bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 4499: Cytotoxicity, biochemical activity, and structural analysis of ONC201 and comparisons to a biologically inactive isomer
Authors: Wagner Jessica , Kline Christina Leah , Pottorf Richard S. , Nallaganchu Bhaskara Rao , Olson Gary L. , Dicker David T. , Allen Joshua E. , El-Deiry Wafik S. 
Published: August 2015

Abstract
We previously identified TRAIL-inducing compound 10 (TIC10), also known as NSC-350625, as a small molecule being developed under the name ONC201 that has potent anti-tumor efficacy and a benign safety profile in preclinical cancer models. Further investigation of the preclinical profile of this drug candidate led in early 2014 to the FDA acceptance of the investigational drug application (IND) for oral ONC201 to treat patients with advanced cancer. The initially disclosed chemical structure of ONC201 provided by Stahle et. al in an expired patent was described as an imidazo[1,2-a]pyrido[4,3-d]pyrimidine derivative. Our first report of its anticancer activity by Allen et. al. included mass spectrometry and 1H NMR that indicated both were consistent with the structure depicted by Stahle et. al and the National Cancer Institute. A recent publication reported that the structure of ONC201 differs from the initial description and is in fact an angular [3,4-e] isomer of the previously depicted structure. Here, we report X-ray crystallography and other structural studies of ONC201 produced by Oncoceutics in a dihydrochloride salt form for clinical use that confirm the angular [3,4-e] structure and indicate that the material is not a mixture of the two isomers. Furthermore, we confirm that although fragmentation by mass spectrometry for the isomers is identical, the angular [3,4-e] isomer can be definitively identified as ONC201 by implementing specific various spectroscopy techniques to identify differences between ONC201 and the linear isomer. In accordance with our structural analysis, in vitro activity assays in cancer cells indicate that the previously disclosed anti-cancer activity and mechanism of action are indeed associated exclusively with the [3,4-e] structure and not the [4,3-d] linear isomer. Together these studies confirm the angular [3,4-e] structure of ONC201 as the highly active and pure anti-cancer drug candidate that was utilized in prior preclinical pharmacology studies and is now entering clinical trials in several oncology indications.
Citation Format: Jessica Wagner, Christina Leah Kline, Richard S. Pottorf, Bhaskara Rao Nallaganchu, Gary L. Olson, David T. Dicker, Joshua E. Allen, Wafik S. El-Deiry. Cytotoxicity, biochemical activity, and structural analysis of ONC201 and comparisons to a biologically inactive isomer. [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 4499. doi:10.1158/1538-7445.AM2015-4499
Abstract 4532: Functional evaluation of novel Tubulysin analogs as payloads for antibody-drug conjugates
Authors: Jia Junxiang , Zhou Xiaomai , Huang Yuanyuan , Xie Hongsheng , Guo Huihui , Gai Shun , Qu Lan , Li Wenjun , Chen Lin , Li Xing , Sun Sanxing , Yang Qingliang , Zhuo Xiaotao , Ye Hangbo , Zhao Robert 
Published: August 2015

Abstract
Antibody-drug conjugates (ADCs) couple tumor cell targeting specificity of monoclonal antibodies with potency of small molecule cytotoxic payloads to overcome the limitations of antibody's moderate cytotoxicity and narrow therapeutic window /poor pharmacokinetics of chemotherapeutic agents[1]. Most of the small molecule drugs used in ADCs now target either microtubules or DNA. Since the highly cytotoxic drugs linked to antibodies may be partially released, which leads to side-effects before they are delivered into the target cancer cells [2], it is important to choose appropriate cytotoxic molecules, linkage structures and conjugation strategies, in order to achieve maximal therapeutic window. To this end, we have designed and synthesized a series of Tubulysin B analogs and then conjugated these articles to anti-Her2 antibodies using different conjugation techniques. Functional assays in vitro based on Her2+ cancer cells showed that some of these novel molecules had significantly lower cytotoxicities as free drugs due to their favorable physiochemical and biological properties, in comparisons with the maytansinoid DM1derivatives, but were more potent than DM1 conjugates in killing the target cells when linked to identical anti-Her2 antibodies. Consistently, in comparisons with T-DM1, our novel ADCs demonstrated improved efficacy as well as reduced systemic side toxicities in Her2-positive xenograft tumor models. The conjugate structures and results from functional assays at both cellular and animal model levels are detailed in the presentation.
References:
1. Goldmacher, V.S. and Y.V. Kovtun, Antibody-drug conjugates: using monoclonal antibodies for delivery of cytotoxic payloads to cancer cells. 2011 2(3):. 397-416..
2. Xie, H., et al., Pharmacokinetics and biodistribution of the antitumor immunoconjugate, cantuzumab mertansine (huC242-DM1), and its two components in mice. J Pharmacol Exp Ther, 2004. 308(3): 1073-1082.
Citation Format: Junxiang Jia, Xiaomai Zhou, Yuanyuan Huang, Hongsheng Xie, Huihui Guo, Shun Gai, Lan Qu, Wenjun Li, Lin Chen, Xing Li, Sanxing Sun, Qingliang Yang, Xiaotao Zhuo, Hangbo Ye, Robert Zhao. Functional evaluation of novel Tubulysin analogs as payloads for antibody-drug conjugates. [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 4532. doi:10.1158/1538-7445.AM2015-4532
Abstract 4535: Graphene/Pectin-NaCl based gel-biosensor for tracing skin cancer and delivery of anticancer drug paclitaxel
Authors: Shaheen Sharif M. , Gromadzki Daniel , Abdelkader Amor , Rangelov Stanislav 
Published: August 2015

Abstract
Graphene(GO)/Pectin/NaCl gel-patch was prepared and evaluated for its bio-sensing. Physical and chemical analyses were carried out to focus the properties of new bio-sensing gel. Afterwards paclitaxel was loaded in the graphene based gel and drug delivery was carried out for dermal delivery, using a biomembrane, a fish swim-bladder in vitro. Kinetic studies were evaluated for feasibility as dermal delivery. Getting information from the kinetic parameters, paclitaxel was delivered to the melanoma cell lines from the gel and cell apoptosis was performed by trypan blue staining. FTIR studies were performed to evaluate the IR-signal transmission between the GO/Pectin/NaCl blend gel and Pectin/NaCl gel. And the same signal was evaluated from that of paclitaxel loaded GO/Pectin/NaCl treated melanoma cells and normal endothelial cells. All our data suggests that GO/Pectin/NaCl blend gel might be a future diagnostic as well as curable anticancer carrier for local cancer therapy.
Note: This abstract was not presented at the meeting.
Citation Format: Sharif M. Shaheen, Daniel Gromadzki, Amor Abdelkader, Stanislav Rangelov. Graphene/Pectin-NaCl based gel-biosensor for tracing skin cancer and delivery of anticancer drug paclitaxel. [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 4535. doi:10.1158/1538-7445.AM2015-4535
Abstract 456: Defined co-mutation subgroups of KRAS-mutated NSCLC display distinct immune profiles
Authors: Denning Warren L. , Diao Lixia , Skoulidis Ferdinandos , Lou Yanyan , Byers Lauren , Wang Jing , Weinstein John , Gibbons Don , Heymach John 
Published: August 2015

Abstract
Traditional pathological divisions of lung cancer are giving rise to molecular classifications that identify unique drivers of tumor malignancy. Of these molecular classifications, KRAS represents about 30% of all lung adenocarcinomas. Our group has recently investigated if co-mutations within KRAS-mutated lung tumors can aid in identifying a unique therapeutic strategy for patient treatment. Given that tumors exert a strong influence over the immune system and the recent successes in immune targeting via checkpoint blockade therapy in various cancers, including lung, we hypothesized that co-mutational subgroups of KRAS-mutant NSCLC elicit distinct immune profiles and support a rationale for evaluating these subgroups in conjunction with appropriate immunotherapies for further clinical testing. To investigate this phenomenon, we performed a supervised analysis of 86 immune-related genes from The Cancer Genome Atlas data set in lung adenocarcinomas with KRAS mutations and TP53 or STK11(LKB1) co-mutations. The results from our analysis revealed that KRAS-mutant NSCLC with LKB1 (KL) and TP53 (KP) co-mutations have distinct immune profiles. KP tumors have an increase in (1) PD-L1 and PD-L2; (2) co-stimulation via CD40, CD80, CD86; (3) antigen presentation HLA-I, HLA-II, and CD1; (4) FOXP3 and CD4, indicating T regulatory populations; (5) CD33, CD11b, and CD11c, which are potentially suppressive myeloid cell populations. We conclude that KRAS co-mutations can create significantly different immune microenvironments; KRAS + TP53 (KP) mutant tumors may specifically benefit from checkpoint blockade, depletion of immunosuppressive myeloid and T regulatory populations, but could support de novo anti-tumor T cell expansion due to high expression of co-stimulatory molecules and HLA-I and HLA-II expression. Conversely, KRAS + LKB1 (KL) mutant tumors have an immunosuppressed or inert phenotype and may potentially benefit from adoptive cell transfer of anti-tumor T cells in conjunction with or in lieu of checkpoint blockade.
Citation Format: Warren L. Denning, Lixia Diao, Ferdinandos Skoulidis, Yanyan Lou, Lauren Byers, Jing Wang, John Weinstein, Don Gibbons, John Heymach. Defined co-mutation subgroups of KRAS-mutated NSCLC display distinct immune profiles. [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 456. doi:10.1158/1538-7445.AM2015-456
Abstract 4560: Targeting chronic lymphocytic leukemia with p53 deficiency with phenethyl isothiocyanate
Authors: Liu Jinyun , Chen Gang , Pelicano Helen 
Published: August 2015

Abstract
Chronic lymphocytic leukemia (CLL) is the most common adult leukemia in the United States and Europe. Despite recent advance in new therapeutic agents that have improved treatment outcomes, CLL remains incurable. CLL patients with loss of p53 due to unfavorable cytogenetic alterations such as chromosome 17p deletion often exhibit more malignant disease phenotype, are resistant to many standard therapeutic agents, and have poor clinical outcomes. Thus, finding effective treatment for CLL with p53 deficiency represents a significant challenge, and development new agents and therapeutic strategies to effectively kill CLL cells with loss of p53 function would have profound clinical implications in CLL treatment. We have recently created a mouse model with Tcl1-Tg:p53-/- genotype that resembles the aggressive human CLL disease with p53 deficiency (17p-deletion). We showed that leukemia cells isolated from this mouse model as well as primary human leukemia cells with 17p deletion isolated from CLL patients are resistant to standard anti-CLL agents. Because p53 plays important roles in regulation of apoptosis and in maintaining mitochondrial function/normal metabolism/redox homeostasis, we hypothesized that a loss of p53 function in CLL with 17p- or p53 mutations would on one hand lead to drug resistance and poor therapeutic response to conventional treatment, and would on the other hand also cause mitochondrial dysfunction and high ROS stress. Our study tested the possibility to use the high oxidative stress as a biochemical basis to effectively target the drug-resistant CLL cells with p53 deletion using redox-modulating strategy in vitro and in vivo. Our results showed that ROS-mediating strategies could overcome drug resistance of CLL cells with p53 deficiency, and was able to effectively eliminate fludarabine-resistant CLL cells using phenethyl isothiocyanate (PEITC), which induced rapid glutathione depletion and caused severe ROS accumulation leading to massive death of CLL cells in culture. Importantly, PEITC also exhibited promising in vivo therapeutic activity in the CLL mouse model as a single agent, leading to a significant prolongation of the mouse survival time. Since PEITC is a natural compound found in vegetables with very low toxicity to normal cells, the results of this study may have important therapeutic implications. Our study suggests that PEITC may potentially be used for clinical treatment of CLL with 17p deletion and improve the outcome of this subpopulation of CLL patients, who would otherwise refractory to standard therapeutics.
Citation Format: Jinyun Liu, Gang Chen, Helen Pelicano. Targeting chronic lymphocytic leukemia with p53 deficiency with phenethyl isothiocyanate. [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 4560. doi:10.1158/1538-7445.AM2015-4560
Abstract 4564: TCF4 is a molecular target of resveratrol-induced apoptosis in colon cancer
Authors: Jeong Jin Boo , Kim Kui-Jin , Lee Seong-Ho 
Published: August 2015

Abstract
TCF-4 (T cell factor-4) is a member of the TCF/LEF (lymphoid enhancer factor) family of transcription factors. Although dysregulation of β-catenin is decisive for the initiation and progression of colorectal cancer, the role of TCF4 in transcriptional regulation of their target gene remained poorly understood. The current study was performed to see if TCF4 could be molecular target for anti-cancer compounds. Several phytochemicals including resveratrol repressed expression of TCF4 in human colorectal cancer cells. Resveratrol decreases accumulation of ectopically expressed TCF4 protein without changes of TCF4 transcription. Pre-treatment of MG-132 and lactacystin ameliorates resveratrol-stimulated downregulation of TCF4. Resveratrol-treated cells showed longer half-life of TCF4. Resveratrol increased phosphorylation of TCF4 at serine/threonine residues through ERK and p38-dependent pathways. Knockdown of TCF4 decreased TCF/β-catenin-mediated transcriptional activity and sensitized resveratrol-induced apoptosis. The current study provides new mechanistic link between TCF4 downregulation and significant benefits of phytochemicals.
Citation Format: Jin Boo Jeong, Kui-Jin Kim, Seong-Ho Lee. TCF4 is a molecular target of resveratrol-induced apoptosis in colon 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 4564. doi:10.1158/1538-7445.AM2015-4564
Abstract 4565: ATM genotyping modulates the risk of radiation-associated breast cancer among atomic-bomb survivors
Authors: Hayashi Tomonori , Hu Yiqun , Yoshida Kengo , Ohishi Waka , Hida Ayumi , Hayashi Ikue , Kyoizumi Seishi , Kusunoki Yoichiro , Nakachi Kei 
Published: August 2015

Abstract
Objective: RERF epidemiological studies among atomic-bomb (A-bomb) survivors have demonstrated significantly-increased incidence of selected cancers with increased radiation dose. It is noteworthy that a great deal of inter-individual variation in susceptibility to radiation-associated cancers could not be explained solely by radiation dose and age at exposure, suggesting the possibility that this variation might be partly ascribed to inter-individual differences in DNA repair capacity. Of 11 known single nucleotide polymorphisms (SNPs) of the DNA repair gene ATM, we selected a particular SNP (rs189037; located in the 5′ untranslated region and therefore thought to be associated with ATM gene expression) and examined the association with radiation-associated breast cancer in the context of an RERF A-bomb survivor cohort study.
Materials and Methods: A follow-up survey during 1981-2005 of 2,944 female members of the RERF Immunogenome Study Cohort identified a total of 100 breast cancer cases. ATM genotypes (ATM-G/G, -G/A, and -A/A) were determined by the TaqMan assay method for all cohort members. Relative risks (RRs) of breast cancer were estimated for radiation dose, the ATM genotypes, and the combined categories of dose levels and genotypes.
Results and Discussion: Disregarding the genotype effects, RR of breast cancer significantly increased with increased radiation dose (RR = 1.51/Gy, 95% CI: 1.25-1.83). For overall radiation dose levels, A-bomb survivors with ATM-G/G homozygote revealed a significantly-increased RR of breast cancer (RR = 1.85, 95%CI: 1.24-2.75), using as reference the risk of those with ATM-A/A homozygotes combined with ATM-G/A heterozygotes. When radiation dose was categorized into three levels (&lt; 5 mGy referred to as “non-exposed,” 5-530 mGy, and &gt;530 mGy), the survivors with ATM-A/A who were exposed to the highest dose level (&gt;530 mGy) showed the highest risk of breast cancer (RR = 4.76, 95%CI: 2.30-9.88), using as reference the risk of “non-exposed” survivors with ATM-T/T or ATM-A/T. These results suggest the possibility that the ATM genotyping may be involved in individually differing susceptibility to radiation-associated breast cancer.
Citation Format: Tomonori Hayashi, Yiqun Hu, Kengo Yoshida, Waka Ohishi, Ayumi Hida, Ikue Hayashi, Seishi Kyoizumi, Yoichiro Kusunoki, Kei Nakachi. ATM genotyping modulates the risk of radiation-associated breast cancer among atomic-bomb survivors. [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 4565. doi:10.1158/1538-7445.AM2015-4565
Abstract 4567: Activation of T-cell protein tyrosine phosphatase suppresses keratinocyte survival and proliferation following UVB irradiation
Authors: Lee Hyunseung , Kim Mihwa , Morales Liza D. , Slaga Thomas J. , Kim Dae Joon 
Published: August 2015

Abstract
Chronic exposure of UV radiation can contribute to the development of skin cancer by promoting PTK signaling. Studies show that exposure to UV radiation increases the ligand-independent activation of PTKs and induces PTP inactivation. In the present work, we report that TC-PTP activity is stimulated during the initial response to UVB irradiation which leads to suppression of keratinocyte cell survival and proliferation via the down-regulation of STAT3 signaling. Our results show that TC-PTP-deficient keratinocyte cell lines expressed a significantly increased level of phosphorylated STAT3 after exposure to low dose UVB. This increase corresponded with increased cell proliferation in TC-PTP-deficient keratinocytes following UVB irradiation. Loss of TC-PTP also reduced UVB-induced apoptosis. In corroboration with these results, overexpression of TC-PTP in keratinocyte cell lines yielded a decrease in phosphorylated STAT3 levels, which corresponded with a significant decrease in cell proliferation in response to low dose UVB. We demonstrate that TC-PTP activity was increased upon UVB exposure and overexpression of TC-PTP in keratinocyte cell lines further increased its activity in the presence of UVB. Treatment of TC-PTP-deficient keratinocytes with the STAT3 inhibitor STA21 significantly reduced cell viability following UVB exposure in comparison with untreated TC-PTP-deficient keratinocytes, confirming that the effect of TC-PTP on cell viability is mediated by STAT3 dephosphorylation. Combined, our results indicate that UVB-mediated activation of TC-PTP plays an important role in the STAT3-dependent regulation of keratinocyte cell proliferation and survival. Furthermore, these results suggest that TC-PTP may be a novel potential target for the prevention of UVB-induced skin cancer.
Note: This abstract was not presented at the meeting.
Citation Format: Hyunseung Lee, Mihwa Kim, Liza D. Morales, Thomas J. Slaga, Dae Joon Kim. Activation of T-cell protein tyrosine phosphatase suppresses keratinocyte survival and proliferation following UVB irradiation. [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 4567. doi:10.1158/1538-7445.AM2015-4567
Abstract 4622: Common genetic variants in epigenetic machinery genes and risk of upper gastrointestinal cancers
Authors: Sung Hyuna , Yang Howard H. , Zhang Han , Yang Qi , Hu Nan , Tang Ze-Zhong , Su Hua , Wang Lemin , Wang Chaoyu , Ding Ti , Fan Jin-Hu , Qiao You-Lin , Wheeler William , Giffen Carol , Burdett Laurie , Wang Zhaoming , Lee Maxwell P. , Chanock Stephen J. , Dawsey Sanford M. , Freedman Neal D. , Abnet Christian C. , Goldstein Alisa M. , Yu Kai , Taylor Philip R. , Hyland Paula L. 
Published: August 2015

Abstract
Background: Populations in north central China are at high risk for esophageal squamous cell carcinoma (ESCC) and gastric cancer (GC), and genetic variation in epigenetic machinery genes and pathways may contribute to this risk. Methods: We used the adaptive multilocus joint test (AdaJoint) to analyze 191 epigenetic genes involved in DNA methylation, chromatin remodeling, and microRNA biosynthesis in 1942 ESCC and 1758 GC cases [1126 cardia (GCA) and 632 non-cardia adenocarcinoma (GNCA)] and 2111 controls with Chinese ancestry. We examined the regulatory function of risk SNPs using in silico analyses and expression quantitative trait loci (eQTL) analysis in normal esophageal and gastric tissues. Results: Significant pathway-based associations were observed for the overall epigenetics (P = 3.4E-02) and chromatin remodeling (P = 3.9E-02) pathways with GCA risk, but not GC, GNCA or ESCC. SETD1B, CBX4, KAT5, ZGPAT, BTD, EED, SMARCD1, POLE3, AGO2, RING1 and MBD3L1 were associated with ESCC risk, and SUV42OH1, ASH1L, KAT5, JARID2, PRMT1, MBD3L1, SRRT, KDM5A, DROSHA and KAT6A were associated with GC risk overall (nominal P &lt; 0.05). We identified EED rs10898459 (rho = -0.22, P = 2.9E-02) as a potential esophageal eQTL; DICER1 rs7157322 (rho = -0.42, P = 1.4E-02) and PPP1CA rs1790733 (rho = -0.41, P = 2.1E-03) as potential gastric eQTLs; and ASH1L rs12724079 and rs8179271 as potential gastric subtype eQTLs. Significance: As one of the first attempts to investigate epigenetic gene and pathway-level associations, our results suggest that chromatin remodeling and epigenetic pathways warrant further evaluation in relation to GC risk in other populations.
Citation Format: Hyuna Sung, Howard H. Yang, Han Zhang, Qi Yang, Nan Hu, Ze-Zhong Tang, Hua Su, Lemin Wang, Chaoyu Wang, Ti Ding, Jin-Hu Fan, You-Lin Qiao, William Wheeler, Carol Giffen, Laurie Burdett, Zhaoming Wang, Maxwell P. Lee, Stephen J. Chanock, Sanford M. Dawsey, Neal D. Freedman, Christian C. Abnet, Alisa M. Goldstein, Kai Yu, Philip R. Taylor, Paula L. Hyland. Common genetic variants in epigenetic machinery genes and risk of upper gastrointestinal cancers. [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 4622. doi:10.1158/1538-7445.AM2015-4622