir (SAQ) in combination with Cisplatin (CIS) or Paclitaxel (TAX) versus first line therapy, CIS+TAX, in platinum-resistant OVCAR-3 cells.
Method: OVCAR-3cells were treated with varying concentrations of SAQ (20μM, 40μM, 60μM and 100μM). OVCAR-3 cells were treated with SAQ (100μM), SAQ+CIS(26μM), SAQ+TAX(1.5nM) and CIS+TAX. Cells were treated over a 24hr period in triplicate. Media only and DMSO only treated cells were used as controls. The cytotoxic effect of each treatment was determined using the automated Trypan Blue exclusion protocol and DNA fragmentation assay was performed to evaluate the mechanisms of induced cell death.
Results: Dose dependent and statistically significant (p &lt;0.05) cytotoxic effects were seen with SAQ in OVCAR-3 cells. An IC50 value of 84μM for SAQ was determined in OVCAR-3 cells. Significant cytotoxic effects (p&lt;0.05) in OVCAR-3 treated cells were observed with SAQ, SAQ+TAX, SAQ+CIS AND CIS+TAX combinations when compared to controls. However, SAQ+CIS was the only combination that showed more significant cytotoxicity when compared to CIS+TAX (p = 0.041). SAQ+CIS combination produced an average percentage cell death of 73.25% in OVCAR-3 cells. Cell death by apoptosis was confirmed from observed fragmented DNA in OVCAR-3 cells treated with SAQ+TAX, SAQ+CIS and CIS+TAX.
Conclusion: SAQ+CIS produced more significant cytotoxic effect than first line therapy, CIS+TAX, in platinum-resistant ovarian cancer cells. This data supports further evaluation of SAQ for its potential utilization in the treatment of platinum-resistant ovarian cancer.
Note: This abstract was not presented at the meeting.
Citation Format: Terry-Ann E. Waite, Monique Reboe, Arkene Levy, Sivanesan Dhandayuthapani, Appu Rathinavelu. A comparative efficacy study of Saquinavir in combination with cisplatin or paclitaxel in platinum-resistant ovarian cancer cells. [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 4549. doi:10.1158/1538-7445.AM2015-4549
Abstract 4554: An evaluation of the role of Mucin in drug resistant ovarian cancer
Authors: Richards Steven M. , Campbell Robert B. 
Published: August 2015

Abstract
MUC1 is a transmembrane glycoprotein that is overexpressed in epithelial ovarian cancer. Due to extensive O-glycosylation, mucins form a physical barrier that limits the intracellular accumulation and cytotoxic effect of chemotherapeutic drugs. Our investigation represents a key step in determining if drug resistance in ovarian cancer develops due to altered MUC1 expression and glycosylation. Immunoblotting and ELISA techniques were utilized to characterize the extent of membrane-bound and shed MUC1 expression in drug-resistant and drug-sensitive ovarian cancer cells. An (anti-MUC1) antibody-based in vitro model was employed to determine if the inhibition of O-glycosylation enhanced functional access of small molecule drugs using FACS and fluorescence microscopic analyses. Expression of MUC1 was detected in both the drug resistant ovarian cancer cell line SK-OV-3 (MDR) and the parent cell line SK-OV-3 (WT), with the highest levels observed in the drug resistant sub-clone. The greatest improvement in functional anti-MUC1 antibody access following inhibition of O-glycosylation was observed in the drug-resistant ovarian cancer cells. Our results provide evidence to support drug resistance in ovarian cancer due in part to a mucin barrier mesh. The inhibition of mucin O-glycosylation may be a viable strategy to improve drug delivery and efficacy of small molecule delivery to ovarian carcinomas.
Citation Format: Steven M. Richards, Robert B. Campbell. An evaluation of the role of Mucin in drug resistant ovarian 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 4554. doi:10.1158/1538-7445.AM2015-4554
Abstract 4557A: Development of the proteasome deubiquitinase inhibitor VLX1570 for treatment of multiple myeloma
Authors: Wang Xin , Mohanty Chitralehka , D'Arcy Padraig , Olofsson Maria Hägg , Bossler Felicitas , Chanan-Khan Asher , Linder Stig 
Published: August 2015

Abstract
Inhibitors of the proteasome-ubiquitin system have been found to be effective in the clinical management of multiple myeloma. We here describe the compound VLX1570, an optimized lead of the 19S deubiquitinase inhibitor b- AP15. VLX1570 was shown to inhibit the enzymatic activities of both USP14 and UCHL5 in vitro, and was shown to induce accumulation of high molecular weight polyubiquitinated proteins in multiple myeloma cells. The compound showed limited inhibitory activity of a panel of kinases. VLX1570 induces apoptosis and cell death of multiple myeloma cell lines at submicromolar concentrations. Importantly, a multiple myeloma cell line selected for bortezomib resistance was found to be sensitive to VLX1570. VLX1570 was found to be able to overcome apoptosis resistance by these cells. Induction of the phosphorylation of stress-activated kinases (JNK and p38) and inhibition of ERK phosphorylation was observed in multiple myeloma cells. We finally showed that VLX1570 confers antineoplastic activity in two different myeloma xenograft models and conclude that VLX1570 is a candidate agent for treatment of multiple myeloma.
Citation Format: Xin Wang, Chitralehka Mohanty, Padraig D'Arcy, Maria Hägg Olofsson, Felicitas Bossler, Asher Chanan-Khan, Stig Linder. Development of the proteasome deubiquitinase inhibitor VLX1570 for treatment of multiple myeloma. [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 4557A. doi:10.1158/1538-7445.AM2015-4557A
Abstract 4561: Cancer preventive effect of antioxidants for spontaneous liver cancer in XPA(-/-) mice
Authors: Fu Ying , Silverstein Shana , Dyba Marcin , Coia Heidi , Sinclair Elizabeth , Pan Jishen , Kallakury Bhaskar , Johnson Michael D. , Chung Fung-Lung 
Published: August 2015

Abstract
γ-Hydroxy-1, N2-propanodeoxyguanosine (γ-OHPdG), a widely studied acrolein-derived cyclic adduct arisen from oxidized ω-3 and ω-6 polyunsaturated fatty acids (PUFAs), is a mutagenic lesion that is repaired by nucleotide excision repair (NER) pathway. C3H/HeN xeroderma pigmentosum group A (XPA) knockout mice which are deficient on NER pathway showed a significant elevation in liver tumors. We hypothesized that accumulation of γ-OHPdG is playing a role in liver tumorigenesis of XPA(-/-) mice; suppressing the formation of γ-OHPdG by dietary antioxidants should result in the prevention of liver cancer in this model. In this work, we investigated the chemoprotective efficacy of three antioxidants: α-lipoic acid, polyphenon E and vitamin E against liver tumorigenesis in XPA(-/-) mice. Autopsy at 19 months of age revealed that all the antioxidants exhibited significant inhibition effects on the development of liver tumors. Polyphenon E showed the most potent effects with 80% of the mice showing complete protection. The formation γ-OHPdG was measured in the livers of XPA(-/-) mice. An age-dependent increase of γ-OHPdG was found in the liver DNA of XPA(-/-) mice, but not in lungs (a non-target tissue). All the antioxidants decreased the formation of γ-OHPdG. Immunohistochemistry (IHC) for Ki-67 (proliferation index marker) was performed on all the liver samples, and the results showed that dietary antioxidants significantly decrease the proliferation in the liver tumors. α-Lipoic acid and vitamin E showed significant inhibitory effect, although to a lesser extent than Polyphenon E, against the spontaneous liver carcinogenesis in XPA gene-deficient mice model. A correlation between the cancer preventive efficacy and suppression of γ-OHPdG adduct level is observed, indicating a possible role of γ-OHPdG in the liver cancer development in this model. We also explored the feasibility of next-generation sequencing (NGS) to validate the mutation frequency changes as a result of feeding the antioxidant diets. This work was supported by the NCI grant: RO1-CA-134892. Y.F. thanks the Prevent Cancer Foundation for his fellowship (Marcia and Frank Carlucci Charitable Foundation Award in Cancer Prevention and Early Detection)
Note: This abstract was not presented at the meeting.
Citation Format: Ying Fu, Shana Silverstein, Marcin Dyba, Heidi Coia, Elizabeth Sinclair, Jishen Pan, Bhaskar Kallakury, Michael D. Johnson, Fung-Lung Chung. Cancer preventive effect of antioxidants for spontaneous liver cancer in XPA(-/-) mice. [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 4561. doi:10.1158/1538-7445.AM2015-4561