bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 4698: BET protein inhibitors prevent TKI-induced drug resistance in solid tumors
Authors: Zhao Yuan , Wu Yiyuan , Wang Hexiang , Ren Bo , Liu Ye , Wei Min , Zhou Changyou , Luo Lusong 
Published: July 2016

Abstract
Acquired drug resistance is one of the major challenges for clinical application of tyrosine kinase inhibitor (TKI) in cancer treatment. TKI-induced drug resistance could develop as a result of adaptive cell reprogramming that leads to pathway feedback activation in the same signaling pathway or parallel pathways or gatekeeper mutations abolishing drug binding. The findings of reversible drug response and lack of genetic mutations in TKI-resistant tumor cells suggest epigenetic basis during resistance development process. Targeting epigenetic modifiers and readers, in particular, the bromodomain and extra-terminal (BET) protein family, has shown promising efficacies against both primary and drug-resistant hematological malignancies via modulating transcription profile and suppressing the MYC oncogene. BGB-3619 is a novel, potent inhibitor of BET family proteins (BRD2, BRD3, BRD4 and BRDT) with IC50 ranging from 20 to 49 nM. It demonstrates superior anti-proliferation activity than iBET762 in multiple leukemia and lymphoma cell lines. In this study, we investigated the effect of BGB-3619 and iBET762 on solid tumor cells during and after TKI-resistance development. From cell killing assays, BET inhibitors were found to be much more potent to TKI-resistant cells (vemurafenib-resistant A375, HT29, SK-MEL-5, cells and erlotinib-resistant HCC827 cells) than their parental cells. Notably, long-term colony formation assays showed that combination of low dose BET inhibitors and TKI effectively suppressed the expansion of TKI-tolerated cell populations. The enhanced sensitivity of TKI-resistant cells to BET inhibitor was due to strong G1 phase arrest rather than induction of apoptosis. Furthermore, BET inhibitors blocked cell proliferation independent of c-Myc inhibition, suggesting they might affect a broad transcription network and provide favorable epigenetic state to induce cell cycle arrest. Taken together, these findings suggested potential therapeutic activity of BET inhibitor in TKI-resistant solid tumors and a strategy of combining BET inhibitors with TKIs to overcome resistance to targeted cancer therapies.
Citation Format: Yuan Zhao, Yiyuan Wu, Hexiang Wang, Bo Ren, Ye Liu, Min Wei, Changyou Zhou, Lusong Luo. BET protein inhibitors prevent TKI-induced drug resistance in solid tumors. [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 4698.
Abstract 4734: Inhibitory effects of metformin on epithelial-mesenchymal transition of CD44+/CD117+ ovarian cancer stem cells
Authors: Xiao Gary G. , Zhang Rongrong , Zhang Ping , Wang Hong , Hou Dongming , Li Wentao , Li Chenwei 
Published: July 2016

Abstract
Background: Although metformin, a first-line drug for treating diabetes, may play an important role in inhibition of epithelial ovarian cancer cell growth and cancer stem cells (CSCs), metformin at low dose showed less effect on proliferation of ovarian cancer cells. In this study, we evaluated the effect of metformin at low dose on ovarian CSCs in order to understand the molecular mechanisms underlying ovarian tumorigenesis.
Methods: The inhibitory effects of metformin at los dose on proliferation and population of ovarian cancer cells including SKOV3 and A2780 were assessed by cell proliferation assay and flow cytometry. Quantitative real-time PCR assays on expression of Bcl-2, Survivin and Bax were performed to determine the effect of the metformin at low dose on epithelial-mesenchymal transition (EMT) of cancer cells and CSCs. Tumor sphere formation assay was also performed to evaluate the effect of metformin on spheres forming ability of CSCs. The therapeutic efficacy and the anti-CSC effects of metformin at low dose were investigated by using both SKOV3 cells and primary tumor xenografts. In addition, the CSC frequency and EMT in tumor xenograft models were also assessed by flow cytometry and quantitative real-time PCR.
Results: Metformin at low dose did not affect proliferation of ovarian cancer cells, however, it inhibited the population of the CD44+/CD117+ selectively, neither CD133+ nor ALDH+ cells. It suppressed expression of snail2, twist and vimentin significantly in cancer cells and CD44+/CD117+ CSCs in vitro. Low dose of metformin reduced survivin expression in CSCs leading to arrest of cell cycle. Metformin at low concentration inhibited the secondary and the tertiary tumor sphere formation, decreased the growth of either SKOV3 or primary ovarian tumor xenograft, enhanced the anticancer effect of the cisplatin, and lowered the proportion of the CD44+/CD117+ CSCs in the xenograft tissue. Metformin was also associated with a reduction of snail2, twist, and vimentin in CD44+/CD117+ ovarian CSCs in vivo.
Conclusions: Our results implicate that metformin at low dose inhibits selectively CD44+/CD117+ ovarian CSCs through inhibition of EMT and potentiates the effect of the cisplatin.
Citation Format: Gary G. Xiao, Rongrong Zhang, Ping Zhang, Hong Wang, Dongming Hou, Wentao Li, Chenwei Li. Inhibitory effects of metformin on epithelial-mesenchymal transition of CD44+/CD117+ ovarian cancer stem 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 4734.
Abstract 4735: Designing novel warheads for targeted therapies: SAR and efficient strategies for the synthesis of analogues of tubulysin
Authors: Vlahov Iontcho , You Fei , Kleindl Paul , Vetzel Marilynn , Reddy Joseph , Leamon Christopher 
Published: July 2016

Abstract
Background: Tubulysins are natural products isolated from myxobacterial species. They are potent mitotic poisons as they inhibit the polymerization of tubulin into microtubules. Structurally, tubulysins are linear tetrapeptides comprised of N-Me pipecolic acid (Mep), isoleucine (Ile), tubuvaline (Tuv) and tubutyrosine (Tut). All natural tubulysins possess an acid-, base-, and enzyme-sensitive N-acyloxymethyl substituent, as well as a labile acetate group. For the natural tubulysins, both of these functional groups are essential for their potent cytotoxicity. The focus of this presentation is on design and synthesis of chemically stable analogs of tubulysin with improved biological activity.
Methods: To explore the influence of tubulysin's functional groups on its cytotoxicity, we designed novel analogs, incorporating ether, thioether, amide and carbamate-based side chains. We also suggested basic SAR-rules for the activity of these synthetic analogs.
Results: Structural features, critical for the tubulysin's cytotoxicity, were investigated. e.g., changing the (R)-OAc group of Tuv to (S)-NHAc completely abolished cytotoxicity, while analogs possessing (R)-NHAc on the Tuv moiety still exhibited activity. On the other hand, exchange of Tuv's (R)-OAc group with (R)-OMe had no influence activity. Replacement of the O-acyl part of N-acyloxymethyl substituent (dotted circle) with an alkyl or alkylthiol group resulted in N,O-acetals or N,S-thioacetals possessing similar or higher activity. Tup and Tut are interchangeable in terms of the activities of their respective tubulysin analogs.
Conclusion: We designed and synthesized tubulysin analogs which are less prone to degradation under acidic and basic conditions, as well as enzymic influences. Structural features, essential for the cytotoxicity of the tubulysin analogs, were established. Some of the new compounds, especially those with N,S-thioacetal side chains, have increased cytotoxicity in comparison to natural tubulysins. These novel tubulysin analogs were used as warheads for folate receptor(FR)-targeted therapy.
Citation Format: Iontcho Vlahov, Fei You, Paul Kleindl, Marilynn Vetzel, Joseph Reddy, Christopher Leamon. Designing novel warheads for targeted therapies: SAR and efficient strategies for the synthesis of analogues of tubulysin. [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 4735.
Abstract 4736: PDE10A overexpression in cancer cells and tumors as compared to normal cells and tissues
Authors: Lindsey Ashley S. , Lee Kevin , Zhu Bing , Arora Ritu , Otali Dennis , Ramirez-Alacantara Veronica , Grizzle William , Piazza Gary 
Published: July 2016

Abstract
Phosphodiesterase 10A (PDE10A) is a cGMP and cAMP degrading PDE isozyme that is expressed in areas of the brain related to motor function and cognition. An elevation in neural PDE10A expression has been strongly linked to many diseases that affect cognition, including schizophrenia and Huntington's disease. Recently, high levels of PDE10A were shown to be expressed in colon tumor cells in vitro and in vivo compared with cells derived from normal colon and normal colonic mucosa (Li et al., Oncogene 2015). PDE10A inhibition by small molecules or genetic silencing, attenuated tumor cell growth by a mechanism involving cGMP/PKG activation, the suppression of β-catenin and a decrease in TCF transcriptional activity (Li et al., Oncogene 2015). These observations suggest that PDE10A may play an important role in tumorigenesis and PDE10A could serve as a novel therapeutic target for colorectal cancer. However, the expression and role of PDE10A in other cancer cell types has yet to be elucidated. Here we report that PDE10A expression is elevated (compared to controls) in tumor cells and solid tumors from xenograft, as well as, genetic models from the colon, breast, and lung using western blot and immunohistochemistry. The human colon adenocarcinoma cell line, HT29, the human breast adenocarcinoma cell line, MDA-MB-231, and the human lung carcinoma cell line, A549, showed elevated expression of PDE10A as compared to the normal colon mucosal epithelial cell line, NCM460, normal human mammary epithelial cells, and normal human airway epithelial cells, respectively. Solid tumors collected from the colons of heterozygous APCmin mice displayed an elevation in PDE10A levels as compared to uninvolved mucosa from the APCmin mice and wild type colon mucosa. Solid tumors collected from the mammary glands of viral transgenic FVB-MMTV-Her2 mice also possessed high levels of PDE10A as compared to FVB wild type mice. These findings suggest that PDE10A could be a novel therapeutic target for not only colorectal cancer, but breast and lung cancers as well.
Citation Format: Ashley S. Lindsey, Kevin Lee, Bing Zhu, Ritu Arora, Dennis Otali, Veronica Ramirez-Alacantara, William Grizzle, Gary Piazza. PDE10A overexpression in cancer cells and tumors as compared to normal cells and tissues. [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 4736.
Abstract 475: NTF2 regulates nuclear size in mammalian cells and may contribute to altered nuclear size in melanoma
Authors: Vukovic Lidija D. , Stohr Bradley A. , Levy Dan L. 
Published: July 2016

Abstract
Nuclear size and morphology are distinct cancer features that pathologists use for diagnostic purposes. Proteins that regulate nuclear size have been identified in Xenopus, where nuclear import rates correlate with nuclear size. The levels of two nuclear import factors, importin α and NTF2, were shown to be particularly important in nuclear size regulation. It has also been shown that importin α2 is a potential biomarker in non-small cell lung cancer, as well as importin α1 in breast cancer. Our data implicate that NTF2 is a possible cancer biomarker.
Our main goal is to analyze how these nuclear scaling factors affect nuclear size during carcinogenesis and to test how nuclear size impacts cancer growth characteristics. We find that manipulating the levels of importin α2 and NTF2 in HeLa and MRC-5 cells leads to altered nuclear size, demonstrating a conserved function for these factors in nuclear size regulation. To place these results in a cancer context, we are focusing on melanoma cell lines, including radial and vertical growth primary melanomas and metastatic melanomas. We find that, compared to normal melanocytes, the nuclear-to-cytoplasmic (N/C) volume ratio is increased in the cancer cell lines. Western blot analysis revealed an inverse correlation between NTF2 protein levels and nuclear size. We confirmed these results using a melanoma tissue microarray, finding similar differences in nuclear size and NTF2 expression levels between benign nevi and melanomas.
We next performed transient transfection experiments with our melanoma cell lines. Importin α2 knock down led to smaller nuclear size, while knocking down the levels of NTF2 increased nuclear size, consistent with our Xenopus results. We also observed reduced nuclear size when NTF2 was ectopically expressed. Currently we are generating stable, inducible melanoma cell lines where we can precisely alter NTF2 and importin α expression levels using doxycycline. We will use these inducible cell lines to examine how altering nuclear size impacts cell proliferation rates, invasiveness, and apoptosis. We will also investigate how nuclear size affects gene positioning using FISH, focusing on genes involved in melanoma formation and metastasis. In the long term, we plan to move these studies into a mouse model where we can test how nuclear size affects in vivo metastatic capacity.
Citation Format: Lidija D. Vukovic, Bradley A. Stohr, Dan L. Levy. NTF2 regulates nuclear size in mammalian cells and may contribute to altered nuclear size in melanoma. [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 475.
Abstract 4750: Characterization of the cytoskeletal protein MACF1 in lung cancer
Authors: Afghani Najlaa , Quick Quincy A. 
Published: July 2016

Abstract
Genetic variation between cancer patients with the same tumor and intratumor genetic heterogeneity have broadened the complexity of factors that contribute to clinical therapeutic resistance and poor response outcomes. This has made it imperative to identity atypical expressed outliers that influence the maintenance and progression of cancers. We have identified and investigated the spectraplakin protein, Microtubule Actin Cross-Linking Factor 1 (MACF1) which functions as an actin-microfilament and microtubule crosslinker for its role in lung cancers. Genomic data generated by the Cancer Genome Atlas (TCGA) and the International Cancer Genome Consortium (ICGC) indicate that the MACF1 gene is mutated and/or amplified in ∼15% of squamous lung cancers and 25% of lung cancers, respectively. Further examination with immunohistochemistry expression analysis revealed that MACF1 is highly expressed in several lung cancer subtypes, particularly adenocarcinomas and squamous cell carcinomas, as compared to normal lung tissue. Additionally, functional studies showed that suppression of MACF1 with RNA interference significantly impaired the reproductive capacity of these solid tumors. Taken together, MACF1 represents a unique target with genetic alterations and diagnostic biomarker potential in lung cancers, the leading cause of cancer deaths in the United States.
Citation Format: Najlaa Afghani, Quincy A. Quick. Characterization of the cytoskeletal protein MACF1 in lung 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 4750.
Abstract 4758: Benzaldehyde suppresses multiple signal pathways in cancer cells by regulating 14-3-3ζ-mediated protein-protein interactions
Authors: Saitoh Jun , Saya Hideyuki 
Published: July 2016

Abstract
Benzaldehyde is the simplest aromatic aldehyde constituent of almonds and many fruits. Anticancer effect of Benzaldehyde was first reported in 1980, and multi-institutional clinical trials were performed in those days in Japan. However trial was over without determination of effectiveness, only its safety was confirmed. The underlying mechanism why Benzaldehyde specifically suppresses growth of some particular cancer cells but not that of normal cells has not been elucidated. Therefore, we attempted to clarify the mechanism of anticancer effect of Benzaldehyde. In pancreatic cancer cell BxPC3 and in non-small cell lung cancer cell A549, we found that Benzaldehyde inhibits PI3K/AKT/mTOR, STAT3, NFκB and ERK pathways, those are major signaling pathways activated in cancer cells. Effects of Benzaldehyde on multiple signaling pathways are found to be derived from regulation of 14-3-3 family proteins which interact with phosphorylation sites of various proteins of multiple signals. In BxPC3 cells, Benzaldehyde treatment reduced the phosphorylation levels of 14-3-3-binding sites. Furthermore, we ectopically expressed seven isoforms of 14-3-3 in HEK293T cells and found that Benzaldehyde treatment significantly suppressed association of 14-3-3ζ with client proteins such as mTOR, Rictor, cRaf, STAT3 and FOXOs. The interaction of other isoforms of 14-3-3 with their client proteins was also partially reduced. But, the expression levels of those seven 14-3-3 isoforms were not significantly changed. Those data indicate that Benzaldehyde suppresses the interaction of 14-3-3ζ with its client proteins. Recent reports have shown that 14-3-3ζ is overexpressed in many cancers and acts as a signaling hub controlling the network of oncogenic pathways, suggesting that 14-3-3ζ associates with carcinogenesis, metastasis and resistance for chemotherapy and radiation. Hence, Benzaldehyde is considered to be a new class of anti-cancer agent inhibiting 14-3-3ζ-mediated tumor promoting and/or maintaining signals.
Citation Format: Jun Saitoh, Hideyuki Saya. Benzaldehyde suppresses multiple signal pathways in cancer cells by regulating 14-3-3ζ-mediated protein-protein interactions. [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 4758.
Abstract 4762: Gremlin 2 is repressed in invasive endometrial cancer and inhibits cell growth in vitro
Authors: Tsubamoto Hiroshi , Inoue Kayo , Sakata Kazuko , Shibahara Hiroaki , Miyoshi Yasuo 
Published: July 2016

Abstract
Background: There are limited therapeutic opportunities for the treatment of advanced or metastatic endometrial cancer (EC), and limited diagnostic tools of myometrial invasion for fertility sparing management of early stage EC. Novel approach based on molecular profiling of EC cells are required. Patients and Methods: We used microarray analysis of EC tumour samples in order to identify tumour-specific changes in gene expression. Identified the most frequently and lowest repressed gene was subjected to immunohistochemistry of tissues of EC. MTT assay and migration assay using EC cells were also conducted to evaluate the antitumor activity of the identified gene. Results: The most significantly suppressed gene in EC compared with the control was Gremlin 2 with an 8.5-fold reduction (p&lt;0.001). Immunohistochemistry revealed that Gremlin 2 was expressed in 4 of 4 tissues of normal endometrium, in 4 of 4 tissues of atypical endometrial hyperplasia and 5 of 5 tissues of low grade EC with FIGO stage IA without myometrial invasion. Among 13 patients with low-grade FIGO stage I with myometrial invasion, Gremlin 2 was partially expressed in the myometrial invasion front in 11 (85%) patients. The MTT assay revealed the proliferation of Ishikawa cells incubated with 1.0 ìg/ml and 5.0 ìg/ml of Gremlin 2 and HEC-1A cells incubated with 5.0 ìg/ml of Gremlin 2 were significantly reduced (P = 0.029, P = 0.025, and P = 0.048, respectively). The proliferation of Ishikawa cells was significantly attenuated after incubation with Gremlin 2 for 72 h (P = 0.024). On the other hand, the migration assay did not show influence of Gremlin 2 on Ishikawa or HEC-1A cells. Conclusion: Gremlin 2, formerly known as protein related to Dan and cerberus (PRDC), has been implicated in development of the embryo and the ovarian follicle in animals, however, there is no report of Gremlin 2 in association with neoplasm or cancer. Gremlin 2 downregulation may lead to carcinogenesis and progression of EC. We suggest that re-activation of Gremlin 2-associated pathways could suppress EC progression, and should thus be explored as a potential novel therapeutic approach as well as diagnostic tool of myometrial invasion.
Citation Format: Hiroshi Tsubamoto, Kayo Inoue, Kazuko Sakata, Hiroaki Shibahara, Yasuo Miyoshi. Gremlin 2 is repressed in invasive endometrial cancer and inhibits cell growth in vitro. [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 4762.
Abstract 4773: Gene-targeted apoptosis as a novel therapeutic strategy for HER2-positive breast cancer
Authors: Rogers Faye A. , Kaushik Meetu 
Published: July 2016

Abstract
The ability to target HER2-driven breast cancers using anticancer agents with mechanisms of actions that are independent of the HER2 cellular growth function, represents a powerful new tool to circumvent drug resistance experienced with traditional HER2-targeted therapies. We have discovered that manipulation of the balance between the DNA repair response and apoptotic pathways provides an alternative strategy to induce targeted apoptosis in HER2-amplified breast cancers. Our recent finding that triplex-induced DNA damage can activate apoptosis in human cells has yielded the opportunity to develop a new class of HER2-targeted therapies. Here, we have uncovered the novel finding that triplex-induced apoptosis only occurs when multiple triplex structures are formed, while NER (nucleotide excision repair)-dependent repair prevails in the presence of one or two structures. With this in mind, we have designed sequence-specific DNA-binding molecules that create chromosomal triplex structures and activate tumor-specific apoptosis through the induction of excessive DNA damage at the HER2 locus. Importantly, this only occurs in malignant cells with multiple copies of the HER2 gene. We have evaluated the efficacy of the HER2-targeted triplex-forming molecules using cell growth and apoptosis assays and demonstrate that these molecules are particularly effective in eliciting tumor specific apoptosis in HER2-amplified breast cancer cell lines. Furthermore, these molecules have the ability to suppress the growth and metastasis of human HER2-positive breast cancers in a xenograft mouse model. Moreover, we demonstrate that the NER protein, XPD mediates the survival-death decision in response to triplex-induced DNA damage via a p53-independent mechanism that involves phosphorylation of the H2AX tyrosine 142 residue, which stimulates the signaling pathway to recruit pro-apoptotic factors to the damage site. Our results establish an alternative and novel method to specifically target HER2-positive breast cancers by exploiting the cell's own DNA damage response machinery. This study introduces a new paradigm for gene-targeted drugs that can be used in the treatment of HER2-positive and drug-resistant breast cancers with minimal potential for toxicity to normal tissue.
Citation Format: Faye A. Rogers, Meetu Kaushik. Gene-targeted apoptosis as a novel therapeutic strategy for HER2-positive breast 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 4773.