bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract B112: Development and preclinical evaluation of a novel BET inhibitor FF-1027T
Authors: Makita Keiko , Saeki Kazunori , Tanaka Tadashi , Kawanishi Yasutomo , Kimura Toshifumi , Watanabe Shinichi , Kakinuma Chihaya , Hagiwara Shinji , Shimada Yasuhiro 
Published: August 2018

Abstract
Bromodomain and extra-terminal (BET) family of proteins regulate gene expression by binding acetylated-lysine residue in histone at the gene promoter and enhancer elements through the two bromodomains (BD1 and BD2). Subsequently, they activate transcriptional elongation at the binding sites. Small-molecule compounds inhibiting the interaction between BET proteins and acetylate-lysine in histone have been expected as a promising strategy for cancer therapy. They can show pharmacologic action by regulating the transcription of MYC and other cancer-associated genes. We identified a novel BET inhibitor, FF-1027T, that is structurally different from the (+)JQ-1 class BET inhibitors such as OTX015. FF-1027T is more soluble in aqueous solution than known BET inhibitors, which offers an advantage in the application of drug formulations. Through the TR-FRET assay, FF-1027T exhibited binding to BRD2/3/4 with a preference for BD1 over BD2. FF-1027T showed antiproliferative activity in vitro across broad cancer cell lines derived from hematologic malignancies or solid tumors. In accordance with the previous report about BET inhibitors, FF-1027T displayed higher antiproliferative activity to hematologic malignancies than solid tumor-derived cell lines with less than 100 nM GI50 values (12 out of 21 cells lines). In particular, FF-1027T showed anti-proliferative activities against cell lines derived from solid tumors, such as colon, lung, breast, and prostate cancer, with less than 300 nM GI50 values in almost 30% of the cell lines. In AML xenograft tumor models, oral or intravenous administration of FF-1027T resulted in almost complete reduction of tumor growth. Intravenous treatment was achieved by high solubility in an aqueous solution of FF-1027T. Our present results suggested that gastrointestinal tract (GI) damage through topical effects of BET inhibitors on the mucosal surface can be avoided by intravenous administration. These results demonstrated that FF-1027T is a potent BET inhibitor and supports the clinical further development of FF-1027T in hematologic malignancies and solid tumors.
Citation Format: Keiko Makita, Kazunori Saeki, Tadashi Tanaka, Yasutomo Kawanishi, Toshifumi Kimura, Shinichi Watanabe, Chihaya Kakinuma, Shinji Hagiwara, Yasuhiro Shimada. Development and preclinical evaluation of a novel BET inhibitor FF-1027T [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2017 Oct 26-30; Philadelphia, PA. Philadelphia (PA): AACR; Mol Cancer Ther 2018;17(1 Suppl):Abstract nr B112.
Abstract B113: Development of a novel synthetic consensus DNA vaccine that targets multiple MAGE-A family members for anticancer immune therapy
Authors: Duperret Elizabeth K. , Trautz Aspen , Paik Megan , Reed Charles , Yan Jian , Weiner David B. 
Published: August 2018

Abstract
Cancer/testis (CT) antigens have emerged as attractive targets for cancer immune therapy due to their overexpression in tumor tissues and lack of expression in normal tissues. In particular, several clinical studies have been initiated to target the MAGE-A family of CT antigens for melanoma. These have included recombinant protein immunization and TCR-based gene therapy for MAGE-A3. The recombinant protein immunizations resulted in poor CD8+ T-cell responses and lack of efficacy thus far in the clinic. TCR-based gene therapy induced robust immune responses but unexpected toxicity. There is therefore a need to develop safe and effective therapies targeting the MAGE-A family of proteins for cancer therapy. In this study we performed a thorough analysis of MAGE-A RNA expression in The Cancer Genome Atlas (TCGA) and demonstrated that a high proportion of patients, in particular patients with melanoma and lung squamous cell carcinoma, exhibit expression of multiple MAGE-A family members simultaneously within the same tumor sample. Based on this information, we designed a consensus MAGE-A DNA vaccine that retains high homology (&gt;85%) to multiple MAGE-A isoforms. Because mice and human MAGE-A family members are poorly conserved, we designed separate consensus constructs for testing in mice and in primates. Upon delivery of this mouse consensus MAGE-A vaccine intramuscularly followed by electroporation (EP) in C57Bl/6 mice, we detected robust IFN-γ and TNF-α CD8+ T-cell responses against multiple MAGE-A isoforms, including MAGE-A1, MAGE-A2, MAGE-A3, MAGE-A5, MAGE-A6, and MAGE-A8 (p&lt;0.005). Furthermore, we detected robust cytotoxic CD107a/IFN-γ/T-bet triple-positive CD8+ T cells in mice immunized with the consensus mouse MAGE-A vaccine. We evaluated the potency and cross-reactivity of this consensus mouse MAGE-A DNA vaccine in genetically diverse, outbred mice. We found that the majority of these mice (14/15) were capable of mounting a cross-reactive immune response and breaking tolerance to multiple MAGE-A isoforms simultaneously. We also demonstrated that this consensus mouse MAGE-A DNA vaccine is capable of slowing tumor growth in a therapeutic tumor challenge using the YUMM1.7 melanoma tumor model and the TC-1 lung tumor model. These results support the use of optimized MAGE-A consensus vaccines for cancer immune therapy.
Citation Format: Elizabeth K. Duperret, Aspen Trautz, Megan Paik, Charles Reed, Jian Yan, David B. Weiner. Development of a novel synthetic consensus DNA vaccine that targets multiple MAGE-A family members for anticancer immune therapy [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2017 Oct 26-30; Philadelphia, PA. Philadelphia (PA): AACR; Mol Cancer Ther 2018;17(1 Suppl):Abstract nr B113.
Abstract B122: 3,3′-bis(2-aminoethanol)-2,2′-binaphthoquinone promotes killing of acute myeloid leukemia cells by augmenting oxidative stress and inhibiting indoleamine dioxygenase
Authors: Chang Elizabeth Tsuying , Carter-Cooper Brandon A. , Dash Smaraki , Ferraris Dana , Emadi Ashkan , Lapidus Rena G. 
Published: August 2018

Abstract
Introduction: Acute myeloid leukemia (AML) is a genetically heterogeneous neoplasm with poor clinical outcome after treatment with current conventional chemotherapy. New treatments are therefore needed to combat this aggressive cancer. One of the hallmarks of AML blasts is disrupted cellular oxidative state resulting from elevated level of reactive oxygen species (ROS) and overexpressed antioxidant proteins. Another characteristic of AML blasts is escaping host immune surveillance mediated in part by overexpression of the tryptophan-metabolizing enzyme, indoleamine 2,3-dioxygenase (IDO). We have designed and synthesized a novel hydroxylamine dimeric naphthoquinone (MCD-66), which can kill leukemia cells by dual mechanisms: 1) negatively perturbing cellular oxidative balance, and 2) effectively inhibiting IDO-1. Results: Two AML cell lines (MV4-11 and MOLM14) were treated with increasing doses of the clinically used naphthoquinones, atovaquone, and vitamin K, as well as with MCD-66, and IC50 curves were generated. With nanomolar range IC50s, MCD-66 was 25-30 fold more potent than other naphthoquinones against AML cells. MCD-66 effectively inhibited clonogenicity of AML cells in a dose-dependent manner. When MV4-11 cells were treated with MCD-66 at IC50 concentration, ROS levels significantly peaked after 2 hours and returned to baseline within 24 hours. The augmented production of ROS led to concomitant increase in DNA damage, evidenced by γH2AX foci in treated AML blasts. Additionally, MCD-66 inhibited IDO-1 activity at 1 µM (37%) and 10 µM (79%), but not its isozymes IDO-2 or tryptophan-2,3-dioxygenase (TDO). Conclusion: The novel amino-alcohol dimeric naphthoquinone MCD-66 has shown promising activity against AML blast in vitro with dual mechanisms of action. The in vivo studies focusing on tolerability and efficacy, including modulating immune surveillance in xenograft models of AML, are ongoing.
Citation Format: Elizabeth Tsuying Chang, Brandon A. Carter-Cooper, Smaraki Dash, Dana Ferraris, Ashkan Emadi, Rena G. Lapidus. 3,3′-bis(2-aminoethanol)-2,2′-binaphthoquinone promotes killing of acute myeloid leukemia cells by augmenting oxidative stress and inhibiting indoleamine dioxygenase [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2017 Oct 26-30; Philadelphia, PA. Philadelphia (PA): AACR; Mol Cancer Ther 2018;17(1 Suppl):Abstract nr B122.
Abstract B133: Identification of elatol as a novel eIF4A inhibitor and stress response activator
Authors: Peters Tara L. , Tillotson Joseph , Li Lingxiao , Chapman Eli , Schatz Jonathan H. 
Published: August 2018

Abstract
It is well established that protein translation can contribute the most adaptable regulation of protein-coding gene expression, is frequently hijacked during oncogenesis, and can be targeted therapeutically. Most regulation of protein translation occurs at the initiation step with formation and function of the eIF4F complex. Many different avenues, both direct and indirect, have been explored to inhibit eIF4F and thus protein translation initiation, in particular drugs targeting eIF4F’s core-enzymatic subunit, the DEAD-box RNA helicase eIF4A. Despite extensive preclinical evaluation and high antitumor activity of these compounds, none has progressed to evaluation in cancer patients, due to a variety of pharmacokinetic and pharmacodynamic issues. We designed a novel screen to identify eIF4A inhibitors by measuring ATP hydrolysis and screened a collection of ~1,200 natural compounds and purified extracts. The marine natural product elatol was the top hit in our screen, that not only showed selectivity for eIF4A over other dead box family helicases and a panel of 97 common kinases, but also induced apoptosis in a broad range of cancer cell lines from the NCI-60 cancer cell line and CCLE panels. Elatol is well tolerated in mice at a single dose of up to 65mg/kg and showed antitumor activity. Elatol treatment reduced global protein translation measured through polysome profiling and O-propargyl puromycin incorporation as well as cap-dependent translation measured by luciferase reporter and Western blotting. The effects of elatol are similar to the rocaglate silvestrol, which inhibits eIF4A although through a very different mechanism, but elatol requires higher concentrations to achieve these effects. Interestingly, elatol treatment causes strong immediate induction of the stress response transcription factor ATF4, though assessment in ATF4-deficient cells showed the toxicity of elatol is not dependent on ATF4. Unlike with silvestrol treatment, loss of translationally regulated proteins MYC and CYCLIN D3 following elatol treatment can be partially rescued by blocking the eIF2α-mediated stress response with ISRIB. Which eIF2α kinase may be mediating these effects is still under investigation. The novel mechanism of inhibition of ATP hydrolysis may be driving these unique observations compared to other eIF4A inhibitors. We believe this study provides a novel approach for identification of small molecules that have greater clinical promise for eIF4A inhibition.
Citation Format: Tara L. Peters, Joseph Tillotson, Lingxiao Li, Eli Chapman, Jonathan H. Schatz. Identification of elatol as a novel eIF4A inhibitor and stress response activator [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2017 Oct 26-30; Philadelphia, PA. Philadelphia (PA): AACR; Mol Cancer Ther 2018;17(1 Suppl):Abstract nr B133.
Abstract B137: Novel potent salicylic, benzoic, and benzohydroxamic acid-based small-molecule STAT3 inhibitors induce antitumor effects in breast cancer xenografts
Authors: Yue Peibin , Lopez-Tapia Francisco , Brotherton-Pleiss Christine , Tius Marcus , Turkson James 
Published: August 2018

Abstract
We investigated the molecular determinants for the activity of the previously reported salicylic BP-1-102 (IC50 6.8 ± 2.5 μM), benzoic SH4-54 (IC50 4.4 ± 0.3 μM), and benzohydroxamic acid SH5-07 (IC50 3.9 ± 0.6 μM) small-molecule STAT3 inhibitors in order to derive structurally optimum analogs with improved potency and pharmacokinetic parameters. All three leads are based on N-methylglycinamide scaffold, with its two amine groups condensed with three different functionalities. The three functionalities were separately modified to generate various series of new analogs. The inhibitory activities of the new analogs against STAT3 DNA-binding in vitro were determined by electrophoretic motility shift assay. Some new analogs show dramatically improved potency compared to the corresponding lead compounds. Notably, analogs H098, H127, H142, H145, H152, and H155 showed more than 10-fold improved potency in inhibiting STAT3 DNA-binding activity in vitro, with IC50 of 300 - 600 nM. Using analogs H105 and H120, we show that the new analogs decreased STAT3 DNA-binding activity and phosphorylation at Tyr705 in MDA-MB-231 and MDA-MB-468 cells, two human triple-negative breast cancer lines harboring constitutively active STAT3, within as early as 30 min. Furthermore, the new analogs potently inhibited the growth and viability of the human cancer cells with persistently active STAT3, with IC50 of 1.2 - 2.0 µM. The potent analogs specifically disrupted STAT3 DNA-binding activity in vitro over that of STAT1 and STAT5, and they further showed minimum inhibitory effect on the proliferation of human cancer cells that do not harbor persistently active STAT3. Initial in vivo efficacy study in nude mouse model showed that oral administration of H105 and H120 suppressed the growth of tumor xenografts generated from human breast cancer line harboring constitutively active STAT3. Thus, we have made substantial progress and broken the nanomolar barrier in developing STAT3 inhibitors, and these compounds are the first nanomolar STAT3 inhibitors reported to date that are direct disruptors of STAT3 activation, which show in vivo activity.
Citation Format: Peibin Yue, Francisco Lopez-Tapia, Christine Brotherton-Pleiss, Marcus Tius, James Turkson. Novel potent salicylic, benzoic, and benzohydroxamic acid-based small-molecule STAT3 inhibitors induce antitumor effects in breast cancer xenografts [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2017 Oct 26-30; Philadelphia, PA. Philadelphia (PA): AACR; Mol Cancer Ther 2018;17(1 Suppl):Abstract nr B137.
Abstract B142: The anticancer agent Dp44mT upregulates the AMPK-dependent energy homeostasis pathway in cancer cells
Authors: Krishan Sukriti , Sahni Sumit , Richardson Des R. 
Published: August 2018

Abstract
Background: Iron plays a crucial role in cellular energy transducing pathways and tumor cell proliferation. Therefore, metals (such as iron) could play an important role in the regulation of the AMPK-dependent pathway regulating cellular energy homeostasis. This investigation examined the effect of the iron and copper chelator and potent anticancer agent, di-2-pyridylketone 4,4-dimethyl-3-thiosemicarbazone (Dp44mT), on AMPK-mediated energy homeostasis. Methods and Results: These studies demonstrated that Dp44mT, which forms intracellular redox-active complexes with iron and copper, significantly activated AMPK (i.e., p-AMPK/AMPK ratio) in 5 different tumor cell-types. Furthermore, examination of the Dp44mT-metal complexes demonstrated that the effect of Dp44mT on AMPK was due to a dual mechanism: (1) its ability to chelate metal ion; and (2) the generation of reactive oxygen species (ROS). The activation of the AMPK pathway by Dp44mT was mediated by the upstream kinase, liver kinase B1 (LKB1), which is a known tumor suppressor. Moreover, using AMPKα1-selective silencing, we demonstrated that Dp44mT activated AMPK, resulting in inhibition of acetyl CoA carboxylase 1 (ACC1) and raptor, and activation of Unc-51 like kinase (ULK1). Conclusions: These effects are vital for inhibition of fatty acid synthesis, suppression of protein synthesis, and autophagic activation, respectively. Together, this AMPK-mediated repair response aims to rescue the loss of metal ions via chelation and the induction of cytotoxic damage mediated by redox cycling of the Dp44mT-metal ion complex. In conclusion, this study demonstrates for the first time that chelators target the AMPK-dependent energy homeostasis pathway.
Citation Format: Sukriti Krishan, Sumit Sahni, Des R. Richardson. The anticancer agent Dp44mT upregulates the AMPK-dependent energy homeostasis pathway in cancer cells [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2017 Oct 26-30; Philadelphia, PA. Philadelphia (PA): AACR; Mol Cancer Ther 2018;17(1 Suppl):Abstract nr B142.
Abstract B147: A phase 1 PK/PD study of ASN003, a novel, highly selective BRAF and PI3K dual inhibitor, in patients with advanced solid tumors
Authors: Rasco Drew , Lakhani Nehal , Sullivan Ryan , Mita Monica , Shah Jaimini , Usansky Helena , Reddy Sanjeeva , Rao Niranjan , Denis Louis J. , Tolcher Anthony , Flaherty Keith 
Published: August 2018

Abstract
Background: RAS-RAF-MEK and PI3K-AKT-mTOR are two major pathways involved in tumor cell signaling and growth. Components of these pathways are frequently mutated in a broad range of tumors. ASN003 is a highly selective and potent (low nM IC50) inhibitor of BRAF and PI3K-α and -δ (low affinity for PI3K-β). ASN003 shows strong antitumor activity in tumor models harboring BRAF and PIK3CA or PTEN mutations, and also in patient-derived xenograft (PDX) models that are resistant to selective BRAF and MEK inhibitors. Patients and Methods: Oral once-daily ASN003 is being evaluated for safety/tolerability and preliminary efficacy in eligible patients with advanced solid tumors using an accelerated dose titration design (Part A) and enrolling cohorts of patients diagnosed with melanoma, CRC, NSCLC, and other solid tumors with a BRAF, PIK3CA, or PTEN mutation at MTD (Part B). Pharmacokinetic (PK) profile and the pharmacodynamic (PD) effects of ASN003 on tumor tissue biomarkers such as pERK and pS6 are investigated in both parts of the study. Results: Patient accrual in Part A is ongoing. As of June 2017, nine eligible patients are enrolled in dose levels ranging from 10 - 240 mg QD. ASN003 has been well tolerated. Treatment-related adverse events (TRAEs) were mild (G1) to moderate (G2). TRAEs include diarrhea (G2) (n=1), nausea/vomiting (G1), blurred vision (G1), and dry mouth/lips/skin (G1). Transient G1 elevation of glucose and insulin c-peptide levels has been noted in 1 pt. No G3/4 or serious TRAEs have been observed to date. The PK profile showed dose-dependent, systemic exposure with Cmax ranging from 74 to 1055 ng/mL, AUCT from 912 to 20100 ng.h/mL. Conclusions: ASN003 is a novel small molecule, with uniquely selective and potent inhibition of BRAF, PI3K-α and -δ kinases. To date, ASN003 was well tolerated at doses up to 240 mg QD and achieved good systemic exposure. Updated and detailed clinical safety/efficacy and PK/PD results will be presented.
Citation Format: Drew Rasco, Nehal Lakhani, Ryan Sullivan, Monica Mita, Jaimini Shah, Helena Usansky, Sanjeeva Reddy, Niranjan Rao, Louis J. Denis, Anthony Tolcher, Keith Flaherty. A phase 1 PK/PD study of ASN003, a novel, highly selective BRAF and PI3K dual inhibitor, in patients with advanced solid tumors [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2017 Oct 26-30; Philadelphia, PA. Philadelphia (PA): AACR; Mol Cancer Ther 2018;17(1 Suppl):Abstract nr B147.
Abstract B153: CDK4/6 inhibitor synergizes with mTOR inhibitor to suppress cholangiocarcinoma pathogenesis
Authors: Song Xinhua , Liu Xianqiong , Wang Jingxiao , Chen Xin 
Published: August 2018

Abstract
Intrahepatic cholangiocarcinoma (ICC) is an aggressive cancer. It lacks effective therapies and is associated with high mortality rate as well as poor prognosis. Our recent study suggests that treatment of pan-mTOR inhibitor MLN0128 leads to stable disease in murine ICC model induced by activated AKT and Yap (AKT/YapS127A) via inducing apoptosis without affecting tumor cell proliferation. Palbociclib is a pan CDK4/6 inhibitor that has been approved by the FDA for the treatment of HR-positive advanced-stage breast cancer. However, its efficacy in ICC has not been investigated. ICC cells are known to be highly proliferative. Here we hypothesize that palbociclib is effective against ICC by inhibiting tumor cell proliferation. Furthermore, it may synergize with MLN0128 to inhibit ICC growth in vivo. We tested the therapeutic efficacy of palbociclib alone or in combination with MLN0128 in human ICC cell lines as well as in AKT/YapS127A ICC model.
We found that in vitro palbociclib inhibits ICC cell growth via inhibiting cell cycle progression. The long-term cell growth, but not the short-term cell survival, to palbociclib is RB-dependent. Concomitant treatment of palbociclib with MLN0128 has a synergistic effect in inhibiting ICC cell viability. In AKT/YapS127A ICC preclinical model, treatment with palbociclib or MLN0128 alone all led to stable disease. In striking contrast, combined treatment of palbociclib with MLN0128 resulted in significant tumor regression. Mechanistically, we found that combined palbociclib with MLN0128 has a profound inhibitory effect in inhibiting ICC cell proliferation both in vivo and in vitro. In summary, our study suggests that palbociclib synergizes with MLN0128 to inhibit ICC cell proliferation, and combined treatment of palbociclib with MLN0128 represents promising novel therapeutics against this deadly malignancy.
Citation Format: Xinhua Song, Xianqiong Liu, Jingxiao Wang, Xin Chen. CDK4/6 inhibitor synergizes with mTOR inhibitor to suppress cholangiocarcinoma pathogenesis [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2017 Oct 26-30; Philadelphia, PA. Philadelphia (PA): AACR; Mol Cancer Ther 2018;17(1 Suppl):Abstract nr B153.