bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 3503: Gilenya and Alimta interact to kill breast cancer cells
Authors: Roberts Jane L. , Tavallai Seyedmehrad , Poklepovic Andrew , Booth Laurence , Dent Paul 
Published: August 2015

Abstract
The present studies sought to determine whether the anti-folate pemetrexed (Alimta) and the sphingosine-1-phosphate receptor modulator FTY720 (Fingolimod, Gilenya) interacted to kill tumor cells. FTY720 and pemetrexed interacted in a greater than additive fashion to kill breast, brain and colorectal cancer cells. Loss of p53 function weakly enhanced the toxicity of FTY720 whereas deletion of activated RAS strongly or expression of catalytically inactive AKT facilitated killing. In contrast, expression of activated forms of AKT, p70 S6K and mTOR or inhibition of JNK and p38 MAPK suppressed the toxic interaction between FTY720 and pemetrexed. Indeed, combined drug exposure reduced the activity of AKT, p70 S6K and mTOR and activated JNK and p38 MAPK. Expression of activated forms of AKT, p70 S6K and mTOR or inhibition of JNK and p38 MAPK suppressed the toxic interaction between FTY720 and pemetrexed. Treatment of cells with FTY720 and pemetrexed increased the numbers of autophagosomes in cells that correlated with increased LC3 processing and increased p62 levels. Knock down of ATG5 or Beclin1 suppressed autophagosome formation and cell killing by the drug combination. Sorafenib was previously shown to potently interact with pemetrexed to kill tumor cells. Sorafenib significantly enhanced the lethality of [FTY720 + pemetrexed] treatment in vitro and in vivo. Collectively our findings argue that pemetrexed, sorafenib and FTY720 could be a novel adjunct modality for breast cancer treatment.
Note: This abstract was not presented at the meeting.
Citation Format: Jane L. Roberts, Seyedmehrad Tavallai, Andrew Poklepovic, Laurence Booth, Paul Dent. Gilenya and Alimta interact to kill breast cancer cells. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 3503. doi:10.1158/1538-7445.AM2015-3503
Abstract 3506: Targeting breast cancer stem cells and non-stem breast cancer cells through combination therapies
Authors: Hii Ling-Wei , Chung Felicia Fei-Lei , Tan Boon-Shing , Lim Yang Mooi , Cheong Soon-Keng , Leong Chee-Onn 
Published: August 2015

Abstract
Cancer stem cells (CSCs), as a subset of tumor cells with enhanced capacity to generate tumors, have recently been attributed to driving cancer recurrence and metastasis. Although the current CSC model highlights the importance of developing strategies to target CSCs, it is conceivable that the depletion of CSCs within a tumor would not lead to complete regression since non-CSCs might still be capable of sustaining tumor growth or regaining CSC potential. As either of these possibilities would confound the effectiveness of therapeutic agents that exclusively target CSCs, we aimed to rapidly identify combination therapies that could synergistically target both breast cancer cells and breast CSCs. Using a comprehensive small chemical library screen consisting of more than 1600 compounds, we identified a total of 193 small molecules, including 45 FDA approved drugs, which could target both breast CSCs and non-CSCs. When combined with conventional chemotherapeutic agents (e.g. cisplatin, doxorubicin or paclitaxel), histone deacetylase (HDAC) inhibitors exhibited significant synergistic effects in targeting both breast CSCs and non-CSCs. In summary, our data suggests that HDAC inhibitors represent a class of agents that could synergize with chemotherapeutic agents in refractory breast cancer cells and warrant further investigations.
Citation Format: Ling-Wei Hii, Felicia Fei-Lei Chung, Boon-Shing Tan, Yang Mooi Lim, Soon-Keng Cheong, Chee-Onn Leong. Targeting breast cancer stem cells and non-stem breast cancer cells through combination therapies. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 3506. doi:10.1158/1538-7445.AM2015-3506
Abstract 3520: Small molecule inhibitors of ring1B-Bmi1 E3 ligase target polycomb repressive complex 1 activity and regulate cell proliferation
Authors: Shukla Shirish , Zhao Qingjie , Ying Weijang , Gray Felicia , Vandenberg Kelly , Lund George , Boytsov Bohdan , He Shihan , Grembecka Jolanta , Cierpicki Tomasz 
Published: August 2015

Abstract
Emerging evidence implicates the role of Ring1B and Bmi1 in the maintenance of embryonic stem cells and regulating adult stem cells self-renewal. Both Ring1B and Bmi1 are part of Poly-comb Repressive Complex 1(PRC1) and execute gene silencing through histone H2A lysine119 ubiquitination (UbH2A K119). In addition, Bmi1 is also required for the self-renewal capacity of leukemic stem cells, suggesting that Poly-comb Group proteins may contribute to oncogenic transformation by regulating stem cell self-renewal. Targeting cancer stem cell self-renewal has been proposed as a therapeutic goal and could be an effective approach to control tumor growth. In this study, we report the development and characterization of small molecule inhibitors against Ring1B-Bmi1 complex which interfere with its E3 ligase function. We developed ligands binding to Ring1B-Bmi1 employing NMR fragment-based screening. We further performed extensive medicinal chemistry optimization and synthesized over 80 analogs of the initial fragment hit and improved its binding affinity to Ring1B-Bmi1 complex by more than 1000-fold. The activity of developed small molecule inhibitors was analyzed by cellular and biochemical studies including in vitro ubiquitination assay and quantitative analysis of p16 expression. Mechanistically, we found that our most potent compounds inhibit E3 ligase activity of Ring1B-Bmi1 at low micromolar concentrations. As expected, treatment of HeLa and leukemic cell lines with these compounds demonstrated reduced UbH2A K119 levels and increased expression of p16. In addition, presence of the lead compounds also reduces leukemic cell proliferation as determined by MTT assays. Furthermore, the comparison between knockdown effects of Ring1B/Bmi1 with small molecule inhibitors revealed on target effect of the lead compounds. To our knowledge, these compounds represent the first small molecule inhibitors that directly bind to Ring1B-Bmi1 and inhibit its E3 ubiquitin ligase activity and have a strong potential for further development into potent anticancer agents.
Citation Format: Shirish Shukla, Qingjie Zhao, Weijang Ying, Felicia Gray, Kelly Vandenberg, George Lund, Bohdan Boytsov, Shihan He, Jolanta Grembecka, Tomasz Cierpicki. Small molecule inhibitors of ring1B-Bmi1 E3 ligase target polycomb repressive complex 1 activity and regulate cell proliferation. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 3520. doi:10.1158/1538-7445.AM2015-3520
Abstract 3531: Companion diagnostics-based telomerase-specific oncolytic virotherapy: preclinical evaluation in human colorectal cancer cell lines differentially affected in the RAS/RAF/MEK signaling pathway
Authors: Tamura Shuta , Tazawa Hiroshi , Hori Naoto , Koujima Takeshi , Kikuchi Satoru , Kuroda Shinji , Kishimoto Hiroyuki , Nagasaka Takeshi , Nishizaki Masahiko , Urata Yasuo , Kagawa Shunsuke , Fujiwara Toshiyoshi 
Published: August 2015

Abstract
Colorectal cancers harboring KRAS or BRAF mutations often show resistance to anti-cancer drugs, and are poor prognostic disease that causes metastasis and recurrence compared to those with wild type KRAS and BRAF. KRAS/BRAF-wild type colorectal cancers are sensitive to both cetuximab and panitumumab that are epidermal growth factor receptor (EGFR)-targeting agents. However, KRAS/BRAF-mutant colorectal cancers are resistant to EGFR-targeting agents because of constitutive activation of the EGFR-downstream RAS/RAF/MEK signaling pathway. Therefore, the development of novel therapeutic strategy is required to improve the clinical outcome in patients with KRAS/BRAF-mutant colorectal cancers. We developed two types of telomerase-specific replication-competent oncolytic adenoviruses, OBP-301 and OBP-702 armed with the wild-type p53 tumor suppressor gene. In this study, we established the companion diagnostics-based selection algorithm for our oncolytic viruses. We compared the antitumor effects of OBP-301 and OBP-702 in human colorectal cancer cells with wild type KRAS/BRAF (SW48, Colo320DM), mutated KRAS (DLD-1, SW620) and mutated BRAF (RKO, HT29). We evaluated the antitumor effect of OBP-301 and OBP-702 in human colorectal cancer cells using XTT assay. Oncolytic adenovirus-mediated induction of apoptosis- and autophagy-related cell death was analyzed by Western blot analysis. KRAS-mutant colorectal cancer cells were sensitive to both OBP-301 and OBP-702 as well as KRAS/BRAF-wild type cells. In contrast, BRAF-mutant colorectal cancer cells were sensitive to OBP-702 rather than OBP-301. Western blot analysis showed that OBP-301 induced autophagy, whereas OBP-702 induced both autophagy and apoptosis. Taken together, our data suggest that oncolytic viruses should be used according to the genetic background of the RAS/RAF/MEK signaling pathway, especially in patients with colorectal cancer.
Citation Format: Shuta Tamura, Hiroshi Tazawa, Naoto Hori, Takeshi Koujima, Satoru Kikuchi, Shinji Kuroda, Hiroyuki Kishimoto, Takeshi Nagasaka, Masahiko Nishizaki, Yasuo Urata, Shunsuke Kagawa, Toshiyoshi Fujiwara. Companion diagnostics-based telomerase-specific oncolytic virotherapy: preclinical evaluation in human colorectal cancer cell lines differentially affected in the RAS/RAF/MEK signaling pathway. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 3531. doi:10.1158/1538-7445.AM2015-3531
Abstract 3565: Gli2 induces melanoma tumor growth and progression: A critical role of c-Myc
Authors: Fofaria Neel Manoj , Srivastava Sanjay K. 
Published: August 2015

Abstract
Gli2 is one of the key transcription factors in sonic hedgehog (Shh) pathway. Aberrant activation of Gli2 has been reported in several malignancies. However, the role of Gli2 in melanoma progression is unclear. Our results showed that knock down of Gli2 in melanoma cells inhibited the proliferation as well as induced apoptosis in melanoma cells in vitro, which was associated with down-regulation of c-Myc. Melanoma cells with stable Gli2 knockdown demonstrated diminished tumor growth when injected subcutaneously in athymic nude mice. In addition, Gli2 inhibitors GANT58 and GANT61 significantly inhibited the growth of melanoma cell lines. Furthermore, oral administration of 5mg/kg piplartine (PL), an alkaloid inhibited the growth of melanoma tumor xenograft by 84% as compared to control. The tumor suppression by PL was associated with inhibition of Gli2 and c-Myc as observed by western blot and immunohistochemistry analysis. The concentration of PL achieved in plasma was 8.5μM whereas in tumor was 6μmol/gm as analyzed by LC-MS/MS. Interestingly, the IC50 of PL at 48 hours was around 3-4μM in a panel of 15 melanoma cells lines, correlating well with the concentrations achieved in vivo. Melanoma cells treated with 2.5, 5 and 7.5μM PL for 48 hours induced significant apoptosis, with concomitant inhibition of Gli2 as well as c-Myc. Gli2 overexpression and treatment with Shh ligand significantly blocked PL mediated inhibition of cell proliferation and induction of apoptosis, establishing the role of Gli2 in PL-mediated growth suppression of melanoma cells. PL inhibited nuclear translocation as well as DNA binding of Gli2 as observed by analysis of Gli2 in nuclear fraction and Chromatin Immunoprecipitation (ChIP) assay, indicating the importance of Gli2 transcriptional activity in melanoma cell proliferation. In conclusion, our results provide convincing evidence that Gli2 mediated induction of c-Myc plays an important in melanoma tumor growth and subsequently establishes that PL mediated inhibition of melanoma cells in vitro and in vivo is associated with inhibition of Gli2. [Supported in part by R01 grant CA129038 (to S.K.S) awarded by the National Cancer Institute].
Citation Format: Neel Manoj Fofaria, Sanjay K. Srivastava. Gli2 induces melanoma tumor growth and progression: A critical role of c-Myc. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 3565. doi:10.1158/1538-7445.AM2015-3565
Abstract 3577: Targeting localization and function of the RNA helicase DDX5/p68 with 1-(3,5-dimethoxyphenyl)-4-[(6-fluoro-2-methoxyquinoxalin-3-yl) aminocarbonyl] piperazine (RX-5902)
Authors: Remenyi Judit , Yang Mi Young , Lee Young Bok , Kim Deog Joong , Fuller-Pace Frances V. 
Published: August 2015

Abstract
The DEAD box RNA helicase DDX5/p68 is aberrantly expressed and post-translationally modified in several cancers. Several studies have indicated that p68 plays important roles in cell proliferation and tumor progression; in particular, p68 that is phosphorylated on Tyr593 has been shown to be associated with cell transformation, epithelial mesenchymal transition and cell migration. Therefore, p68 may be a promising target for novel anti-cancer therapeutics.
We previously reported that 1-(3,5-dimethoxyphenyl)-4-[(6-fluoro-2-methoxyquinoxalin-3-yl) aminocarbonyl] piperazine (RX-5902) inhibits the growth cancer cell lines by interacting and interfering with the function of phosphorylated p68 at low nanomolar concentrations, and inhibit tumor growth in several human xenograft models in nude mice.
Although p68 is largely a nuclear protein, it has been found to shuttle between the nucleus and cytoplasm in cells, a function that appears to be critical for its role in epithelial-mesenchymal transition. Furthermore, our previous work demonstrated that the nuclear localization of p68 alters during the cell cycle suggesting that alterations in localization of p68 may also be important for cell cycle control and proliferation.
We therefore investigated the effect of RX-5902 on the cellular localization of phosphorylated p68 in cancer cell lines. Our results suggest that treatment with RX5902 results in a significant alteration in the localization of phosphorylated p68, providing a possible mechanism(s) by which RX-5902 may affect phosphorylated p68 function. Further ongoing studies are aimed at examining the effect of RX-5902 on cellular motility in wound healing assays to determine whether RX-5902 could additionally affect the potential function of phosphorylated p68 in cell migration.
Citation Format: Judit Remenyi, Mi Young Yang, Young Bok Lee, Deog Joong Kim, Frances V. Fuller-Pace. Targeting localization and function of the RNA helicase DDX5/p68 with 1-(3,5-dimethoxyphenyl)-4-[(6-fluoro-2-methoxyquinoxalin-3-yl) aminocarbonyl] piperazine (RX-5902). [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 3577. doi:10.1158/1538-7445.AM2015-3577
Abstract 3585: HER3 and IGF1R are major mediators of both acquired and intrinsic cetuximab resistance in head and neck squamous cell carcinomas
Authors: Kjaer Ida , Lindsted Trine , Fröhlich Camilla , Horak Ivan D. , Kragh Michael , Olsen Jesper V. , Pedersen Mikkel W. 
Published: August 2015

Abstract
Head and neck squamous cell carcinoma (HNSCC) is among the leading causes of death worldwide. HNSCC originates from the squamous epithelium of the upper aerodigestive tract, including the lip, oral cavity, pharynx, larynx and paranasal sinuses. The epidermal growth factor receptor (EGFR) has been found to play an essential role in driving the malignancy of HNSCC. The monoclonal antibody targeting EGFR, cetuximab, has been approved for clinical use in HNSCC patients, in combination with either radiation or chemotherapy. However, intrinsic and acquired cetuximab resistance is a major problem for effective therapy. Thus, a better understanding of the mechanisms responsible for cetuximab resistance is valuable for development of the next generation of antibody therapeutics.
In order to investigate the molecular mechanisms behind cetuximab resistance in HNSCC, we screened a panel of cell lines for sensitivity to cetuximab. As expected, the cell lines exhibited a varied response to cetuximab. The most sensitive cell line, HN5, was used to establish a number of cetuximab-resistant clones. These resistant clones had lower EGFR levels but remained partially dependent on EGFR, as demonstrated by EGFR gene knockdown and treatment with a mixture of two anti-EGFR antibodies.
HER3 and IGF1R are known to be major drivers of resistance to EGFR targeting therapies, and therefore we investigated the role of the two receptors in resistant clones with a mixture of antibodies against EGFR, HER3 and IGF1R. The antibody mixture, which simultaneously blocked EGFR, HER3 and IGF1R signaling, resulted in near total growth inhibition of cetuximab resistant clones. These results were extended to HNSCC cell lines with intrinsic resistance to cetuximab and also in these cell lines the three target mAb mixture led to effective growth inhibition.
In conclusion, our results demonstrate that HNSCC cell lines have a heterogeneous response to cetuximab and that HER3 and IGF1R effectively compensate for EGFR inhibition in both the acquired and intrinsic cetuximab resistant setting. Our results thus provide a rationale for simultaneous targeting of EGFR, HER3, and IGF1R in HNSCC.
Citation Format: Ida Kjaer, Trine Lindsted, Camilla Fröhlich, Ivan D. Horak, Michael Kragh, Jesper V. Olsen, Mikkel W. Pedersen. HER3 and IGF1R are major mediators of both acquired and intrinsic cetuximab resistance in head and neck squamous cell carcinomas. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 3585. doi:10.1158/1538-7445.AM2015-3585
Abstract 3597: EZH2 D1 domain mutants confer acquired resistance to EZH2-targeted inhibitors and reprogram B-cell transcription
Authors: Gonzalvez Francois , Baker Theresa , Pritchard Justin , Rivera Victor M. , Garner Andrew 
Published: August 2015

Abstract
Aberrant epigenetic changes play an important role in the onset and progression of numerous tumor types, and targeting enzymes that regulate these processes holds significant promise for cancer treatment. The identification of Y641 and A677 oncogenic mutations in the histone methyl-transferase EZH2 in hematological cancers and melanoma, has led to a surge of interest in exploring the therapeutic potential of targeting EZH2. Several potent and selective small-molecule inhibitors targeting EZH2 (EZH2i) have recently been generated. The most advanced compounds, EPZ-6438 (E7438) and GSK126 (GSK2816126), are currently tested in lymphoma and advanced solid tumors, with EPZ-6438 exhibiting preliminary evidence of efficacy (ENA, 2014). As observed with other targeted cancer therapies, acquired resistance may pose a major clinical challenge to EZH2i. However, at this early stage in clinical development, mechanisms of acquired resistance to EZH2i remain unidentified. Nonetheless, it is critical to anticipate future clinical resistance mechanisms in order to develop effective patient treatment strategies.
To explore EZH2i resistance, we used an innovative forward genetic approach that combined a mutagenesis screen with next-generation sequencing technologies. Using this strategy, we identified a hotspot of EZH2 missense mutations (Y111 and I109) that conferred cross-resistance to both EPZ-6438 and GSK126. Surprisingly, the mutation hotspot lies outside the EZH2 catalytic region in its D1 domain, signifying a unique allosteric mechanism of drug resistance. Importantly, to drive resistance, the EZH2 mutants still required an active histone methyl-transferase catalytic domain and the main components of the polycomb repressive complex 2. Furthermore, we also uncovered an unexpected neomorphic role for these mutations in controlling the expression of genes typically involved in B-cell differentiation. This work describes the first evidence of acquired resistance to EZH2i, and identifies potential clinically relevant resistance mutations. Moreover, our findings provide new mechanistic insights into the function of EZH2, and importantly, suggest that acquired-resistance to EZH2i may arise in the clinic in a manner that remains targetable by inhibitors, thus, providing a foundation for the discovery of second-generation EZH2i to treat relapsed patients.
Citation Format: Francois Gonzalvez, Theresa Baker, Justin Pritchard, Victor M. Rivera, Andrew Garner. EZH2 D1 domain mutants confer acquired resistance to EZH2-targeted inhibitors and reprogram B-cell transcription. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 3597. doi:10.1158/1538-7445.AM2015-3597