bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 2690: A novel antibody-drug conjugate directed to the ALK receptor tyrosine kinase demonstrates efficacy in models of neuroblastoma
Authors: Sano Renata , Krytska Kateryna , Larmour Colleen , Ligon Gwenda F. , Lillquist Jay S. , Cucchi Ulisse , Orsini Paolo , Rizzi Simona , McMahon Gerald , Alvarado Diego , Mosse Yael P. 
Published: July 2016

Abstract
Activated ALK by mutation or amplification is a validated therapeutic target in a subset of patients with high-risk neuroblastoma, and tyrosine kinase inhibitors are being developed to abrogate ALK signaling (Bresler et al, 2014). Native ALK is expressed on the surface of the majority of neuroblastoma tumors, but not on normal tissue, giving it properties of a tumor antigen. We hypothesized that ALK-targeted antibodies may be useful in neuroblastoma as single-agent immunotherapy or in combination with small-molecule ALK inhibitors - especially where mutations reduce kinase inhibitor sensitivity. In this work, an anti-ALK monoclonal antibody (anti-ALK2) was conjugated to a cytotoxic agent (ALK2-ADC) and its anti-tumor activity was investigated in a panel of extensively characterized human neuroblastoma cell lines (n = 10) harboring wild type and mutant ALK. Cell surface ALK was quantified using flow cytometry and revealed differential antigen expression. Using in vitro growth inhibition assays, there was evidence for a dose-dependent cytotoxicity to neuroblastoma cells at subnanomolar concentrations that correlated with ALK expression and was independent of underlying mutation status. In order to evaluate the therapeutic potential of ALK2-ADC in vivo, mice bearing Felix-patient-derived xenograft (PDX) tumors, containing the third most common ALK mutation (R1245C), were used to demonstrate that ALK2-ADC led to a significant reduction in tumor growth compared to unconjugated antibody and a control ADC (p&lt;0.0001). Although ALK2-ADC binds potently to mouse ALK as well as human ALK, doses of up to 10 mg/kg in the rodent model appeared to be well tolerated with no overt toxicity noted. Additional in vivo studies are ongoing to assess the antitumor potential of the ADC in a broader range of ALK-expressing neuroblastoma models. Thus, targeting human ALK-expressing with an ALK antibody-drug conjugate demonstrated early signs of favorable efficacy and tolerability supporting future development of this approach as a potential novel therapeutic for patients with neuroblastoma.
Citation Format: Renata Sano, Kateryna Krytska, Colleen Larmour, Gwenda F. Ligon, Jay S. Lillquist, Ulisse Cucchi, Paolo Orsini, Simona Rizzi, Gerald McMahon, Diego Alvarado, Yael P. Mosse. A novel antibody-drug conjugate directed to the ALK receptor tyrosine kinase demonstrates efficacy in models of neuroblastoma. [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 2690.
Abstract 2711: Spatiotemporal progression patterns in metastatic lung cancer treated with bevacizumab
Authors: Mason Jeremy M. , Newton Paul K. , In Gino K. , Lin Sonia , Kuhn Peter , Nieva Jorge J. 
Published: July 2016

Abstract
We describe a Markov chain mathematical model of lung cancer progression based on a longitudinal dataset of 722 lung cancer patients. Specifically, we investigate the patterns of metastatic spread in lung cancer and how the VEGF inhibitor, bevacizumab, alters these metastatic patterns. Stochastic models were used to simulate metastatic spread by means of random walk processes on directed graphs. We created spatiotemporal diagrams of cancer progression to analyze the differences between patients treated and not treated with bevacizumab. Patients with squamous lung cancer or brain metastases at baseline were ineligible for bevacizumab and excluded from analysis. Our results demonstrated that not only does bevacizumab extend survival, but it also alters patterns of metastatic spread. Patients treated with bevacizumab were characterized by greater heterogeneity in their pathways of metastatic progression, compared to those patients not treated with bevacizumab, which showed more homogeneity in their pathways. Furthermore, we quantify this spread and characterize metastatic sites as ‘spreaders’ and ‘sponges’ based on their probability of spreading the disease.
Citation Format: Jeremy M. Mason, Paul K. Newton, Gino K. In, Sonia Lin, Peter Kuhn, Jorge J. Nieva. Spatiotemporal progression patterns in metastatic lung cancer treated with bevacizumab. [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 2711.
Abstract 2713: Combination of PLK1 and PI3K inhibitors shows strong synergy in anaplastic thyroid cancer
Authors: Yilmaz Emrullah , Orlacchio Arturo , Di Cristofano Antonio 
Published: July 2016

Abstract
Anaplastic thyroid cancer (ATC) is the most aggressive thyroid cancer with median of 6 months of survival from diagnosis. Molecular alterations are well defined recently. p53 mutations, and activation of PI3K, RAS and BRAF are among the most common alterations. PLK1 overexpression has also been identified in ATC.
We have previously shown that PLK1 inhibitors are effective in ATC cell lines. However PLK1 inhibition in cell lines with PI3K activation resulted in escaping growth arrest and subsequent mitotic catastrophe through mitotic slippage. Since the PI3K activation is common in ATC, there is risk of generating polyploid, genetically unstable cell populations by targeting these tumors with a PLK1 inhibitor. So we tested the effect of combining PLK1 and PI3K inhibitors in ATC cell lines.
We combined PLK1 inhibitor BI6727 and PI3K inhibitor BKM120 and measured the cell viability using Alamar Blue. Combination of these two drugs resulted in significant synergy in mouse derived PTEN deleted ATC cell lines. We observed the same synergy in the human ATC cell lines with PIK3CA mutations.
BI6727 showed significant G2/M arrest in the cell lines. The combination two drugs enhanced the G2/M arrest. In a low dose that the single drugs showed no inhibition in cell cycle, combination resulted in G2/M arrest.
We treated the cells with a dual PI3K and PLK1 inhibitor Rigosertib. Although we have seen some sensitivity of the cells with PIK3CA mutation, the cell lines with PTEN were strongly resistant to Rigosertib.
Our results show that combination of PLK1 and PI3K inhibitors is an effective treatment for ATC cells with PI3K activation. This combination results in cell cycle arrest suggesting the role of using combination therapies in this aggressive cancer.
Citation Format: Emrullah Yilmaz, Arturo Orlacchio, Antonio Di Cristofano. Combination of PLK1 and PI3K inhibitors shows strong synergy in anaplastic thyroid 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 2713.
Abstract 2717: Reintroduction of DAXX suppresses alternative lengthening of telomeres in osteosarcoma
Authors: Driest Kathryn E. , Waterfall Joshua J. , Walker Robert L. , Pineda Marbin A. , Abaan Ogan , Zhu Yuelin J. , Wang Yonghong , Ester Corbin D. , Davis Sean R. , Bilke Sven , Meltzer Paul S. 
Published: July 2016

Abstract
The unlimited proliferative capacity of cancer cells is closely linked to maintenance of their telomeres, which shorten with each cell division in normal cells. Cancer cells are able to maintain telomere length by multiple mechanisms, including activation of telomerase and the recombination based alternative lengthening of telomeres (ALT) pathway. ALT is prevalent in osteosarcoma, with approximately 50% of osteosarcoma cases using ALT for telomere maintenance. Mutations in the ATRX/DAXX chromatin remodeling complex and histone H3.3 correlate with activation of the ALT pathway in several tumor systems. While loss of ATRX is a frequent event in osteosarcoma tumors, alterations of DAXX have not been reported. We characterized the telomere maintenance mechanisms utilized by 11 osteosarcoma cell lines. Of these, 45% (5/11) were ALT positive and 45% (5/11) were telomerase positive. One cell line possessed features of both telomere maintenance mechanisms. Among ALT positive osteosarcoma cell lines, we observed frequent loss of ATRX expression (4/5) and a previously unreported translocation resulting in disruption of DAXX. The translocation abolishes recruitment of DAXX to nuclear PML bodies and prevents normal DAXX function. By reintroducing full length DAXX, we were able to suppress telomere maintenance by ALT as evidenced by multiple assays including loss of C-circles and ALT-associated PML bodies, thus demonstrating that continued DAXX deficiency is necessary for maintenance of the ALT mechanism. Suppression of ALT by DAXX reintroduction did not result in compensatory activation of telomerase. This first demonstration of ALT suppression by DAXX supports a mechanistic connection between loss of the ATRX/DAXX chromatin remodeling complex and telomere maintenance by ALT. Understanding this relationship may uncover vulnerabilities specific to ALT tumors that could potentially lead to the development of targeted therapies for diverse cancers that depend on the ALT pathway.
Citation Format: Kathryn E. Driest, Joshua J. Waterfall, Robert L. Walker, Marbin A. Pineda, Ogan Abaan, Yuelin J. Zhu, Yonghong Wang, Corbin D. Ester, Sean R. Davis, Sven Bilke, Paul S. Meltzer. Reintroduction of DAXX suppresses alternative lengthening of telomeres in osteosarcoma. [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 2717.
Abstract 272: Metformin enhances the anti-prostate cancer activity of abiraterone and enzalutamide
Authors: Xie Yi , Wang Linbo , Hussain Arif 
Published: July 2016

Abstract
The standard treatment for advanced castration sensitive prostate cancer (CSPC) is androgen deprivation therapy (ADT), generally in the form of suppression of gonadally produced androgens via medical or surgical castration. The selective inhibitor of androgen biosynthesis Abiraterone (Abi), and the androgen receptor (AR) antagonist Enzalutamide (MDV3100), are second line hormonal therapies used to treat PC patients failing ADT. However, these drugs provide treatment response for a limited duration of time due to the development of resistance to them. Included among the mechanisms leading to resistance to ABI or MDV is the expression of the AR variant AR-V7. Metformin, a widely used oral anti-diabetic drug, has been reported to reduce prostate cancer mortality in PC patients with type II diabetes. In this study, we explored the effects of ABI, MDV and metformin in a pre-clinical model of PC. Both Abi and MDV inhibited cell proliferation and the expression of prostate specific antigen (PSA) in androgen-sensitive LNCaP cells. However, neither induced cell death, and in fact MDV appeared to actually inhibit apoptosis in LNCaP cells. Both agents increased AR and AR-V7 expression, which in part may account for development of resistance to ABI or MDV. In contrast, metformin inhibited AR, AR-V7 and PSA expression in a dose-dependent manner, and induced apoptotic cell death in PC cells. Metformin, in combination with ABI or MDV, further enhanced apoptosis and inhibited expression of PSA than it did as single agent. Interestingly, at near physiological concentrations metformin induced apoptosis in a caspase-independent manner rather than by a caspase-dependent apoptotic program that is reported to occur with high doses of metformin. In conclusion, Abi or MDV inhibits AR signaling and PC cell proliferation, but also induces AR and AR-V7 expression. Metformin decreases AR and AR-V7 expression and induces apoptotic cell death. The combination of metformin with androgen biosynthesis/AR inhibitors results in caspase-independent apoptotic cell death in addition to inhibition of both cell proliferation and AR signaling. Further studies will be needed to evaluate the clinical efficacy of these combination treatments in patients with PC.
Citation Format: Yi Xie, Linbo Wang, Arif Hussain. Metformin enhances the anti-prostate cancer activity of abiraterone and enzalutamide. [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 272.
Abstract 2727: LOX is a novel mitotic spindle-associated protein essential for mitosis
Authors: Boufraqech Myriem , Wei Darmood , Weyemi Urbain , Zhang Lisa , Quezado Martha , Kalab Petr , Kebebew Electron 
Published: July 2016

Abstract
Lysyl oxidase (LOX) is a copper-dependent amine oxidase that plays a critical role in the biogenesis of connective tissue matrices. LOX is highly expressed in aggressive cancers; has been associated with a shorter survival and regulates cancer progression in a variety of human malignancies. Here, we report a new function of LOX in mitosis in anaplastic thyroid cancer cell line (THJ-16T), breast cancer cell line (MDA-MB231) and HeLa cells. We show that LOX co-localizes to mitotic spindles from metaphase to telophase, and p-H3(Ser10)-positive cells harbor strong LOX staining. Further, purification of mitotic spindles from synchronized cells show that LOX fails to bind to microtubules in the presence of nocodazole, whereas paclitaxel treated samples showed enrichment in LOX expression suggesting that LOX binds to stabilized microtubules only. Functional studies of LOX depletion resulted in decreased cellular proliferation, G2/M cell cycle arrest, and formation of gigantic nuclei. Further, LOX knockdown led to reduced p-H3(Ser10), cyclin B1, CDK1, and Aurora B expression. Lastly, LOX knockdown significantly increased sensitivity of cancer cells to chemotherapeutic agents that target microtubules and this effect was synergistic. Our results show identify a novel function of LOX in cancer cell mitosis, and that loss of LOX expression in cancer cells can enhanced effects of anti-microtubules agents used in cancer therapy.
Citation Format: Myriem Boufraqech, Darmood Wei, Urbain Weyemi, Lisa Zhang, Martha Quezado, Petr Kalab, Electron Kebebew. LOX is a novel mitotic spindle-associated protein essential for mitosis. [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 2727.
Abstract 2739: Carnosic acid induces cell cycle arrest of B16F10 cells and synergizes with carmustine and lomustine in vitro and in vivo
Authors: Lin Kun-I , Lin Chih-Chien , Chen Ming-Feng , Chen Chang-Han , Shiu Li-Yen 
Published: July 2016

Abstract
Carnosic acid (CA), one of the purified components of rosemary, has shown anti-inflammatory, chemo-preventive, and anticancer activities. In this study, we treated melanoma cell line B16F10 with CA and detected the anticancer effects. After 24-hour treatment, CA decreased cell proliferation rate, wound healing activity, and inhibited colony formation of B16F10. Additionally, CA induced G0/G1 cell cycle arrest, up-regulated p21 expression, and down-regulate cyclin E, cyclin D and CDK4 expression. Carmustine (BCNU) and Lomustine (CCNU) are used in clinical treatment of melanoma. To assay the combinational effects of CA and BCNU or CCNU, B16F10 cells were treated with CA, BCNU, CCNU alone, or CA combined with BCNU or CCNU. Our results showed, BCNU and CCNU arrested cell cycle at G2/M phase after 24-hour treatment. Dramatically, CA enhenced BCNU- and CCNU-induced cell cycle arrest at G2/M phase, and decreased cyclin B1 and p-CDK1 expresion. In the in vivo xenograft model, B16F10 cells (5×105) were inoculated subcutaneously in C57BL/6 mice, and the tumor grew for one week. The mice were divided into six groups and provided different treated strategies: control, CA (50 mg/kg) alone, BCNU (50 mg/kg) alone, CCNU (25 mg/kg) alone, CA combined with BCNU, and CA combined with CCNU. After two-week treatment, compared with control group, CA had better treated effects than BCNU or CCNU. Compared with CA, BCNU or CCNU treatment alone, the combined strategies inhibited the tumor growth in melanoma mice model more effectively. Furthermore, BCNU and CCNU treatment in melanoma mice caused high values of aspartate aminotransferase (AST) and alanine aminotransferase (ALT). However, CA significantly decreased AST and ALT values caused by BCNU and CCNU in combined trestment group. Therefore, CA is more safe and effective than BCNU and CCNU, and the combined treatment strategies of CA and BCNU or CCNU result in an increased antitumor efficacy. CA may be suitable for translation to future clinic.
Citation Format: Kun-I Lin, Chih-Chien Lin, Ming-Feng Chen, Chang-Han Chen, Li-Yen Shiu. Carnosic acid induces cell cycle arrest of B16F10 cells and synergizes with carmustine and lomustine in vitro and 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 2739.
Abstract 2742: USP37 promote oncogenesis by stabilizing protein involved in DNA damage repair pathway and provides a novel way to modulate Chk1 activity
Authors: singh mayank , Burrows Amy C. , Dickson Andrew , Summers Matthew 
Published: July 2016

Abstract
Dysregulation of the Ubiquitin proteasome system (UPS), which comprises nearly 1000 different components is associated with many aspects of oncogenesis and has emerged as a novel therapeutic target. We have previously shown that USP37 (Ubiquitin specific peptidase 37) antagonizes the tumor suppressor APCCDH1and it promotes S phase entry while data from other groups have shown that it stabilizes oncoproteins, such as c-Myc. We have found USP37 protein levels to be high in many cancerous cell lines as compared to untransformed cells and it appears to help tumor survive the high level of replication stress associated with oncogene expression. It was found that USP37 over expression confers survival advantage to cancer cells while its depletion enhances chemo sensitization in response to variety of replication stresses. USP37 over expressing cells were able to resolve γ-H2AX foci much more effectively then the wild type or cells in which USP37 was depleted. Our data indicate that USP37 binds and stabilizes the active form of CHK1 as evident by its protein levels when USP37 over expressing or depleted cells were exposed to replication stress. Mechanistically, our analyses indicate that USP37 stabilizes CHK1 by its deubiquitination, preventing its degradation. As CHK1 has been pursued as a therapeutic target with limited success our work defines a novel way to modulate activity of CHK1 while simultaneously targeting multiple oncogenes and thereby providing a rationale to evaluate USP37 inhibitor over CHK1 inhibitor as a potential therapeutic target in different cancers.
Citation Format: mayank singh, Amy C. Burrows, Andrew Dickson, Matthew Summers. USP37 promote oncogenesis by stabilizing protein involved in DNA damage repair pathway and provides a novel way to modulate Chk1 activity. [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 2742.
Abstract 2761: Cellular consequences of human tyrosyl-DNA phosphodiesterase I dysregulation
Authors: Cuya Selma M. , Regal Kellie M. , Van Waardenburg. Robert C.A.M. 
Published: July 2016

Abstract
Tyrosyl-DNA phosphodiesterase I (Tdp1) is a highly conserved eukaryotic DNA repair enzyme that catalyzes the resolution of 3’ and 5’ phospho-DNA adducts. Tdp1 has been implicated in the repair of DNA topoisomerase I (Topo1)-DNA covalent complexes reversibly stabilized by camptothecins (CPTs) such as the FDA approved CPT derivatives topotecan and irinotecan. Tdp1 utilizes a two-step catalytic cycle that centers on the formation of an obligatory Tdp1-DNA covalent complex (Tdp1-cc) through its nucleophilic histidine (Hisnuc), resulting in dissociation of the adduct, while its general acid/base histidine (Hisgab) mediates Tdp1 dissociation. A Tdp1Hisgab to Arg (H493R) mutant stabilizes the Tdp1-cc and is associated with autosomal recessive ataxia SCAN1. Alternative substitutions of Hisgab or substitutions of the Hisnuc transforms yeast Tdp1 into a potent toxin via stabilization of Tdp1-cc. We propose that stabilization of this Tdp1-DNA covalent complex is a potential novel therapeutic anti-cancer strategy. As proof-of-concept, we analyzed two catalytic Hisgab (H493R or H493N) mutants and one Hisnuc (H263A) mutant of hTdp1 in HEK293 cells. Doxycycline-induced expression of Tdp1H263A, Tdp1H493R, and Tdp1H493N mutant enzymes induced Tdp1-dependent cytotoxicity without additional genotoxic stress. Utilizing two different immuno-assays, we validated that the observed Tdp1-dependent toxicity correlates with stabilization of their enzyme-DNA covalent complex. Moreover, all of these Tdp1 catalytic mutants show reduced catalytic activity compared to wild type hTdp1, but they do not all show a stabilized Tdp1-cc in this in vitro assay. This indicates a significant difference between in vitro Tdp1 activity and cellular Tdp1 activity, which is most likely due to the difference in substrate; a small oligonucleotide with a 3’phospho-tyrosyl modification versus covalent complex of full length Topo1 with genomic DNA. However, these results confirm our previous yeast studies: Stabilization of the Tdp1-cc converts a DNA repair enzyme into a cellular toxin, which constitutes a potential novel therapeutic strategy to treat cancer. In addition, we are comparing schedule dependent ‘drug’-combinations of our toxic Tdp1 mutant expression with topotecan, etoposide (targets Topo2-cc) and cisplatin to evaluate the potential therapeutic value of this novel Tdp1 targeted strategy.
This work is in part supported by the ADDA, UAB ACS-IRG, and DOD OCRP WX81WH-15-1-0198.
Citation Format: Selma M. Cuya, Kellie M. Regal, Robert C.A.M. Van Waardenburg. Cellular consequences of human tyrosyl-DNA phosphodiesterase I dysregulation. [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 2761.