bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 92: Epigenetic inhibitors targeting colon cancer stem cells
Authors: Chen Yufeng 
Published: August 2015

Abstract
Colon cancer is one of the top leading causes of death in the world. Even after surgery and chemotherapy, there are still many patients who will experience relapse. Cancer stem or initiating cells (CSCs) are a small subset of self-renewing and highly tumorigenic cells, which are resistant to existing chemotherapy. In addition, CSCs are often enriched following chemotherapy, and are responsible for relapse and subsequent metastasis. One mechanism that possibly leads to chemotherapeutic failure is epigenetic changes which involve aberrant chromatin modifications in cancer and CSCs. Here, we performed microarray to investigate the gene expression profiles of CSCs and non-CSCs populations identified by ALDEFLUOR assay. Several genes were found to be highly expressed in CSCs in different colon cancer cell lines. Then we performed inhibitor screening to identify small molecules which can inhibit CSCs. Several compounds inhibiting histone methylations were found to be effective in reducing the CSCs population and expression of CSCs’ related genes. These results support the use of epigenetic inhibitors together with chemotherapy in refractory colon cancer.
Citation Format: Yufeng Chen. Epigenetic inhibitors targeting colon cancer stem 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 92. doi:10.1158/1538-7445.AM2015-92
Abstract 932: A plasma microRNAs test predicts prognosis and disease status at follow-up in screening-detected lung cancer patients
Authors: Sozzi Gabriella , Sestini Stefano , Boeri Mattia , Verri Carla , Marchiano' Alfonso , Galeone Carlotta , Sverzellati Nicola , La Vecchia Carlo , Pastorino Ugo 
Published: August 2015

Abstract
Background: We previously reported that a miRNA signature classifier (MSC) based on 24 plasma circulating microRNAs is a sensitive and early biomarker for lung cancer, able to increase the specificity of low dose computed tomography (LDCT) in screening trials (Boeri et al. PNAS 2011; Sozzi et al. JCO 2014). In the present study, we have investigated the capacity of plasma MSC to predict prognosis and monitor the disease status at follow-up in LDCT screening detected lung cancer patients.
Methods: Between 2000 and 2010, 3411 heavy smokers were enrolled in a screening program, with annual (2225) or biennial (1186) LDCT. During the first five years of screening, a total of 77 lung cancer patients underwent plasma MSC analysis, with three levels of risk: High, Intermediate or Low. Median follow-up of the alive patients was 4.5 years (Inter Quartile Range, IQR = 6.5). Changes of MSC risk profile at follow-up was assessed in 33 patients, with longitudinal plasma samples (n = 96) collected before and after surgical resection.
Results: Five-year survival was 78% for low- to intermediate risk MSC (median nc), and 35% for High risk MSC (median 2.9 yrs, p&lt;0.01). The prognostic power of MSC persisted when the analysis was restricted to LDCT-detected cases after exclusion of interval cancers (5-years survival: 87% vs. 38% respectively, p&lt;0.01). Within stage I, the 5-years survival was 100% in Low to Intermediate risk MSC and 77% in High risk MSC (p = 0.10). Reduction of MSC risk profile after surgery was observed in 73% of the 26 analyzable subjects who remained disease free, at median time of 18 months (IQR = 24). In all relapsing patients the MSC test returned to Intermediate or High risk at the time of second primary or metastatic progression.
Conclusions: Plasma MSC predicted lung cancer outcome and tumor recurrence at follow-up, showing potential efficacy in LDCT screening and lung cancer management.
Citation Format: Gabriella Sozzi, Stefano Sestini, Mattia Boeri, Carla Verri, Alfonso Marchiano', Carlotta Galeone, Nicola Sverzellati, Carlo La Vecchia, Ugo Pastorino. A plasma microRNAs test predicts prognosis and disease status at follow-up in screening-detected lung cancer patients. [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 932. doi:10.1158/1538-7445.AM2015-932
Abstract 950: Antitumor activity of a novel phosphodiesterase 10 inhibitor in an orthotopic mouse model of lung cancer
Authors: Ramirez-Alcantara Veronica , Schuler Michele , Zhu Bing , Li Nan , Gurpinar Evrim , Otali Dennis , Canzoneri Joshua , Keeton Adam , Gary Bernard , Russo Suzanne , Coward Lori , Gorman Gregory , Grizzle William , Chen Xi , Boyd Michael , Piazza Gary 
Published: August 2015

Abstract
BACKGROUND: We recently reported that phosphodiesterase 10A (PDE10) is elevated in certain tumor types and essential for tumor cell growth (Li et al., Oncogene 2014). Here we evaluate anti-tumor efficacy, pharmacokinetics, tissue distribution, and tolerance of a novel PDE10 inhibitor, ADT-048, in mice. METHODS: ADT-048 was orally administrated to C57BL/6 mice and free levels quantified in plasma and tissues by LC-MS. Anti-tumor activity was evaluated in athymic nude-Foxn1nu mice after inoculating the left lung with 1×106 A549 lung tumor cells transfected with luciferase. Tumor growth was monitored by in situ bioluminescence using the In Vivo Imaging System and efficacy was evaluated by necropsy grading. RESULTS: ADT-048 inhibited A549 lung tumor cell growth with an IC50 value of 0.7 μM, while appreciably higher concentrations were required to inhibit the growth of normal airway epithelial cells (IC50 = 35 μM). Pharmacokinetic studies demonstrated a half-life suitable for once a day dosing, while tissue distribution studies demonstrated a unique capacity to achieve high concentrations in lungs relative to plasma and other tissues. ADT-048, at a dose of 100 mg/Kg, displayed significant anti-tumor activity as evident by reduced luminescence and tumor grading following 28 days of treatment. CONCLUSIONS: A novel PDE10 inhibitor, ADT-048, was found to display highly potent and selective tumor cell growth inhibitory activity in vitro. ADT-048 was well tolerated in mice and had attractive pharmaceutical properties with a unique capacity to achieve high lung concentrations following oral administration. Efficacy studies demonstrate strong anti-tumor activity of ADT-048, which represents a candidate for clinical development. Supported by NIH grants 1R01CA155638 and 1R01CA131378 (Piazza).
Citation Format: Veronica Ramirez-Alcantara, Michele Schuler, Bing Zhu, Nan Li, Evrim Gurpinar, Dennis Otali, Joshua Canzoneri, Adam Keeton, Bernard Gary, Suzanne Russo, Lori Coward, Gregory Gorman, William Grizzle, Xi Chen, Michael Boyd, Gary Piazza. Antitumor activity of a novel phosphodiesterase 10 inhibitor in an orthotopic mouse model of lung cancer. [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 950. doi:10.1158/1538-7445.AM2015-950
Abstract 97: CARM1 preferentially methylates H3R17 over H3R26 through a random kinetic mechanism
Authors: Jacques Suzanne L. , Aquino Katrina P. , Gureasko Jodi , Boriack-Sjodin P Ann , Copeland Robert A. , Riera Thomas V. 
Published: August 2015

Abstract
CARM1 (PRMT4) is a type I arginine methyltransferase involved in the regulation of transcription, pre-mRNA splicing, cell cycle progression and the DNA damage response. Overexpression of CARM1 has been implicated in breast, prostate, and colorectal cancers. Since CARM1 appears to be a good target for the development of therapies against these cancers, we studied the substrate specificity and kinetic mechanism of the full-length human enzyme. CARM1 has been shown to methylate both residues R17 and R26 of histone H3. Substrate specificity was examined by testing CARM1 activity with several H3-based peptide substrates using a radiometric assay. Comparison of kcat/KM values reveal that methylation of H3R17 is preferred over H3R26. An R17/R26K peptide produced 8-fold greater kcat/KM value compared to the corresponding R17K/R26 peptide. These effects are KM-driven as kcat values remain relatively constant for the peptides tested. Shortening the peptide at the C-terminus by 5 amino acid residues greatly reduced the specificity (16-24-fold), demonstrating the contribution of distal residues to substrate binding. In contrast, adding residues to the N-terminus of the shortened peptide had a negative effect on activity. CARM1 displays little preference for monomethylated over unmethylated H3R17 (2-5-fold by kcat/KM) suggesting that it operates through a distributive mechanism. Previous crystallographic studies with mouse CARM1 showed that part of the substrate binding groove was formed by cofactor binding, thereby suggesting an ordered kinetic mechanism (Yue et al., EMBO J., 2007). Our results from dead-end and product inhibition studies performed with human CARM1, however, are consistent with a random kinetic mechanism. SAH and sinefungin demonstrate competitive inhibition with respect to SAM and produced noncompetitive inhibition patterns with respect to peptide. Both dimethylated R17 product peptide and dead-end R17K peptide exhibited noncompetitive inhibition patterns with respect to SAM. Furthermore, binding of SAM and peptide substrates were shown to be independent of each other in initial velocity experiments where both substrates were varied. Together, these results elucidate the kinetic mechanism of CARM1 and highlight elements important for binding affinity.
Citation Format: Suzanne L. Jacques, Katrina P. Aquino, Jodi Gureasko, P Ann Boriack-Sjodin, Robert A. Copeland, Thomas V. Riera. CARM1 preferentially methylates H3R17 over H3R26 through a random kinetic mechanism. [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 97. doi:10.1158/1538-7445.AM2015-97
Abstract 98: Genetic alterations of KDM4 subfamily and therapeutic effect of novel demethylase inhibitor in breast cancer
Authors: Holowatyj Andreana N. , Ye Qin , Wu Jack , Liu Hui , Zhang Lihong , Suzuki Takayoshi , Yang Zeng-Quan 
Published: August 2015

Abstract
The histone lysine demethylase KDM4 subfamily, comprised of four members (A, B, C, and D), play critical roles in controlling transcription, chromatin architecture and cellular differentiation. Although KDM4 family members have a high degree of homology, they may play different roles in various types of breast cancer. The goal of this study is to analyze the genomic and transcriptomic alterations of the KDM4 subfamily in different subtypes of breast cancer, and explore the therapeutic potential of a novel KDM4 inhibitor in aggressive basal breast cancer.
We conducted a large-scale meta-analysis of KDM4A, B, C, and D in breast cancer and identified associations among recurrent copy number alterations, gene expression and breast cancer subtypes. We examined KDM4 expression in a panel of non-tumorigenic and cancerous breast epithelial cell lines using quantitative RT-PCR and Western blot assays, and assessed global histone 3 methylation levels by Western blot in a panel of breast cancer cell lines. Next, we tested a novel inhibitor of the KDM4 demethylases, small molecule NCDM-32B, for its ability to attenuate basal breast cancer cell growth and impair metastatic potential. Finally, to examine gene expression changes induced by NCDM-32B, we conducted expression profiling and pathway analyses.
We found that the KDM4 members show different expression patterns in subtypes of breast cancer. Our findings suggest that H3 global methylation levels vary among different breast cancer cell lines. We demonstrated that NCDM-32B significantly impaired viability, cellular growth and transforming phenotypes of basal breast cancer in vitro. Furthermore, NCDM-32B impaired several critical pathways and classical oncogenes, including MET, CDC26, and CDK6, that drive cellular proliferation and transformation in breast cancer.
In summary, our findings add layers of information to the genomic and transcriptomic profiles of the KDM4 subfamily in different subtypes of breast cancer. We provide the first evidence that a novel KDM4 demethylase inhibitor, the small molecule NCDM-32B, led to significant inhibition of cellular growth of basal breast cancer in vitro. These findings lay the foundation for evaluating KDM4 inhibitors as therapeutic approaches against aggressive breast cancer.
Citation Format: Andreana N. Holowatyj, Qin Ye, Jack Wu, Hui Liu, Lihong Zhang, Takayoshi Suzuki, Zeng-Quan Yang. Genetic alterations of KDM4 subfamily and therapeutic effect of novel demethylase inhibitor in breast cancer. [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 98. doi:10.1158/1538-7445.AM2015-98
Abstract 983: Gas6/Axl mediation of prostate cancer cell dormancy requires cooperation with additional bone marrow niche components
Authors: Axelrod Haley , Pienta Kenneth J. 
Published: August 2015

Abstract
Early metastatic events are often responsible for the recurrence and lethality of prostate cancer. The most frequent site of metastasis is the bone marrow, where small populations of disseminated tumor cells (DTCs) preferentially take residence in the hematopoietic stem cell (HSC) niche. These micro-metastases may survive in a benign, dormant state for years before they become “reawakened” to form full metastases, and are thus difficult to detect and treat. It is unknown what induces and maintains DTC dormancy, and it remains a key question with regard to metastatic prostate cancer treatment and prevention strategies. An essential component of the HSC niche is the osteoblast population to which DTCs bind for support and uptake of secreted factors. We have previously shown that dormant DTCs in the HSC niche display high levels of the receptor tyrosine kinase Axl, and are bound to osteoblasts that secrete its ligand, Gas6. The requirement of Gas6/Axl in DTC dormancy is striking in vivo, but in vitro is not replicable. Addition of Gas6 to prostate cancer cells expressing Axl does not have a significant inhibitory effect on cell proliferation, suggesting the cooperation with other niche factors absent in culture. As the elements of the DTC niche are still being actively explored, this study further supports the complex nature of the mechanisms governing DTC dormancy and preferential survival in the bone marrow niche. Selective targeting of these elements may allow for long term maintenance of the benign, dormant state of DTCs, or coerced reawakening to a more chemotherapy-sensitive state.
Citation Format: Haley Axelrod, Kenneth J. Pienta. Gas6/Axl mediation of prostate cancer cell dormancy requires cooperation with additional bone marrow niche components. [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 983. doi:10.1158/1538-7445.AM2015-983
Abstract CT208: Preliminary results of a phase II trial of an adenovirus/PSA vaccine in men with recurrent prostate cancer
Authors: Lubaroff David M. , Vaena Daniel , Brown James , Nepple Kenneth , Zehr Pamela , Griffith Karen , Brown Erica , Eastman Julie , Zamba Gideon , Williams Richard 
Published: August 2015

Abstract
Introduction and Objectives: A phase II clinical trial of an adenovirus/PSA (Ad/PSA) vaccine was carried out in men with recurrent prostate cancer using two protocols. The objectives of the study were to determine whether the vaccine produced beneficial immune and clinical responses in men with a low burden of tumor.
Methods: In Protocol #1 men with recurrent prostate cancer following definitive initial treatment for their disease were placed in one of two arms: Arm A; men received the vaccine alone at days 0, 30, and 60; Arm B; men received the vaccine 14 days after the initiation of androgen deprivation therapy (ADT). In Protocol #2 men with hormone refractory disease received the vaccine alone using the same 3 injection schedule. Each injection consists of 108 pfu of the Ad/PSA vaccine suspended in a collagen matrix. All patients returned at regular intervals for physical, chemical, radiologic, and immunologic evaluations.
Results: We enrolled all of our targeted 82 patients, 50 in protocol 1 (25 Arm A, 25 Arm B) and 32 in protocol 2. All patients have been followed a minimum of 12 months with the longest being over 6 years. Eighty nine percent (89%) of all patients produced anti-PSA T cell immune responses; 71% in protocol 1 Arm A, 100% in protocol 1 Arm B, and 100% in protocol 2. Clinically, 58% of patients in protocol 1 Arm A and 75% of patients in protocol 2 demonstrated a decrease in serum PSA or an increase in PSA doubling times (PSADT). As of the submission date the PSA levels of 2 patients declined to 0.07 ng/ml and undetectable (&lt;0.03).
Conclusions: Preliminary results of patients thus far studied in a phase II clinical trial of the Ad/PSA vaccine are very encouraging, demonstrating both immunologic and clinical responses to the 3-vaccination therapy. PSA responses indicate at least a decline in the growth and perhaps a destruction of recurrent prostate tumors in men immunized in two separate protocols. Data collection continues that include completion of immune assays on all 82 patients as well as monitoring PSA levels, PSADT, and radiologic changes.
Citation Format: David M. Lubaroff, Daniel Vaena, James Brown, Kenneth Nepple, Pamela Zehr, Karen Griffith, Erica Brown, Julie Eastman, Gideon Zamba, Richard Williams. Preliminary results of a phase II trial of an adenovirus/PSA vaccine in men with recurrent prostate cancer. [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 CT208. doi:10.1158/1538-7445.AM2015-CT208
Abstract DDT01-01: PT2385: First-in-class HIF-2α antagonist for the treatment of renal cell carcinoma
Authors: Wallace Eli M. , Cao Zhaodan , Cheng Tzuling , Czerwinski Robert , Dixon Darryl D. , Du Xinlin , Goggin Barry , Grina Jonas , Halfmann Megan , Han Guangzhou , Huang Heli , Josey John A. , Maddie Melissa A. , Olive Sarah , Rizzi James , Schlachter Stephen T. , Tan Hui-Ling , Wang Bin , Wang Keshi , Wehn Paul M. , Xie Shanhai , Xu Rui , Yang Hanbiao 
Published: August 2015

Abstract
Hypoxia-inducible factors (HIFs), including HIF-1α and HIF-2α, are transcription factors that mediate cellular response to changes of oxygen supply. These proteins become stabilized under hypoxia and subsequently activate the expression of genes to facilitate cell survival and proliferation. HIF proteins are activated in many types of cancers due to the tumor hypoxic microenvironment and have been implicated in cancer initiation, progression and metastasis. The oncogenic role of HIF-2α is pertinent in clear cell renal carcinoma (ccRCC). In the majority of ccRCC tumors, the von Hippel-Lindau protein (VHL) that targets HIF-2α for degradation is inactivated, leading to the accumulation of HIF-2α and the activation of genes that drive kidney cancer tumorigenesis. We have identified small molecules that bind to the PAS-B domain of HIF-2α protein and block it's dimerization with ARNT (aryl hydrocarbon receptor nuclear translocator, HIF-1β), a prerequisite for its transcriptional activities. Specifically, we describe PT2385, a selective, orally active HIF-2α antagonist with potent anti-cancer activity in mouse models of ccRCC. PT2385 is currently under evaluation in Phase I clinical trials for the treatment of ccRCC.
Citation Format: Eli M. Wallace, Zhaodan Cao, Tzuling Cheng, Robert Czerwinski, Darryl D. Dixon, Xinlin Du, Barry Goggin, Jonas Grina, Megan Halfmann, Guangzhou Han, Heli Huang, John A. Josey, Melissa A. Maddie, Sarah Olive, James Rizzi, Stephen T. Schlachter, Hui-Ling Tan, Bin Wang, Keshi Wang, Paul M. Wehn, Shanhai Xie, Rui Xu, Hanbiao Yang. PT2385: First-in-class HIF-2α antagonist for the treatment of renal cell carcinoma. [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 DDT01-01. doi:10.1158/1538-7445.AM2015-DDT01-01
Abstract LB-033: FAK promotes the Wnt/β-catenin pathway and intestinal tumorigenesis by phosphorylating GSK3ββ
Authors: Gao Chenxi , Chen Guangming , Kuan Shih-Fan , Zhang Dennis H. , Hu Jing 
Published: August 2015

Abstract
Aberrant activation of Wnt/β-catenin signaling plays an unequivocal role in colorectal cancer (CRC), but identification of effective Wnt inhibitors for use in cancer remains a tremendous challenge. New insights into the regulation of this pathway could reveal new therapeutic point of intervention, therefore are greatly needed. Glycogen synthase kinase 3β(GSK3β) is a major component of the Wnt/β-catenin pathway, how GSK3β is regulated in Wnt signaling and tumorigenesis remains largely unknown. This study investigated the function and regulation of GSK3β phosphorylation in Wnt/β-catenin signaling and Wnt-driven intestinal tumorigenesis. The function of GSK3β phosphorylation at tyrosine 216 (Y216) in Wnt/-catenin signaling and CRC cells was analyzed by a series of biochemistry experiments and anchorage independent growth assays. Phosphorylation of GSK3βY216 by focal adhesion kinas (FAK) was studied in in vitro reconstitution system and in cells. The role of FAK-mediated phosphorylation of GSK3βY216 was tested by examining adenoma formation and associated molecular changes in control and FAK inhibitor-treated APCmin/+ mice. Immunohistochemistry was used to evaluate the expression levels of FAK, p-GSK3βY216 and β-catenin in CRC patients. Our results showed that GSK3βY216 phosphorylation was required for the activation of the Wnt/β-catenin pathway. Pharmacological inhibition of FAK suppressed adenoma formation in APCmin/+ mice accompanied by reduced intestinal levels of p-GSK3βY216 and β-catenin. FAK, p-GSK3βY216 and β-catenin were elevated and positively correlated in human CRC tissues. Together, our findings indicate that FAK/GSK3βY216 axis is critical for the activation of Wnt/β-catenin signaling in APC-driven intestinal tumorigenesis, thus providing a compelling mechanistic justification for clinical exploration of FAK inhibitors in colorectal cancer patients carrying APC mutations.
Citation Format: Chenxi Gao, Guangming Chen, Shih-Fan Kuan, Dennis H. Zhang, Jing Hu. FAK promotes the Wnt/β-catenin pathway and intestinal tumorigenesis by phosphorylating GSK3ββ. [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 LB-033. doi:10.1158/1538-7445.AM2015-LB-033