bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 163: Glioblastoma, cancer stem cells, and reactive species balances: A case for GTP cyclohydrolase 1
Authors: Tran Anh N. , Walker Kiera , Harrison David G. , Chen Wei , Mobley James , Hocevar Lauren , Hackney James R. , Sedaka Randee , Pollock Jennifer , Goldberg Matthew S. , Hambardzumyan Dolores , Cooper Sara J. , Gillespie G Yancey , Hjelmeland Anita B. 
Published: August 2018

Abstract
Glioblastoma (GBM), or grade IV astrocytoma, is a deadly disease due in part to the high degree of intratumoral heterogeneity that contributes to treatment failures. Previous studies have shown the importance of reactive species balances, partially controlled by the coupling of nitric oxide synthases (NOS) with their cofactor, in maintenance of glioma stem cell (GSC) phenotype as well as survival of cancer cells in general. In this study, we investigated the roles of GTP cyclohydrolase 1 (GCH1), which is the first and rate-limiting enzyme of the pathway producing of NOS cofactor producing pathway, in GBM stem cell phenotypes via redox balances. We found that GCH1 RNA and protein expression were increased in GSCs in comparison to non-GSCs, but that GCH1 was not exclusive to the GSC fraction. Indeed, GCH1 was elevated in GBM in comparison to normal brain. Overexpression of GCH1 in GBM cells increased cell growth in vitro and neurosphere-forming capability and decreased survival in an intracranial GBM mouse model. In contrast, GCH1 knockdown with short hairpin RNA in GBM cells led to growth inhibition in vitro as well as increased survival in animal models. GCH1 increased CD44 expression and was upregulated in the detrimental mesenchymal GBM subtype in which CD44 served as a marker. Mechanistically, we found that the expression of GCH1 increased BH4 production, as well as augmented multiple antioxidant pathways, including the expression of PARK7, was critical for controlling reactive species balance, including suppressing reactive oxygen species production. In silico analyses demonstrated that higher GCH1 levels in glioma patients correlate with higher glioma grade, recurrence and worse survival. Together, our data suggest that upregulation of GCH1 in GSCs promotes tumor maintenance and is a key regulator of reactive oxygen species in GBM, and GCH1 pathway is a potential target for therapy.
Citation Format: Anh N. Tran, Kiera Walker, David G. Harrison, Wei Chen, James Mobley, Lauren Hocevar, James R. Hackney, Randee Sedaka, Jennifer Pollock, Matthew S. Goldberg, Dolores Hambardzumyan, Sara J. Cooper, G Yancey Gillespie, Anita B. Hjelmeland. Glioblastoma, cancer stem cells, and reactive species balances: A case for GTP cyclohydrolase 1 [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 163.
Abstract 1638: Is short interval colonoscopy at the discretion of the gastroenterologist
Authors: Brim Hassan , Tushir Abhimanyu , Manchegowda Shashidhar , Farsi Negin , Lee Edward L. , Adeyinka Laiyemo O. , Nouraie Seyed M. , Ashktorab Hassan 
Published: August 2018

Abstract
BACKGROUND: Gastroenterologists do not always follow guidelines for performing colonoscopies. Short interval colonoscopies are recommended at the discretion of gastroenterologists depending on various factors. We here evaluated such factors in an African American patient population.
AIM: To assess factors contributing to short interval (within 3 months) colonoscopies.
METHODS: Data was retrieved retrospectively from Howard University Hospital database (Jan. 2010 to Dec. 2016). African American patients who had repeated colonoscopies within a period of 3 months were selected for this study. We analyzed patients' demographics, family history, polyp characteristics, and reasons for repeat colonoscopy along with latest follow-up findings.
RESULTS: There were 36 patients who underwent two colonoscopies within 3 months, 13 females and 23 males with mean age of 61 years. Out of these, 7 patients (19.4%) had poor bowel preparation. For the remaining 29 patients, the reason for second colonoscopy were partial removal and suspicion of partial removal (61.1%), difficult access (16.7%), and follow-up for Crohn's disease (2.8%). Follow-up of these 36 patients after their last colonoscopy revealed that 8 patients (22.2%) had colon cancer/resection, 4 other patients (11.1%) had cancer of other organs. Of the remaining, 6 (16.6%) had future colon polyp resection, 3 (8.3%) had normal screening colonoscopy and 4 (11.1%) visited the hospital for reasons unrelated to gastroenterology while 11 patients (30.6%) had no follow up.
CONCLUSION: Even though there are no recommendations to repeat colonoscopy within 3 months, endoscopists perform such colonoscopies at their own discretion based on factors like high risk individuals, poor bowel preparation, multiple lesions, type of lesions and resection clearance. Of interest, a significant number of patients in our study had colon cancer/resection on eventual follow-ups.
Citation Format: Hassan Brim, Abhimanyu Tushir, Shashidhar Manchegowda, Negin Farsi, Edward L. Lee, Laiyemo O. Adeyinka, Seyed M. Nouraie, Hassan Ashktorab. Is short interval colonoscopy at the discretion of the gastroenterologist [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 1638.
Abstract 1649: Impact of linker and conjugation site on tubulysin M ADC stability and in vivo activity
Authors: Burke Patrick J. , Hamilton Joseph Z. , Pires Thomas A. , Leiske Christopher I. , Cochran Julia H. , Setter Jocelyn R. , Emmerton Kim K. , Waight Andrew B. , Senter Peter D. , Lyon Robert P. , Jeffrey Scott C. 
Published: August 2018

Abstract
The tubulysins are a potent class of microtubule-disrupting agents consisting of natural products and designed analogues that have become a compelling cytotoxic payload for drug-targeting applications. This is due in large part to their high cytotoxic potency on cancer cells, including those that express transporters conferring the multidrug resistance (MDR+) phenotype. All potent tubulysin natural products contain an acetoxy group at the C11-position in the central tubuvaline residue. Deacetylation results in &gt;100-fold loss of cellular and biochemical potency, underscoring the importance of this structural element. Recently, we developed quaternary ammonium linker systems to conjugate tertiary amine-containing payloads, and applied them to the tubulysins. In this work, protease- and β-glucuronidase-cleavable quaternary ammonium linkers of tubulysin M were evaluated as ADC payloads. In vitro, both dipeptide and glucuronide linker systems provided ADCs with comparable biologic properties. However, in vivo, linker chemistry and conjugation site were important parameters impacting acetate group stability. Higher degrees of stability translated to greater activity in xenograft models. ADCs were prepared with both dipeptide and glucuronide linkers as heterogeneous ADCs loaded at an average of 4-drugs/Ab (DAR 4), and as homogeneous ADCs loaded at 2-drugs/Ab (DAR 2) at the engineered S239C sites. Increased in vivo acetate stability was observed for glucuronide-based conjugates relative to the dipeptide analogue. Further stabilization was achieved by conjugating at the S239C sites (DAR 2) relative to native antibody cysteines (DAR 4). Tubulysin M acetate stabilization by both linker and conjugation site selection resulted in increased ADC potency in preclinical models and, combined, serves as an enabling strategy for antibody-mediated tubulysin M drug delivery.
Citation Format: Patrick J. Burke, Joseph Z. Hamilton, Thomas A. Pires, Christopher I. Leiske, Julia H. Cochran, Jocelyn R. Setter, Kim K. Emmerton, Andrew B. Waight, Peter D. Senter, Robert P. Lyon, Scott C. Jeffrey. Impact of linker and conjugation site on tubulysin M ADC stability and in vivo activity [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 1649.
Abstract 1651: In vitro and in vivo profile of the preclinical candidate and MPS1 kinase inhibitor CCT289346
Authors: Woodward Hannah , Innocenti Paolo , Cheung Kwai-Ming J. , Naud Sébastien , Faisal Amir , Mak Grace W. , Hayes Angela , O'Fee Lisa , Saville Harry , Brandon Alexis De Haven , Roberts Jennie , Box Gary , Valenti Melanie , Heneley Alan T. , Walsh Katie , Burke Rosemary , Eccles Suzanne A. , Raynaud Florence I. , Montfort Rob L. van , Blagg Julian , Linardopoulos Spiros , Hoelder Swen 
Published: August 2018

Abstract
The mitotic kinase MPS1 (also known as TTK) is one of the main components of the spindle assembly checkpoint. MPS1 is required for chromosome alignment and kinetochore-microtubule error correction. Cancer cells are dependent on MPS1 to cope with chromosomal instability resulting from aberrant numbers of chromosomes. Moreover, MPS1 has been found to be deregulated in a large number of tumor types. MPS1 kinase inhibitors induce cancer cells to prematurely exit mitosis with incorrectly attached and unaligned chromosomes, causing severe chromosome mis-segregation, aneuploidy and cell death. These data stimulated us to pursue MPS1 as a cancer target. Extensive work by us and other groups has shown that MPS1 inhibitors are effective against a variety of cancers, particularly when used in combination with other drugs, such as paclitaxel. Here we disclose CCT289346, an MPS1 inhibitor currently completing late stage preclinical development. We describe the final stages of chemical optimisation and the data driven selection and nomination of CCT289346 as our preclinical candidate. We report key in vitro and in vivo preclinical data such as kinase profiling, PK in mouse, rat and dog, PK/PD relationship and efficacy in different in vivo models.
Citation Format: Hannah Woodward, Paolo Innocenti, Kwai-Ming J. Cheung, Sébastien Naud, Amir Faisal, Grace W. Mak, Angela Hayes, Lisa O'Fee, Harry Saville, Alexis De Haven Brandon, Jennie Roberts, Gary Box, Melanie Valenti, Alan T. Heneley, Katie Walsh, Rosemary Burke, Suzanne A. Eccles, Florence I. Raynaud, Rob L. van Montfort, Julian Blagg, Spiros Linardopoulos, Swen Hoelder. In vitro and in vivo profile of the preclinical candidate and MPS1 kinase inhibitor CCT289346 [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 1651.
Abstract 1654: Chemical and structure-guided optimization of BAX trigger site activators for cancer therapy
Authors: Reyna Denis E. , Kopp Felix , Gavathiotis Evripidis 
Published: August 2018

Abstract
Cancer cells evade mitochondrial apoptosis most commonly by over-expressing anti-apoptotic BCL-2 proteins that suppress the activation of pro-apoptotic proteins. Pro-apoptotic BAX is a critical BCL-2 family effector protein that upon death stimuli is activated and induces mitochondrial outer membrane permeabilization that leads to cell death. The vast majority of cancer cells express wild-type BAX, therefore, direct BAX activation represents a potential therapeutic strategy in cancer. We previously presented the discovery of BTSA1 as a selective BAX activator with anti-leukemic activity and provided proof-of-concept for BAX as a druggable target in acute myeloid leukemia (AML) (Reyna et al, Cancer Cell, 2017). Here, we investigated chemical optimization of BTSA1 core scaffold to rationally optimize the potency and efficacy of the BAX trigger site activators in AML models. We designed compounds using a structural model of BTSA1 bound to the BAX trigger site that also fits with the previous established pharmacophore model. Synthesized compounds were evaluated for binding potency using a fluorescence polarization binding assay that measures compound competition of the fluorescein-label stapled BIM BH3 peptide from the BAX trigger site. Compounds with improved binding activity were evaluated for their potency in biochemical assays of BAX activation using isolated liposomal and mitochondrial membrane assays. Improved binding to BAX of BTSA1 derivatives correlated with better activation capacity. Moreover, compounds were evaluated for their efficacy in induction of BAX-mediated cell death in AML cell lines including Venetoclax-resistant cells. We have identified compounds with similar or superior cellular efficacy compared to BTSA1. Compounds were evaluated for ADME and in vivo pharmacokinetic profiles and these are compared to efficacy and pharmacodynamics data using in vivo AML xenograft models. Our work highlights our strategy for chemical and structure-guided optimization of BTSA1 demonstrating the potential for improved therapeutic induction of apoptosis in AML by BAX Trigger Site Activators.
Citation Format: Denis E. Reyna, Felix Kopp, Evripidis Gavathiotis. Chemical and structure-guided optimization of BAX trigger site activators for cancer therapy [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 1654.
Abstract 1656: First-in-class, fluorinated folate receptor specific agents that target tumor cells via inhibition of serine hydroxymethyltransferase 2 (SHMT2) and 5-aminoimidazole-4-carboxamide formyltransferase (AICARFTase)
Authors: Nayeen Md Junayed , Shah Khushbu , Gangjee Aleem , Dekhne Aamod , Hou Zhanjun , Matherly Larry H. 
Published: August 2018

Abstract
Tumor-specific folate receptor (FR) targeting over the ubiquitous reduced folate carrier (RFC) allows for specific tumor targeting without the attending dose-limiting toxicity of all clinically used cytotoxic agents. In an attempt to provide selectivity for FRα and/or β, folic acid has been conjugated with a variety of cytotoxic payloads to alleviate dose-limiting toxicities since folic acid is not transported via RFC (the major tissue folate transporter) to any significant extent. These conjugates have been unsuccessful in clinical trials likely in part due to the instability of the linkers used for conjugation. Premature cleavage results in the cytotoxic component being released prior to tumor penetration, thus precluding any possibility of selective tumor targeting. We designed novel pyrrolo[3,2-d]pyrimidine compounds in which both the targeting component and the cytotoxic component are in the same molecule. These compounds do not require any conjugation or linkers and hence do not suffer any premature cleavage. In this report, we synthesized and evaluated a “first-in-class” series of fluorinated analogues that target FRα/β and have limited transport via RFC, thus providing selectivity for tumors expressing FRα and/or FRβ. Two lead molecules, AGF347 and AGF355, were potent inhibitors of KB human tumor cell proliferation in vitro (IC50 = 1.05 nM and 6.25 nM respectively). Based on protection experiments with glycine, thymidine, adenosine and 5-aminoimidazole-4-carboxamide (AICA), AGF347 and AGF355 were identified as dual inhibitors of serine hydroxymethyltransferase 2 (SHMT2), a key enzyme in mitochondrial one-carbon metabolism and reported oncodriver, and AICA ribonucleotide formyltransferase (AICARFTase), the 2nd folate-dependent step in de novo purine biosynthesis. These compounds are currently being evaluated in preclinical studies as potential candidates for clinical trials.
Citation Format: Md Junayed Nayeen, Khushbu Shah, Aleem Gangjee, Aamod Dekhne, Zhanjun Hou, Larry H. Matherly. First-in-class, fluorinated folate receptor specific agents that target tumor cells via inhibition of serine hydroxymethyltransferase 2 (SHMT2) and 5-aminoimidazole-4-carboxamide formyltransferase (AICARFTase) [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 1656.
Abstract 1662: Synthesis and biologic evaluation of diethylbenzaldehyde analogues to probe functional activity of aldehyde dehydrogenase activity in cancer
Authors: Ibrahim Ali , Sadiq Maria , Presa Daniela , Ntafoulis Ioannis , Alkawi Ahmad , Frame Fiona , Maitland Norman J. , Cournia Zoe , Loadman Paul M. , Moreb Jan , Pors Klaus 
Published: August 2018

Abstract
The human aldehyde dehydrogenases (ALDHs) play a major role in detoxifying highly reactive aldehydes into carboxylic acids. Deregulation of ALDHs has implications in a number of cancers. They play an important role as a cancer stem cell (CSC) marker due to high activity found in CSCs, while high expression is also known to lead to resistance to chemotherapeutic drugs. Although the exact roles of ALDHs are not fully understood, emerging information indicates several isoforms from the ALDH1 family, ALDH3A1 and ALDH7A1, play key roles in several cancer types. To probe the role of ALDH functional activity, we here report on the perturbation of ALDH expression and function using diethylbenzaldehyde (DEAB) analogues. The H1299 lung cancer cell line has negligible amount of ALDH activity, and ALDH-expressing variants were used to study the novel DEAB analogues. H1299 wild-type cells (WT) and cells expressing RFP were used as controls. Expression of the proteins was confirmed by Western blots and ALDH enzymatic activity assay. We used cell culture, colorimetric MTT assay, aldefluor assay and in vitro treatment with DEAB analogues. ALDH-expressing lysates were used to obtain biochemical inhibition data of the DEAB analogues using propionaldehyde as substrate with NAD+ as a co-factor. DEAB has been shown to covalently bind to ALDH7A1, and computational modeling was employed to understand how chemical modifications to DEAB affected the binding mode. Selected ALDH-affinic probe compounds were tested in a panel of colon, lung and prostate cancer cell lines including docetaxel-resistant variant and patient samples to investigate if DEAB analogues had an effect on cell viability as single agents or in combination with docetaxel. In conclusion, the novel DEAB analogues aid us to understand ALDH functional activity and provide a platform for discovering more selective ALDH inhibitors
Citation Format: Ali Ibrahim, Maria Sadiq, Daniela Presa, Ioannis Ntafoulis, Ahmad Alkawi, Fiona Frame, Norman J. Maitland, Zoe Cournia, Paul M. Loadman, Jan Moreb, Klaus Pors. Synthesis and biologic evaluation of diethylbenzaldehyde analogues to probe functional activity of aldehyde dehydrogenase activity in cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 1662.
Abstract 1664: 4-Bromophenylhydrazinyl benzenesulfonylphenylureas inhibit indoleamine 2,3-dioxygenase in vitro and in vivo
Authors: Ueng Shau-Hua , Kuo Ching-Chuan , Lin Shu-Yu , Yeh Teng-Kuang , Song Jen-Shin , Hung Ming-Shiu , Chen Chiung-Tong 
Published: August 2018

Abstract
Indoleamine 2,3-dioxygenase has been considered as a promising anti-cancer drug target. Several pharmaceutical companies, including Pfizer, Merck, and Bristol-Myers Squibb, are known to be in pursuit of IDO inhibitors, and Incyte recently reported good results in the phase II clinical trial of the IDO inhibitor Epacadostat. In previous work, we developed a series of IDO inhibitors based on a high-throughput screening core structure, sulfonylhydrazide. Further, we developed the 4-bromophenylhydrazinyl benzenesulfonylphenylurea, as a potent IDO inhibitor with an IC50 value within 100 nM in inhibiting IDO in vitro. This compound demonstrated a 30% reduction in tumor weight in a murine CT26 syngeneic model on day 18 with 100 mg/kg oral administration twice daily, indicating that the 4-bromophenylhydrazinyl benzenesulfonylphenylurea may have potential for further investigation in the development of anti-tumor drugs.
Citation Format: Shau-Hua Ueng, Ching-Chuan Kuo, Shu-Yu Lin, Teng-Kuang Yeh, Jen-Shin Song, Ming-Shiu Hung, Chiung-Tong Chen. 4-Bromophenylhydrazinyl benzenesulfonylphenylureas inhibit indoleamine 2,3-dioxygenase in vitro and in vivo [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 1664.
Abstract 1673: Ras degrading small molecules inhibit the transformation of colorectal cancer cells independently of beta-catenin signaling
Authors: Hwang Jeong-Ha , Ro Eun Ji , Shin Wookjin , Choi Kang-Yell 
Published: August 2018

Abstract
Development of drugs controlling Ras is an emerging issue in cancer therapy; however, no clinically applicable drug is currently available. On the basis of the mechanism of Ras protein stability regulation via the Wnt/β-catenin signaling pathway, we previously identified small molecules inhibiting the proliferation and transformation of various colorectal cancer (CRC) cells via degradation of both β-catenin and Ras. Due to the absence of Ras degradation in cells expressing non-degradable mutation in β-catenin, and the need to determine an alternative mechanism for Ras degradation, we established a cell-based system to screen compounds that degrade Ras independently of the Wnt/β-catenin signaling pathway. A cell-based high-content screening (HCS) system monitoring the level of EGFP-K-RasG12V was established using HCT-116 cells harboring a non-degradable mutant β-catenin (ΔS45). Through HCS of a chemical library composed of 10,000 compounds, and by subsequent characterization of candidate compounds, we identified several compounds that degraded Ras without affecting β-catenin levels. KY7749, the most effective compound, inhibited the proliferation and transformation of CRC cells, including those resistant to the EGFR monoclonal antibody, cetuximab, due to KRAS mutations. Small molecules that degrade Ras independently of β-catenin would be a potential treatments for cancers caused by aberrant EGFR, Ras, and β-catenin.
Citation Format: Jeong-Ha Hwang, Eun Ji Ro, Wookjin Shin, Kang-Yell Choi. Ras degrading small molecules inhibit the transformation of colorectal cancer cells independently of beta-catenin signaling [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 1673.