bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 3486: Synergistic effect of quinacrine in combination with decitabine for the treatment of acute myeloid leukemia cells in vitro: implication for treatment of AML in the elderly
Authors: Wang Wenge , Dicker David T. , Claxton David F. , Wang Hong-Gang , El-Deiry Wafik S. 
Published: August 2015

Abstract
Demethylating agents remain one of the few options for treatment of AML in the elderly; however, the response rate is limited. In searching for p53 pathway activating agents for cancer therapy, we found that quinacrine is a potent p53 stimulator and induces tumor cell death. Quinacrine also induces expression of Death Receptor 5 (DR5), reduces expression of anti-apoptotic Mcl-1, and suppresses NFkB activity in tumor cells. Because of its acceptable toxicity profile, history of use in humans, and relevance of the target pathways modulated by quinacrine we explored whether it may serve as a potent anti-leukemia drug as most leukemia cells carry a wild-type p53. We tested the cytotoxic effects of quinacrine on malignant hematopoietic cell lines derived from patients with myeloid leukemia, including HL-60, MOLM-13, and MV4-11. We found that quinacrine induces massive cell death in the cell lines tested, at concentrations from as less as 1 microM to 5 microM, 2-10 times lower than required to induce solid tumor cell death. Most interestingly, quinacrine facilitates cell death in decitabine pre-treated leukemia cells in a synergistic manner. Further mechanistic studies showed that quinacrine stabilizes p53, induces Mcl-1 degradation, and PARP cleavage in treated cells. Our work supports translational efforts to advance the use of quinacrine from the bench to the clinic and provides a preliminary rationale for its combination with decitabine for the treatment of AML.
Citation Format: Wenge Wang, David T. Dicker, David F. Claxton, Hong-Gang Wang, Wafik S. El-Deiry. Synergistic effect of quinacrine in combination with decitabine for the treatment of acute myeloid leukemia cells in vitro: implication for treatment of AML in the elderly. [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 3486. doi:10.1158/1538-7445.AM2015-3486
Abstract 3489: Novel translational pharmacology approaches on dose reduction and alternative scheduling for the combination of JAK inhibitor, ruxolitinib, PIM inhibitor, LGH447, and CDK4/6 inhibitor, LEE011 in a preclinical model of myeloproliferative neoplasia
Authors: Pinzon-Ortiz Maria , Rong Xianhui , Vanasse Gary , Cao Z. Alexander 
Published: August 2015

Abstract
The JAK-STAT pathway is an important signaling pathway downstream of multiple cytokine and growth factor receptors. It has been implicated in the pathogenesis of multiple human diseases. The genetic aberration of JAK2V617F and the associated activation of STAT in myeloproliferative neoplasia (MPN) is one example of the involvement of this pathway in human cancer. We have shown the combination benefits of combining ruxolitinib (Jak1, 2 inhibitor), with LGH447 (PIM inhibitor) and LEE011 (CDK4/6 inhibitor) in a Ba/F3-JAK2V617F-driven MPN model. This triple combination resulted in ∼99% reduction of total tumor burden and a ∼96% reduction of spleen weight. Furthermore, the triple combination of ruxolitinib, LGH447 and LEE011 reduced JAK2V617F allele burden by &gt; 80%. To translate this combination from preclinical setting to the clinic, it is critical to evaluate dose to efficacy relationship for each agents and scheduling to efficacy correlation for this combination. Here, the preclinical doses for ruxolitinib, LGH447 and LEE011 were determined, based on their clinically achieved exposure. We then examined “intermittent dosing” of this combination in the same preclinical model. Our data suggest that the combination efficacy of ruxolitinib-LGH447-LEE011 is dependent on continuous administration of the agents. Finally, we examined the effect of dose reduction for each of the three agents on the combination efficacy in the Ba/F3-JAK2V617F-driven MPN model. By modifying the doses for ruxolitinib, LGH447 and LEE011 separately in the combination, our study reveals that the triple combination efficacy is most sensitive to LEE011 dose reduction, and it is least sensitive to LGH447 dose reduction. In summary, our studies aim to design novel preclinical approaches to inform and the design of clinical dose escalation in novel combination therapies.
Citation Format: Maria Pinzon-Ortiz, Xianhui Rong, Gary Vanasse, Z. Alexander Cao. Novel translational pharmacology approaches on dose reduction and alternative scheduling for the combination of JAK inhibitor, ruxolitinib, PIM inhibitor, LGH447, and CDK4/6 inhibitor, LEE011 in a preclinical model of myeloproliferative neoplasia. [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 3489. doi:10.1158/1538-7445.AM2015-3489
Abstract 350: HER3 mediates acquired resistance to HER2-targeted therapy in esophageal adenocarcinoma
Authors: Ebbing Eva A. , Medema Jan Paul , Meijer Sybren L. , Krishnadath Kausilia K. , van Berge Henegouwen Mark I. , Bijlsma Maarten F. , van Laarhoven Hanneke W. M. 
Published: August 2015

Abstract
Esophageal adenocarcinoma is an aggressive malignancy and its incidence is rapidly increasing. Despite multimodality treatment, patients face a poor 5-year survival of 15-25%, underscoring the urgency to improve treatment strategies. Receptor tyrosine kinases of the HER-family are involved in the development and progression of multiple epithelial tumors, and have consequently become widely used targets for the development of new anti-cancer therapies. Trastuzumab, an antibody against HER2, has shown potent growth inhibitory effects on HER2 overexpressing tumors, including gastro-esophageal cancer, however, resistance to this therapy is inevitable. Unfortunately, a paucity of data on cellular mechanisms of resistance to targeted therapeutic agents exist in esophageal adenocarcinoma. In order to study the effect of HER2 inhibition in vitro and in vivo, we established unique primary cultures of esophageal adenocarcinoma and patient-derived xenograft models. Using these novel tools, we demonstrate a conserved, hard-wired mechanism in which HER3 is upregulated upon trastuzumab-induced resistance in esophageal adenocarcinoma. Furthermore, blocking upregulated HER3 effectively resulted in a strong decrease in cell viability and induced cell death. Taken together, our data provide preclinical insight that strategies targeting HER3 in combination with trastuzumab could possibly prevent acquired resistance.
Citation Format: Eva A. Ebbing, Jan Paul Medema, Sybren L. Meijer, Kausilia K. Krishnadath, Mark I. van Berge Henegouwen, Maarten F. Bijlsma, Hanneke W. M. van Laarhoven. HER3 mediates acquired resistance to HER2-targeted therapy in esophageal adenocarcinoma. [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 350. doi:10.1158/1538-7445.AM2015-350
Abstract 3515: RRx-001: A double action systemically non-toxic epigenetic agent for cancer therapy
Authors: Zhao Hongjuan , Ning Shoucheng , Scicinski Jan , Oronsky Bryan , Knox Susan , Peehl Donna M. 
Published: August 2015

Abstract
RRx-001 (also known as ABDNAZ, 1-bromoacetyl-3,3-dinitroazetidine) is a novel aerospace-derived compound that demonstrated anticancer activity in the absence of systemic toxicities in a recent phase I clinical trial and is now in phase II studies. With a highly energetic heterocyclic scaffold, RRx-001 generates reactive oxygen species (ROS) and nitric oxide (NO), modulates intracellular redox status, and triggers caspase-independent apoptosis in cancer cells. Here we showed that RRx-001 as a single chemical entity regulates at least two epigenetic processes, histone acetylation and DNA demethylation. Specifically, RRx-001 at its therapeutic concentrations (0.5-5 μM) significantly decreased global DNA methylation, i.e., 5-methylcytosine levels, in SCC VII tumor cells as determined by ELISA. Consistently, treatment of SCC VII cells with 0.5-5 μM RRx-001 significantly decreased Dnmt1 and Dnmt3a protein expression in a dose- and time-dependent manner as determined by Western blots. In addition, global methylation profiling using Illumina Infinium HumanMethylation450 BeadChip® identified differentially methylated genes in SCC VII cells treated with 0.5, 2, and 5 μM RRx-001 compared to control cells. Of 111 genes demethylated by RRx-001 identified using GenomeStudio software, methylation levels of 3 genes (FAM20C, STON1-GTF2A1L and TRIAP1) were decreased by at least 2-fold across all three concentrations of RRx-001. Validation of these changes by pyrosequencing is underway. Pathway enrichment analysis by IPA suggested that RRx-001 demethylated genes involved in hepatic fibrosis, G protein signaling, leucine degradation and remodeling of epithelial adherens junctions. Moreover, RRx-001 at 2 μM significantly increased global acetylated histone H3 and H4 levels in SCC VII cells after 24 hour treatment as determined by a fluorometric assay, suggesting that RRx-001 regulates global acetylation in cancer cells. Western blot analysis also showed significant increases in acetylated histone H3 and H4 levels in SCC VII cells in a dose and time-dependent manner after RRx-001 treatment. Taken together, our results demonstrated that, in contrast to the traditional “one drug one target” paradigm, RRx-001 has multi(epi)target features, which contribute to its anticancer activity.
Citation Format: Hongjuan Zhao, Shoucheng Ning, Jan Scicinski, Bryan Oronsky, Susan Knox, Donna M. Peehl. RRx-001: A double action systemically non-toxic epigenetic agent for cancer therapy. [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 3515. doi:10.1158/1538-7445.AM2015-3515
Abstract 352: Up-regulation of CD44 in the development of metastasis, recurrence and drug resistance of ovarian cancer
Authors: Gao Yan , Foster Rosemary , Hornicek Francis J. , Amiji Mansoor M. , Duan Zhenfeng 
Published: August 2015

Abstract
Purpose: The clinical significance of Cluster of differentiation 44 (CD44) remains controversial in human ovarian cancer. The aim of this study is to evaluate the clinical significance of CD44 expression by using a unique tissue microarray, and then to determine the biological functions of CD44 in ovarian cancer.
Experimental Design: A unique ovarian cancer tissue microarray (TMA) was constructed with paired primary, metastatic, and recurrent tumor tissues from 26 individual patients. CD44 expression in TMA was assessed by immunohistochemistry. Western blotting and Immunofluorescence assay determined the expression of CD44 and/or P-glycoprotein (Pgp) in ovarian cancer cell lines and the tumor tissues of a paclitaxel treated ovarian cancer xenograft mouse model. MTT assay, wound healing assay, and matrigel invasion assay were utilized to assess the proliferation, drug sensitivity, and migration/invasion ability, respectively.
Results: Both the metastatic and recurrent ovarian cancer tissues expressed higher level of CD44 than the patient-matched primary tumor. A significant association has been shown between CD44 expression and both the disease free survival and overall survival. A strong increase of CD44 was found in the tumor recurrence of mouse model. Finally, when CD44 was knocked down, proliferation, migration/invasion activity, and spheroid formation were significantly suppressed, while drug sensitivity was enhanced.
Conclusions: Up-regulation of CD44 represents a crucial event in the development of metastasis, recurrence, and drug resistance to current treatments in ovarian cancer. Developing strategies to target CD44 may prevent metastasis, recurrence, and drug resistance in ovarian cancer.
Citation Format: Yan Gao, Rosemary Foster, Francis J. Hornicek, Mansoor M. Amiji, Zhenfeng Duan. Up-regulation of CD44 in the development of metastasis, recurrence and drug resistance of ovarian 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 352. doi:10.1158/1538-7445.AM2015-352
Abstract 3525: The BET inhibitor INCB054329 is efficacious as a single agent or in combination with targeted agents in colorectal cancer models
Authors: Liu Xuesong , Li Jun , He Xin , Stubbs Matthew , Favata Margaret , Wen Xiaoming , Chang Hong , Rumberger Beth R. , Li Yanlong , Maduskuie Thomas , Sparks Richard , Falahatpisheh Nikoo , Polam Padmaja , Combs Andrew P. , Huber Reid , Hollis Gregory , Scherle Peggy , Liu Phillip C. 
Published: August 2015

Abstract
The Bromodomain and extra-terminal (BET) family of proteins consists of BRD2, BRD3, BRD4 and BRDT. Each BET protein contains two bromodomains (BD1 and BD2) that recognize acetylated histones at enhancer and promoter regions of a select number of genes. BET proteins function as transcriptional regulators that are critical for the expression of oncogenes such as c-Myc; thus, BET proteins are important for cancer cell proliferation and survival. We have identified INCB054329, a potent and selective BET protein inhibitor that targets BD1 and BD2 of BRD2, BRD3 and BRD4. In this study, we characterized the pharmacology of INCB054329 in solid tumor cell lines. In a panel of colon cancer cell lines, more than 50% are sensitive to INCB054329 treatment with IC50 values below 500 nM in cell proliferation assays. INCB054329 down-regulated c-Myc expression, and induced cell cycle arrest and apoptosis in sensitive colon cancer cell lines. Moreover, INCB54329 was efficacious in the RKO colon cancer xenograft model. To understand whether BRD inhibition would synergize with other signaling pathway inhibitors and standard of care agents for colon cancer, we employed a high throughput combination screening strategy. Several combinations were active in a panel of colon cancer cell lines and demonstrated synergistic interactions based on combination index values. As an example, strong synergy was observed between INCB054329 and MEK inhibitors. The combination of INCB054329 and MEK inhibitors synergistically blocked expression of c-Myc protein and inhibited the MEK/ERK signaling pathway. Our data suggest the potential utilization of INCB054329 as a single agent or in combination with other targeted therapies for the treatment of colon cancer.
Citation Format: Xuesong Liu, Jun Li, Xin He, Matthew Stubbs, Margaret Favata, Xiaoming Wen, Hong Chang, Beth R. Rumberger, Yanlong Li, Thomas Maduskuie, Richard Sparks, Nikoo Falahatpisheh, Padmaja Polam, Andrew P. Combs, Reid Huber, Gregory Hollis, Peggy Scherle, Phillip C. Liu. The BET inhibitor INCB054329 is efficacious as a single agent or in combination with targeted agents in colorectal cancer models. [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 3525. doi:10.1158/1538-7445.AM2015-3525
Abstract 3529: BET bromodomain proteins regulate the canonical WNT signaling and drug resistance in colorectal cancer
Authors: Wang Lihong , Ma Yufang , Lee Ethan , Wang Jialiang 
Published: August 2015

Abstract
The canonical WNT signaling is aberrantly activated in the vast majority of colorectal cancer (CRC) and results in activation of beta-catenin and its downstream target MYC. These two oncogenic transcription factors play central roles in CRC pathogenesis, but are refractory to direct pharmacological interventions. The recurrent mutations of APC or β-catenin in CRC also limit the utilities of currently available WNT inhibitors that mostly target upstream regulators. The bromodomain and extra-terminal domain (BET) family epigenetic readers recently emerged as a key regulator of MYC expression. In the present study, we demonstrated that BET proteins regulated beta-catenin-mediated MYC expression in CRC. Inhibition of BET proteins repressed activities of both wild type and constitutively active β-catenin mutants. Pharmacological or genetic targeting of BET proteins broadly impaired proliferation and survival in CRC cells, including KRAS or BRAF-mutant lines. Furthermore, BET bromodomain inhibitors synergistically sensitized CRC cells to inhibitors of the MAPK pathway. The ability of BET inhibitors to augment the efficacy of the MAPK pathway inhibitors is potentially secondary to altered balance among pro-survival and pro-apoptotic regulators. Using KRAS- or BRAF-mutant CRC xenograft models, we showed that a combination of BET inhibitor and MEK inhibitor, but not either agent alone, induced significant tumor regression. Our findings suggest that BET-based epigenetic therapy can be utilized as an alternative approach to block the canonical WNT signaling in CRC and potentially other human cancers, in particular those carrying APC or beta-catenin mutations. Our results also identify a novel combination therapy for treating CRCs, including those refractory to currently available therapeutic options.
Citation Format: Lihong Wang, Yufang Ma, Ethan Lee, Jialiang Wang. BET bromodomain proteins regulate the canonical WNT signaling and drug resistance in colorectal 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 3529. doi:10.1158/1538-7445.AM2015-3529
Abstract 3536: Targeting β-catenin with a Dicer-substrate siRNA (DsiRNA) in a sleeping beauty transposon-driven murine hepatoblastoma model
Authors: Abrams Marc T. , Tao Junyan , Ganesh Shanthi , Cyr Wendy , Ying Bo , Koser Martin , Arvan Rokhand , Chopda Girish , Dudek Hank , Lai Cheng , Wang Weimin , Brown Bob , Monga Satdarshan 
Published: August 2015

Abstract
Hepatoblastoma (HB), the commonest pediatric liver tumor is frequently associated with an N-terminal deletion in the CTNNB1 gene, which encodes stable β-catenin and promotes nuclear localization and transactivation activity. In 80% of patients, nuclear localization of β-catenin and Yes Associated Protein (YAP), a Hippo-related transactivator, is seen together. Further, stable hepatic co-expression of Δ90-CTNNB1 and active-YAP in mice causes rapid and aggressive HB. Dicer-substrate siRNAs (DsiRNAs) are potent RNA interference (RNAi) triggers that that are efficacious in preclinical tumor models of diverse origin, and are currently under clinical evaluation. To determine if CTNNB1-targeting DsiRNAs have potential as a therapy in HB, we encapsulated this oligonucleotide payload into lipid nanoparticles (LNPs), and systemically administered into mice bearing CTNNB1/YAP-induced HB. The LNP platform used, termed EnCore (because of its specific Envelope and Core lipid components), enables high encapsulation efficiency, long-term stability, and consistent analytical criteria. Downstream of LNP-mediated DsiRNA delivery, both qPCR and in situ hybridization were used to visualize changes in CTNNB1 expression in both tumor and normal liver. Robust and specific silencing of CTNNB1 mRNA was achieved in the tumors. The distribution of mRNA knockdown within each tumor nodule suggests efficient extravasation and internalization of the LNP and its payload into the tumor parenchyma, in contrast to previous reports of vascular-channel limited nanoparticle accumulation in tumors. Intriguingly, a “liver-centric” LNP formulation, which delivers cargo efficiently to a normal liver due to rapid hepatic extraction and apolipoprotein-mediated internalization, was inactive in the tumors. Further evaluation demonstrated efficacy of β-catenin targeting in this model. In conclusion, we report a highly relevant modality of RNAi delivery in a mouse model of hepatoblastoma to target a classically-undruggable oncogene.
Citation Format: Marc T. Abrams, Junyan Tao, Shanthi Ganesh, Wendy Cyr, Bo Ying, Martin Koser, Rokhand Arvan, Girish Chopda, Hank Dudek, Cheng Lai, Weimin Wang, Bob Brown, Satdarshan Monga. Targeting β-catenin with a Dicer-substrate siRNA (DsiRNA) in a sleeping beauty transposon-driven murine hepatoblastoma model. [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 3536. doi:10.1158/1538-7445.AM2015-3536
Abstract 3540: Novel targeted combinational therapies for melanoma
Authors: Suriano Robert , Tuli Neha Y. , Geliebter Jan , Tiwari Raj K. , Wallack Marc 
Published: August 2015

Abstract
The BRAFV600E mutation is frequently observed in over 60% of melanomas. Development of the small molecule inhibitor PLX4032, which specifically targets the mutated BRAF protein, offers a novel therapeutic approach by effectively blocking the activation of key signaling molecules of the mitogen-activated protein kinase (MAPK) pathway, such as Mek and Erk, effectively leading to arrest in cell proliferation. Provided that MAPK signaling targets the micropthalmia transcription factor (MITF), which is linked to the expression of various melanoma associated antigens (MAAs), we hypothesized that the inhibition of BRAFV600E can modulate the expression of MAAs. Since MAAs are essential in the development of a melanoma vaccine, due to their increased immunogenicity, altering their expression can be a useful immunotherapeutic approach to targeting melanoma. Using patient derived melanoma cell lines, which express various MAAs; our laboratory has developed a vaccinia virus based immunotherapeutic vaccine. These melanoma cell lines have been characterized by their status of BRAFV600E mutation and found to be either homozygous or heterozygous for the mutation. Inhibition of two key MAPK pathway molecules, namely Mek and Erk, denotes that the melanoma cell lines are responsive to PLX4032. Phenotypically, the cells’ invasive and migratory properties were also modulated upon treatment with PLX4032. Moreover, we observed that the expression of various MAAs was enhanced upon treatment with PLX4032. An amplification of gp100, MART-1 and tyrosinase expression on the RNA level as well as on the protein level was observed. Lastly, expression of MMAs was conserved in vivo following the analysis of melanoma cell xenografts in BALB/c nude mice. Based on our observations in that PLX4032 modulates MMA expression, further studies are warranted to determine the clinical effectiveness of combinational immunologic therapy using BRAFV600E inhibitors with our vaccinia virus melanoma cell line derived preparation.
Citation Format: Robert Suriano, Neha Y. Tuli, Jan Geliebter, Raj K. Tiwari, Marc Wallack. Novel targeted combinational therapies for melanoma. [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 3540. doi:10.1158/1538-7445.AM2015-3540