bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 266: Relationship between BAG3 expression and the cytotoxicity of laromustine in HL60 cells
Authors: Clarke Stanley R. , Naccara Allie H. , Loya Amanda J. , Marchant Sam W. , Wang Xiaoou , LaJoie Thomas J. , Smith Jordyn N. , Rice Kevin P. 
Published: August 2019

Abstract
Laromustine is an experimental sulfonylhydrazine prodrug with clinical potential against acute myelogenous leukemia and glioblastoma multiforme. Cytotoxicity is largely due to DNA crosslinking activity from an electrophilic subspecies of laromustine generated in situ. However, methylisocyanate, another electrophile cogenerated upon base-catalyzed activation of laromustine, induces acute toxicity in cultured leukemia cells. Isocyanate-mediated cytotoxicity likely involves apoptotic processes revealed in experiments presented herein showing PARP cleavage, caspase 3/7 activation, and annexin-V staining. We demonstrate that compounds that yield methylisocyanate, including laromustine, cause substantial dysregulation of gene transcription patterns that are not observed with a derivative of laromustine that possesses the DNA crosslinking activity but not the methylisocyanate. Purified mRNA from promyelocytic HL60 cells treated with either 100 µM agent or an equivalent volume of DMSO was measured using real-time RT-PCR experiments and GeneChip analyses. Among the nearly 3,000 genes dysregulated upon exposure to both laromustine and its methylisocyanate-bearing analog, BCL2-associated athanogene 3 (BAG3) emerged as a promising candidate for further investigation. This anti-apoptotic gene was significantly upregulated in these conditions. So as to assess the significance its gene product in cell death or survival in cultured cells treated with laromustine, a stable cell line expressing an shRNA construct to knock down BAG3 was engineered from HL60 cells using lentiviruses. Preliminary evidence suggests that these cells are more susceptible to the cytotoxic effects of laromustine. These data suggest that BAG3 may be part of a defensive strategy for promyelocytic leukemia cells to survive treatment with laromustine.
Citation Format: Stanley R. Clarke, Allie H. Naccara, Amanda J. Loya, Sam W. Marchant, Xiaoou Wang, Thomas J. LaJoie, Jordyn N. Smith, Kevin P. Rice. Relationship between BAG3 expression and the cytotoxicity of laromustine in HL60 cells [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 266.
Abstract 2683: Biomarkers of glucose homeostasis and inflammation and risk of prostate cancer: A case-cohort study
Authors: Wang Ying , Campbell Peter T. , Stevens Victoria L. , Newton Christina C. , Jacobs Eric J. , Pollak Michael , Gapstur Susan M. 
Published: August 2019

Abstract
Background: Type 2 diabetes (T2DM) is associated with a lower risk of prostate cancer especially low-grade and localized prostate cancer. The association with aggressive prostate cancer is inconclusive. Few studies have directly examined the associations of diabetes biomarkers with prostate cancer risk. Methods: Among a cohort of 13,994 men who were on average 70.2 years (SD=5.5) and cancer free at blood draw between 1998 and 2001, 1,206 developed non-aggressive prostate cancer and 313 developed aggressive prostate cancer (AJCC stage 3-4 or Gleason score 8-10) during follow-up through June 2013. We conducted a case-cohort study including a random sub-cohort of 1,303 men, 391 non-aggressive cases and 313 aggressive cases to examine circulating hemoglobin A1c (HbA1c), c-peptide, and C-reactive protein (CRP) in relation to prostate cancer risk.
Results: HbA1c, a biomarker of hyperglycemia, was inversely associated with non-aggressive prostate cancer after adjusting for age, race, family history of prostate cancer, prostate-specific antigen screening, smoking, alcohol intake, physical activity, and total energy intake (relative risk (RR) per unit increase: 0.89, 95% confidence interval (CI): 0.79-1.00, P=0.04). Further adjustment for body mass index (BMI) attenuated the association. In contrast, HbA1c was associated with a higher risk of aggressive prostate cancer after adjusting for the covariates including BMI (RR per unit increase: 1.11, 95% CI: 0.98-1.25, P=0.11). In an analysis combining self-reported T2DM and HbA1c, men with T2DM and poor blood glucose control (HbA1c ≥6.5%) had a lower risk of developing non-aggressive prostate cancer (RR: 0.53, 95% CI: 0.30-0.95) than men without T2DM and good blood glucose control (HbA1c &lt;6.5%). After excluding men with self-reported T2DM, HbA1c was statistically significantly positively associated with risk of aggressive prostate cancer (RR per unit increase: 1.25, 95% CI: 1.04-1.51, P=0.02) but was not associated with non-aggressive prostate cancer. C-peptide and CRP were not associated with risk of either aggressive or non-aggressive prostate cancer.Conclusions: The present study suggests that men with hyperglycemia may have a lower risk of developing non-aggressive but a higher risk of developing aggressive prostate cancer. Further studies are needed to examine the role of hyperglycemia in the etiology of aggressive prostate cancer and in prostate cancer progression.
Citation Format: Ying Wang, Peter T. Campbell, Victoria L. Stevens, Christina C. Newton, Eric J. Jacobs, Michael Pollak, Susan M. Gapstur. Biomarkers of glucose homeostasis and inflammation and risk of prostate cancer: A case-cohort study [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 2683.
Abstract 2702: Contribution of effector regulatory T cells to the regulation of antitumor immunity
Authors: Dixon Michael L. , Luo Lin , Leavenworth Jianmei W. 
Published: August 2019

Abstract
Regulatory T cells (Treg) belonging to the FoxP3 lineage stringently control immune responses and self-tolerance. Follicular regulatory T (TFR) cells, an effector Treg (eTreg) subset, not only suppress cellular responses but also regulate the magnitude and quality of the germinal center (GC)-antibody (Ab) response through interactions with activated follicular helper T (TFH) cells and GC B cells. Although the Blimp1 transcription factor has been used as a phenotypic marker for eTreg, its contribution to the lineage stability and suppressive activity of eTreg, particularly TFR, has been clouded in uncertainty. In contrast to the current view that Blimp1 may have a negative impact on the TFR response, our recent analysis of mice that harbor a FoxP3-specific deletion of Blimp1 has shown that expression of Blimp1 in eTreg (including TFR) is essential for the maintenance of FoxP3 expression and stable eTreg suppressive phenotype. We then generated B16 melanoma model in these mice and investigated the impact of Blimp1 deficient eTreg on the tumorigenesis. These mice had delayed tumor growth compared to WT controls. The enhanced antitumor immunity in mice with Blimp1 deficient eTreg reflected reprogramming of unstable eTreg into T-cells with effector activity (Teff) specifically within the tumor and loss of suppression on TFH-Ab responses, leading to intratumoral TFH expansion, Ab deposition and enhanced CD8+ T-cell and NK cell effector function. Further analysis of mice expressing a conditional and tamoxifen-inducible Blimp1 deletion within the FoxP3+ lineage revealed the specific contribution of Blimp1 deficient TFR cells to antitumor immune response. These results suggest that induction of eTreg lineage instability provokes intratumoral eTreg conversion into Teff −a new source of effector activity by T-cells within the tumor and enhances robust Ab responses. The increased cellular and humoral responses cooperatively promote antitumor immunity. Insights from our studies may suggest new approaches to manipulate eTreg for better vaccines or combined immunotherapeutic approaches to melanoma or other types of cancer.
Citation Format: Michael L. Dixon, Lin Luo, Jianmei W. Leavenworth. Contribution of effector regulatory T cells to the regulation of antitumor immunity [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 2702.
Abstract 2717: Role of NAD+ level by NQO1 enzymatic action in regulation of hair regrowth that prevents chemotherapy-induced alopecia
Authors: Khadka Dipendra , Oh Gi-Su , Kim Hyung-Jin , Lee SeungHoon , Lee Su-bin , Sharma Subham , Kim Seon Young , Kwak Tae Hwan , Yang Sei-Hoon , Sim Hyuk , So Hong-Seob 
Published: August 2019

Abstract
Various types of chemotherapeutic agents are widely used to treat a variety of human neoplasms. Nonetheless, its clinical use is hampered because of severe adverse side effects such as alopecia, neutropenia, pain, cachexia, conception impairment etc. Chemotherapy-induced alopecia (CIA) is one of the fundamental unsolved problems of clinical oncology that often encountered in cancer treatment. CIA has been reported to be caused by skin inflammation through oxidative stress, DNA damage, and inflammatory responses. However, the best remedy for CIA is still not established. In a new strategy, we show that WK0202 compound as a strong NQO1 substrate that modulates the intracellular NAD+ levels by NAD(P)H quinone oxidoreductase 1 (NQO1) enzymatic action and plays important role in hair regrowth response to single (cyclophosphamide-CYP) or combined (taxol, adriamycin and cyclophosphamide-TAC) cancer therapy. Particularly, we demonstrated that cellular NAD+ levels as well as SIRT1 activity and its expression was decreased in skin with hair follicles after CYP and TAC treatment, and PARP-1 hyperactivation was associated with CIA through increased nuclear factor (NF)-κB p65 and p53 acetylation in wild type, NQO1-/- and K14-/- C57BL/6 mice. However, an increase in NAD+ levels by WK0202 completely restored SIRT1 activity and its expression, and subsequently deacetylated NF-κB p65 and p53 in wild type, however not in NQO1-/- and K14-/- mice thereby attenuating CIA. Therefore, modulation of NAD+ levels by NQO1 may be a novel therapeutic approach to prevent chemotherapy-associated hair loss, including CIA.
Citation Format: Dipendra Khadka, Gi-Su Oh, Hyung-Jin Kim, SeungHoon Lee, Su-bin Lee, Subham Sharma, Seon Young Kim, Tae Hwan Kwak, Sei-Hoon Yang, Hyuk Sim, Hong-Seob So. Role of NAD+ level by NQO1 enzymatic action in regulation of hair regrowth that prevents chemotherapy-induced alopecia [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 2717.
Abstract 2731: A novel PDE10/beta-catenin inhibitor, MCI-048, suppresses lung tumorigenesis to block metastasis
Authors: Zhu Bing , Ramirez-Alcantara Veronica , Ward Antonio , Berry Kristy , Keeton Adam B. , Boyd Michael R. , Maxuitenko Yulia , Chen Xi , Piazza Gary A. 
Published: August 2019

Abstract
We previously reported that phosphodiesterase 10A (PDE10) is overexpressed during early stages of lung cancer and is essential for lung tumor cell growth. Here we characterize a novel PDE10 inhibitor, MCI-048, that was identified by screening a library of indene compounds. MCI-048 potently inhibited the growth and induced apoptosis of multiple human lung cancer cell lines expressing PDE10, while normal human airway epithelial cells lacking PDE10 expression were appreciably less sensitive. The mechanism of action of MCI-048 involves PDE10 inhibition, cGMP elevation, PKG activation, and phosphorylation of β-catenin at key residues that induce ubiquitination and proteosomal degradation of the oncogenic pool of β-catenin in cytoplasm to suppress the translocation of active β-catenin to the nucleus and Lef/Tcf-mediated transcription of genes encoding for proteins such as c-myc, cyclin D, and survivin, which are essential for tumor cell proliferation and survival. Pharmacokinetic and tissue distribution studies revealed a unique feature of MCI-048 to accumulate at high concentrations in lungs relative to plasma and other tissues. To assess the potential of MCI-048 for the treatment of lung cancer and blocking metastasis, we tested the drug in two mouse models of lung cancer involving either orthotopic implantation of KRAS mutant A549 lung tumor cells or the chemical carcinogen, urethane. Oral administration of MCI-048 significantly inhibited tumor growth and extended survival in the orthotopic model using two different protocols to either treat the primary tumor or metastasis. Similarly, MCI-048 significantly reduced tumor burden as measured by both surface counting and histopathological analysis in the urethane-induced model of lung tumorigenesis. Biochemical analysis showed that MCI-048 reduced levels of urethane-induced active Ras-GTP and PDE10 levels, as well as other oncogenic markers, including pEGFR and c-Myc. Both mouse models revealed that MCI-048 was well tolerated with no discernable toxicity, thus supporting preclinical development for the treatment of lung cancer. Funding provided by NCI grants R21CA182941, R01CA131378, R01CA148817, R01CA197147, and R01CA155638.
Citation Format: Bing Zhu, Veronica Ramirez-Alcantara, Antonio Ward, Kristy Berry, Adam B. Keeton, Michael R. Boyd, Yulia Maxuitenko, Xi Chen, Gary A. Piazza. A novel PDE10/beta-catenin inhibitor, MCI-048, suppresses lung tumorigenesis to block metastasis [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 2731.
Abstract 2735: Targeting HDAC prevents smoking-induced pancreatic cancer metastasis
Authors: Yang Jiyong , Chheda Chintan , Hauptschein Dina , Zayou Latifa , Tang Josiah , Wang Qiang , Pandol Stephen J. , Edderkaoui Mouad 
Published: August 2019

Abstract
Background: Cigarette smoking is an established risk factor for pancreatic ductal adenocarcinoma (PDAC). Among patients with metastatic PDAC, 90% have liver and 50% have lung metastasis. In this project we investigated the effect of smoking on pancreatic cancer invasion and metastasis in vitro and in vivo.
Methods: Pancreatic cancer cells were treated with different doses of 4-(methylnitro-s-amino)-1-(3-pyridyl)-1-butanone (NNK) and cigarette smoke extract (CSE) and cancer cell survival, markers of epithelial to mesenchymal transition (EMT) as well as invasion were measured by MTT assay, Western, RT-PCR and Matrigel Invasion Assay. In a syngeneic mouse model of pancreatic cancer mice were pre-treated with NNK for 4 weeks and mouse cancer cells were injected in the spleen of mice. Progression of the disease including metastasis to liver and lung was monitored by imaging and tissues were collected and analyzed after 6 weeks.
Results: Smoking compounds slightly but significantly increased cancer cell survival. They significantly promoted expression of EMT markers and promoted invasion of the cancer cells. Inhibition of histone deacetylase (HDAC) (class I and II), and especially HDAC4, prevented the pro-EMT and invasion effect of smoking compounds. NNK increased the protein level of HDAC4 and the level of Yes-associated protein 1 (Yap) translocated to the nucleus. Inhibition of HDAC4 reversed this effect. Analysis of Yap binding proteins showed presence of HDAC4 in the Yap protein complex. HDAC inhibition decreased the level of Yap-HDAC4 complex formation. In vivo, NNK promoted metastasis of pancreatic cancer cells to mice lung and liver; whereas, inhibition of HDAC decreased the number of metastases to a level lower than control treated mice. Smoking promoted liver and lung fibrosis and inflammation and measured by the level of collagen staining, stellate cells activation and immune cells staining. HDAC inhibition reversed these effects of smoking.
Conclusion: We showed for the first time in an animal model that smoking promotes metastasis of PDAC to the lung. We found that HDAC4 is key mediator of this effect. Inhibiting HDAC4 is a promising strategy for preventing PDAC metastasis.
Citation Format: Jiyong Yang, Chintan Chheda, Dina Hauptschein, Latifa Zayou, Josiah Tang, Qiang Wang, Stephen J. Pandol, Mouad Edderkaoui. Targeting HDAC prevents smoking-induced pancreatic cancer metastasis [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 2735.
Abstract 2751: Development of a specific Wee-1 inhibitor
Authors: Watson Mandy , Pesnot Tom , Scott Andrew , Huxley Anthony , Nelson Gary , Shelbourne Montserrat , Morton Jen , Bingham Tilly 
Published: August 2019

Abstract
Somatic mutations in the TP53 gene are one of the most frequent alterations in human cancers. The resulting TP53-deficient cancer cells rely on WEE1 to trigger a G2/M arrest, which allows for DNA repair and survival. Inhibition of WEE1 has therefore emerged as an attractive therapeutic strategy to selectively sensitise TP53-deficient tumours to DNA damaging agents. The WEE1 kinase inhibitor adavosertib is the only agent undergoing evaluation in a range of clinical trials to validate this hypothesis. It has also been the tool compound of choice to interrogate WEE1 biology for over a decade.
However, recent reports show adavosertib has antiproliferative single agent activity, which is counter intuitive considering its postulated mode of action. Other studies suggest adavosertib exerts poor kinase selectivity, and inhibits PLK1 with similar potency as WEE1. Since PLK1 is a well-established mitotic regulator with biological functions throughout the cell cycle, its inhibition may contribute to the clinical efficacy and toxicity observed for adavosertib. Other reported WEE1 inhibitors also suffer from low selectivity and single agent toxicity, making then unsuitable tool compounds. There is a clear need to identify a selective Wee1 tool compound.
Using a structure-based drug design approach, we exploited subtle active site differences to identify novel, potent WEE1 inhibitors that display high selectivity over PLK1. These compounds allowed us to demonstrate the distinct effects of WEE1 and PLK1 inhibition on cellular toxicity, and confirm that adavosertib’s single agent efficacy is unlikely to be mediated solely through the inhibition of WEE1. Our ongoing studies aim to provide a WEE1 selective tool compound that more rigorously probes WEE1 biology, and eventually leads to the development of less toxic therapeutic agents.
Citation Format: Mandy Watson, Tom Pesnot, Andrew Scott, Anthony Huxley, Gary Nelson, Montserrat Shelbourne, Jen Morton, Tilly Bingham. Development of a specific Wee-1 inhibitor [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 2751.
Abstract 2752: Recognition of the hybrid-1 human telomeric G-quadruplex by a platinum(II)-based compound
Authors: Liu Wenting , Lin Clement , Mao Zong-wan , Yang Danzhou 
Published: August 2019

Abstract
The human telomeric DNA, which consists of tandem repeat sequences of d(TTAGGG)n, plays an important role in cancers and cell aging. Previous studies in human cancer cells have demonstrated DNA G-quadruplex (G4) structure formation in telomeres. G-quadruplexes are four-stranded structures formed in guanine-rich sequences that are held together by guanine-guanine Hoogsteen hydrogen bonding, and G-quadruplex stabilization by small molecules induces tumor cell senescence and apoptosis by repressing telomerase activity and the DNA damage response pathway. Additionally, telomeric-overhang DNA can form biologically relevant higher-order DNA structures containing consecutive G-quadruplexes which provides additional binding sites for small molecules. Thus, telomeric DNA G-quadruplexes have attracted increasing interest as potential drug targets for cancer therapy. Here, we found that a novel platinum (II)-based tripod (Pt-tripod) specifically recognizes the hybrid-1 human telomeric G4, which is formed in the physiologically relevant K+ solution. Pt-tripod strongly represses telomerase activity and exhibits DNA-targeted photodynamic therapy anticancer activity. Using NMR, we show that Pt-tripod binds the hybrid-1 human telomeric G4 over other G-quadruplex structures and dsDNA. We determined solution structures of the 1:1 and the dimeric 4:2 Pt-tripod-hybrid-1 telomeric G4 complexes by NMR. Our 1:1 complex structure shows preferential binding of the Pt-tripod to the 5′-end of hybrid-1 telomeric G4. At higher ligand ratio, Pt-tripod binds to the 3′-end of the hybid-1 G4 and induces an unprecedented dimeric 4:2 structure interlocked by a non-canonical A:A pair at the 3′-end. The specific binding of the Pt-tripod with the hybrid-1 G4 is achieved by unique interaction modes including the π-π stacking, hydrogen bonding, and electrostatic interactions with the loop and flanking segments. The non-planar tertiary amine conformation and three properly sized cationic platinum arms are critical for the specific and strong binding. Our structures provide significant insights into understanding the dynamic binding of small molecules with G-quadruplexes, and a structural basis for future rational anticancer drug design of non-planar small molecules targeting the human telomeric G4. Our studies also provide a potential handle to study the specific protein interactions and biological functions of hybrid-1 human telomeric G4.
Citation Format: Wenting Liu, Clement Lin, Zong-wan Mao, Danzhou Yang. Recognition of the hybrid-1 human telomeric G-quadruplex by a platinum(II)-based compound [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 2752.