bluuebunny/crossref_metadata_2025 huggingface dataset:
Abstract 4718: ABBV-075, a novel BET family bromodomain inhibitor, represents a promising therapeutic agent for a broad spectrum of cancer indications
Authors: Sarthy Aparna , Li Leiming , Albert Daniel H. , Lin Xiaoyu , Scott Warder , Faivre Emily , Bui Mai H. , Huang Xiaoli , Wilcox Denise M. , Magoc Terry , Buchanan Fritz G. , Tapang Paul , Sheppard George S. , Wang Le , Fidanze Steve D. , Pratt John , Liu Dachun , Hasvold Lisa , Hessler Paul , Uziel Tamar , Lam Lloyd , Rajaraman Ganesh , Fang Guowei , Elmore Steven W. , Rosenberg Saul H. , McDaniel Keith , Kati Warren , Shen Yu
Published: July 2016

Small molecule inhibitors of the bromodomain and extraterminal domain (BET) proteins have emerged as a promising option for cancer therapy. ABBV-075 is a potent and selective BET family bromodomain inhibitor that recently entered Phase 1 clinical trials. It binds bromodomains of BRD2/4/T with similar affinities (Ki of 1-2.2 nM), but exhibits roughly 10-fold weaker potency towards BRD3 (Ki of 12.2 nM). ABBV-075 is highly selective for 18 bromodomain proteins tested (Kd > 1 μM; more than 600-fold selectivity vs. BRD4) and has moderate activity towards CREBBP (Kd = 87 μM; 54-fold selectivity vs. BRD4). ABBV-075 exhibited robust single agent activity in cell viability assays across cancer cell lines derived from solid tumors, leukemia and lymphomas. Further characterization of cancer cell responses to ABBV-075 indicated that ABBV-075 manifested diverse mechanisms of action in different cancer settings. These include 1): disruption of cell cycle control leading to G1 arrest followed by senescence, 2) inhibition of oncogenesis drivers leading to apoptosis and 3) potentially targeting tumor microenvironment to provide additional therapeutic benefit. Consistent with its broad spectrum of activities in vitro, ABBV-075 has comparable or superior efficacies to standard of care agents in flank xenograft mouse models of non-small-cell and small cell lung cancers, pancreatic, breast, prostate, head & neck cancers, multiple myeloma, diffuse large B cell lymphoma and leukemia. These results support the development of ABBV-075 in diverse hematological malignancies and solid tumor indications.

Citation Format: Aparna Sarthy, Leiming Li, Daniel H. Albert, Xiaoyu Lin, Warder Scott, Emily Faivre, Mai H. Bui, Xiaoli Huang, Denise M. Wilcox, Terry Magoc, Fritz G. Buchanan, Paul Tapang, George S. Sheppard, Le Wang, Steve D. Fidanze, John Pratt, Dachun Liu, Lisa Hasvold, Paul Hessler, Tamar Uziel, Lloyd Lam, Ganesh Rajaraman, Guowei Fang, Steven W. Elmore, Saul H. Rosenberg, Keith McDaniel, Warren Kati, Yu Shen. ABBV-075, a novel BET family bromodomain inhibitor, represents a promising therapeutic agent for a broad spectrum of cancer indications. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 4718.
Abstract 4719: Varlitinib demonstrates potent antitumor efficacy in patient-derived gastric cancer xenograft models
Authors: Ooi A. G. Lisa , Lindmark Bertil E. , McHale Mark , Hung Huynh T. , Ong Richard
Published: July 2016

Varlitinib is a potent, reversible pan-HER inhibitor of the ATP-binding site of EGFR (IC50 = 7 nM), HER2 (IC50 = 2 nM) and HER4 (IC50 = 4 nM). Gastric Cancer is the fifth most common cancer worldwide, with 952,000 cases diagnosed in 2012, constituting 6.8% of total cancer diagnosis. Prognosis for gastric cancer is poor, with the overall 5-year survival rate for gastric cancer in the US at ∼29%. Current clinical guidelines recommend use of trastuzumab combined with chemotherapy for HER2+ (amplified) patients with advanced gastric cancer. However the majority of patients (∼80%) do not have HER2 amplification. Studies have implicated dysregulation of HER signaling in gastric cancer and there is strong scientific rationale for testing of pan-HER therapies in Gastric Cancer. We tested the anti-tumour activity of Varlitinib as a single agent in patient-derived gastric cancer xenograft in SCID mice (GC22-0808 & GC11-0414) with over-expression of HER proteins. Varlitinib is very active in tumour growth inhibition studies, causing dose-dependent inhibition with tumour stasis observed at dosing of 50 mg/kg BID and tumour regression observed at dosing of 100 mg/kg BID. Tumour protein lysates after two-day treatment with Varlitinib and vehicle were also analysed to elucidate the mechanism of action. Multiple proliferation and anti-apoptosis pathways were inhibited by Varlitinib, including AKT, PI3K and Survivin pathways. In view of the robust anti-tumour activity inhibiting multiple survival and proliferation pathways, as well as the safe tolerabilty profile of Varlitinib, ASLAN has initiated Phase 2 clinical trials of Varlitinib in gastric cancer.

Citation Format: A. G. Lisa Ooi, Bertil E. Lindmark, Mark McHale, Huynh T. Hung, Richard Ong. Varlitinib demonstrates potent antitumor efficacy in patient-derived gastric cancer xenograft models. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 4719.
Abstract 4723: Innovative cancer treatment of human lung cancer cells PC-9 with a synthetic retinoid Am80 and EGCG via inhibition of HDAC4 and HDAC5
Authors: Suganuma Masami , Oya Yukiko , Umsumarng Sonthaya , Iida Keisuke , Rawangkhan Anchalee , Sakai Ryo , Kagechika Hiroyuki , Shudo Koichi , Fujiki Hirota
Published: July 2016

A synthetic new retinoid Am80 (tamibarotene) is used for treatment of acute promyelocytic leukemia (APL) patients with resistance of all-trans-retinoic acid (ATRA). To potentiate efficacy of Am80, we challenged combination treatment of Am80 and EGCG on human lung cancer cell line PC-9. It is now well accepted that EGCG acts as synergist with numerous anticancer compounds, and that the average reduction of tumor volume for in vivo genograft mouse models implanted using various human cancer cell lines was 70.3% with combinations of 13 anticancer compounds and EGCG. We previously reported that combinations of NSAIDs (sulindac and celecoxib) or other retinoids (ATRA, 13-cis-RA and 9-cis-RA) and EGCG synergistically induced apoptosis of the cells along with strong expression of growth arrest and DNA-damage inducible gene 153 (GADD153) and death receptor (DR5) gene. Our objective was to investigate the mechanism of the synergistic induction for GADD153-DR5 apoptosis pathway. The proteomic analysis of lysine-acetylated proteins was conducted with a shotgun analysis using nanoLC-ESI-MS/MS in PC-9 cells. We found that the numbers of acetylated proteins were different: 551 acetylated proteins were found in non-treated cells, 331 proteins in cells treated with combination, and 59 proteins were common in both cases. Acetylation was mainly found in non-histone proteins, chaperons, transcription factors, and enzymes. The combination increased acetylated p53 (Lys382) about 3-fold compared with non-treated cells. In addition, combination significantly decreased the protein amounts of histone deacetylase (HDAC) 4 and HDAC 5 to 50% and 20%, respectively, but not HDAC6 among Class II HDACs. Class I HDACs (HDAC1, 2, and 3) were not decreased. All the results suggest that combination of Am80 and EGCG induces GADD153-DR5 apoptotic pathway, and reduces the amounts of HDAC4 and HDAC5 resulting in changing protein acetylation.

Citation Format: Masami Suganuma, Yukiko Oya, Sonthaya Umsumarng, Keisuke Iida, Anchalee Rawangkhan, Ryo Sakai, Hiroyuki Kagechika, Koichi Shudo, Hirota Fujiki. Innovative cancer treatment of human lung cancer cells PC-9 with a synthetic retinoid Am80 and EGCG via inhibition of HDAC4 and HDAC5. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 4723.
Abstract 4738: The BET family bromodomain inhibitor ABBV-075 is a promising therapeutic agent for acute myeloid leukemia and myelodysplastic syndrome
Authors: Bui Mai H. , Lin Xiaoyu , Huang Xiaoli , Li Leiming , Sarthy Aparna , Albert Daniel , Magoc Terry , Lam Lloyd , Hessler Paul , Uziel Tamar , Elmore Steven , McDaniel Keith , Kati Warren , Shen Yu
Published: July 2016

Small molecule inhibitors of the bromodomain and extraterminal domain (BET) proteins exhibit interesting activities in preclinical models of various cancer indications, and several of these inhibitors are currently under clinical investigation. ABBV-075 is a potent and selective BET family bromodomain inhibitor that recently entered Phase 1 studies. Upon characterizing cellular responses to BET inhibitors across a large panel of cancer cell lines, we identified AML/MDS as one of the few cancer indications where BET inhibitors triggered robust apoptosis in cancer cell lines and in patient-derived cancer cells. The induction of apoptosis by BET inhibitors in AML/MDS cells may be partly attributed to their abilities to down regulate Bcl-XL and Bcl-2, and combining BET inhibitors with the Bcl-2 inhibitor venetoclax (ABT-199) resulted in robust cytotoxicity in AML/MDS cells. ABBV-075 exhibited significant antitumor efficacy as a monotherapy in flank xenograft models of AML and MDS. Furthermore, combining low doses of ABBV-075 with the standard of care agent azacitidine in the SKM1 model led to significant tumor regression, and the combination regimen was better tolerated than BETi monotherapy at doses that produced a similar degree of therapeutic benefit. Expression profiling of SKM1 tumors from mice treated with the ABBV-075/azacitidine combination or each of these agents as monotherapies revealed that ABBV-075 and azacitidine regulated a common set of biologic pathways. The combination of ABBV-075/azacitidine led to a more robust impact on these common pathways, which may partially contribute to the enhanced efficacy of the ABBV-075/azacitidine combination in the SKM-1 model.

Citation Format: Mai H. Bui, Xiaoyu Lin, Xiaoli Huang, Leiming Li, Aparna Sarthy, Daniel Albert, Terry Magoc, Lloyd Lam, Paul Hessler, Tamar Uziel, Steven Elmore, Keith McDaniel, Warren Kati, Yu Shen. The BET family bromodomain inhibitor ABBV-075 is a promising therapeutic agent for acute myeloid leukemia and myelodysplastic syndrome. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 4738.
Abstract 4741: Targeting tumor growth in a medullary thyroid carcinoma mouse model using a combinatorial treatment with a tyrosine kinase inhibitor and histone deacetylase inhibitor
Authors: Pozo Karine , Zahler Stefan , Tan Chunfeng , Ishimatsu Keisuke , Takahashi Masaya , Bibb James
Published: July 2016

Neuroendocrine tumors are rare forms of cancers arising from hormone-producing cells that are scattered throughout the body. Medullary thyroid carcinoma (MTC) originates from the thyroid gland parafollicular cells. Treatment options for progressive, metastatic MTC patients are limited to the recently FDA-approved tyrosine kinase inhibitors (TKIs), Vandetanib and Cabozantinib, which target multiple receptor tyrosine kinases, including VEGFR2. However, the efficacy of TKIs is limited and development of TKI resistance is common.

Here we examined, the effect of a combinatorial drug therapy using the TKI, Nintedanib, and the histone deacetylase (HDAC) inhibitor, Romidepsin, on MTC growth in the NSE/p25-gfp bi-transgenic mouse line, an inducible MTC mouse model (see Pozo et al. 2013). The TKI- and HDAC inhibitors were administered intraperitoneally for 3 weeks and tumor growth progression was monitored using a T2 weighted magnetic resonance imaging on a 7 Tesla system. Tumor tissues were analyzed for oncogenic signaling pathways by immunoblotting and immunohistochemistry.

We find that co-administration of Nintedanib and Romidepsin stops tumor growth and increases the number of necrotic foci within the tumor tissue. Interestingly, Nintedanib treatment alone reduced tumor vascularization as shown by decreased density of the vascular marker, CD31, but did not stop parafollicular cell proliferation. Taken together, these results suggest that a combinatorial drug therapy with a TKI- and an HDAC inhibitor may be a more efficient strategy to target MTC progression and overcome recurrence.

Citation Format: Karine Pozo, Stefan Zahler, Chunfeng Tan, Keisuke Ishimatsu, Masaya Takahashi, James Bibb. Targeting tumor growth in a medullary thyroid carcinoma mouse model using a combinatorial treatment with a tyrosine kinase inhibitor and histone deacetylase inhibitor. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 4741.
Abstract 4844: Thymoquinone induces apoptosis through inhibition of JAK2/STAT3 signaling via production of ROS in human renal cancer Caki cells
Authors: Chae In Gyeong , Chun Kyung-Soo
Published: July 2016

Thymoquinone (TQ), a compound isolated from black seed oil (nigella sativa), has been reported to possess anti-inflammatory and anticancer activities. However, the molecular mechanisms underlying the anticancer effects of TQ in renal cell carcinoma (RCC) remain poorly understood. This study revealed that treatment with TQ significantly reduced the cell viability and induced apoptosis in Caki cells as evidenced by the induction of p53 and Bax, release of cytochrome c, cleavage of caspase-9, and -3 and PARP and the inhibition of Bcl-2 and Bcl-xl expression. TQ inhibited the constitutive phosphorylation of signal transducer and activator of transcription-3 (STAT3) in Caki cells by blocking the phosphorylation of upstream Janus-activated kinase-2 (JAK2) kinases. Moreover, TQ attenuated the expression of STAT3 target gene products, such as survivin, cyclin D1, and D2. Since ROS is a universal entity mediating apoptosis, we examined whether TQ induced apoptosis via ROS formation. Treatment with TQ generated ROS in these renal cancer cells. Pretreatment of cells with ROS scavenger N-acetyl cysteine (NAC) abrogated the inhibitory effect of TQ on the JAK2/STAT3 signaling and rescued cells from TQ-induced apoptosis by blocking the induction of p53, and the cleavage of caspase-3, -9 and PARP in Caki cells. In conclusion, TQ induced apoptosis in Caki cells via generation of ROS, induction of p53, activation of caspases and inhibition of STAT3 signaling pathway.

Citation Format: In Gyeong Chae, Kyung-Soo Chun. Thymoquinone induces apoptosis through inhibition of JAK2/STAT3 signaling via production of ROS in human renal cancer Caki cells. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 4844.
Abstract 4863: PF-06840003: a highly selective IDO-1 inhibitor that shows good in vivo efficacy in combination with immune checkpoint inhibitors
Authors: Tumang Joseph , Gomes Bruno , Wythes Martin , Crosignani Stefano , Bingham Patrick , Bottemanne Pauline , Cannelle Hélène , Cauwenberghs Sandra , Chaplin Jenny , Dalvie Deepak , Denies Sofie , De Maeseneire Coraline , Folger Peter , Frederix Kim , Guo Jie , Hardwick James , Hook Ken , Jessen Katti , Kindt Erick , Letellier Marie-Claire , Liao Kai-Hsin , Li Wenlin , Maegley Karen , Marillier Reece , Miller Nichol , Murray Brion , Pirson Romain , Preillon Julie , Rabolli Virginie , Ray Chad , Scales Stephanie , Srirangam Jay , Solowiej Jim , Streiner Nicole , Torti Vince , Tsaparikos Konstantinos , Vicini Paolo , Driessens Gregory , Kraus Manfred
Published: July 2016

Tumors use tryptophan-catabolizing enzymes such as Indoleamine 2,3-dioxygenase-1 (IDO-1) to induce an immunosuppressive microenvironment. IDO-1 expression is upregulated in many cancers and described to be a resistance mechanism to immune checkpoint therapies. IDO-1 is induced in response to inflammatory stimuli such as IFN-ã and promotes immune tolerance through the catabolism of tryptophan and accumulation of tryptophan catabolites including kynurenine. IDO-1 activity leads to effector T-cell anergy and enhanced Treg function through upregulation of FoxP3. As such, IDO1 is a nexus for the induction of key immunosuppressive mechanisms and represents an important immunotherapeutic target in oncology. We have identified and characterized a new IDO-1 inhibitor. PF-06840003 is a highly selective orally bioavailable IDO-1 inhibitor. PF-06840003 reversed IDO-1-induced T-cell anergy in vitro. In vivo, PF-06840003 reduced intratumoral kynurenine levels in mice by >80% and inhibited tumor growth in multiple preclinical syngeneic models in mice, in combination with immune checkpoint inhibitors. PF-0684003 has favorable predicted human pharmacokinetic properties, including a predicted t1/2 of 16-19 hours. These studies highlight the strong potential of PF-06840003 as a clinical candidate in Immuno-Oncology.

Citation Format: Joseph Tumang, Bruno Gomes, Martin Wythes, Stefano Crosignani, Patrick Bingham, Pauline Bottemanne, Hélène Cannelle, Sandra Cauwenberghs, Jenny Chaplin, Deepak Dalvie, Sofie Denies, Coraline De Maeseneire, Peter Folger, Kim Frederix, Jie Guo, James Hardwick, Ken Hook, Katti Jessen, Erick Kindt, Marie-Claire Letellier, Kai-Hsin Liao, Wenlin Li, Karen Maegley, Reece Marillier, Nichol Miller, Brion Murray, Romain Pirson, Julie Preillon, Virginie Rabolli, Chad Ray, Stephanie Scales, Jay Srirangam, Jim Solowiej, Nicole Streiner, Vince Torti, Konstantinos Tsaparikos, Paolo Vicini, Gregory Driessens, Manfred Kraus. PF-06840003: a highly selective IDO-1 inhibitor that shows good in vivo efficacy in combination with immune checkpoint inhibitors. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 4863.
Abstract 4917: High expression of miR-181c in tumor tissue as a recurrence marker of Dukes B colorectal cancer
Authors: Koga Yoshikatsu , Yamazaki Nobuyoshi , Taniguchi Hirokazu , Kojima Motohiro , Kanemitsu Yukihide , Saito Norio , Matsumura Yasuhiro
Published: July 2016

Background & Aims: A standard treatment for Dukes B colorectal cancer (CRC) which invades deeply through the muscularis propria without lymph node metastasis and distant metastasis is surgical resection without any additional chemotherapy. However, tumor recurrence is occurred in approximately 20% of these patients after curative resection. To date, there were no biomarkers for detecting the high risk group for tumor recurrence of Dukes B CRC. In the present study, miRNAs extracted from both frozen tissues and formalin-fixed paraffin-embedded (FFPE) tissues of CRC were investigated for a candidate for detecting the high risk group in Dukes B CRC.

Methods: Patients with histologically confirmed as Dukes B CRC were enrolled; 10 patients (5 patients with recurrence and 5 patients without recurrence) for preliminary study, 80 patients for training cohort, and 57 patients for validation cohort. First, comprehensive analysis of miRNAs was performed to select candidate miRNAs associated with recurrence using a high-sensitivity miRNA array chip in the preliminary study. Next, the candidate miRNAs were analyzed by real-time RT-PCR using miRNA extracted from frozen tissue and FFPE tissue in the training cohort. Finally, miR-181c was assessed by real-time RT-PCR using miRNA extracted from FFPE tissue in the validation cohort.

Results: In the preliminary study, 15 miRNAs were expressed significantly higher in the cancer tissue with recurrence than that without recurrence (P < 0.05) and selected as candidates for further study. Regarding let-7a, -7d, -7e, miR-23c, -26b, -128a, -151-5p, and -181c, tumor recurrence in the high expression group of these miRNAs was observed significantly higher than that in the low expression group in the training cohort using frozen tissue (P < 0.05). According to multivariate analysis including pathological factors, the high expression of miR-181c was detected as an independent predictive factor for recurrence (P = 0.001, OR: 9.43, 95%CI: 2.57-34.48). The same result was observed in the training cohort using FFPE tissue (P = 0.003, OR: 7.46, 95%CI: 1.97-28.57). In the validation cohort using the FFPE tissue, the recurrence rates of Dukes B CRC patients with high miR-181c expression and low miR-181c expression were 4.5% and 38.5%, respectively (P < 0.001).

Conclusions: miR-181c expression in CRC tissue (both frozen and FFPE) may be a useful predictive biomarker for tumor recurrence of Dukes B CRC.

Citation Format: Yoshikatsu Koga, Nobuyoshi Yamazaki, Hirokazu Taniguchi, Motohiro Kojima, Yukihide Kanemitsu, Norio Saito, Yasuhiro Matsumura. High expression of miR-181c in tumor tissue as a recurrence marker of Dukes B colorectal cancer. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 4917.
Abstract 5004: APX005M, a humanized anti-CD40 antibody with strong immune-modulatory activities capable of tumor eradication in vivo
Authors: Björck Pia , Filbert Erin , Yang Xiaodong , Trifan Ovidiu C.
Published: July 2016

The success of immune checkpoint inhibitors validates the concept that immunotherapy is an effective approach for the treatment of solid tumors. In addition to reversing tumor-induced immune suppression, immune activating antibodies are being explored as the next generation of immuno-oncology therapeutics. CD40, which is expressed on antigen presenting cells such as dendritic and B cells initiates and regulates both innate and adaptive immunity and is essential for the activation of antigen-specific T cells. APX005M is a humanized IgG1 CD40 agonistic antibody developed using Apexigen's APXiMAB™ discovery platform. APX005M binds with high affinity to human (Kd = 0.12nM) and monkey (Kd = 0.37nM) CD40. It recognizes a unique epitope that overlaps with the CD40 ligand binding sites and thus blocks the binding of CD40 to CD40L. APX005M is a potent CD40 agonistic antibody capable of activating antigen presenting B cells (EC50 = 12pM) and dendritic cells (EC50 = 0.49nM). Its CD40 agonistic activity requires crosslinking by Fc-gamma receptors since F(ab)’2 fragment of APX005M loses the agonistic activity. Upon binding to CD40 expressing tumor cells APX005M induces antibody-dependent cellular phagocytosis (ADCP) and apoptosis. In vivo APX005M completely eradicates CD40+ lymphoma tumors and inhibits the growth of rituximab-resistant tumors. The data suggest that a CD40 agonistic mAb such as APX005M, that activates CD40 through binding to the CD40L binding site while being dependent on crosslinking via Fc-gamma receptors, may represent an ideal immune activating antibody drug candidate for stimulating effective immune responses against tumors. APX005M is currently being evaluated in clinical trials for the treatment of patients with solid tumors.

Citation Format: Pia Björck, Erin Filbert, Xiaodong Yang, Ovidiu C. Trifan. APX005M, a humanized anti-CD40 antibody with strong immune-modulatory activities capable of tumor eradication in vivo. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 5004.
Abstract 5112: Galactose probes hit neuroblastoma cells through a specific galactose-galectin association
Authors: Simone Giuseppina , Ponzoni Mirco , Pastorino Fabio
Published: July 2016

Galectins are a family of proteins that decorate the cell membrane and form extracellular molecular associations with β-galactoside sugars.

In order to mimic multivalent molecular recognitions, galactoside moieties have been immobilized on microbeads and used in cytofluorimetric analysis and in microfluidic assay to study the molecular association between carbohydrates and proteins in neuroblastoma (NB) cells. The hypothesis behind this investigation was that the molecular mechanisms by which glycans modulate neural metastatic cells involve protein-carbohydrate association.

To evaluate the binding between microbeads and tumor cells, two human NB cell lines were used in cellular association experiments. GI-LI-N cells, derived from the peripheral blood of a bone marrow-infiltrated, high risk, stage IV NB patient, were chosen for metastatic characteristics; IMR-32 cells were chosen because derived from the primary tumor in the abdominal site of an unknown-stage NB patient.

In vitro experiments have revealed molecular binding preferences of the metastatic NB cells. This result underscores that the efficiency of the cellular association might be related to the differences in the expression of the galectins between the two cell lines (GI-LI-N cells >> IMR-32 cells) and that the formation of the molecular association galectin-galactose could discriminate the tumor stages.

Ex vivo investigations have supported in vitro results; indeed, galactose moieties mostly recognized GI-LI-N cells derived from orthotopic tumor-bearing mice respect to explanted IMR-32 cells. This molecular association was tumor cells specific because it discriminated healthy tissues.

The understanding of this mechanism of recognition, and of possible cellular discrimination, can be relevant for the diagnostic monitoring of metastatic NB cells, and for producing probes tailored to interfere with galectin activities associated with the malignant phenotype.

Citation Format: Giuseppina Simone, Mirco Ponzoni, Fabio Pastorino. Galactose probes hit neuroblastoma cells through a specific galactose-galectin association. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 5112.
Abstract 5249: Crocin prevents early lesions of liver cancer:system biology approach
Authors: Amin Amr , Hamza Alaaeldin A. , Daoud Sayel , Khazanehdari Kamal , Al Hrout Ala’a , Baig Badriya , Chaiboonchoe Amphun , Adrian Thomas E. , Zaki Nazar , Salehi-Ashtiani Kourosh
Published: July 2016

The angiogenesis inhibitor, sorafenib, remains the only available therapy of the poorly diagnosed hepatocellular carcinoma (HCC). Only recently patents of VEGF receptors-3 inhibitors are developed.; hence,Thus, a novel approach against HCC is essential for a better therapeutic outcome. Saffron and its active constituents were reported to have anti-tumor properties. Objective: The aims of this study were to examine the chemopreventive action of saffron's main biomolecule, crocin, against chemically-induced liver cancer in rats, and to explore the mechanisms by which crocin employs its anti-tumor effects. Method: We investigated the anti-cancer effect of crocin on an experimental carcinogenesis model of liver cancer by studying the anti-oxidant, anti-inflammatory, anti-proliferation, pro-apoptotic activities of crocin in vivo. In addition, we provided a network analysis of differentially expressed genes in tissues of animals pre-treated with crocin in comparison to induced-HCC animals’ tissues. To further support our results, in vitro analysis was carried out. We assessed the effects of crocin on HepG2 cells viability by treating them with various concentrations of crocin; in addition, effects of crocin on cell cycle distribution of HepG2 cells were investigated. Results: Findings reported herein demonstrated the anti-proliferative and pro-apoptotic properties of crocin when administrated in induced-HCC model. Crocin exhibited anti-inflammatory properties where NF-kB, among other inflammatory markers, was inhibited. In vitro analysis confirmed crocin's effect in HepG2 by arresting the cell cycle at G2/M phase, inducing apoptosis and down regulating inflammation. Network analysis identified NF-kB as a regulatory hub, and therefore, a candidate therapeutic drug target. Conclusion: Taken together, our findings introduce crocin as a candidate chemopreventive agent against HCC.

Citation Format: Amr Amin, Alaaeldin A. Hamza, Sayel Daoud, Kamal Khazanehdari, Ala’a Al Hrout, Badriya Baig, Amphun Chaiboonchoe, Thomas E. Adrian, Nazar Zaki, Kourosh Salehi-Ashtiani. Crocin prevents early lesions of liver cancer:system biology approach. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 5249.
Abstract 5270: The UCSC Xena system for integrating and visualizing functional genomics
Authors: Goldman Mary , Craft Brian , Zhu Jingchun , Swatloski Teresa , Cline Melissa , Haussler David
Published: July 2016

UCSC Xena (http://xena.ucsc.edu/) is a bioinformatics tool to visualize functional genomics data from multiple sources simultaneously, including both public and private data. The Xena system consists of a set of federated data hubs and the Xena browser, which integrates across hubs, providing one location to analyze and visualize all data. The lightweight Xena data hubs are straightforward to install on Windows, Mac and Linux operating systems and easily allow hub administrators to authenticate users, ensuring that only authorized users have access to secure data. Loading data into a Xena hub is easy using either our application or command line interface. Hosting public data from major projects, such as TCGA, on public Xena hubs gives users access without having to download these large datasets. The Xena system makes it easy to aggregate across many hubs, allowing users to integrate public datasets and private secure data together or view them separately. This system of the browser and hubs helps researchers combine new or preliminary results from their laptops or internal servers, or even data from a new paper, securely with vetted data from the public sphere.

The largest public Xena hub, based at UCSC, currently hosts an expanding set of searchable data, including 806 public datasets from several large consortiums including TCGA (The Cancer Genome Atlas), ICGC (International Cancer Genome Consortium), Treehouse Childhood Cancer Project, CCLE (Cancer Cell Line Encyclopedia), and more. Xena hubs are flexible enough to handle most data types, including gene, exon, miRNA and protein expression, copy number, DNA methylation and somatic mutation data along with phenotypes, subtype classifications and genomic biomarkers. Dynamic Kaplan-Meier survival analysis helps investigators to assess survival stratification by any information while scatter plots and bar graphs offer new insights into the data. Integration with Galaxy gives users access to a myriad of bioinformatics tools for further analysis and hypothesis testing.

Citation Format: Mary Goldman, Brian Craft, Jingchun Zhu, Teresa Swatloski, Melissa Cline, David Haussler. The UCSC Xena system for integrating and visualizing functional genomics. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 5270.
Abstract 5292: An online tool for biomarker analysis in Gene Expression Omnibus (GEO) datasets
Authors: Dumas Jasmine , Gargano Michael , Dancik Garrett M.
Published: July 2016

The Gene Expression Omnibus (GEO) is a public repository of gene expression and sequence-based datasets, that currently includes >42,000 datasets with gene expression profiles obtained by microarray, and >12,000 datasets containing the keyword “cancer”. Although GEO has its own analysis tool (GEO2R) for identifying differentially expressed genes, evaluation of a single gene is not straightforward, and GEO2R was not designed to identify prognostic biomarkers based on survival analyses. In this work, we describe an online, easy-to-use tool for biomarker analysis in GEO datasets.

shinyGEO is a web-based tool that allows a user to download the expression and sample data from a GEO dataset, select a gene of interest, and perform a survival or differential expression analysis in order to evaluate gene expression diagnostic or prognostic biomarkers. For both analyses, shinyGEO produces publication-ready graphics and generates R code ensuring that all analyses are reproducible. The tool is developed using shiny, a web application framework for R, a language for statistical computing and graphics.

The web application and source code is available at the following link: http://bioinformatics.easternct.edu/shinyGEO/

Citation Format: Jasmine Dumas, Michael Gargano, Garrett M. Dancik. An online tool for biomarker analysis in Gene Expression Omnibus (GEO) datasets. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 5292.
Abstract 58: Metformin impacts IGF-1R/ Akt signaling and energy metabolism in lung adenocarcinoma
Authors: Lobato Gabriela C. , Li Steve , Tarhoni Imad , Lie Wen-Rong , Borgia Jeffrey A.
Published: July 2016

Introduction: Clinical outcomes for type II diabetes patients diagnosed with NSCLC are superior for those receiving metformin relative to other diabetic medications, though the mechanism for this effect remains incompletely elucidated. We hypothesized that metformin induces changes in Akt-based signaling via AMPK that increases glycolytic flux, and adversely affects survival in cell-line models of lung adenocarcinoma. The objective for these studies is to investigate therapeutic strategies involving metformin that have the potential to synergize with strategies targeting IGF-1R/Akt signaling.

Methods: The lung adenocarcinoma cell lines, A549 and H358, were treated with 0, 1, 5, 10 mM metformin for 24, 48, and 72 hours and evaluated for changes in expression and activity of IGF-1R/Akt signaling, as well as the expression of 17 enzymes involved in glycolytic and oxidative energy metabolism, all using Luminex® immunobead assays. In parallel, MTT assays were performed for up to 5 days to document changes in cellular proliferation/ death rates. Extracellular acidification was also monitored as a measure of glycolytic flux. All findings were collated and statistically evaluated using SPSS v19 (Chicago, IL) using independent t-tests or one-way ANOVA.

Results: We observed that metformin decreased IGF-1R/Akt signaling while increasing the expression of the protein levels of the signaling intermediates. Treatment with metformin increased the expression of Akt, IRS-1, PTEN, GSK3alpha and TSC2 (p<0.05 for all). Further, metformin treatment decreased the mean ratio of phospho-/total pyruvate dehydrogenase and increased the expression of ATP Synthase (both p<0.05), and were associated (p<0.05) with a dose-dependent increase in extracellular acidification. Lower doses (0.1 mM) of metformin did not have a significant impact on cell proliferation at 5 days, but a dose-dependent decrease in cell numbers was observed, with 37% and 29% reduction in cell numbers documented (p<0.05) at 5 mM for the H358 and A549 cells, respectively.

Conclusion: This study links changes with Akt signaling with changes in glycolytic flux and oxidative metabolism. This study suggests metformin may make an attractive adjunct for advanced NSCLC patients receiving therapy that mechanistically involves targeting Akt signaling and metabolic control, such as IGF1R inhibition.

Citation Format: Gabriela C. Lobato, Steve Li, Imad Tarhoni, Wen-Rong Lie, Jeffrey A. Borgia. Metformin impacts IGF-1R/ Akt signaling and energy metabolism in lung adenocarcinoma. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 58.
Abstract 608: Comprehensive drug testing of patient-derived conditionally reprogrammed cells from castration-resistant prostate cancer
Authors: Saeed Khalid , Rahkama Vesa , Eldfors Samuli , Bychkov Dmitrii , Mpindi John Patrick , Yadav Bhagwan , Aittokallio Tero , Horvath Peter , Peehl Donna , Paavolainen Lassi , Heckman Caroline , Wennerberg Krister , Mirtti Tuomas , Rannikko Antti , Kallioniemia Olli , Östling Päivi , af Hällström Taija
Published: July 2016

Culture of human prostate cancer (PCa) progenitor cells would facilitate the discovery and testing of new, potentially curative therapies for PCa. Here, we established and characterized patient-derived conditionally reprogrammed cells (CRCs) from seven patients to determine their biological properties (genomic, transcriptomic, protein expression) and to apply these cells to test efficacies of 306 emerging and clinically approved drugs. The patient samples came from both primary prostate cancer as well as from advanced Castration-Resistant Prostate Cancer (CRPC).

Patients with primary prostate cancer generated six benign CRC cultures which all had an androgen receptor (AR)-negative, basal/transit-amplifying phenotype with few CNAs. In 3D cell culture, these cells could re-express AR. The CRCs from a CRPC patient (HUB.5) displayed multiple CNAs, many of which were shared with the parental tumor. We carried out high-throughput drug-response studies with 306 emerging and clinical cancer drugs. Bcl-2 family inhibitor navitoclax emerged as the most potent cancer-specific drug for the CRCs from CRPC patient. Other drug efficacies observed included taxanes, mepacrine and retinoids, thus covering both existing (and clinically validated) as well as new drug efficacies.

In conclusion, comprehensive cancer-pharmacopeia-wide drug testing of CRCs from a CRPC patient highlighted both known and novel drug sensitivities in PCa, including navitoclax, which is currently tested in clinical trials of CRPC.

Citation Format: Khalid Saeed, Vesa Rahkama, Samuli Eldfors, Dmitrii Bychkov, John Patrick Mpindi, Bhagwan Yadav, Tero Aittokallio, Peter Horvath, Donna Peehl, Lassi Paavolainen, Caroline Heckman, Krister Wennerberg, Tuomas Mirtti, Antti Rannikko, Olli Kallioniemia, Päivi Östling, Taija af Hällström. Comprehensive drug testing of patient-derived conditionally reprogrammed cells from castration-resistant prostate cancer. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 608.
Abstract 823: Prevention of pancreatic cancer by cAMP control
Authors: Banerjee Jheelam , Papu John Arokya M. , Al-Wadei Mohammed H. , Schuller Hildegard M.
Published: July 2016

Smoking and alcoholism are risk factors for the development of pancreatitis-associated pancreatic ductal adenocarcinoma (PDAC). Using a hamster model of pancreatitis-associated PDAC induced by treatment with ethanol in the drinking water and the nicotine-derived nitrosamine 4-methylnitrosamino-(3-pyridyl)-1-butanone (NNK) by subcutaneous injection as well as immunohistochemistry of human PDAC tissue microarrays, we have previously shown that these cancers overexpressed stress neurotransmitters and cAMP while the inhibitory neurotransmitter ã-aminobutyric acid (GABA) was suppressed. Using our hamster model, the current study has tested the hypothesis that cAMP control by GABA supplementation in the drinking water prevents the development of pancreatitis-associated PDAC. Our data reveal strong preventive effects of GABA supplementation on the development of PDAC and pancreatic intraductal neoplasia (PanIN). ELISA assays and immunohistochemistry revealed significant decreases in the levels of cyclic adenosine monophosphate (cAMP) and interleukin 6 accompanied by reductions in the expression of several cancer stem cell markers, phosphorylated signaling proteins associated with cell proliferation and migration in pancreatic exocrine cells of GABA treated animals. We conclude that cAMP control by GABA supplementation inhibits multiple cancer supporting pathways at the level of cancer stem cells, differentiated cancer cells and the immune system, identifying this approach as promising novel tool for the prevention of PDAC in individuals with a history of smoking and alcoholism.

Citation Format: Jheelam Banerjee, Arokya M. Papu John, Mohammed H. Al-Wadei, Hildegard M. Schuller. Prevention of pancreatic cancer by cAMP control. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 823.
Abstract 838: Natural plant extracts induced DNA damage and apoptosis through oxidative stress in transgenic mouse model
Authors: Yedjou Clement G. , Tchounwou Paul B. , Miele Lucio , Payton Marinelle
Published: July 2016

One of the most frightening events that women will ever face is being diagnosed with breast cancer. One in eight women in the United States will be diagnosed with this life-threatening disease during her lifetime. Even with all the advances in pharmaceutical technology, mortality rates for breast cancer have remained stagnant for the past few decades. The development of new drugs from natural products is considered important. The specific aim of the present study was to use transgenic mouse mammary tumors as a test model to explore the therapeutic mechanisms of a novel natural product as anti-cancer agent in the treatment of breast cancer. To achieve our specific aim, we performed both in vitro and in vivo studies. Acridine orange and propidium iodide (AO/PI) staining were used to visualize live and dead cells with the means of Cellometer Vision. Tumor volume and weight were measured. Tumor histology was assessed by immunohistochemistry, and enzymatic activities were determined by spectrophotometry. The extent of DNA damage was evaluated by the Comet assay. Cell/tissue apoptosis was measured by the flow cytometry. Data obtained from the AO/PI dye assessment indicated that the tested natural product significantly reduced the number of live cells in a dose-dependent manner, showing a gradual increase in the loss of viability in treated cells. We observed tumor growth inhibition after 4 weeks of daily intraperitoneal administration of plant extracts to trangenic mice. There was a significant increase in DNA damage in treated mice compared to the control mice. Flow cytometry data showed a strong dose-response relationship between plant extracts treatment and annexin V/PI positive cells. Similarly, a statistically significant and dose-dependent increase (p< 0.05) was recorded with regard to caspase 3 activity. Data from enzyme analysis (alaninine transaminase, aspartate transaminase, and creatinine) revealed that plant extract administration is not toxic to treated mice. These results suggest that induction of cell death, DNA damage, and cell/tissue apoptosis may be involved in the therapeutic mechanisms of plant extracts in breast cancer. Collectively, the findings from this study provide convincing evidence that the tested plant extracts may represent a potential anticancer candidate against breast cancer. Research supported by NIH Grant No. NIMHD-G12MD007581) and Grant No. P20GM103476.

Citation Format: Clement G. Yedjou, Paul B. Tchounwou, Lucio Miele, Marinelle Payton. Natural plant extracts induced DNA damage and apoptosis through oxidative stress in transgenic mouse model. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 838.
Abstract 925: IL-4 / IL-13 mediated cell-to-cell fusion in prostate cancer progress
Authors: Uygur Berna , Leikina Evgenia , Chernomordik Leonid
Published: July 2016

Poorly understood interactions between prostate cancer (PCa) cells and their microenvironment direct the epithelial to mesenchymal transition (EMT) during disease progression. Cell-to-cell fusion, such as cell fusion in muscles and placenta, is one of the ways in which cells can drastically change their properties. Cell fusion has been proposed to promote tumor cell diversity and the ability to metastasize. Metastatic disease has been also suggested to depend on the interleukin 4 (IL-4) signaling. Patients with hormone-refractory PCa have elevated levels of IL-4 and it has been proposed that targeting IL4 -receptor interactions limits metastatic disease. Here, to mimic conditions at the interphase between rhabdosphincter myofibers and apical anterior regions of prostatic gland we explored interactions of PC3 cells (human PCa cell line) with skeletal muscle cells. Co-culturing of these cells resulted in an elevated concentration of related cytokines IL-4 and/or IL-13 in the tissue culture medium from the co-cultured cells but not from muscle cells cultured on their own. The co-culturing (i); the application of the conditioned medium from the co-cultured cells (ii); and treating PC3 cells with recombinant IL-4 (iii) resulted in a robust fusion between PC3 cells, in a significant increase in the percentage of PC3 cells expressing stem cell marker CD133, in the drug resistance, in an increase of the expression of mesenchymal-characteristic markers pAKT, MMP9, desmin, and in the loss of E-cadherin that is another marker for EMT. The described effects required co-culturing of the PC3 cells and muscle cells. Moreover, the co-culturing and recombinant IL-4 application also upregulated the expression of the two proteins - annexin A5 and syncytin that play important role in several cell-cell fusion processes. Significantly, application of either (i) IL-4-neutralizing antibodies or (ii) peptide inhibitors of syncytin; and (iii) lowering annexin A5 expression suppressed cell proliferation and fusion. Our findings substantiate a hypothesis that IL-4 and IL-13 in the microenvironment of PCa cells promote the EMT and raise metastatic potential of PCa cells by their fusion mediated by upregulated syncytin- and annexin A5.

Citation Format: Berna Uygur, Evgenia Leikina, Leonid Chernomordik. IL-4 / IL-13 mediated cell-to-cell fusion in prostate cancer progress. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 925.