bluuebunny/crossref_metadata_2025 huggingface dataset:
Abstract 2685: Regulation of Ras stability via inhibition of Wnt/β-catenin pathway as a potential therapeutic strategy to treat colorectal cancers
Authors: Cha Pu-Hyeon , Cho Yong-Hee , Jeong Woo-Jeong , Kim Hyun-Yi , Choi Kang-Yell
Published: May 2015

Ras is a well-characterized proto-oncogene, and its various mutations contribute to transformation and tumorigenesis in a wide variety of human cancers. Although the GTP/GDP loading switch is known as a major regulatory mechanism of Ras, other mechanisms affecting Ras activity are poorly understood. Here, we report a mechanism for controlling Ras activity by regulating its degradation and describe this regulatory mechanism in the suppression of cellular transformation and tumors induced by Ras mutations. We found that negative regulators of Wnt/β-catenin signaling contributed to the polyubiquitin-dependent degradation of Ras following phosphorylation by glycogen synthase kinase 3β (GSK3β) and subsequent recruitment of β-TrCP-E3 ligase. We found a positive association between tumorigenesis and Ras stabilization due to the aberrant activation of Wnt/β-catenin signaling. Our results indicate an essential role for phosphorylation and degradation of Ras and suppression of Ras-induced transformation via the Wnt/β-catenin pathway and provide insight into the role of this novel regulatory mechanism for Ras in tumorigenesis of colorectal cancers (CRCs). Because both Ras and Wnt/β-catenin pathways are frequently activated in CRCs, these results suggest that the regulation of Ras stability through inhibition of the Wnt/β-catenin pathway could be an ideal therapeutic approach for treatment of CRC.

Citation Format: Pu-Hyeon Cha, Yong-Hee Cho, Woo-Jeong Jeong, Hyun-Yi Kim, Kang-Yell Choi. Regulation of Ras stability via inhibition of Wnt/β-catenin pathway as a potential therapeutic strategy to treat colorectal cancers. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 2685. doi:10.1158/1538-7445.AM2014-2685
Abstract 2688: Drugging MYCN through an allosteric transition in Aurora A kinase
Authors: Gustafson William C. , Meyerowitz Justin G. , Nekritz Erin A. , Charron Elise A. , Chanthery Yvan , Simonds Erin , Matthay Katherine , Hertz Nicholas , Shokat Kevan , Weiss William A.
Published: May 2015

MYC genes contribute to a range of cancers including neuroblastoma, where amplification of MYCN confers a poor prognosis. Proteolytic degradation of MYCN protein is regulated in part by a kinase-independent function of Aurora kinase A. We describe a class of inhibitors that disrupts the native conformation of Aurora A and causes degradation of MYCN protein across MYCN-expressing neuroblastoma cell lines. Comparison of co-crystal structures with structure- activity relationships across multiple inhibitors and chemotypes, coupled with mechanistic studies and biochemical assays, delineates an Aurora A conformation-specific effect on proteolytic degradation of MYCN, rather than simple nanomolar-level inhibition of Aurora A kinase activity. This new class of inhibitors, which disrupts stabilizing interactions between Aurora A and MYCN, represents candidate agents to target MYCN-driven and potentially MYC-driven cancers.

Citation Format: William C. Gustafson, Justin G. Meyerowitz, Erin A. Nekritz, Elise A. Charron, Yvan Chanthery, Erin Simonds, Katherine Matthay, Nicholas Hertz, Kevan Shokat, William A. Weiss. Drugging MYCN through an allosteric transition in Aurora A kinase. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 2688. doi:10.1158/1538-7445.AM2014-2688
Abstract 2696: PPAR beta/delta is a novel therapeutic target in acute myeloid leukemia
Authors: Hu Sophia , Wald David , Parameswaran Reshmi
Published: May 2015

Acute myeloid leukemia (AML) is characterized by the differentiation arrest and rapid proliferation of abnormal white blood cells. Current therapeutics involves the use of chemotherapeutic agents, which possess high toxicities and poor efficacies. Thus, there is an unparalleled need to identify low-toxicity therapies to improve the mortality of these patients. Facilitating the maturation of acute myeloid leukemia cells induces their growth arrest and death without the need for high doses of overt toxicity from chemotherapies. Therefore, we seek to identify differentiating agents capable of inducing monocytic differentiation without deleterious side-effects on normal hematopoietic tissues. One possible approach to promote AML cellular differentiation is manipulating the activity or expression of proteins, such as PPAR delta, that are known to modulate cellular growth processes. PPAR delta is part of a family of nuclear hormone receptors that function as transcription factors to induce the activation of genes related to cellular growth, development, and metabolism. PPAR alpha and PPAR gamma have been extensively characterized in the context of leukemia. However, little is known about PPAR delta. In the current study, we sought to delineate the role of PPAR delta in AML and analyze whether inhibiting the PPAR delta pathway would induce differentiation in AML cells. Inhibiting PPAR delta led to a significant increase in monocytic differentiation in AML cell lines in vitro, as measured by immunophenotyping by flow cytometry and NBT reduction assays. For instance, we observed 3% CD11b expression in untreated HL60, OCI, NB4, and U937 cell lines and 40% CD11b expression after PPAR inhibition. Importantly, PPAR delta does not lead to toxic effects on non-leukemic cells at similar doses. These results were further supported by morphological evidence of monocytic differentiation seen from Wright-Giemsa staining and a 40% decrease in AML cell proliferation following PPAR delta inhibition using the MTT cell proliferation assay. A 34% decrease in self-renewal capabilities of leukemic cells after PPAR delta inhibition suggests permanent effects on differentiation and growth arrest, as determined by colony assays. Consistent with growth inhibition, treatment with PPAR delta inhibitors induced the expression of cell cycle and proliferation-related genes such c-Myc, p21, and p27 in a dose-dependent manner. Overall, our findings suggest that PPAR delta inhibitors may possess promising clinical relevance as potential candidates for non-toxic alternatives to chemotherapy.

Note: This abstract was not presented at the meeting.

Citation Format: Sophia Hu, David Wald, Reshmi Parameswaran. PPAR beta/delta is a novel therapeutic target in acute myeloid leukemia. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 2696. doi:10.1158/1538-7445.AM2014-2696
Abstract 2699: Identification and characterization of active components of antrodia cinnamomea mycelia on targeting cancer initiating cells
Authors: Wu Meng-Chia , Lo Jeng-Fan
Published: May 2015

Background: Cancer initiating cells (CICs) are a subtype of cancer cells, which have the enhanced stemness properties and tumorigenic abilities. CICs are also considered to render resistance of chemotherapy, then, result in recurrence and metastasis. Recent researches and our discovery show that elevated activity of aldehyde dehydrogenase (ALDH) is closely related to CICs. Development of drugs that can specific target cancer initiating cells as a therapeutic method to against the disease would benefit for treatment of cancer patients.

Methods: We first used the ALDH assay to screen for purified compounds of the myceluim from Antrodia Cinnamomea with inhibitory activity in cancer cells. Then, we find out 4-acetylantroquinonol B (4-AAQN B) significantly down regulated the ALDH activity after its administration. Further, the anticancer activity of 4-AAQN B by targeting CICs will be identified both in vitro and in vivo.

Results: Our results showed that ALDH activity and stemness marker CD44, uPAR, CCN1 significantly decreased after 4-AAQN B administration. We also observed the decreased cell viability in cancer cells. On note, 4-AQQN B reduced ROS high cells, which are considered as activated CICs.

Conclusion: The anticancer activity of has been reported before. However, we are the first group to confirm that 4-AAQN B can selectively target CICs. The abovementioned findings provide an alternative therapeutics for future cancer treatment in combination with conventional chemotherapy.

Citation Format: Meng-Chia Wu, Jeng-Fan Lo. Identification and characterization of active components of antrodia cinnamomea mycelia on targeting cancer initiating cells. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 2699. doi:10.1158/1538-7445.AM2014-2699
Abstract 27: Label-free, real-time analysis of endothelial cell morphogenesis using iPSC-derived endothelial cells
Authors: Mann David , Belair David , Carlson Coby , Thompson Arne , Abassi Yama , Irelan Jeff
Published: May 2015

Endothelial cell (EC) morphogenesis during the early stages of angiogenesis is a highly dynamic process tightly regulated by growth factor activity in the extracellular milieu. Other in vitro models for the analysis of EC morphogenesis have previously been developed to understand the cellular processes and the impact of soluble cues and pharmacological inhibitors. However, these assays typically utilize end-point analysis of primary endothelial cells (eg. HUVEC), which are a physiologically relevant vascular cell type but do exhibit variability from the diversity of donors. Additionally, current methods for measuring morphogenesis (eg. proliferation and migration) only capture a snapshot of cell function owing to potentially destructive labeling of the cells and do not capture the complexity of cellular processes involved in EC morphogenesis Here, we describe use of a real-time system for monitoring of cellular processes using electronic cell sensor array technology. The cellular model tested on this impedance-based platform was a well-defined human induced pluripotent stem cell (iPSC)-derived endothelial cells. Following assay optimization and workflow improvement, we assessed the impact of serum, growth factors (e.g. VEGF, EGF, FGF-2), and small-molecule angiogenesis inhibitors (e.g. Sunitinib, SU1498) on the proliferation, migration, and invasion of iPSC-derived ECs compared to primary cells. We observed that real-time monitoring of such cellular processes offers distinct and important advantages over traditional end-point assays - specifically, the ability to measure receptor activation and quantify morphologic and adhesive remodeling of EC upon growth factor activation or signaling inhibition. By better understanding cellular morphogenesis in vitro, we can generate a picture of what soluble cues regulate the process and how pharmacological agents can modulate the different cell fates underlying morphogenesis. The use of iPSC-derived endothelial cells provides a robust and reproducible source of cells that perform equivalently to the standard that is HUVEC. The combination of iPSC-derived EC together with a real time monitoring system provides a biologically relevant human model system.

Citation Format: David Mann, David Belair, Coby Carlson, Arne Thompson, Yama Abassi, Jeff Irelan. Label-free, real-time analysis of endothelial cell morphogenesis using iPSC-derived endothelial cells. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 27. doi:10.1158/1538-7445.AM2014-27
Abstract 2701: Antitumor effects of peptide Rb4 derived from proteolipid protein 2 (PLP2) in a syngeneic murine melanoma model
Authors: Maia Vera S C , Berzaghi Rodrigo , Arruda Denise C. , Melo Pollyana M S , Travassos Luiz R.
Published: May 2015

Peptides have increasingly being investigated as drug candidates for treatment of pathologies ranging from Alzheimer`s disease to cancer. Literature shows that over expression of proteolipid protein 2 (PLP2) was associated with metastasis of B16F10 melanoma. Authors showed later that knock-down of PLP2 inhibited growth and metastasis of melanoma cells. The present work aimed at studying the antitumor activity of peptide Rb4 derived from protein PLP2. Peptide Rb4, tested as synthetic peptide on B16F10-Nex2 cells showed antitumor effects in vitro and in vivo. Rb4 induces a remarkable F-actin depolymerization, and also antagonizes thapsigargin blockade of calcium channels on the endoplasmic reticulum (ER). Such effects on actin dynamics and calcium flow cause apoptosis in murine melanoma B16F10-Nex2, and reduce the viability of several human cancer cell lines. Chromatin condensation, DNA fragmentation, caspase 9 and caspase 3 activation are compatible with tumor cell apoptosis. Early effects of the peptide were cell rounding and aggregation, followed by substrate detachment. In vivo, peptide Rb4 reduced metastatic activity of B16F10-Nex2 cells and delayed the subcutaneous growth of murine melanoma in the syngeneic model. The protective effect of Rb4 observed in the metastatic melanoma model was not, however, observed in immunodeficient mice. Peptide Rb4 induces the expression of two DAMPs (damage-associated molecular patterns), HMGB1 and calreticulin in B16F10-Nex2. Apart from a direct adjuvant effect of Rb4 on dendritic cells (DCs), the expression of DAMPs by tumor cells may also contribute to DCs activation thus explaining the protective effect of the peptide in vivo against B16F10-Nex2 melanoma. In conclusion, we suggest that peptide Rb4 is a promising compound to be developed as an anticancer drug. Supported by FAPESP grant 2010/51423-0 and the Brazilian National Research Council (CNPq).

Citation Format: Vera S C Maia, Rodrigo Berzaghi, Denise C. Arruda, Pollyana M S Melo, Luiz R. Travassos. Antitumor effects of peptide Rb4 derived from proteolipid protein 2 (PLP2) in a syngeneic murine melanoma model. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 2701. doi:10.1158/1538-7445.AM2014-2701
Abstract 2703: Effect of route and dosing regimen on efficacy of SH7139 in mouse Burkitt's lymphoma xenografts
Authors: Balhorn Rodney , Mirick Gary , DeNardo Gerald L. , Beckett Laurel , Li Judy , Hok Saphon , Balhorn Monique
Published: May 2015

SH7139, our most advanced small molecule therapeutic for non-Hodgkin's lymphoma, was designed to bind to a unique site on HLA-DR10, a cell surface receptor found on B-cell lymphocytes and over-expressed on B-cell derived malignancies. Studies conducted with lymphoma and other cell lines have shown that SH7139 binds selectively and is highly cytotoxic only to tumor cells expressing HLA-DR10. A previous study also showed SH7139 to be highly effective in treating human Burkitt's lymphoma (Raji) in a mouse xenograft model. We have used this same mouse model to compare the efficacy of SH7139 delivered by different routes and using different treatment regimens. The results show that the greatest survival times were achieved with mice given SH7139 by i.p. injection on days 0, 7 and 14. Doses delivered i.p. on days 0, 2 and 4 and orally on days 0,7,14,21,28 and 35 were slightly less effective, and a single dose delivered i.p. on day 0 and three doses delivered orally on days 0, 7, and 14 were the least effective. The concentration of SH7139 that achieved these effects in vivo, which was determined by measuring xenograft uptake of 111-In-labeled SH7139, was found to be in the sub-nanomolar range. In addition to identifying the best route and dosing regimen for future studies and confirming the drug works in vivo at concentrations similar to those found to be effective in cells cultured in vitro, these studies also show the drug can be effective when administered orally.

Citation Format: Rodney Balhorn, Gary Mirick, Gerald L. DeNardo, Laurel Beckett, Judy Li, Saphon Hok, Monique Balhorn. Effect of route and dosing regimen on efficacy of SH7139 in mouse Burkitt's lymphoma xenografts. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 2703. doi:10.1158/1538-7445.AM2014-2703
Abstract 2707: In vitro and in vivo evaluation of SNG1153, a synthetic modulator of ER-α36
Authors: Zhang Bo , Meng Kun , Shang Xiao , Wang Zhaoyi , Zhang Yanzhong , Fang Fang , Wang Jing , Wang Zonghui , Wang Jun , Guo Yuming , Liu Shiyang , Chen Feng , Ding Hongxia , Zhang Jiancun , Bao Jun
Published: May 2015

Background: ER-α36, a novel truncated variant of estrogen receptor α, was recently discovered and extensively studied as a potential therapeutic target. ER-α36 was found to be overexpressed in many cancers including estrogen-positive and negative breast cancer, lung cancer, prostate cancer, endometrial cancer, liver cancer and other cancers. This suggests that ER-α36 is potentially a promising target for the development of novel anticancer agents with broader clinical applications. This study aims to evaluate the in vitro and in vivo performance of SNG1153, an orally available, synthetic modulator of ER-α36. Methods: the viabilities of ER-α36 overexpressed cancer cells were evaluated using a CCK-8 assay after exposure to SNG1153. Pharmacokinetic study was conducted in rat and SNG1153 was administered orally in escalated doses. In-vivo efficacies of SNG1153 were evaluated in Bcap-37 xenograft model, Ishikawa xenograft model and SPC-A-1 xenograft model. Results: SNG1153 showed significant inhibition at low micromolar concentrations in ER-α36 overexpressed cell lines including the one resistant to tamoxifen. SNG1153 exhibited a linear PK profile with a bioavailability of more than 55% in the rat PK study. In the in-vivo efficacy studies, 3 doses were investigated and SNG1153 showed dose-dependent inhibition. The tumor growth inhibition at high dose was 57% in the breast cancer Bcap-37 xenograft model, 65% in the endometrial cancer Ishikawa xenograft model and 52% in lung adenocarcinoma SPC-A-1 xenograft model. No signs of toxicity were observed in these models. Conclusion: SNG1153, as a synthetic ER-α36 modulator, showed promising activities in many in vitro and in vivo models. It is currently in preclinical development stage.

Citation Format: Bo Zhang, Kun Meng, Xiao Shang, Zhaoyi Wang, Yanzhong Zhang, Fang Fang, Jing Wang, Zonghui Wang, Jun Wang, Yuming Guo, Shiyang Liu, Feng Chen, Hongxia Ding, Jiancun Zhang, Jun Bao. In vitro and in vivo evaluation of SNG1153, a synthetic modulator of ER-α36. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 2707. doi:10.1158/1538-7445.AM2014-2707
Abstract 271: Rising rates of acute lymphocytic leukemia in Hispanic children: A review of trends in childhood leukemia incidence from 1973-2010
Authors: Barrington-Trimis Jessica , Cockburn Myles , Metayer Catherine , Gauderman W. James , Wiemels Joseph , McKean-Cowdin Roberta
Published: May 2015

Background: Childhood leukemia is the most common cancer in children under 20 years of age in the United States, and incidence rates have increased over the last few decades. The incidence rate for all childhood leukemia is higher among Hispanic children [2006-2010 age-adjusted incidence rate (AAIR)= 5.71; 95%CI: 5.47, 5.97] than among non-Hispanic White children (2006-2010 AAIR=3.95; 95%CI: 3.81, 4.09). This analysis aims to describe secular trends from 1992-2010 in the incidence of childhood leukemia, independently for Hispanic and non-Hispanic children.

Methods: Surveillance, Epidemiology and End Results (SEER) data were used to evaluate trends in the incidence of childhood leukemia diagnosed in children less than 20 years of age between 1992-2010 by ethnicity. Trends among Hispanic and non-Hispanic children were examined overall and by age, gender, and histologic subtype. AAIRs, annual percent change (APC) estimates, and 95% confidence intervals (95%CIs) were calculated using SEER*stat v.8.0.4.

Results: Hispanic children were more likely than non-Hispanic children to be diagnosed with leukemia (all subtypes combined), and with acute lymphocytic leukemia when examined by gender and by age (0-4, 5-9, 10-14, 15-19 years at diagnosis). A greater increase in AAIRs was observed for Hispanic children as compared to non-Hispanic children for all types of leukemia from 1992-2010 (APCHispanic=1.16; 95%CI: 0.55, 1.76; APCnon-Hispanic=0.52; 95%CI: 0.01, 1.03). When restricting to acute lymphocytic leukemias (ALL), statistically significant increases were observed for Hispanic children (APC=1.31; 95%CI:0.68, 1.94), but not for non-Hispanic children (APC=0.50; 95%CI: -0.19, 1.19). Among Hispanic children, the strongest increase was found among children diagnosed from 10-19 years of age. Incidence rates were higher for Hispanic males (AAIR=5.26; 95%CI: 4.93, 5.60;) than for Hispanic females (AAIR=4.07; 95%CI: 3.78, 4.39).

Conclusion: Incidence rates of childhood leukemia rose from 1992-2010, with the greatest increase for ALL among older Hispanic children (aged 10-19 years). In future studies aimed at evaluating exposures responsible for increasing incidence rates of childhood ALL, researchers should consider risk factors that may explain the rising rates among Hispanic children.

Citation Format: Jessica Barrington-Trimis, Myles Cockburn, Catherine Metayer, W. James Gauderman, Joseph Wiemels, Roberta McKean-Cowdin. Rising rates of acute lymphocytic leukemia in Hispanic children: A review of trends in childhood leukemia incidence from 1973-2010. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 271. doi:10.1158/1538-7445.AM2014-271
Abstract 2711: CARP-1 functional mimetics are a novel class of small molecule inhibitors of malignant pleural mesothelioma cells
Authors: Jamal Shazia , Cheriyan Vino T. , Muthu Magesh , Munie Sara , Levi Edi , Ashour Abdelkader E. , Pass Harvey I. , Wali Anil , Singh Mandip , Rishi Arun K.
Published: May 2015

Malignant pleural mesothelioma (MPM) is an asbestos-related thoracic malignancy that is characterized by late metastases, and resistance to therapeutic modalities. The toxic side-effects of MPM therapies often limit their clinical effectiveness, thus necessitating development of new agents to effectively treat and manage this disease in clinic. CARP-1 functional mimetics (CFMs) are a novel class of compounds that inhibit growth of diverse cancer cell types. Here we investigated MPM cell growth suppression by the CFMs and the molecular mechanisms involved. CFM-1, -4, and -5 inhibited MPM cell growth, in vitro, in part by stimulating apoptosis. Apoptosis by CFM-4 involved activation of pro-apoptotic stress-activated kinases (SAPKs) p38 and JNK, elevated CARP-1 expression, cleavage of PARP1, and loss of the oncogene c-myc as well as mitotic cyclin B1. Treatments of MPM cells with CFM-4 resulted in depletion of NF-κB signaling inhibitor ABIN1 and Inhibitory κB (IκB)α and β, while increasing expression of pro-apoptotic death receptor (DR) 4 protein. CFM-4 enhanced expression of serine-phosphorylated podoplanin and cleavage of vimetin. CFMs also attenuated biological properties of the MPM cells by blocking their abilities to migrate, form colonies in suspension, and invade through the matrix-coated membranes. Both podoplanin and vimentin regulate processes of cell motility and invasion, and their expression often correlates with metastatic disease, and poor prognosis. The fact that phosphorylation of serines in the cytoplasmic domain of podoplanin interferes with processes of cellular motility, CFM-4-dependent elevated phosphorylated podoplanin and cleavage of vimentin underscore a metastasis inhibitory property of these compounds, and suggest that CFMs and/or their future analogs have potential as anti-MPM agents.

Citation Format: Shazia Jamal, Vino T. Cheriyan, Magesh Muthu, Sara Munie, Edi Levi, Abdelkader E. Ashour, Harvey I. Pass, Anil Wali, Mandip Singh, Arun K. Rishi. CARP-1 functional mimetics are a novel class of small molecule inhibitors of malignant pleural mesothelioma cells. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 2711. doi:10.1158/1538-7445.AM2014-2711
Abstract 2712: ISC-4, a novel inhibitor of hedgehog-Gli signaling, inhibits growth of CSC and CTC of melanoma patients
Authors: Sharma Arun K. , Jani Jitesh , Sharma Cristian , Cleary Patrick , Sharma Michael , Satish Shruthi , Gomez Esteban , Prez Michael , Amezcua Natalee , Navel Mariam , Karelia Deepkamal N. , Desai Dhimant , Amin Shantu , Sharma Jay
Published: May 2015

Melanoma is one of the most aggressive cancers, and its incidence and mortality rate are on rise since no treatment options are available for metastatic disease. Recent evidences from in vitro and in vivo studies have demonstrated that aberrant reactivation of the Sonic Hedgehog (SHH) signaling pathway regulates genes that promote cellular proliferation in various human cancer stem cells (CSC) 36118-45. In melanoma cells, RAS-MEK and AKT signaling has also been shown to regulate the nuclear localization and transcriptional activity of Gli-1. Therefore, the agents that inhibit activation of Gli transcription factors have emerged as promising novel therapeutic drugs for pancreatic cancer. Through extensive structure-activity studies in our laboratory, based on naturally occurring isothiocyanates (ITCs) and their isosteric selenium analogs, we have recently identified phenylbutyl isoselecynate (ISC-4) as a promising agent that significantly retarded melanoma tumor growth without any systemic toxicity. We demonstrate here the effect of ISC-4 on the proliferation of CSC and 36118-45CTC (circulating tumor cell) cells isolated from a melanoma patient. ISC-4 treatments resulted in a dose-dependent inhibition of SHH signaling (SMO, PTCH-1, Gli1, Gli2, and Gli3) and induced significant growth inhibition of CSC and CTC cells. The data demonstrate that Hh signaling regulates proliferation of CSC and CTC of human melanoma and treatment with agents like ISC-4 might be a novel approach to prevent growth and metastasis of human melanoma.

Citation Format: Arun K. Sharma, Jitesh Jani, Cristian Sharma, Patrick Cleary, Michael Sharma, Shruthi Satish, Esteban Gomez, Michael Prez, Natalee Amezcua, Mariam Navel, Deepkamal N. Karelia, Dhimant Desai, Shantu Amin, Jay Sharma. ISC-4, a novel inhibitor of hedgehog-Gli signaling, inhibits growth of CSC and CTC of melanoma patients. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 2712. doi:10.1158/1538-7445.AM2014-2712
Abstract 2716: Discovery of novel TAM family kinase inhibitors
Authors: Zhang Zaihui , Li Rick , Lee Erica , Hu Yuxiang , Yan Jun , Sanghera Jasbinder
Published: May 2015

TAM family (Tyro3, Axl, and Mer) of receptor tyrosine kinases mediated signaling is involved in cell survival, proliferation, migration and adhesion, vascular smooth muscle homeostasis, platelet function and erythropoiesis, and regulation of inflammatory cytokine release. These RTKs are frequently co-expressed in vascular, reproductive, nervous, and immune system in adults. TAM family kinases can be activated by vitamin K-dependent ligands GAS6 and Protein S. Tyro3, Axl, and Mer also display ectopic or overexpression in numerous cancers, including myeloid and lymphoblastic leukemias, melanoma, breast, lung, colon, liver, gastric, kidney, ovarian, uterine, and brain cancers. Therefore, they represent another class of kinase targets for development of cancer therapy. In this study, we report the discovery of a new class of potent and selective inhibitors of TAM family. These new compounds have demonstrated in vitro potency in nM range against these kinases and selectivity against other kinases in a selected panel. Many of these new compounds can dramatically reduce the pAkt levels in several cancer cell lines in a dose dependent manner. In thymidine incorporation assay, some compounds showed inhibition of cell proliferation at sub-micromolar concentrations. Furthermore, some compounds have demonstrated efficacy in colony formation assays. The most promising compounds are now being selected for in vivo proof-of-concept studies. The pharmaceutical properties of these compounds together with ADME profile were also evaluated. Taken together, the data generated so far indicates that these new inhibitors of TAM family kinases represent a new approach for cancer therapy.

Citation Format: Zaihui Zhang, Rick Li, Erica Lee, Yuxiang Hu, Jun Yan, Jasbinder Sanghera. Discovery of novel TAM family kinase inhibitors. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 2716. doi:10.1158/1538-7445.AM2014-2716
Abstract 2718: Targeting ribosome biogenesis with CX5461 as a potential treatment for melanoma and ovarian cancer
Authors: Sheppard Karen E. , Brajanovski Natalie , Hannan Katherine M. , Ahearn Jessica , Ellul Jason , Drygin Denis , O'Brien Sean , McArthur Grant , Hannan Ross D. , Pearson Richard B.
Published: May 2015

Ribosome biogenesis provides the molecular machinery required for protein synthesis, thus it dictates the ability of a cell to grow and proliferate. We have recently demonstrated that inhibiting ribosome biogenesis with a small molecule that inhibits RNA Polymerase (POL) I driven transcription (CX5461) selectively killed B-lymphoma cells in vivo while maintaining a viable wild-type B cell population (Bywater et al., Cancer Cell 22: p51, 2012). The therapeutic effect was mediated via nucleolar disruption and activation of p53-dependent apoptotic signalling. Although this response was dependent on p53, cell lines from solid tumors with mutant p53 also respond to CX5461 (Drygin et al., Cancer Res 71: p1418, 2011).

Dysregulation of both the PI3K and RAS/ERK pathways are common in ovarian cancer and BRAF is mutated and activated in over 50% of melanomas; a cancer that also commonly expresses wild type-p53. Given that both these pathways are critical regulators of ribosome biogenesis, we hypothesized that targeting ribosome biogenesis may be a new and potent approach to treating these cancers.

To determine the efficacy of CX5461 a panel of ovarian cancer and melanoma cell lines were treated with CX5461 and cell proliferation assessed. The majority of cell lines were sensitive to CX5461 and differential gene expression between resistant and sensitive ovarian cancer cell lines revealed sensitivity was associated with signatures of increased MYC signalling and BRCA1 and 2 mutation. Gene expression and assessment of rDNA transcription suggested that resistance in both ovarian cancer and melanoma cell lines was associated with an inability of CX5461 to inhibit POL1 driven transcription. These studies indicate that targeting ribosome biogenesis and function may provide a new therapeutic option for treating ovarian cancer and melanoma.

Citation Format: Karen E. Sheppard, Natalie Brajanovski, Katherine M. Hannan, Jessica Ahearn, Jason Ellul, Denis Drygin, Sean O'Brien, Grant McArthur, Ross D. Hannan, Richard B. Pearson. Targeting ribosome biogenesis with CX5461 as a potential treatment for melanoma and ovarian cancer. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 2718. doi:10.1158/1538-7445.AM2014-2718
Abstract 2721: Novel biisoquinoimidazolium-derivatives for breast cancer therapy
Authors: Narayan Satya , Jaiswal Aruna S. , Hong Sukwon
Published: May 2015

Breast cancer is the most frequently diagnosed cancer in women. This cancer is classified according to its expression of hormone/growth factor receptors. It is divided into three groups: (i) Estrogen receptor (ER) and progesterone receptor (PR)-positive; (ii) Human epidermal growth factor receptor 2 (HER2)-positive; and (iii) ER, PR, and HER2-negative (triple-negative). Most chemotherapeutic anti-cancer drugs used in the clinical practice include an anti-estrogenic agent that interferes with ER and prevents tumor progression; however, it is still a big challenge to manage the triple-negative breast tumors. Mitosis and other distinct pathways of apoptosis are considered as a potential target for the development of novel anti-mitotic drugs. In the present investigation, we designed the biisoquinoimidazoliums class of drugs which is structurally similar to anti-mitotic drugs. We synthesized various derivatives of biisoquinoimidazoliums, tested their potency, and suitability as therapeutic agents in preclinical biological system using clonogenic assay. Results showed a strong growth inhibitory effect of these compounds on both triple-positive and triple-negative breast cancer cell lines in the following order: DHO2-93-1 ≥ DHO2-85-3 ≥ DHO2-75-3 ≥ DHO2-85-1. DH02-75-1 also showed some activity, while DHO2-75-2 and DHO2-107-1 did not show any growth inhibitory effect on these cells. From these results, we concluded that DHO2-93-1 may have therapeutic implication as a novel anti-tumor drug for the intervention of both triple-positive and triple-negative breast cancers.

Citation Format: Satya Narayan, Aruna S. Jaiswal, Sukwon Hong. Novel biisoquinoimidazolium-derivatives for breast cancer therapy. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 2721. doi:10.1158/1538-7445.AM2014-2721
Abstract 2730: RNAi knockdown or chemical inhibition of anaphase-promoting complex components is synthetic lethal with HSP90 inhibition
Authors: Howes Jennifer , Lu Bing-Feng , Powers Marissa , Mitsopoulos Costas , Al-Lazikani Bissan , Linardopoulos Spiros , Clarke Paul , Workman Paul
Published: May 2015

The molecular chaperone heat shock protein 90 (HSP90) maintains the conformation, stability and function of oncogenic client proteins, many of which are mutated or overexpressed. Therefore, HSP90 is an important cancer therapeutic target. To further increase the efficacy of HSP90 inhibitors, combinatorial therapeutic strategies may be beneficial. Here we report an unbiased global screening approach to identify genes that encode potentially druggable proteins that modulate cellular responses to HSP90 inhibition. From the 7,593 genes that were tested, three components of the anaphase-promoting complex (APC/C) were among the genes which when silenced caused significant HSP90 inhibitor sensitisation. siRNA knockdown of ANAPC1, -8 or -4 produced up to three-fold sensitisation to HSP90 inhibitors 17-AAG and AUY922 in human colon cancer cells. Intriguingly, we show that combinatorial siRNA-mediated ANAPC1 knockdown and HSP90 inhibition induced an accumulation of mitotic cells exhibiting a tri-polar spindle formation. A marked increase in cyclin B1 and aurora A protein levels was observed in response to combinatorial ANAPC1 knockdown and HSP90 inhibition. These effects may have been responsible for the observed formation of aberrations in the mitotic spindle architecture. Furthermore, after a period of prolonged mitotic arrest, cancer cells treated with combinational ANAPC1 knockdown and HSP90 inhibition were committed to apoptosis. Mimicking siRNA knockdown, treatment with the APC/C inhibitor proTAME synergistically sensitised human colon carcinoma cells to HSP90 inhibition. These exciting results provide a mechanistic explanation underlying the HSP90 inhibitor sensitisation phenotype, and suggest that the APC/C may represent an interesting therapeutic target to exploit in combination with HSP90 inhibitors. Furthermore, therapeutic approaches may be developed which exploit the vulnerability of mitotic cancer cells in the context of HSP90 inhibition.

Citation Format: Jennifer Howes, Bing-Feng Lu, Marissa Powers, Costas Mitsopoulos, Bissan Al-Lazikani, Spiros Linardopoulos, Paul Clarke, Paul Workman. RNAi knockdown or chemical inhibition of anaphase-promoting complex components is synthetic lethal with HSP90 inhibition. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 2730. doi:10.1158/1538-7445.AM2014-2730
Abstract 2736: Thymidine catabolic and salvage pathways are responsible for the heterogeneity of anticancer agent dT-QX in liver cancer cells
Authors: Zhou Qibing , Wei Qiong , Zhang Dejun
Published: May 2015

Thymidine analog 3′-deoxythymidine phenylquinoxaline conjugate (dT-QX) can selectively kill cancer cell lines while is low cytotoxic towards normal liver cells. However, the cytotoxicity of dT-QX varied among cell lines of the same type cancer. Thus, the mechanism of the heterogeneity towards dT-QX was investigated. Considering that dT-QX is a thymidine analog, pathways of cellular thymidine metabolism were studied including catabolic and salvage pathways. The expression levels of enzymes of these two pathways among different cell lines of liver cancer were determined and compared. In addition, the impact on the activity of dT-QX by overexpressing and silencing the enzymes of these two pathways was assessed. Furthermore, a series of dT-QX analogs were synthesized and tested to reveal the potential structure-activity relationship to address the heterogeneity. Our initial results indicated that there was dramatic difference on the enzyme levels of thymidine catabolic and salvage pathways among the different cell lines of liver cancer. Modulation of the level of these enzymes resulted in significant impact on the activity of dT-QX. Variation on the cytotoxic activity was even observed with different structural analogs tested on these liver cancer cell lines. Our data suggested that thymidine catabolic and salvage pathways counteracted toward each other and thus were responsible for the heterogeneity of dT-QX in liver cancer cells.

Citation Format: Qibing Zhou, Qiong Wei, Dejun Zhang. Thymidine catabolic and salvage pathways are responsible for the heterogeneity of anticancer agent dT-QX in liver cancer cells. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 2736. doi:10.1158/1538-7445.AM2014-2736
Abstract 2738: Expression of p73 isoforms regulates proliferation and chemotherapeutic response in diffuse large B-cell lymphoma
Authors: Hassan Hesham M. , Varney Michelle L. , Singh rakesh K. , Dave Bhavana J.
Published: May 2015

Diffuse large B-cell lymphoma (DLBCL) is the most common subtype of non-Hodgkin lymphoma (NHL). TP73 gene is a member of the p53 tumor suppressor gene family, which is critical in the regulation of cell cycle and apoptosis. TP73 is located in distal 1p36 chromosomal region that is commonly disrupted in DLBCL. TP73 gene function is controlled by a balance between two isoforms with opposing functions, the full length TAp73 protein (pro-apoptotic) and the NH2-terminally truncated ΔNp73 protein (anti-apoptotic by antagonizing both TAp73 and p53). Up-regulated expression of -Np73 isoforms has been reported in activated and germinal center B- cells as compared to very low levels in memory B- cells and follicular mantle cells, suggesting temporal expression of -Np73 isoforms during specific B- cell developmental stages. In the present study we have investigated the biological relevance of p73 isoforms in DLBCL. The DLBCL cell line DHL-16 was transfected with TAp73 encoded mammalian expression vector. The ‘control cells’ comprised of DHL-16 cells transfected with control vector. To evaluate growth differences under basal conditions as well as with serum deprivation, phenotypic comparison was performed between the two cell lines. Further, to evaluate the response to chemotherapy and to determine the differences in transcriptional targets, the p73 transfected and control cells were studied for the expression of p73 transcriptional targets PUMA, BIM, and GRAMD4. TAp73-transfected cells were more sensitive to serum deprivation and chemotherapy and showed an increased expression of the pro-apoptotic p73 transcriptional targets compared to control cells. We transfected DHL-16 cells with a truncated p73 isoform functionally similar to ΔNp73. These ΔNp73-transfected cells were resistant to serum deprivation and chemotherapy and showed a reduction in the expression of the pro-apoptotic p73 transcriptional targets PUMA, BIM, and GRAMD4 compared to control-vector transfected cells. Together, our data demonstrate that modulation of p73 isoform expression can alter the behavior of DLBCL and highlights p73 as a potential new therapeutic target in DLBCL.

Note: This abstract was not presented at the meeting.

Citation Format: Hesham M. Hassan, Michelle L. Varney, rakesh K. Singh, Bhavana J. Dave. Expression of p73 isoforms regulates proliferation and chemotherapeutic response in diffuse large B-cell lymphoma. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 2738. doi:10.1158/1538-7445.AM2014-2738
Abstract 2742: The PARP inhibitor niraparib demonstrates robust activity in a subset of patient-derived triple-negative breast cancer xenograft models
Authors: Wang Yan , Cairo Stefano , Nicolle Delphine , Cristescu Razvan , Loboda Andrey , Nebozhyn Michael , Zhang Theresa , Judde Jean-Gabriel , Wilcoxen Keith
Published: May 2015

Triple negative breast cancer (TNBC), which comprises 15% of all breast cancers, has a poor prognosis and currently lacks effective treatment. TNBCs are highly proliferative, genomically unstable and share molecular characteristics with BRCA1-/- breast cancer. Poly(ADP-ribose) polymerase-1 (PARP) is a key DNA repair enzyme that mediates single strand break (SSB) repair through the base excision repair (BER) pathway. PARP inhibitors have been demonstrated to selectively kill tumor cells that harbor BRCA1 and BRCA2 mutations. In addition, pre-clinical and preliminary clinical data suggest that PARP inhibitors are selectively cytotoxic for tumors with homologous recombination repair deficiency caused by mutations in genes other than BRCA1 or BRCA2. Niraparib is a potent, orally active PARP inhibitor that is being evaluated in Phase 3 clinical studies for ovarian cancer and BRCA related breast cancer. In exploring additional tumor indications that may be sensitive to niraparib, we investigated niraparib monotherapy activity in a panel of 17 basal breast cancer (BBC) patient-derived xenograft (PDX) models. Thirteen of the seventeen BBC models are TNBC models. Niraparib was administered po at a dose of 50 mg/kg once per day for 28 consecutive days, and tumor volume and body weight were measured twice weekly. Niraparib was well tolerated in nude mice bearing human TNBC PDXs growing subcutaneously, as there was no indication of body weight loss or decreased body weight gain relative to the vehicle control. Niraparib exhibited robust efficacy in five of the seventeen models tested. All five responsive models were TNBC. To understand the selectivity observed, a comprehensive analysis of the tumors was conducted which included analysis of gene mutation, gene copy number, gene expression and miRNA expression. A number of individual biomarkers and gene expression signatures were identified consistent with niraparib sensitivity across the 17 PDX models and will be discussed. In conclusion, in vivo activity of niraparib in TNBC was demonstrated in a panel of breast cancer PDX models, and several potential markers of niraparib sensitivity have been identified. Collectively this data supports the clinical investigation of niraparib in a subset of TNBC patients.

Citation Format: Yan Wang, Stefano Cairo, Delphine Nicolle, Razvan Cristescu, Andrey Loboda, Michael Nebozhyn, Theresa Zhang, Jean-Gabriel Judde, Keith Wilcoxen. The PARP inhibitor niraparib demonstrates robust activity in a subset of patient-derived triple-negative breast cancer xenograft models. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 2742. doi:10.1158/1538-7445.AM2014-2742
Abstract 2745: Pharmacological characterisation of cell active inhibitors of Poly(ADP-ribose) glycohydrolase (PARG)
Authors: James Dominic , Jordan Allan , Hamilton Nicola , McGonagle Alison , Smith Kate , Stowell Alexandra , Waddell Ian , Waszkowycz Bohdan , Ogilvie Donald
Published: May 2015

Poly(ADP-ribose) glycohydrolase (PARG) is the only enzyme known to catalyse hydrolysis of the O-glycosidic linkages of ADP-ribose polymers, thereby reversing the effects of poly(ADP-ribose) polymerases. Total PARG deficiency leads to cell death whilst PARG depletion, using RNAi, leads to pleiotropic effects such as PAR chain persistence, progression of single- to double-strand DNA lesions and NAD+ depletion.

Whilst efforts to develop small molecule inhibitors of PARG activity have generally been hampered by poor physiochemical properties, off-target pharmacology and a lack of cell permeability, we have now developed a series of PARG inhibitors which have proved to be useful biological tool compounds.

Displaying selective activity in both biochemical and, more importantly, cellular assays of PARG function, these derivatives have allowed an exploration of the phenotypes resulting from reversible, pharmacological PARG inhibition.

Citation Format: Dominic James, Allan Jordan, Nicola Hamilton, Alison McGonagle, Kate Smith, Alexandra Stowell, Ian Waddell, Bohdan Waszkowycz, Donald Ogilvie. Pharmacological characterisation of cell active inhibitors of Poly(ADP-ribose) glycohydrolase (PARG). [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 2745. doi:10.1158/1538-7445.AM2014-2745