bluuebunny/crossref_metadata_2025 huggingface dataset:
Abstract 4484: BTP-114: An albumin binding cisplatin prodrug with improved and sustained tumor growth inhibition
Authors: Moreau Benoit , Alargova Rossitza , Brockman Adam , Whalen Kerry , Quinn Jamie , Meetze Kristan , Bazinet Patrick , DuPont Michelle , Krawiec Beata , Kriksciukaite Kristina , Lemelin Charles , LimSoo Patrick , Oller Haley , Ramstack Mike , Rockwood Danielle , Shinde Rajesh , Singh Sukhjeet , White Brian , AuYeung Tsun , Dunbar Craig , Bilodeau Mark , Wooster Richard
Published: August 2015

Platinum drugs have proven to be effective in treating cancer, for example >90% of men with testicular cancer are cured with a platinum therapeutic. Platinum drugs are also widely used for the adjuvant treatment of common cancers such as those of the lung, colon and ovary. However for the majority of tumor types the clinical response rates for platinum therapies are low, for example the 1 year survival rate for lung cancer patients treated with platinum therapeutics is ∼30%. The key limitations of the existing platinum therapies are the dose limiting toxicities that restrict dose and/or duration of therapy and the absence of personalization that targets the drugs to the patients most likely to benefit. To address these issues we have designed a novel prodrug of cisplatin, BTP-114. On infusion into the blood a maleimide group on BTP-114 covalently attaches to serum albumin. This prolongs the circulation of BTP-114 in plasma and alters the biodistribution of the compound. Importantly the dose of platinum can be increased and the amount of platinum that accumulated in xenograft tumor tissue and the amount of platinum bound to tumor DNA are both increased relative to cisplatin. An elevation of DNA damage in tumor cells in vivo is observed with BTP-114. Together the properties of BTP-114 result in pronounced and sustained tumor growth inhibition compared to cisplatin. In parallel to the discovery of BTP-114 we have explored potential biomarkers to predict which tumors are most likely to respond. These data will be presented towards developing BTP-114 as a personalized platinum medicine for cancer patients.

BM and RA contributed equally to this work.

Citation Format: Benoit Moreau, Rossitza Alargova, Adam Brockman, Kerry Whalen, Jamie Quinn, Kristan Meetze, Patrick Bazinet, Michelle DuPont, Beata Krawiec, Kristina Kriksciukaite, Charles Lemelin, Patrick LimSoo, Haley Oller, Mike Ramstack, Danielle Rockwood, Rajesh Shinde, Sukhjeet Singh, Brian White, Tsun AuYeung, Craig Dunbar, Mark Bilodeau, Richard Wooster. BTP-114: An albumin binding cisplatin prodrug with improved and sustained tumor growth inhibition. [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 4484. doi:10.1158/1538-7445.AM2015-4484
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

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

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

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

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

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

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

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 (< 5 mGy referred to as “non-exposed,” 5-530 mGy, and >530 mGy), the survivors with ATM-A/A who were exposed to the highest dose level (>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

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

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 < 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
Abstract 4627: A novel computational re-analysis of published GWAS data suggests new risk loci for melanoma susceptibility
Authors: Cymerman Rachel M. , Bigio Benedetta , Seybold Martin P. , Polsky David , Wittkowski Knut M.
Published: August 2015

Purpose: Multiple melanoma GWAS have identified significant associations between single nucleotide polymorphisms (SNPs) and melanoma. As multiple variants within a given genetic locus may contribute to disease risk in different individuals, a novel computational approach to analyzing GWAS data by ‘wide-locus’ region has been shown to increase analytical power, and, in other diseases, has led to the discovery of new susceptibility loci. To date, this approach has not been applied to the study of germline genetic risk factors for melanoma. We applied this method to publically available melanoma GWAS data to identify novel germline risk factors for melanoma.

Methods: We re-analyzed data from the M.D. Anderson Cancer Center melanoma GWAS study (dbGap accession: phs000187.v1.p1). In the original study, 1,977 cases and 1,047 controls of European ancestry were genotyped on an Illumina OMNI1-Quad chip. We age-matched cases and controls using “age-censoring” to account for differences in melanoma risk across different age groups. Biostatistical analysis of ‘wide-loci’ was performed across all SNPs to evaluate risk loci based on the influence of neighboring SNPs. The re-analysis was performed by individuals blinded to specific results of the original study. Genome-wide significance for each wide locus was based on number of regions examined, and was set at p<10−6.16.

Results: Using the ‘wide-locus’ approach, we identified 21 risk loci on 16 chromosomes that met genome-wide significance. Firstly, we replicated all of the genome-wide significant findings of the original, single-SNP analysis, identifying specific SNPs at HERC2 and wide loci at MC1R and AFG3L1 that met genome-wide significance. Secondly, we identified additional SNPs not replicated to genome-wide significance in the original analysis but previously discovered in other populations. These additional SNPs reside in the MC1R, OCA2, CPNE7, DBNDD1, and AFG3L1 loci. Finally, we identified 15 new candidate loci meeting genome-wide significance, with the most significant findings located at KLK12 (associated with carcinogenesis in other cancers), PDE8 (involved with cAMP intra-cellular signaling and immune activation), and LY86 (involved in immune cell activation).

Conclusion: Applying ‘wide-locus’-based statistical analysis to melanoma GWAS data replicated the findings of prior single-SNP analyses and identified multiple, new candidate risk loci worthy of further investigation.

Citation Format: Rachel M. Cymerman, Benedetta Bigio, Martin P. Seybold, David Polsky, Knut M. Wittkowski. A novel computational re-analysis of published GWAS data suggests new risk loci for melanoma susceptibility. [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 4627. doi:10.1158/1538-7445.AM2015-4627
Abstract 4654: Antitumorigenic activity of trans-chalcone in osteosarcoma
Authors: Silva Gabriel da , Marins Mozart , Fachin Ana Lúcia , Baek Seung J.
Published: August 2015

Background and Aims: Osteosarcoma is the most common bone cancer, and it affects mostly teenagers and children. Although the emergence of multidrug therapies has improved available treatments for osteosarcoma, approximately 30% of patients will still develop metastasis. Thus, there is a clear need to identify new anticancer therapies. Currently, much anticancer therapy uses drugs that affect molecular targets, such as up-regulation of p53 and down-regulation of Sp1. Building on this knowledge, our aims in this work were to evaluate the ability of trans-Chalcone to reduce viability, induce apoptosis, and to alter the levels of p53 and Sp1 in human osteosarcoma cell lines. Chalcones are secondary metabolites of plants and have been demonstrated to induce apoptosis in human cancer cells. Methods: Osteosarcoma cell viability and apoptosis were evaluated by MTT assay and flow cytometry, respectively. The expression of p53 and sp1 was assessed by Western blotting. Transcriptional and post-translational regulation were measured by luciferase assay and proteasomal inhibitor experiments. Results: We identified that cell growth was inhibited by trans-Chalcone in a dose- and time-dependent manner, with a significant inhibition at 10 μM after 48 hours. After 24 hours of treatment with trans-Chalcone, apoptosis was induced in a dose-dependent manner-fold induction at 1.9 and 3.6 at 10 μM and 50 μM, respectively, compared to control. Western blot analysis indicated that trans-chalcone reduced Sp1 and induced p53 expression, compared to control cells. Further experiments suggest that trans-Chalcone affected Sp1 down-regulation at the transcriptional level, whereas trans-chalcone up-regulated p53 expression at the post-translational level. These results were confirmed by a luciferase assay of the MDM2 promoter and a proteasomal degradation assay using several inhibitors. Conclusions: Trans-Chalcone inhibits cell growth and induces apoptosis in osteosarcoma cells and targets p53 tumor suppressor and Sp1 oncogenic proteins in osteosarcoma. Thus, trans-chalcone could be the focus of future clinical trials to develop an anti-cancer drug for osteosarcoma patients.

Support: The University of Tennessee Center of Excellence in Livestock Diseases and Human Health and a grant (No. process: BEX 3159/14-0) from the CAPES Foundation, an agency under the Ministry of Education of Brazil.

Citation Format: Gabriel da Silva, Mozart Marins, Ana Lúcia Fachin, Seung J. Baek. Antitumorigenic activity of trans-chalcone in osteosarcoma. [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 4654. doi:10.1158/1538-7445.AM2015-4654
Abstract 4661: Preventive effects of branched-chain amino acid supplementation on the spontaneous development of hepatic preneoplastic lesions in C57BL/KsJ-db/db obese mice
Authors: Ideta Takayasu
Published: August 2015

In the present study, the effects of BCAA supplementation on the spontaneous development of hepatic premalignant lesions, foci of cellular alteration, in db/db obese mice were examined. Male db/db mice were given a basal diet containing 3.0% of either BCAA or casein, a nitrogen-content-matched control of BCAA, for 36 weeks. On killing the mice, supplementation with BCAA significantly inhibited the development of foci of cellular alteration when compared with casein supplementation by inhibiting cell proliferation, but inducing apoptosis. BCAA supplementation increased the expression levels of peroxisome proliferator-activated receptor-γ(PPARγ), p21(CIP1) and p27(KIP1) messenger RNA and decreased the levels of c-fos and cyclin D1 mRNA in the liver. BCAA supplementation also reduced both the amount of hepatic triglyceride accumulation and the expression of interleukin (IL)-6, IL-1β, IL-18 and tumor necrosis factor-α mRNA in the liver. Increased macrophage infiltration was inhibited and the expression of IL-6, TNF-α, and monocyte chemoattractant protein-1 mRNA in the white adipose tissue were each decreased by BCAA supplementation. BCAA supplementation also reduced adipocyte size while increasing the expression of PPARα, PPARγand adiponectin mRNA in the white adipose tissue compared with casein supplementation. These findings indicate that BCAA supplementation inhibits the early phase of obesity-related liver tumorigenesis by attenuating chronic inflammation in both the liver and white adipose tissue. BCAA supplementation may be useful in the chemoprevention of liver tumorigenesis in obese individuals.

Citation Format: Takayasu Ideta. Preventive effects of branched-chain amino acid supplementation on the spontaneous development of hepatic preneoplastic lesions in C57BL/KsJ-db/db obese mice. [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 4661. doi:10.1158/1538-7445.AM2015-4661
Abstract 467: Oxidized lipids contribute to the suppression function of myeloid derived suppressor cells in cancer
Authors: Veglia Filippo , Tyurin Vladimir , Kagan Valerian , Gabrilovich Dmitry
Published: August 2015

Immune evasion is an emerging hallmark of cancer progression. It is established that the defects in the function of antigen presenting cells and the accumulation of myeloid derived suppressive cells (MDSCs) are critical drivers of tumor mediated immune evasion. MDSCs represent a heterogeneous population of immature and pathologically activated myeloid cells that are expanded in many cancers and suppress immune responses by several defined mechanisms. Our recent findings indicate that the massive accumulation of oxidized lipids in dendritic cells (DCs) resulted in profound defects in their ability to mount antitumor responses. In this study we observed that MDSCs from tumor bearing mice and from cancer patients have higher amount of lipids than their counterpart in tumor free mice and healthy donors, respectively. The content of lipids in MDSC was even much higher in MDSCs infiltrating the tumor, and the accumulation of lipids in MDSC seems be caused by the uptake of extracellular lipids. MDSCs with a highest content of lipids showed a stronger ability to suppress antigen specific CD8 T cell responses than MDSCs with a normal content of lipids. By using mass-spectrometry we identified different oxidized species in lipids accumulated in MDSC from both tumor bearing mice and patients with cancer. Myeloperoxidase (MPO) and reactive oxygen species (ROS) were responsible for the oxidation of lipids in MDSCs. Lack of MPO or ROS in MDSC almost completely abrogated the oxidation of lipids in these cells. Furthermore the reduced amount of oxidized lipids in MDSC from MPO KO mice or following the pharmacological inhibition of their oxidative machinery resulted in a profound defect in MDSC suppressive activity. In line with these findings, unsaturated fatty acids, highly susceptible to oxidation, favored the expansion of highly suppressive MDSC from hematopoietic progenitors in vitro, as oppose to non-oxidizable saturated fatty acids. Together, our data suggest that MDSCs have increased ability to pick up lipids from the microenvironment and to oxidize them via their potent oxidative machinery. In turn oxygenated lipids contribute to the suppressive activity of MDSC. The regulation of the oxidation of lipids in MDSC could be an attractive therapeutic strategy in cancer.

Citation Format: Filippo Veglia, Vladimir Tyurin, Valerian Kagan, Dmitry Gabrilovich. Oxidized lipids contribute to the suppression function of myeloid derived suppressor cells in 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 467. doi:10.1158/1538-7445.AM2015-467
Abstract 4699: Preclinical activity of the AKT inhibitor AZD5363 in PTEN-deficient mouse models of prostate cancer
Authors: De Velasco Marco A. , Hatanaka Yuji , Kura Yurie , Fukushima Emiko , Ando Naomi , Davies Barry R. , Yamamoto Yutaka , Oki Takashi , Shimizu Nobutaka , Yoshimura Kazuhiro , Nozawa Masahiro , Yoshikawa Kazuhiro , Nishio Kazuto , Uemura Hirotsugu
Published: August 2015

Increased phosphoinositide 3-kinase (PI3K) pathway activity is commonly observed in human prostate cancer and constitutes a potential target for therapeutic intervention. AZD5363 is a potent pan-AKT kinase inhibitor that is currently being investigated in phase 1 and 2 clinical trials in solid cancers including prostate. AZD5363 has demonstrated strong anti-tumor activity against human prostate cancer cells in vitro and in vivo. Genetically engineered mouse models mimic the genetic and biological evolution of human prostate cancer and address deficiencies encountered with xenograft models. In the present study, we examined in vivo target validation, pharmacodynamics, and antitumor responses of AZD5363 monotherapy in a PTEN-deficient mouse model of prostate cancer, and show the survival benefit in an advanced prostate cancer model driven by PTEN/P53 inactivation. Downstream targets of AKT were inhibited in a dose-dependent manner and activity of AZD5363 at was observed up to 8 hours after a single dose of 100 mg/kg. Tumor cell proliferation and the induction of apoptosis paralleled the activity of AZD5363. Compared to vehicle treated mice, chronic administration of AZD5363 at 100 mg/kg B.I.D. 5 times per week for 4 weeks inhibited growth of castration-naïve and castration-resistant prostate cancers by 15.9% ±4.3 and 20.2% ±4.4, respectively. Inhibition of S6 phosphorylation was effectively maintained the after chronic administration of AZD5363 and was accompanied by decreased proliferation rates and increase in apoptosis. Furthermore, in a long-term survival study of PTEN/P53 double knockout mice, treatment with AZD5363 significantly improved survival rates from 24 to 37 days, P<0.011. In conclusion, our findings indicate that AZD5363 is effective against autochthonous models of mouse prostate cancer and support further investigation of the AKT inhibitor for the treatment of PTEN-deficient prostate cancer.

Citation Format: Marco A. De Velasco, Yuji Hatanaka, Yurie Kura, Emiko Fukushima, Naomi Ando, Barry R. Davies, Yutaka Yamamoto, Takashi Oki, Nobutaka Shimizu, Kazuhiro Yoshimura, Masahiro Nozawa, Kazuhiro Yoshikawa, Kazuto Nishio, Hirotsugu Uemura. Preclinical activity of the AKT inhibitor AZD5363 in PTEN-deficient mouse models of prostate 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 4699. doi:10.1158/1538-7445.AM2015-4699
Abstract 4715: Regulation of the PI3K pathway through a p85α monomer-homodimer equilibrium
Authors: Cheung Lydia WT , Walkiewicz Katarzyna W. , Besong Tabot , Hawke David , Arold Stefan T. , Mills Gordon B.
Published: August 2015

The canonical action of the p85α regulatory subunit of phosphatidylinositol 3-kinase (PI3K) is mediated by association with the p110 catalytic subunit to allow stimuli-dependent activation of the PI3K pathway. Although the best-characterized role of p85α is p110-dependent, intermolecular interactions of p85α protomers have been suggested to result in p85α homodimerization. However, the function of the p85α homodimer remains to be elucidated. Through structural modeling and biochemical analyses, we demonstrate the p110α-independent role of homodimerized p85α in the positive regulation of PTEN. p110α-free p85α homodimerizes via SH3:proline rich domain and BH:BH intermolecular interactions to selectively bind unphosphorylated activated PTEN. p85α homodimer competes for PTEN binding with the E3 ligase WWP2. As a consequence, homodimeric but not monomeric p85α suppresses the PI3K pathway by protecting PTEN from WWP2-mediated proteasomal degradation. Further, p85α homodimer enhances the lipid phosphatase activity and membrane association of PTEN. Importantly, the homodimerization surface and the PTEN-interaction interface are targeted in cancer patient-derived p85α mutants, providing a plausible mechanism for tumor development. These p85α mutants are oncogenic by destabilizing PTEN and inducing PI3K pathway activation. Together, we provide a mechanistic model of how p85α plays a dual role in regulating the PI3K pathway through forming p85α homodimer or p110-bound heterodimer. Our data suggest that the monomer-dimer equilibrium of p85α regulates the PI3K pathway and thereby associates with cancer development.

Citation Format: Lydia WT Cheung, Katarzyna W. Walkiewicz, Tabot Besong, David Hawke, Stefan T. Arold, Gordon B. Mills. Regulation of the PI3K pathway through a p85α monomer-homodimer equilibrium. [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 4715. doi:10.1158/1538-7445.AM2015-4715
Abstract 472: Galectin-3 modulates glioblastomas (GBM) tumor microenvironment, and is linked to glioblastoma invasion
Authors: Wesley Umadevi V. , Resad Esat , Clark Paul , Larrain Carolina , Kuo John , Dempsey Robert J.
Published: August 2015

Malignant glioblastomas (GBM) are lethal form of brain tumors, and are difficult to treat due to their invasion into the brain parenchyma. Aggressive and invasive nature of GBM is at least partly attributable to GBM associated stem cells (GSC). Soluble factors released by GBM and GSC can recruit inflammatory cells, including brain resident microglia to tumor micro-environment (TME) that support angiogenesis and invasion. We have previously shown that exogenous Galectin-3 (Gal-3), a carbohydrate binding lectin increases the migratory potential of BV2 microglial cells, and promotes the formation of pro-angiogenic structures in an in vitro HUVEC culture and 3D matrigel model. Furthermore, Gal-3 supports the survival of microglial cells under hypoxic environment. In this study, we investigated the role of Gal-3 in GBM by utilizing the biochemical and molecular approaches. Using well characterized GBM tumor cell lines, and GSC lines that exhibit various degrees of invasive potential, we have identified that the expression of the Gal-3 is significantly up-regulated in GSCs that are highly invasive as compared to those that form only focal tumors in a mouse xenotransplantation model. Gal-3 is also highly expressed in microglia that accumulated in and around the GSC tumors in mouse brain, as indicated by co-localization of Gal-3 and Iba1, the maker for activated microglia. Furthermore, Gal-3 expression is significantly increased in GBM tumor cells when exposed to in vitro hypoxic conditions. Importantly, Gal-3 increased the migratory potential of GBM tumor cells in vitro, indicating its role as a chemo-attractant. Taken together, these results suggest that Gal-3 plays a critical role in promoting GBM invasion through modulating the interaction of microglia in TME and GBM. Thus Gal-3 may be a potential therapeutic target for GBM.

Citation Format: Umadevi V. Wesley, Esat Resad, Paul Clark, Carolina Larrain, John Kuo, Robert J. Dempsey. Galectin-3 modulates glioblastomas (GBM) tumor microenvironment, and is linked to glioblastoma invasion. [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 472. doi:10.1158/1538-7445.AM2015-472
Abstract 4722: Inactivation of neogenin promotes castration resistance and bone metastasis in prostate cancer models
Authors: Chakraborty Goutam , Gadiya Mayur , Kossai Myriam , Gao Dong , Su Weijing , Gao Hua , Chen Yu , Scher Howard I. , Rubin Mark A. , Giancotti Filippo
Published: August 2015

Increasing evidence suggests that exposure to new generation agents targeting the AR promotes the emergence of castration-resistant stem-like clones ultimately leading to treatment failure. In order to develop improved therapies for castration-resistant prostate cancer (CRPC), it is important to understand the origin and biology of these stem-like clones. We have observed significantly diminished levels of Neogenin (encoded by NEO1) in CRPC. Neogenin functions as a neuronal guidance receptor but has also been implicated in epithelial branching morphogenesis and is homologous to DCC, which functions as a suppressor of tumor progression in breast and colorectal cancer. We found that silencing of neogenin induces androgen receptor (AR) dependent prostate cancer cells to undergo an epithelial to mesenchymal transition (EMT) and acquire neuroendocrine (NE) differentiation features. In addition, the neogenin-silenced cells expressed high levels of the stem cell markers β4 integrin and CD44 and formed rapidly growing tumor spheres in vitro. Intriguingly, these cells had become castration resistant due to loss of AR expression and were able to efficiently colonize the bone upon intracardiac injection in immunodeficient mice. Genomic and molecular pathology studies indicated that NEO1 expression is lost in CRPC and NEPC. To examine the relationship between the acquisition of the castration resistant phenotype and loss of neogenin, we have generated a series of casodex- and enzalutamide-resistant clones from LNCaP cells. Interestingly, we observed that a significant fraction of these clones have lost expression of neogenin and acquired expression of the β4 integrin and are highly metastatic in immunodeficient mice, similar to the characteristics of CRPC observed in the clinic. To validate these results, we sought to identify a population of β4-positive cells in the peripheral blood of patients with CRPC. By using immunofluorescent staining and FACS analysis, we were able to identify β4-positive circulating tumor cells (CTCs) from the peripheral blood of CRPC patients. These cells were not detected in the blood of healthy normal donors but their numbers increased with disease progression. These findings identify a novel tumor progression pathway that is likely to operate in at least a fraction of CRPC cases.

Citation Format: Goutam Chakraborty, Mayur Gadiya, Myriam Kossai, Dong Gao, Weijing Su, Hua Gao, Yu Chen, Howard I. Scher, Mark A. Rubin, Filippo Giancotti. Inactivation of neogenin promotes castration resistance and bone metastasis in prostate cancer models. [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 4722. doi:10.1158/1538-7445.AM2015-4722