bluuebunny/crossref_metadata_2025 huggingface dataset:
Abstract 3210: Targeting PTP4A3 phosphatase in ovarian cancer with the potent noncompetitive inhibitor JMS-631-053
Authors: Lazo John S. , Pekic Paula , Cheung Alex , McQueeney Kelley , Salamoun Joseph , Wipf Peter , Landen Charles N. , Sharlow Elizabeth R.
Published: July 2017

PTP4A3 is a highly attractive molecular target for ovarian cancer (OvCa). Elevated levels of PTP4A3 mRNA and protein in human ovarian tumors correlate with disease progression, poor prognosis and poor survival. Genetic depletion of PTP4A3 in OvCa cell lines diminishes their ability to migrate and reduces their in vivo tumorigenicity while PTP4A3 overexpression increases tumor cell migration, invasion, and dissemination. Together, these data suggest PTP4A3 is a novel molecular target for OvCa; however, the lack of potent and selective PTP4A3 small molecule inhibitors has hindered PTP4A3’s definitive validation in OvCa and in other cancers. To drive the pharmacological validation of PTP4A3, we developed JMS-631-053 (7-imino-2-phenylthieno[3,2-c]pyridine-4,6(5H,7H)-dione), a potent (Ki=3 nM in vitro), specific, noncompetitive, PTP4A3 inhibitor. JMS-631-053 inhibited cellular migration, invasion, and colony formation in soft agar. Potent OvCa cell-based effects were observed by profiling JMS-631-053 against a panel of 8 OvCa cell lines using a 2D drug susceptibility assay, with EC50 values as low as 600 nM. Likewise, JMS-631-053 killed OvCa 3D spheroids, including those derived from high grade serous OvCa cell lines, with EC50 values as low as 300 nM. The OvCa drug resistant cell lines (i.e., A2780CP20 and HeyA8MDR) retained responsiveness to JMS-631-053 (using 2D and 3D culturing conditions) suggesting that inhibition of PTP4A3 may be a viable therapeutic strategy for chemoresistant OvCa. Preliminary data also suggests that JMS-631-053 synergizes with cisplatin when used in combination studies. Hence, JMS-631-053 will be a valuable chemical tool for further validation of PTP4A3 as an OvCa target as well as provide potential leads for future drug discovery.

Citation Format: John S. Lazo, Paula Pekic, Alex Cheung, Kelley McQueeney, Joseph Salamoun, Peter Wipf, Charles N. Landen, Elizabeth R. Sharlow. Targeting PTP4A3 phosphatase in ovarian cancer with the potent noncompetitive inhibitor JMS-631-053 [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 3210. doi:10.1158/1538-7445.AM2017-3210
Abstract 3215: Therapeutic potential of dual-function small molecules for breast cancers
Authors: Nicholas Nicole , Velena Alfredo , Grindrod Scott , Jung Mira
Published: July 2017

Epigenetic silencing of tumor suppressors is an important mechanism in tumor initiation and progression. A tumor suppressor gene, BRCA1, is part of complex molecules in the repair of DNA double-strand breaks (DSBs), and loss of BRCA1 contributes to both sporadic and inherited breast tumor progression. Furthermore, recent studies have shown that the ataxia-telangiectasia mutated (ATM) activity is abnormal in breast cancer. Therefore, we tested the hypothesis that the dual-functional drug that fused the HDAC inhibitor with an ATM activator may enhance killing of breast cancer (BC) cells by increasing ATM activation. In addition, the expression of ATM may enhance the synergistic antitumor effects of HDAC inhibitors in combination with radiotherapy. To determine the HDAC inhibitory potency, SP-1-303 was screened against a panel of Class I and Class II HDAC enzymes in vitro and identified as a pan-HDAC inhibitor (IC50=120 nM). Western blot confirmed that SP-1-303 increased acetylated histone H3/H4, α-tubulin, and phosphorylation of ATM within 30 min - 4 h in a time-dependent manner. Using two ER positive BC cell lines (MCF7 and T-47D), two triple negative breast cancer (TNBC) cell lines (MDA-MB-231 and HCC 1937), and one normal breast epithelial cell line as a control (MCF10A), the effects of SP-1-303 on cell growth and cell death were examined by performing cytotoxicity assays and flow cytometry. SAHA and Tamoxifen were used as controls. SP-1-303 conferred the values of cytotoxicity (IC50) for the ER positive BC cells in a range of 0.25-0.4 μM, while the values are in a range of 1-3 μM for TNBC and 12 μM for normal breast epithelial cells, respectively. Flow cytometry (FACS) analyses demonstrated significant increases in G1 arrest (81%) in MCF7 cells and a further enhancement in the G1 phase (91%) in combination with radiation. The data implies the mechanism of action from this drug—cancer cells are being arrested in the G1 phase of the cell cycle, a radiation sensitive phase, suggesting that SP-1-303 may have a synergistic effect with radiation on cell killing. Taken together, SP-1-303 had the largest impact on ER positive breast cancer over TNBC. These data imply that an increased cell death is occurring in ER positive breast cancers from these dual-action molecules through HDAC inhibition and increased ATM activation, suggesting that SP-1-303 alone or its combination with radiotherapy may improve clinical efficacy.

Citation Format: Nicole Nicholas, Alfredo Velena, Scott Grindrod, Mira Jung. Therapeutic potential of dual-function small molecules for breast cancers [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 3215. doi:10.1158/1538-7445.AM2017-3215
Abstract 3226: The apoptotic mechanism of MT-6, a mitotic inducer, in human ovarian cancer cells
Authors: Mei-Chuan Chen
Published: July 2017

Patients with ovarian cancer are typically diagnosed at an advanced stage, resulting in poor prognosis since there are currently no effective early-detection screening tests for women at average-risk for ovarian cancer. Here, we investigated the effects of MT-6, a derivative of moscatilin, in ovarian cancer cells. Our investigation showed that MT-6 inhibited the proliferation and viability of SKOV3 ovarian cancer cells with submicromolar IC50 values. MT-6-treated SKOV3 cells showed significant cell cycle arrest at G2/M phase, followed by an increase in the proportion of cells in a sub-G1 phase. In addition, MT-6 induced a concentration-dependent increase in mitotic markers, mitotic kinases, cell cycle regulators of G2/M transition, and apoptosis-related markers in SKOV3 cells. MT-6 treatment also induced mitochondrial membrane potential loss, JNK activation, and DR5 expression. Cotreatment of cells with the JNK inhibitor SP600125 considerably attenuated MT-6-induced apoptosis, mitochondria membrane potential loss, DR5 upregulation, and suppression of cell viability. MT-6 also inhibited tumor growth in an SKOV3 xenograft model without significant body weight loss. Together, our findings suggest that MT-6 is a potent anticancer agent with tumor-suppressive activity in vitro and in vivo that could be further investigated for ovarian cancer therapy in the future.

Citation Format: Chen Mei-Chuan. The apoptotic mechanism of MT-6, a mitotic inducer, in human ovarian cancer cells [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 3226. doi:10.1158/1538-7445.AM2017-3226
Abstract 3229: Drug repurposing of topiramate in obesity-driven endometrial cancer
Authors: Tran Arthur-Quan , Sullivan Stephanie A. , Zhou Chunxiao , Kaufman David , Bae-Jump Victoria
Published: July 2017

Introduction: Topiramate (TPM) is a B-D-fructopyranose sulfamate that acts by inhibiting carbonic anhydrases (CAs) and has been implicated as a novel inhibitor of angiogenesis. TPM is commonly used for the treatment of epilepsy and migraine headaches; however, when combined with phentermine, TPM can induce weight loss. Due to its weight loss and anti-angiogenic properties, we assessed TPM’s potential as an anti-tumorigenic agent in endometrial cancer (EC), a highly obesity-driven disease.

Methods: Cell proliferation was assessed by MTT assay after exposure to TPM for 72 hours in the HEC-1A, KLE, Ishikawa and ECC-1 EC cell lines. Two representative cell lines, ECC-1 and Ishikawa, were used to analyze apoptosis, cell cycle progression, cell adhesion and invasion. Apoptosis was analyzed by Annexin V-FITC assay. Inhibition of adhesion and invasion by TPM were assessed by ELISA and transwell assay, respectively. Cell cycle progression was evaluated by Cellometer. Western immunoblotting was performed to assess downstream targets of the MAPK and mTOR pathways. The LKB1fl/flp53fl/fl EC mouse model was utilized to assess the in vivo effects of TPM. AdCre was injected at six weeks of age to induce invasive EC. Eight wks following AdCre injection, mice (N=10 per group) were treated with placebo or TPM (200 mg/kg/day, oral) for four weeks. The expression of phosphorylated-S6 and Ki-67 was assessed by IHC.

Results: TPM inhibited cell proliferation in a dose dependent manner in all four EC cell lines (IC50 range=1500-3000 mM). Treatment with TPM resulted in G1 arrest and induction of apoptosis (p<0.05). TPM also reduced adhesion and invasion in the EC cell lines (p=0.05), with a corresponding decrease in VEGF expression. In addition, TPM significantly inhibited phosphorylation of p42/44 and S6 in the EC cell lines. Lastly, TPM decreased tumor weight in the LKB1fl/flp53fl/fl mice by 68% compared to those treated with placebo (p<0.05), accompanied by a reduction in Ki-67 and phosphorylated-S6 expression (p<0.05).

Conclusion: TPM inhibited cell proliferation and tumor growth in EC cell lines and an EC mouse model. Therefore, TPM may be worthy of drug repurposing as an anti-tumorigenic agent in EC, with the potential added benefit of weight loss in this obesity-linked disease.

Citation Format: Arthur-Quan Tran, Stephanie A. Sullivan, Chunxiao Zhou, David Kaufman, Victoria Bae-Jump. Drug repurposing of topiramate in obesity-driven endometrial cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 3229. doi:10.1158/1538-7445.AM2017-3229
Abstract 3233: Design and synthesis of BPR1K653 and its derivatives targeting the back pocket of Aurora kinases for selective isoform inhibition
Authors: Chi Ya-Hui , Chang Chun-Ping , Ke Yi-Yu , Lin Wen-Hsing , Hsieh Hsing-Pang
Published: July 2017

Guided by computational modeling addressing the back pocket of Aurora kinases, several novel chemical analogs of BPR1K653 were designed and synthesized in two steps with 30-66% yields. All synthesized compounds were evaluated by Aurora-A and Aurora-B enzymatic kinase activity assays, cellular phosphorylation inhibition assays and cell viability assays. Of them, compound 3a that exhibits no substitution at phenylurea showed similar inhibition activity to Aurora-A and -B. Compounds 3b and 3c which harbor tertiary amino group at meta position of phenylurea showed 10-15 fold inhibition selectivity for Aurora-A over Aurora-B in enzymatic assays. In addition, 3b and 3c were more than 200 fold superior in inhibiting T-loop autophosphorylation of Aurora-A compared to Aurora-B in HCT116 colon carcinoma cells. On the other hand, compound 3d with a 4-hydroxypiperidinyl group at ortho position preserves Aurora-B inhibition activity. Molecular docking study revealed that the various steric interaction between the compound and residues in the back pocket of Aurora kinases determines their inhibition selectivity.

Citation Format: Ya-Hui Chi, Chun-Ping Chang, Yi-Yu Ke, Wen-Hsing Lin, Hsing-Pang Hsieh. Design and synthesis of BPR1K653 and its derivatives targeting the back pocket of Aurora kinases for selective isoform inhibition [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 3233. doi:10.1158/1538-7445.AM2017-3233
Abstract 3240: Designer peptides targeting epidermal growth factor as novel anti-breast cancer agents
Authors: Yawson Emmanuel , Garcia Angel , Dhari Husamuldeen , Rajnarayanan Rajendram V.
Published: July 2017

Triple negative breast cancer (TBNC) is the only major type of breast cancer for which no specific FDA approved target therapy is available to improve patient outcomes. TNBC lacks the usual breast cancer targets estrogen receptor (ER), progesterone receptor (PR) and HER2/neu receptor. Studies have shown that TBNC does express the epidermal growth factor receptor and has recently emerged as one of the potential targets in TBNC. Epidermal growth factor (EGF) mediates several cellular functions and processes such as survival, motility, differentiation, proliferation and death. When it is released by epidermal tissues, EGF binds to cell surface receptors such as the Epidermal growth factor receptor (EGFR) causing a conformational change which facilitates its dimerization. This receptor dimerization triggers its tyrosine kinase-mediated signal transduction activity. Apart from EGF, EGFR is reported to bind to Transforming growth factor alpha (TGF-α), Argos and Potato Carboxypeptidase inhibitor (PCI). All of these proteins have unique structural motifs which targets EGFR. PCI’s structure consisting of three disulfide bridges presents a unique knot like binding motif resembling EGF and is able to compete with EGF for its binding site on EGFR preventing receptor dimerization thereby antagonizing its action. We have used an integrated computational drug discovery approach to generate several PCI derived peptidic ligands targeting EGFR protein-protein interactions. PCI- peptides bind to EGFR in silico and block EGFR-mediated cell growth, proliferation and migration in vitro. We believe these designer peptidic inhibitors will provide structural and mechanistic clues towards novel therapeutics to combat TNBC.

Citation Format: Emmanuel Yawson, Angel Garcia, Husamuldeen Dhari, Rajendram V. Rajnarayanan. Designer peptides targeting epidermal growth factor as novel anti-breast cancer agents [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 3240. doi:10.1158/1538-7445.AM2017-3240
Abstract 3242: Synthetic analogs of curcumin as modulators of multidrug resistance-linked ABC transporters
Authors: Obara Megumi , Ohnuma Shinobu , Chufan Eduardo E. , Ishida Masaharu , Kudoh Katsuyoshi , Sugisawa Norihiko , Ohtsuka Hideo , Naitoh Takeshi , Shibata Hiroyuki , Iwabuchi Yoshiharu , Ambudkar Suresh V. , Unno Michiaki
Published: July 2017

Cancer patients often develop resistance to anticancer drugs. ATP-binding cassette (ABC) transporter-mediated drug efflux is one of the mechanisms responsible for development of resistance to anticancer drugs. The present study investigates the use of curcumin, a natural product and a dietary constituent of turmeric, which inhibits the function of three ABC drug transporters including ABCB1, ABCC1 and ABCG2. However, limited bioavailability of curcumin prevents its use for modulation of the function of these transporters in the clinic. We focused on curcumin analogs that were synthesized at Tohoku University and have been shown to exhibit higher bioavailability than natural curcumin to test whether the synthetic analogs also inhibit the function of ABC drug transporters. To investigate this, KB-V1 and K562/BCRP cell lines overexpressing ABCB1 and ABCG2 were used for the experiments. For these studies, we screened nineteen synthetic analogs of curcumin for their effect on the transport function of ABCB1 and ABCG2 by flow cytometry. Four curcumin analogs, GO-Y030, GO-Y078, GO-Y168 and GO-Y172 inhibited efflux of mitoxantrone mediated by ABCG2 and sensitized ABCG2-expressing K562 leukemic cells to the anticancer drug, SN-38 in cell toxicity assays. Some of the curcumin analogs (GO-Y030, GO-Y078, GO-Y172) stimulated ATPase activity of ABCG2 at nanomolar concentrations (EC50 = 480 ± 0.06, 790 ± 0.10, 930 ± 0.12 nM). In addition, GO-Y030, GO-Y078, GO-Y168, GO-Y172 analogs also inhibited photolabeling of ABCG2 in MCF-7-FL plasma membranes with iodoarylazidoprazosin, which is transported by this transporter. These data demonstrate that similar to curcumin, synthetic curcumin analogs also interact at the drug-binding pocket of ABCG2. In aggregate, these results suggest that non-toxic synthetic curcumin analogs with increased bioavailability may be useful to reverse ABCG2-mediated resistance to anticancer agents.

Citation Format: Megumi Obara, Shinobu Ohnuma, Eduardo E. Chufan, Masaharu Ishida, Katsuyoshi Kudoh, Norihiko Sugisawa, Hideo Ohtsuka, Takeshi Naitoh, Hiroyuki Shibata, Yoshiharu Iwabuchi, Suresh V. Ambudkar, Michiaki Unno. Synthetic analogs of curcumin as modulators of multidrug resistance-linked ABC transporters [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 3242. doi:10.1158/1538-7445.AM2017-3242
Abstract 3248: Identification and optimization of a highly active, cross reactive Complex-1 inhibitor
Authors: Mowat Jeffrey , Christian Sven , Sperl Carolyn , Ehrmann Alexander , Menz Stephan , Guenther Judith , Hillig Roman , Bauser Marcus , Haegebarth Andrea , Schwede Wolfgang
Published: July 2017

Mitochondria are key regulators of both energy supply and apoptotic cell death. The mitochondrial electron transport chain (ETC) consists of four enzyme complexes that transfer electrons from NADH to oxygen. During electron transfer, the ETC pumps protons into the inter-membrane space, generating a gradient across the inner mitochondrial membrane that is used by Complex V to drive ATP synthesis. Recent publications have shown that tumor cells harboring specific mutations (LKB1, mIDH and others) are more sensitive to Complex I inhibition, potentially providing an opportunity for selectively targeting tumor cells.

Based on a high throughput screen (HTS), we identified new, albeit moderately active, lead structures with cross reactivity between mouse and human Complex 1. SAR elaboration of the lead structure allowed for optimization of the potency, although compounds still suffered from low metabolic stability. Further improvement of the in vitro and in vivo PK properties finally permitted in vivo animal studies. Herein, we report for the first time the preclinical profile and structure of a highly active, optimized, human/mouse cross-reactive Complex I inhibitor that allowed for the further investigation into the therapeutic potential of Complex I inhibition in cancer.

Citation Format: Jeffrey Mowat, Sven Christian, Carolyn Sperl, Alexander Ehrmann, Stephan Menz, Judith Guenther, Roman Hillig, Marcus Bauser, Andrea Haegebarth, Wolfgang Schwede. Identification and optimization of a highly active, cross reactive Complex-1 inhibitor [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 3248. doi:10.1158/1538-7445.AM2017-3248
Abstract 3252: Synthesis of N-substituted [Benzoylamino]-3-Ethyl-1,2,3,6-tetrahydropyridines as potential anti-cancer agents
Authors: Henderson Elizabeth , Gangapuram Madhavi , Eyunni Suresh , Redda Kinfe , Ardley Tiffany
Published: July 2017

Chronic inflammation is believed to promote cancer through cellular and genomic damage. Inflammation creates a microenvironment within the tissue that enhances cell proliferation. In 2016, American Cancer Society estimates that 1,685,210 new cancer cases are expected to be diagnosed in the United States. Cyclooxygenase (COX) is an enzyme found to play an essential role in inflammation and converts arachidonic acid to prostaglandin-like molecules. The three isomers of COX are COX-1, COX-2, and COX-3. COX-2 has been found to be up-regulated in inflammation and some cancers, such as breast cancer and prostate cancer. Tetrahydropyridines (THPs) developed by our research group were effective in inhibiting inflammation, COX, and the growth of some breast cancer cells. Previous research has shown that pharmacological activities of the THP derivatives depend greatly on the nature and position of the substituents on the THP ring structure. Here, we present the synthesis of a series of novel THP derivatives. 3-Ethylpyridine is reacted with O-mesitylenesulfonylhydroxylamine (O-MSH) to furnish N-amino-3-ethylpyridinium mesitylenesulfonate. The reaction of N-amino-3-ethylpyridinium mesitylenesulfonate with substituted acid chlorides gives the stable crystalline pyridinium ylides. A sodium borohydride reduction of ylides furnishes the target compounds, N-substituted [benzoylamino]-3-ethyl-1,2,3,6-tetrahydropyridines. Five novel N-substituted [benzoylamino]-3-ethyl-1,2,3,6-tetrahydropyridines were synthesized, purified, and characterized. The evaluation of these compounds cytotoxicity studies on MCF-7 estrogen receptor positive breast cancer cells, MDA-MB-231 estrogen receptor negative breast cancer cell lines, and Ishikawa cells, using the CellTiter-Glo (CTG) luminescent cell viability assay is underway.

This research was supported by the National Center for Research Resources and the National Institute of Minority Health and Health Disparities of the National Institutes of Health through Grant Number 8 G12MD007582-28.

Citation Format: Elizabeth Henderson, Madhavi Gangapuram, Suresh Eyunni, Kinfe Redda, Tiffany Ardley. Synthesis of N-substituted [Benzoylamino]-3-Ethyl-1,2,3,6-tetrahydropyridines as potential anti-cancer agents [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 3252. doi:10.1158/1538-7445.AM2017-3252
Abstract 3254: Identification of potent anti-tumor agents from the LOPAC library using a unified 2D/3D cell culture screening approach
Authors: Das Viswanath , Fürst Tomáš , Gurská Soňa , Džubák Petr , Hajdúch Marián
Published: July 2017

Two-dimensional (2D) cultures of immortalized cancer cells have played a significant role cancer drug discovery and development process for decades. However, the limitations imposed by the long-term cultures of cancer cell lines are becoming increasingly apparent only recently. Therefore, there is a general shift towards three-dimensional (3D) cell cultures, which effectively mimic tumor complexities, for lead optimization and to accelerate translation research. 3D cell cultures not only model the in vivo architecture of tumors, but 3D-derived cells also retain numerous signatures of cancer stem cells compared to parental cells in 2D.

In this study, using a unified 2D and 3D cell culture screening approach, we screened the LOPAC library from Sigma-Aldrich as a proof-of-concept study. The drug screening was performed using parental colorectal cancer HCT116 cells as a model cell line. 3D-derived cultures were generated from multicellular spheroids of HCT116 cells. Additionally, utilizing lightsheet fluorescence microscopy (LSFM), we studied the tissue penetration of drugs in spheroids of HCT116 and cells expressing hypoxia-inducible factor-1α (HIF-1α).

We identified cc. 200 compounds from the LOPAC library that showed increased activity in 3D-derived cultures. A dose–response relationship study of top 20% compounds further confirmed the preferential activity of these drugs in 3D than 2D cultures. Next, studies in spheroid cultures resulted in the identification of five lead compounds with potent spheroid-size reducing effects. Three of these compounds were kinase inhibitors, one HIF-1α inhibitor, and one interestingly, a monoamine oxidase inhibitor. LSFM studies in HCT116-HIF-1α spheroids showed that two kinase inhibitors and the HIF-1α inhibitors significantly altered spheroid hypoxia, and presumably spheroid growth. We believe that this proof-of-concept study will further highlight the advantages of a combined 2D/3D screening approach for drug discovery and development, and consequently enable downstream testing at reduced cost.

Citation Format: Viswanath Das, Tomáš Fürst, Soňa Gurská, Petr Džubák, Marián Hajdúch. Identification of potent anti-tumor agents from the LOPAC library using a unified 2D/3D cell culture screening approach [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 3254. doi:10.1158/1538-7445.AM2017-3254
Abstract 3257: Molecular characterization of the human stomach microbiota in gastric cancer patients
Authors: Yu Guoqin , Torres Javier , Hu Nan , Medrano-Guzman Rafael , Herrera-Goepfert Roberto , Humphrys Michael S. , Wang Lemin , Wang Chaoyu , Ding Ti , Ravel Jacques , Taylor Philip R. , Abnet Christian , Goldstein Alisa
Published: July 2017

Background Helicobacter pylori (Hp) is the primary cause of gastric cancer but we know little of its relative abundance and other microbes in the stomach, especially at the time of gastric cancer diagnosis. Here we characterized the taxonomic and derived functional profiles of gastric microbiota in 157 non-malignant gastric tissue samples from two different sets of gastric cancer patients, and compared them with microbial profiles of oral, stool, nasal, vagina and skin samples from Human Microbiome Project.

Results We show that Hp is the most abundant member of gastric microbiota in both Chinese and Mexican samples (51% and 24% respectively), followed by the genera commonly seen in the oral microbiota. Taxonomic (phylum) profiles of stomach microbiota largely resembled oral microbiota when the Helicobacter reads were removed. The functional profiles of stomach microbiota, however, were distinct from those found in other body sites and had higher inter-subject dissimilarity. Gastric microbiota composition did not differ by Hp colonization status or stomach anatomic site, but did differ between paired non-malignant and tumor tissues in either Chinese or Mexican samples.

Conclusions Our study is the first to show that Hp is the dominant member of the gastric microbiota in many gastric cancer patients rather than diminished or depleted as traditionally believed. Our results provide insights on the gastric microbiota composition and function in gastric cancer patients, which may have important clinical implications.

Citation Format: Guoqin Yu, Javier Torres, Nan Hu, Rafael Medrano-Guzman, Roberto Herrera-Goepfert, Michael S. Humphrys, Lemin Wang, Chaoyu Wang, Ti Ding, Jacques Ravel, Philip R. Taylor, Christian Abnet, Alisa Goldstein. Molecular characterization of the human stomach microbiota in gastric cancer patients [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 3257. doi:10.1158/1538-7445.AM2017-3257
Abstract 3263: Is Latin America ready for the use of genomics in cancer care and control
Authors: Perdomo Sandra , Torres Angela , Olivier Javier , Frecha Cecilia , Quezada-Urban Rosalía , Díaz-Velasquez Clara Estela , Vaca Felipe
Published: July 2017

In Latin American (LA) countries cancer is the second most frequent cause of death after cardiovascular disease. Disease patterns have changed from infectious to chronic, the population is increasing and becoming elderly, and countries lack planning to respond adequately to this epidemiological and socio-demographic transition. By 2025 and increment of nearly 30% of new cases and 35% of deaths from cancer are predicted. Genomic studies have profoundly changed cancer management from improved cancer diagnosis to reformulating cancer prognosis and treatment. However, all these key advances have been mainly concentrated in highly developed nations and little is known about the capacities and needs of cancer genomics in the LA context. In order to evaluate the capacity and development of cancer genomics in LA, we collected available information for all countries in Central, South America and Cuba. Data reviewed included: number of NGS platforms, number of cancer research institutions, research groups working in cancer genetics, publications on cancer genetics and genomics in the last 10 years, educational programs on genomics and related national cancer control policies. Currently, there are a total of 212 NGS platforms in LA. Mexico and Brazil are the countries with more users, and Peru and Ecuador have the fewest. 118 research groups in South America have been working in cancer genetics and started developing cancer genomics related projects. No data on research groups was available for countries in Central America. In the last 10 years, 231 articles in cancer genetic/genomic related topics were published by authors affiliated to LA institutions. Educational programs in genomics are scarce, almost exclusive of graduate programs and few applied to cancer. Twelve countries in LA have national cancer control plans (NCCP). All NCCPs reviewed consider secondary prevention strategies for early diagnosis, opportune treatment and decrease of mortality, areas where genomic analysis could be implemented. Only 5 NCCPs include cancer research as an action plan to increase cancer prevention strategies and reduce both incidence and mortality. Despite the recent advances in introducing cancer genomics knowledge and application in LA, the region lacks development of integrated genomic research projects, improved use of platforms, associated educational programs and health policies that might focus on the most frequent cancers and could impact cancer care.

Citation Format: Sandra Perdomo, Angela Torres, Javier Olivier, Cecilia Frecha, Rosalía Quezada-Urban, Clara Estela Díaz-Velasquez, Felipe Vaca. Is Latin America ready for the use of genomics in cancer care and control [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 3263. doi:10.1158/1538-7445.AM2017-3263
Abstract 3279: Circulating inflammatory biomarker C-reactive protein and radiotherapy-related pain in breast cancer patients
Authors: Lee Eunkyung , Nelson Omar L. , Puyana Carolina , Takita Cristiane , Wright Jean L. , Zhao Wei , Reis Isildinha M. , Lin Rick , Hu Jennifer J.
Published: July 2017

Background: Breast cancer is the most frequently diagnosed cancer and the second leading cause of cancer death in American women. Post-surgery adjuvant radiotherapy (RT) significantly improves clinical outcomes. However, many patients develop treatment-related pain that negatively impacts quality of life.

Methods: We evaluated an inflammatory biomarker, C-reactive protein (CRP) in RT-associated pain in a prospective study of 366 breast cancer patients (64% Hispanic whites, 20% African Americans, 16% non-Hispanic whites) undergoing RT. In each patient, we measured pre- and post-RT plasma CRP levels using a highly-sensitive ELISA kit. Pain score was assessed at pre- and post-RT as the mean of four pain severity items (i.e., pain at its worst, least, average, and now) from the Brief Pain Inventory. Pain scores of 4-10 were considered clinically-relevant pain. Association between pain and CRP levels was evaluated using logistic regression models after adjusting for potential confounders.

Results: Overall, 16% patients at pre-RT and 31% patients at post-RT had pain. In multivariable analyses, RT-related pain score change >4 was significantly associated with CRP change >1 mg/L (OR=3.24, 95%CI=1.33, 7.88), age <50 (OR=3.27, 95%CI=1.20, 8.92), and 3+ comorbidity conditions (OR=5.91, 95%CI=1.33, 26.82).

Conclusion: This is the first study to suggest that increased inflammatory biomarker, CRP level was associated with RT-related pain. Impact: Future larger studies are warranted to validate our findings and facilitate the discovery and development of anti-inflammatory agents to protect patients from RT-related pain and improve quality of life in breast cancer patients undergoing RT.

Citation Format: Eunkyung Lee, Omar L. Nelson, Carolina Puyana, Cristiane Takita, Jean L. Wright, Wei Zhao, Isildinha M. Reis, Rick Lin, Jennifer J. Hu. Circulating inflammatory biomarker C-reactive protein and radiotherapy-related pain in breast cancer patients [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 3279. doi:10.1158/1538-7445.AM2017-3279
Abstract 3289: Cutaneous melanocytic nevi and risk of melanoma deaths in women and men: a prospective study
Authors: Li Wen-Qing , Geng Hao , Cho Eunyoung , Qureshi Abrar
Published: July 2017

Background: Increased number of common acquired melanocytic nevi (moles) has been associated with an increased risk of melanoma. It is unclear whether melanocytic nevi may predict melanoma deaths. We prospectively examined the association between number of melanocytic nevi and risk of melanoma deaths based on 77316 women from the Nurses’ Health Study (NHS) and 32454 men from the Health Professionals Follow-up Study (HPFS).

Methods: In both cohorts, diagnosis of melanoma was reported biennially and pathologically confirmed. Deaths were confirmed by next of kin or the National Death Index. Information on the number of moles with ≥3 mm diameter on the upper extremity was collected in 1986. We used Cox regression models to evaluate the associations between number of melanocytic nevi and risk of melanoma deaths in the overall cohorts as well as only among melanoma cases.

Results: A total of 2450 cases of melanoma were documented (1545 in NHS and 905 in HPFS), out of which we identified 192 incident deaths due to melanoma (87 in NHS and 105 in HPFS) during the follow-up (1986-2012). Increased number of melanocytic nevi was associated with melanoma deaths; the multivariate-adjusted hazard ratio (HR) for 3 or more melanocytic nevi compared with no nevi on the upper extremity was 2.55 (95% confidence interval (CI): 1.52-4.28) for women and 3.97 (95% CI: 2.54-6.22) for men. A secondary analysis further found that increased number of melanocytic nevi was associated with both lethal melanoma (melanoma cases that died of melanoma) and non-lethal melanoma. Among melanoma cases, increased number of melanocytic nevi was independently associated with risk of melanoma deaths in men, with a HR of 1.89 (95% CI: 1.17-3.05) for 3 or more melanocytic nevi. The association persisted even after adjusting for Breslow thickness of melanoma and appeared particularly stronger among those with lower Breslow thickness (P for interaction=0.03). However, number of melanocytic nevi was not significantly associated with risk of melanoma deaths among melanoma cases in women (HR=1.03, 95% CI: 0.61-1.76 for 3 or more nevi).

Conclusion: Increased number of melanocytic nevi was significantly associated with risk of melanoma deaths in our cohorts of women and men. A high number of melanocytic nevi may independently predict the risk of melanoma deaths among men with melanoma.

Citation Format: Wen-Qing Li, Hao Geng, Eunyoung Cho, Abrar Qureshi. Cutaneous melanocytic nevi and risk of melanoma deaths in women and men: a prospective study [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 3289. doi:10.1158/1538-7445.AM2017-3289
Abstract 3294: Breast cancer extent and survival in diabetic women in a Finnish population based cohort
Authors: Murto Mika , Artama Miia , Visvanathan Kala , Murtola Teemu
Published: July 2017

Introduction: Breast cancer and diabetes are two major health problems for women. Around 1.7 million new breast cancer cases are diagnosed each year, making breast cancer the most common cancer type in women. Number of people with diabetes is estimated to be 415 million worldwide, thus one in 11 adults have diabetes. However, evidence on the association between diabetes and breast cancer prognosis is controversial. We estimated breast cancer extent at diagnosis and survival in a Finnish population-based cohort of female breast cancer patients.

Materials and methods: All newly diagnosed breast cancer cases among women in Finland between 1995 and 2013 were identified from comprehensive national Finnish Cancer Registry. To minimize possible bias due to differing participation in cancer screening the study population was limited to women with at least one mammography screening before the diagnosis. In total 45,786 cases were included in our study cohort. Information on recorded diagnoses of diabetes, hypertension, hypercholesterolemia and obesity from in- and outpatient hospital visits during 1995-2013 were obtained from national Care Register for Health Care maintained by National Institute for Health and Welfare. Logistic regression was used to evaluate the risk of having cancer extended to axillary lymph nodes or beyond at diagnosis. Cox regression was used to evaluate risk of breast cancer death and overall mortality after the diagnosis. Analyses were adjusted for age, comorbidities and number of mammography screens before the diagnosis. Survival analyses were further adjusted for tumor extent and primary treatment.

Results: In total 1,419 women had diabetes. Compared to non-diabetic women, breast cancer was more often advanced to axillary lymph-nodes (OR 1.19; 95% CI 1.05-1.34) or metastatic at diagnosis (OR 1.58; 95% CI 1.26-1.97) in diabetic women. Nevertheless, during the median follow-up of 6.9 year after the diagnosis, risk of breast cancer death did not differ between diabetic and non-diabetic women (0.99; 95% CI 0.81-1.21). Overall risk of death was elevated among diabetic women (HR 1.34; 95% CI 1.19-1.51).

Conclusion: Diabetic women have more often advanced tumor extent at diagnosis compared to non-diabetic women. However, diabetes did not affect disease-specific survival within 6.9 years after the diagnosis.

Citation Format: Mika Murto, Miia Artama, Kala Visvanathan, Teemu Murtola. Breast cancer extent and survival in diabetic women in a Finnish population based cohort [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 3294. doi:10.1158/1538-7445.AM2017-3294
Abstract 3298: Diindolylmethane and its halogenated analogues induce autophagy in human prostate cancer cells via induction of the astrocyte-elevated gene-1 (AEG-1)
Authors: Draz Hossam , Goldberg Alexander , Sanderson Thomas , Safe Stephen
Published: July 2017

3,3’-diindolylmethane (DIM) and its halogenated derivatives (ring-DIMs) are recently shown to induce protective autophagy in human prostate cancer cells. The mechanism of induction of autophagy by DIM has not been elucidated. As DIM is a mitochondrial ATP synthase inhibitor, we hypothesized that DIM and ring-DIMs induce autophagy via alteration of AMP/ATP ratio and activation of AMPK signaling in prostate cancer cells. Autophagic activity was monitored by LC3B-I to LC3B-II conversion in LNCaP and C42B prostate cancer cells. Autophagic vacuoles were examined using Cyto-ID autophagy detection kit and transmission electron microscope (TEM). Protein levels for AMPK, pAMPK, acetyl-CoA carboxylase (ACC), pACC, AEG-1, pULK-1 and β-actin were measured by western blot. AMPK and AEG-1 gene expression was downregulated using siRNA. DIM and ring-DIMs induced autophagy by increasing autophagic vacuoles and LC3B-I to LC3B-II conversion in LNCaP and C42B cells. These compounds also induced AMPK, ULK-1 and ACC phosphorylation in a time dependent manner. Interestingly, DIM, 4,4’ dibromoDIM and 7,7’ dichloroDIM induced the oncogenic protein AEG-1 time dependently in LNCaP and C42B cells. Downregulation of AEG-1 or AMPK inhibited DIM- and ring-DIM-induced autophagy. Pretreatment with ULK1 inhibitor MRT 67307 or siRNAs targeting AEG-1 or AMPK potentiated the cytotoxicity of DIM and ring-DIMs. Interestingly, downregulation of AEG-1 induced senescence in cells treated with toxic concentrations of DIM or ring-DIMs, and inhibited the onset of apoptosis in response to DIM or ring-DIMs. In summary, we identified a novel mechanism for DIM- and ring-DIM-induced protective autophagy, via induction of AEG-1 and activation of AMPK. Our findings could help towards the development of novel drug therapies for prostate cancer that include selective autophagy inhibitors as adjuvants.

Citation Format: Hossam Draz, Alexander Goldberg, Thomas Sanderson, Stephen Safe. Diindolylmethane and its halogenated analogues induce autophagy in human prostate cancer cells via induction of the astrocyte-elevated gene-1 (AEG-1) [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 3298. doi:10.1158/1538-7445.AM2017-3298
Abstract 3303: Survivin negatively-regulates autophagy through interference with the formation of Atg5-Atg12-Atg16L complex in breast cancer cells
Authors: Chan Hsiu-Han , Coumar Mohane Selvaraj , Cheng Siao-Muk , Tsai Shing-Ling , Lin Chun-Hui , Chen Shang-Hung , Leung Euphemia , Cheung Chun Hei Antonio
Published: July 2017

Survivin, a member of the inhibitors-of-apoptosis proteins family, is highly expressed in different cancers and its expression is correlated with tumorigenesis and tumor metastasis. At the cellular and molecular levels, Survivin is a dual functions protein that promotes mitosis and also inhibits apoptosis. In this study, we found that Survivin is a novel negative-regulator of autophagy. Molecular analysis and computational modeling revealed that Survivin negatively regulates the formation of Atg5-Atg12 conjugates, which plays important roles in the process of autophagosome elongation, in breast cancer cells. It also negatively regulates the expression and activity of cathepsin L in cells. Interestingly, we found that Survivin binds to p62/SQSTM1 and LC3B and is also an autophagic substrate protein, in which its expression is in part directly regulated by autophagy at the protein level. Finally, mechanistic study revealed YM155, a Survivin inhibitor that was originally developed to inhibit Survivin gene transcription, downregulates Survivin expression in part through autophagic protein degradation. Taken together, findings of this study provide new mechanistic insights into both molecular functions and regulations of Survivin and the molecular mechanism of actions of YM155, a drug currently undergoing clinical trials for cancer treatment.

Citation Format: Hsiu-Han Chan, Mohane Selvaraj Coumar, Siao-Muk Cheng, Shing-Ling Tsai, Chun-Hui Lin, Shang-Hung Chen, Euphemia Leung, Chun Hei Antonio Cheung. Survivin negatively-regulates autophagy through interference with the formation of Atg5-Atg12-Atg16L complex in breast cancer cells [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 3303. doi:10.1158/1538-7445.AM2017-3303
Abstract 3310: Atg7 overexpression promotes bladder cancer invasion via autophagic removal of AUF1 protein and subsequently increased RhoGDI2 mRNA stability in vitro and in vivo
Authors: Zhu Junlan , Li Yang , Huang Chuanshu , Huang Haishan
Published: July 2017

Autophagy is the basic catabolic mechanism regulating degradation of unnecessary or dysfunctional cellular components and is regulated by the autophagy-related gene 7 (Atg7). Since invasive bladder cancer (BC) can progress to life threatening metastases, understanding the molecular mechanisms underlying BC invasion is of tremendous importance for potentially reducing the mortality of this disease. In the present study, we for the first time found that the Atg7 was remarkably upregulated in human BC cell lines and the BBN-induced mouse invasive BCs, which is consistent with our most recent finding in human BCs. The knockdown of Atg7 in human BC cells dramatically inhibited cancer cell invasion, suggesting that Atg7 is a key player in regulation of BC invasion. Mechanistic studies revealed that Atg7 overexpression was mediated by miR-190, which was highly upregulated at transcriptional level in BC tissues and cell lines, and was able to bind to 3’-UTR of atg7 mRNA for its stabilization. Moreover, Atg7-mediated autophagic mechanism could remove AUF1 protein and in turn reduced AUF1 interaction with rhogdi2 mRNA, resulting in elevation of rhogdi2 mRNA stability, and subsequently leading to BC cell invasion. Remarkably, inhibition of Atg7-mediated autophagy led to AUF1 protein accumulation, RhoGDI2 downregulation and BC cell invasion attenuation. Collectively, our results demonstrate that overexpressed Atg7 mediates BC cell autophagy, which removes AUF1 protein, thereby reducing its binding with rhogdi2 mRNA and subsequently leading to elevation of rhogdi2 mRNA stability and protein expression, further promoting BC invasion. The identification of miR-190/Atg7 autophagic mechanism regulating AUF1/RhoGDI2 expression provides a significant insight into understanding the nature of BC invasion, and is also highly potential for developing autophagy-based-specific therapeutic strategy for treatment of human BC patients.

Citation Format: Junlan Zhu, Yang Li, Chuanshu Huang, Haishan Huang. Atg7 overexpression promotes bladder cancer invasion via autophagic removal of AUF1 protein and subsequently increased RhoGDI2 mRNA stability in vitro and in vivo [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 3310. doi:10.1158/1538-7445.AM2017-3310