bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 3062: Silencing the epigenetic silencer KDM4A for TRAIL and DR5 simultaneous induction and antitumor therapy
Authors: Wang Junjian , Wang Haibin , Wang Lingyu , Cai Demin , Duan Zhijian , Chen Peng , Zou June X , Xu Jianzhen , Chen Xinbin , Kung Hsing-Jien , Chen Hong-wu 
Published: July 2016

Abstract
Recombinant TRAIL and agonistic antibodies to death receptors (DRs) have been in clinical trial but displayed limited anti-cancer efficacy. Lack of functional DR expression in tumors is a major limiting factor. We report here that chromatin regulator KDM4A/JMJD2A, not KDM4B, plays a pivotal role in silencing tumor cell expression of both TRAIL and its receptor DR5. In TRAIL-sensitive and -resistant cancer cells of lung, breast and prostate, KDM4A small-molecule inhibitor compound 4 (C-4) or genetic silencing strongly induces TRAIL and DR5 expression, and causes TRAIL-dependent apoptotic cell death. KDM4A inhibition also strongly sensitizes cells to TRAIL. C-4 alone potently inhibits tumor growth with marked induction of TRAIL and DR5 expression in the treated tumors and effectively sensitizes them to the newly developed TRAIL-inducer therapeutics ONC201. Mechanistically, C-4 does not appear to act through the Akt-ERK-FOXO3a pathway. Instead, it switches histone modifying enzyme complexes at TRAIL and DR5 transcriptional activator CHOP gene promoters by dissociating KDM4A and NCoR-HDAC corepressor complex, and inducing the recruitment of histone acetylase CBP. Thus, our results reveal KDM4A as a key epigenetic silencer of TRAIL and DR5 in tumors and establish inhibitors of KDM4A as a novel strategy for effectively sensitizing tumors to TRAIL pathway-based therapeutics.
Citation Format: Junjian Wang, Haibin Wang, Lingyu Wang, Demin Cai, Zhijian Duan, Peng Chen, June X Zou, Jianzhen Xu, Xinbin Chen, Hsing-Jien Kung, Hong-wu Chen. Silencing the epigenetic silencer KDM4A for TRAIL and DR5 simultaneous induction and antitumor therapy. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 3062.
Abstract 3070: Potent and selective inhibition of CDK7 by novel covalent inhibitors
Authors: Satyam Leena Khare , Poddutoori Ramulu , Mukherjee Subhendu , Marappan Sivapriya , Gopinath Sreevalsam , Ramachandra Raghuveer , Pothuganti Manoj Kumar , Nayak Shilpa S. , C Nandish , Naik Chandranath , MV Ravindra , Dabbeeru Madhu B. , A Nagaraju , B Mahankali , Antony Thomas , Pandit Chetan , Chelur Shekar , Daginakatte Girish , Samajdar Susanta , Ramachandra Murali 
Published: July 2016

Abstract
Background: Phosphorylation of the RNA polymerase II (RNAPII) in C-terminal domain (CTD) by Cyclin-dependent kinase 7 (CDK7) is an important step in cellular transcription process. Hence pharmacological modulation of CDK7 kinase activity is considered as an interesting approach to treat cancers that critically dependent on transcription to maintain their oncogenic state.
Experimental procedures: Multiple series of novel covalent CDK7 inhibitors were identified by SBDD approach based on the binding mode of known CDK7 inhibitors to find early hits. Iterative medicinal chemistry efforts were performed to identify several lead compounds by optimizing the initial hits to achieve good physicochemical properties, high potency, good selectivity and desirable pharmacokinetic profile.
Summary: Highly potent ATP competitive covalent inhibitors of CDK7 from two distinct chemical series were identified. They show time-dependent inhibition of CDK7 enzyme activity as a proof of covalent binding and exhibit potent anti-proliferative activity in cell lines derived from various tumor types. CDK7 modulation by these compounds was also confirmed by monitoring cellular pS5RNAPII levels. Representative compounds from each series showed very good selectivity profile in broad kinase (332) panel. Lead molecules were identified based on excellent drug-like properties (solubility, permeability and good oral bioavailability). Tolerability and efficacy studies in rodent xenograft models are ongoing with selected leads to test their impact on tumor growth inhibition and to determine therapeutic window by oral administration.
Conclusion: We have identified novel and selective CDK7 covalent inhibitors from two distinct chemical series with optimized drug-like properties including oral bioavailability. These compounds are being evaluated
for anti-tumor activity in mouse xenograft models.
Citation Format: Leena Khare Satyam, Ramulu Poddutoori, Subhendu Mukherjee, Sivapriya Marappan, Sreevalsam Gopinath, Raghuveer Ramachandra, Manoj Kumar Pothuganti, Shilpa S. Nayak, Nandish C, Chandranath Naik, Ravindra MV, Madhu B. Dabbeeru, Nagaraju A, Mahankali B, Thomas Antony, Chetan Pandit, Shekar Chelur, Girish Daginakatte, Susanta Samajdar, Murali Ramachandra. Potent and selective inhibition of CDK7 by novel covalent inhibitors. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 3070.
Abstract 3073: Targeting chronic lymphocytic leukemia by interfering glutathione synthesis using a novel therapeutic enzyme cyst(e)inase (AEB3103)
Authors: Liu Jinyun , Feng Li , Stone Everett M. , Tyler Joseph , Rowlinson Scott W. , Keating Michael J. , Huang Peng 
Published: July 2016

Abstract
Chronic lymphocytic leukemia (CLL) is the most common adult leukemia in the Western countries. Despite recent advance in new therapeutic agents that have improved treatment outcomes, CLL remains incurable due in part to the inability to completely eradicate the leukemia cells in vivo. Previous studies showed that CLL cells have high intrinsic oxidative stress and are highly dependent on cellular antioxidant glutathione (GSH) to maintain redox balance and cell viability. One logical strategy to impact CLL cells would be to abrogate the glutathione protection of CLL cells in vivo. Recently we discovered that primary leukemia cells isolated from CLL patients were unable to effectively utilize cystine for GSH synthesis due to low expression of the cystine transporter Xc-, and that bone marrow stromal cells highly express Xc- and effectively take up cystine for conversion to cysteine (Zhang et al: Nature Cell Biology, 2012). These findings provide a biochemical basis to develop novel strategies to effectively target leukemia cells in the stromal microenvironment and improve in vivo therapeutic activity. In this study, we tested the depletion of extracellular cystine and cysteine using a novel therapeutic enzyme-cyst(e)inase (AEB3103), as a potential way to block GSH synthesis in CLL cells and abolish the stromal protection of the leukemia cells. Our study showed that AEB3103 was very effective in depleting GSH in CLL cells and caused massive CLL cell death even in the presence of stromal cells. Importantly, AEB3103 could also overcome drug resistance of CLL cells with p53 deficiency both in primary leukemia cells isolated from CLL patients with 17p deletion and mouse leukemic cells isolated from mouse model we recently reported (Liu et al: Leukemia, 2014). In addition, AEB3103 showed very low toxicity to normal cells. These promising in vitro data warrant further animal studies, which are currently on ongoing using the CLL mouse model with TCL1-Tg:p53-/- genotype. Our study suggests that AEB3103 and its combination with standard anti-CLL drugs may potentially be useful for clinical treatment of CLL, even for the more aggressive CLL subtypes with unfavorable cytogenetic alterations such as those with chromosome17p deletion and p53 mutations, and may improve in vivo therapeutic activity.
Citation Format: Jinyun Liu, Li Feng, Everett M. Stone, Joseph Tyler, Scott W. Rowlinson, Michael J. Keating, Peng Huang. Targeting chronic lymphocytic leukemia by interfering glutathione synthesis using a novel therapeutic enzyme cyst(e)inase (AEB3103). [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 3073.
Abstract 3081: Novel cucurbitacin analogue Cuc D exhibits potent anti-cancer activity in cervical cancer
Authors: Sikander Mohammed , Hafeez Bilal Bin , Halaweish Fathi T. , Yallapu Murali M. , Jaggi Meena , Chauhan Subhash C. 
Published: July 2016

Abstract
Background: Cervical cancer is one of the leading cause of mortality among women in US. Naturally occurring dietary compounds have gained increasing attention for their anticancer effects. Cucurbitacins, tetracyclic triterpenoid compound, belong to a family of Cucurbitaceae have shown promising anti-cancer activity. Herein, we investigated the potential anti-cancer effects of a novel analogue of cucurbitacin D (Cuc D) against cervical cancer in in vitro and in a xenograft mouse model.
Methods: In our study, we used human cervical cancer cells (CaSki and SiHa). Cells were treated with Cuc D (0.05 to 1μM) for 48 and 72 hrs. MTS and colony formation assays were performed to investigate the effects of Cuc D on cell viability and proliferation. Western Blot analysis was performed to investigate the effects of Cuc D on cell proliferation and apoptotic markers. To determine the therapeutic effects of Cuc D, we used female athymic nude mice and injected CaSki cells (4 × 106) into the cervix to develop orthotopic xenograft tumors. Cuc D (1 mg/kg body weight) was administered through intratumoral injection four weeks post-tumor cell injection. Tumor volume in these mice were recorded bi-weekly.
Results: Cuc D inhibited cell viability of cervical cancer cells in a dose-dependent manner. IC50 of Cuc D was observed 400 nM and 250 nM in Caski and SiHa cells, respectively. Cuc D treatment effectively inhibited growth of cervical cancer cells which was determined by decreased cell proliferation and colony formation assays. Cuc D treatment induced apoptosis in cervical cancer cells as measured by enhanced Annexin V staining. Western blot result also illustrated cleavage in PARP protein in Cuc D treated cells which further confirms apoptosis induction. Cuc D treatment also inhibited PI3K and c-Myc protein levels and phosphorylation of STAT3 and Rb proteins. In addition, Cuc D treatment induced the cell cycle inhibitory proteins (p21 and p27) and PTEN and the expression of a tumor suppressor microRNA, miR-145, as determined by qRT-PCR. In an orthotopic tumor xenograft mouse model, Cuc D treatment effectively inhibited tumor growth as compared to vehicle control treated mice.
Conclusion: Taken together, our results demonstrate potent anti-cancer efficacy of Cuc D in cervical cancer cells via modulation of key onco/tumor suppressor proteins. Thus, Cuc D could be a useful therapeutic agent for cervical cancer treatment.
Citation Format: Mohammed Sikander, Bilal Bin Hafeez, Fathi T. Halaweish, Murali M. Yallapu, Meena Jaggi, Subhash C. Chauhan. Novel cucurbitacin analogue Cuc D exhibits potent anti-cancer activity in cervical cancer. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 3081.
Abstract 3083: Novel inhibitor GZ17-06.12 suppresses pancreatic cancer tumorigenesis
Authors: Paul Santanu , Stehno-Bittel Lisa , Dhar Animesh 
Published: July 2016

Abstract
Purpose: Pancreatic ductal adenocarcinoma (PDAC) or pancreatic cancer is one of the most lethal malignancies in humans. The survival rate for two years is very limited in most of cases (10%) after diagnosis of this disease. This is because current therapeutic regimens have limited effectiveness. Novel therapeutic targets are needed to treat this disease. GZ17-06.12 contains a nutraceutical for its anti-cancer properties, in several cancers. Crude extracts of the plant Arum palaestinum Boiss used in traditional Israeli and Palestinian medicine, have demonstrated cytostatic and cytotoxic activities in colon, prostrate and lung carcinoma. Therefore, we hypothesize that GZ17-06.12 will inhibit tumor progression and metastasis in PDAC.
Experimental Procedure: In this study, we have determined cell proliferation, pancosphere formation and apoptosis following treatment of different doses oGZ17-06.12 for 24-72 hours using MiaPaCa-2 and S2-007 human pancreatic cancer cells. Cell cycle distribution and apoptosis were measured using flow cytometic analysis. Orthotopic pancreatic cancer model in athymic mice was developed and GZ17-06.12 was given orally for 20 days to those mice. Proliferative markers, pEGFR/pAkt and apoptotic markers, Bax/Bcl-2, were monitored following treatment with GZ17-06.12 in both in vivo and in vitro models. Metastatic markers, MMP-2 and MMP-9 were measured in metastatic tissues in orthotopic models.
Results: GZ17-06.12 inhibited proliferation of pancreatic cancer cell lines in a dose- and time-dependent manner. Cell cycle analysis suggested that cells were arrested in S and G2 phase following treatment. In addition, GZ17-06.12 induced apoptosis in both in vitro and in vivo pancreatic cancer. Moreover, the compound significantly inhibited epidermal growth factor receptor and Akt phosphorylation. Furthermore, GZ17-06.12 decreased the number and size of the pancospheres in S2-007 cells with concomitant inhibition of pancreatic cancer stem cell markers, DCLK1, Lgr5 and EpCam. The effect of GZ17-06.12 suppressed tumor growth and metastatic potential as indicative of MMP-2 and MMP-9 activity in primary and metastatic tumors.
Conclusions: GZ17-06.12 significantly reduces tumorigenesis and metastasis in both in vitro and in vivo pancreatic cancer models, inhibiting proliferation with concomitant increase of apoptosis.
Citation Format: Santanu Paul, Lisa Stehno-Bittel, Animesh Dhar. Novel inhibitor GZ17-06.12 suppresses pancreatic cancer tumorigenesis. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 3083.
Abstract 3087: Combination of ONC201 and bevacizumab significantly impacts colorectal cancer growth and metastasis in vivo
Authors: Wagner Jessica , El-Deiry Wafik S. 
Published: July 2016

Abstract
ONC201 is a first-in-class small molecule anti-tumor agent (Allen et al., 2013; Wagner et al., 2014; Prabhu et al., 2015; Kline et al., 2015) that upregulates endogenous TRAIL and activates the integrated stress response leading to increased DR5 expression, among other anti-tumor effects. ONC201 recently completed a phase I clinical trial in advanced solid tumors and is currently in multiple phase I/II clinical trials in select advanced cancers (NCT02250781, NCT02324621, NCT02420795, NCT02392572, NCT02609230, NCT02525692, NCT02038699). Colorectal cancer (CRC) remains one of the leading causes of death from cancer worldwide; predominantly due to its metastatic nature. Increasing clinical evidence including randomized clinical trials has demonstrated that there is an increased efficacy from certain cytotoxic chemotherapeutic agents when placed in combination with molecular agents that target the vascular endothelial growth factor (VEGF) pathway. Bevacizumab (Avastin), a monoclonal antibody that targets VEGF, has become an important therapeutic option for patients with advanced metastatic CRC. The single agent activity of ONC201 in preclinical models of colorectal cancer have been well documented, however a combinatorial regimen for this investigational agent has not been prioritized for this indication. We investigated the efficacy of ONC201 in combination with bevacizumab in preclinical models of colorectal cancer based on the previously reported cooperative efficacy with this combination in preclinical GBM models. While each agent showed efficacy as a single agent, the combination of ONC201 with bevacizumab appeared synergistic in the suppression of CRC xenograft growth including a significant impact on tumor regression and occasional complete tumor regressions. The ONC201 combination with bevacizumab also suppressed metastasis from xenografted human colorectal cancer cells. Mechanistic studies and angiogenesis imaging studies are ongoing to demonstrate the importance of this combination on both tumor growth, migration, and invasion. Our results demonstrate that combining anti-angiogenic bevacizumab with ONC201 enhances anti-tumor efficacy in preclinical models of colorectal cancer and suggest that further testing of the combination is warranted in the clinic.
Citation Format: Jessica Wagner, Wafik S. El-Deiry. Combination of ONC201 and bevacizumab significantly impacts colorectal cancer growth and metastasis in vivo. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 3087.
Abstract 3092: Physiological mimicry to characterize the average topology of the MYC and VEGF promoter G-quadruplexes
Authors: Morgan Rhianna K. , Brooks Tracy A. 
Published: July 2016

Abstract
DNA G-quadruplexes (G4s) have become increasingly present in modern drug discovery efforts. The main focus centers on cancer therapeutic development, as G4s are more concentrated in oncogenic promoters than the rest of the genome. Two of the most well described G4s to date are within the MYC and the VEGF promoters; stabilization of either structure fosters transcriptional silencing. Downregulation of MYC decreases cell proliferation and alters metabolism; it is promising for a number of cancers, such lymphomas, leukemia, colorectal cancer and more. VEGF downregulation would modulate angiogenesis, which is of therapeutic benefit for almost all solid tumors. The physiological structure of both of these promoter G4s has been elucidated using plasmid DMS footprinting, which incorporates DNA supercoiling in addition to stabilizing cations or molecules. The current study examines a variety of anhydrous or crowding co-solvents for their ability to recapitulate the physiological structure in single-stranded ex vivo conditions. The co-solvents tested included glucose, acetonitrile, polyethylene glycol, dextran sulfate, sucrose, ficoll, and extracted nucleoplasm, ranging from 0-40%. Significant changes in structure, including loop directionality and number of competing isoforms, were examined by electronic circular dichroism. Electromobility shift assays differentiated inter- and intra-molecular structures, further distinguishing the distribution of isoforms. DMS footprinting with select molecular crowding and dehydrating agents was performed and compared to plasmid footprints, to validate physiological mimicry ex vivo. Ongoing studies examining the physiological conditions regulating G4 stability and function include moving from plasmid to in cell DMS footprinting in order to most completely identify the physiologic isoform, and to using optimized co-solvents to examine the effects of small molecules ex vivo and better predict active hits for in vitro evaluation. Overall the VEGF and MYC promoter G4 structures are promising therapeutic targets for anti-angiogenic and anti-proliferative therapy, respectively. This comprehensive understanding of physiological principles governing the above G4 formation will best inform future drug discovery efforts for these and other oncogenic promoters.
Citation Format: Rhianna K. Morgan, Tracy A. Brooks. Physiological mimicry to characterize the average topology of the MYC and VEGF promoter G-quadruplexes. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 3092.
Abstract 3097: Structural and biophysical characterization of anti-apoptotic protein Bcl-2 and GTPase Rac1 interaction
Authors: Ajumal Shani , Kang Jia , Joseph Thomas , Pervaiz Shazib , Swaminathan Kunchithapadam 
Published: July 2016

Abstract
We have recently reported a novel mechanism linking the pro-oxidant activity of the anti-apoptotic protein Bcl-2 to its interaction with the small GTPase Rac1. In this current study, we investigate the nature of this interaction using activated (GTP loaded) Rac1 and Bcl-2 peptides (spanning the BH3 domain and its adjacent loop region) using coimmunoprecipitation, isothermal titration calorimetry (ITC), X-ray crystallography, docking/modeling, fluorescence spectroscopy, molecular dynamics and mutational studies. Our results will develop to translational relevance in the treatment of human cancers that are refractory to chemotherapy due to overexpression of Bcl-2.
Citation Format: Shani Ajumal, Jia Kang, Thomas Joseph, Shazib Pervaiz, Kunchithapadam Swaminathan. Structural and biophysical characterization of anti-apoptotic protein Bcl-2 and GTPase Rac1 interaction. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 3097.
Abstract 310: Mechanism of sorafenib resistance in acute myeloid leukemia
Authors: Lindblad Oscar , Cordero Eugenia , Puissant Alexandre , Macaulay Lucy , Kabir Nuzhat N. , Sun Jianmin , Haraldsson Karin , Borg Åke , Levander Fredrik , Stegmaier Kimberly , Pietras Kristian , Rönnstrand Lars , Kazi Julhash U. 
Published: July 2016

Abstract
Activating mutations in FLT3 occur in up to 35% of patients with AML and correlate with poor prognosis. Therapy directed against FLT3 has been shown to induce response in patients with AML, but these responses are almost always transient. Dual PI3K/mTOR inhibitors have displayed promising results in the treatment of solid tumors, and of hematological cancers. In this report we describe that a dual PI3K/mTOR inhibitor is effective against sorafenib-responsive, and -resistant, AML cell lines both in vitro and in vivo. We generated two cell lines by sustained treatment with sorafenib. Parental cell lines carry the FLT3-ITD mutation and are highly responsive to FLT3 inhibitors, while sorafenib-resistant cell lines display resistance to multiple FLT3 inhibitors. Next generation sequencing did not show any significant difference in the mutational burden in between responsive and resistant cell lines. While next generation sequencing identified FLT3-D835Y with an allele-depth of 67:37 in a resistant cell line, Sanger sequencing and protein mass-spectroscopy did not identify any acquired mutations in the kinase domain of FLT3 in the resistant cells. Moreover, sorafenib treatment effectively blocked FLT3 activation in resistant cells, while it was unable to block colony formation or cell survival, suggesting that the resistant cells are no longer dependent on FLT3. Gene expression analysis of sorafenib-sensitive and -resistant cell lines, as well as of blasts from patients with sorafenib-resistant AML, suggested an enrichment of the PI3K/mTOR pathway that correlated with the resistant phenotype, which was further supported by phospho-specific-antibody array analysis. The selective PI3K/mTOR inhibitor, gedatolisib, efficiently blocked proliferation, colony and tumor formation of resistant cell lines as well as induces apoptosis. Taken together, our data suggest that aberrant activation of the PI3K/mTOR pathway results in FLT3-inhibitors-resistance and a dual specific PI3K/mTOR inhibitor is an effective treatment in both tyrosine kinase inhibitor sensitive and resistant AML.
Citation Format: Oscar Lindblad, Eugenia Cordero, Alexandre Puissant, Lucy Macaulay, Nuzhat N. Kabir, Jianmin Sun, Karin Haraldsson, Åke Borg, Fredrik Levander, Kimberly Stegmaier, Kristian Pietras, Lars Rönnstrand, Julhash U. Kazi. Mechanism of sorafenib resistance in acute myeloid leukemia. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 310.