bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract A82: Bardoxolone (5MeCDDO), which induces the antioxidant response element (ARE), is ineffective in inhibiting cancer progression but inhibits cancer initiation in rodent models of cancer. What does it mean for the ARE as a primary prevention target?
Authors: Lubet Ronald A. , Townsend Reid , Clapper Margie L. , Steele Vernon E. , Grubbs Clinton J. 
Published: June 2012

Abstract
The preventive efficacies of the triterprenoid 5MeCDDO were examined in three preclinical models of breast cancer. We initially evaluated 5MeCDDO in an ER+ mammary model in which female Sprague-Dawley rats were administered MNU, i.v., at 50 days of age. 5MeCDDO (27 ppm) was administered in the diet beginning 5 days after MNU, and continuing for the duration of the study. Doses &gt;50 ppm were toxic. 5MeCDDO failed to decrease tumor latency or multiplicity and, in fact, increased the size of the cancers which did develop. This concentration of 5MeCDDO greatly increased liver to body weight ratios. We also examined the preventive efficacy of 5MeCDDO (54 and 27 mg/kg diet) in a bitransgenic model (MMTV-Neu/p53KO) of ER− mammary cancer. In this model, animals develop cancers which overexpress Neu and fail to have a mutation in the transmembrane domain of Neu. Similarly to results in the MNU model, 5 MeCDDO did not alter either tumor latency or multiplicity. The effect of 5MeCDDO was further evaluated in a third model in which ER+ tumors were induced by the procarcinogen dimethylbenzanthracene (DMBA). DMBA was administered by gavage to female Sprague-Dawley rats at 50 days of age. In this model (which examines the ability of an agent to alter the activation of the carcinogen) the preventive agent was administered beginning 7 days prior to DMBA and was continued until 7 days post DMBA. 5,6 Benzoflavone (500 ppm), a positive control, decreased tumor multiplicity &gt;90%, while 5MeCDDO (27 or 2.7 ppm) decreased multiplicity 65 and 35%, respectively. The efficacy observed in this model is in agreement with the ability of the agent to stimulate the ARE, and to induce a variety of ARE related proteins in the liver of treated rats including GST Pi, AKF 1A8, epoxide hydrolase. Thus, as expected, high induction of the ARE was associated with a decrease in DMBA-induced cancer initiation, but not a decrease in the progression stage of mammary cancer development in three cancer models. 5MeCDDO was ineffective in blocking the formation of adenomas in Min mice which have a germline mutation in the APC gene. This latter finding brings into question whether merely measuring induction of the ARE (e.g., quinone reductase) is sufficient to imply the general preventive efficacy of a given agent or mixture.
Supported by NCI contract number HHSN261200433001C.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2011 Nov 12-16; San Francisco, CA. Philadelphia (PA): AACR; Mol Cancer Ther 2011;10(11 Suppl):Abstract nr A82.
Abstract A83: 4-Ketopinoresinol, a novel naturally occurring ARE activator, induces the Nrf2/HO-1 axis and protects against oxidative stress-induced cell injury via activation of PI3K/AKT signaling.
Authors: Kuo Ching-Chuan , Chen Huang-Hui , Chen Yu-Tsen , Huang Yen-Wen , Tsai Hui-Ju 
Published: June 2012

Abstract
The Nrf2/ARE pathway plays an important role in inducing phase II detoxifying enzymes and antioxidant proteins, and has been considered as a potential target for cancer chemoprevention by eliminating harmful reactive oxygen species (ROS) or reactive intermediates generated from carcinogens. The objectives of this study were to identify a novel Nrf2/ARE activator and to investigate the mechanistic signaling pathway involved in the activation of Nrf2-mediated cytoprotective effects against oxidative-induced cell injury. A stable ARE-driven luciferase reporter cell line was established to screen the potentially cytoprotective compound. 4-Ketopinoresinol (4-KPR), the (−) double cyclized type of lignan obtained from adlay (Coix lachrymal-jobi L. var. ma-yuen Stapf), more effectively activates ARE-driven luciferase activity than the classical ARE activator, tert-butylhydroquinone. 4-KPR treatment resulted in a transient increase in AKT phosphorylation and subsequent phosphorylation and nuclear translocation of Nrf2, along with increased expression of ARE-dependent cytoprotective genes, such as heme oxygenase-1 (HO-1), aldo-keto reductases, and glutathione synthetic enzyme, and their protein products. 4-KPR suppresses oxidative stress-induced DNA damage and cell death via up-regulation of HO-1. Inhibition of PI3K/AKT signal by chemical inhibitors or RNA interference suppressed Nrf2 activation and HO-1 up-regulation. These observations in an ARE-regulated gene system suggest that 4-KPR is a novel Nrf2/ARE-mediated transcription activator, activates the Nrf2/HO-1 axis, and protects against oxidative stress-induced cell injury via activation of PI3K/AKT signaling. These results may have relevance to the clinical application of 4-KPR and its significance in cancer chemoprevention.
The study was supported by grants of DOH100-TD-C-111-004, NSC98-2320-B-400-003-MY3, and NSC99-2323-B-400-006.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2011 Nov 12-16; San Francisco, CA. Philadelphia (PA): AACR; Mol Cancer Ther 2011;10(11 Suppl):Abstract nr A83.
Abstract A98: Dual regulation of heme oxygenase-1 (HO-1) expression by retinoic acid in HL-60 cells.
Authors: Kim Jong-Suk , Noh Eun-Mi , Lee Young-Rae , Park Jinny 
Published: June 2012

Abstract
Heme oxygenase (HO)-1 has anti-oxidative, anti-inflammatory, and anti-apoptotic activities. However, little is known about the regulation of HO-1 in acute promyeolocytic leukemia (APML) cells. HL-60 cells are well differentiated by all-trans-retinoic acid (ATRA) and dimethylsulfoxide (DMSO). Here, we found that ATRA and DMSO initially stimulated HO-1 expression in HL-60 cells. However, HO-1 was clearly down-regulated at later times. Interestingly, zinc protoporphyrin (ZnPP), a strong inhibitor of HO-1, induced down-regulation of HO-1 and differentiation of HL-60 cells, as evidenced by a marked increase in the expression of the differentiation marker CD11b following ZnPP treatment. In contrast, treatment with cobalt protoporphyrin (CoPP), a strong activator of HO-1, induced HO-1 up-regulation and decreased CD11b expression. In conclusion, these data indicate that ATRA and DMSO negatively regulate HO-1 expression for inducing the differentiation of HL-60 cells.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2011 Nov 12-16; San Francisco, CA. Philadelphia (PA): AACR; Mol Cancer Ther 2011;10(11 Suppl):Abstract nr A98.
Abstract B119: AF4 mimetic peptide SPK111 prolongs survival of MLL xenografted leukemias.
Authors: Barretto Nisha , Hemenway Charles 
Published: June 2012

Abstract
Acute leukemias with balanced translocations of the MLL gene are aggressive blood cancers with generally poor prognosis. Importantly, MLL leukemias are the most common type of leukemia in babies and account for 70% of the secondary leukemias that arise following treatment with topoisomerase II inhibitors. Only 40% of infants treated for acute lymphoblastic leukemia (ALL) with MLL gene rearrangements survive to the age of five while the survival rate is 90% for patients in the same age group whose disease lacks a translocated MLL gene. Hence, better treatment options for MLL-rearranged leukemias need to be explored.
As results of reciprocal translocations, the 5' coding region of MLL is fused to the 3' coding region of one of many different genes. This results in transcripts that encode chimeric proteins. AF4 and AF9 proteins are the two most frequent fusion partners of MLL. They are components of the protein complex P-TEFb that promotes transcriptional elongation. Misdirection of the transcriptional elongation complex is one proposed mechanism by which oncogenic transformation occurs in MLL leukemias. Our laboratory previously identified the amino acids required for direct physical interaction between AF4 and AF9 and designed an AF4 mimetic peptide that disrupts the AF4 - AF9 interaction. Treatment of cell lines with MLL-AF4 and MLL-AF9 translocations with the mimetic peptide leads to necrotic cell death without affecting normal hematopoietic cells.
In order to further establish the AF4 - AF9 interaction as an effective target for MLL leukemias, we tested effect of a modified peptide designed to enhance its stability in xenografted mice. The peptide, designated SPK-111 exherts effective antitumor activity without causing overt toxicity. It significantly improves the survival of NOD/SCID mice engrafted with human cell lines carrying MLL gene rearrangements when used as a single agent. Here, we describe the in vivo activity of the peptide and propose that it, or other derivatives, may represent a clinically important agent for the treatment of MLL leukemias.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2011 Nov 12-16; San Francisco, CA. Philadelphia (PA): AACR; Mol Cancer Ther 2011;10(11 Suppl):Abstract nr B119.
Abstract B129: RAF inhibition promotes tumorigenesis in a mouse model of HPV-driven squamous cell carcinoma.
Authors: Holderfield Matthew , Lorenzana Edward , Chan John , Ghoddusi Majid , Daniel Dylan , Pryer Nancy , McCormick Frank , Stuart Darrin 
Published: June 2012

Abstract
Recent approval to market the RAF kinase inhibitor vemurafenib for treatment of metastatic melanomas positive for the BRAFV600E mutation highlights the clinical importance of MEK/ERK signaling in human cancers. Vemurafenib treatment resulted in objective responses in 52% of BRAFV600E mutation melanoma patients, although a subset of patients (20–30%) were reported to develop cutaneous squamous-cell carcinomas (cSCCs) and/or keratoacanthomas, which are independent of the melanoma and thought to be related to exposure to the RAF inhibitor. While vemurafenib effectively inhibits proliferation of BRAFV600E mutant melanomas, vemurafenib and other selective RAF kinase inhibitors can paradoxically activate the MAPK pathway and stimulate growth of BRAF wild-type cells. One hypothesis to explain the appearance cSCCs is that paradoxical activation of the MAPK pathway by RAF inhibitor treatment, in the presence of pre-existing genetic lesions, such as the loss of a tumor suppressor(s), is sufficient to promote cSCC growth. To investigate this hypothesis, we used a genetic murine model (K14-HPV16) for cSCC, which is driven by basal keratinocyte-specific expression (Keratin 14 promoter) of human papiloma virus (HPV) type 16 genes E6 and E7, inactivating the p53 and pRB tumor suppressor proteins respectively. The frequency of cSCC in K14-HPV16 mice is ∼10–20% by 8 months of age. Consistent with our hypothesis, 60 day exposure to vemurafenib at a clinically relevant dose increased the cSCC incidence to ∼65%. In addition, the incidence and severity of skin lesions was proportional to the dose of vemurafenib. Mice treated with vemurafenib also exhibited RAF activation as measured by increased levels of MAPK pathway transcriptional targets in dermal tissues where lesions most often arise. Together, these results suggest that hyperactivation of the MAPK pathway caused by vemurafenib promotes tumorigenesis of HPV-driven cSCC.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2011 Nov 12-16; San Francisco, CA. Philadelphia (PA): AACR; Mol Cancer Ther 2011;10(11 Suppl):Abstract nr B129.
Abstract B133: Antitumor effects of novel high-hydrophilic and non-ATP-competitive MEK1/2 inhibitor SMK-17.
Authors: Kiga Masaki , Tanzawa Fumie , Iwasaki Shiho , Inaba Fumi , Fujiwara Kosaku , Iwadare Hayato , Echigo Tomoki , Nakamura Yuji , Shibata Tomoyuki , Suzuki Kanae , Yasumatsu Isao , Nakayama Ayako , Sasazawa Yukiko , Tashiro Etsu , Imoto Masaya , Kurakata Shinichi 
Published: June 2012

Abstract
The mitogen-activated protein kinase (MAPK) signal pathway plays a central role in regulating tumor cell proliferation, survival, and differentiation. The components of this pathway, Ras/Raf/MEK/ERK, are frequently activated in human cancers. Targeting this pathway is considered to be a promising anticancer strategy. In particular, MEK is an attractive drug target due to its high selectivity to ERK. We can expect potent growth inhibitory and proapoptotic effects by inhibiting MEK.
We synthesized derivatives of N-[2-(2-Chloro-4-iodo-phenylamino)-3,4-difluorophenyl] -methanesulfonamide as novel MEK1/2 inhibitors. Among these compounds, we found SMK-17 to be a potent MEK1/2 inhibitor with high aqueous solubility. The in silico docking study suggested that SMK-17 be bound to an allosteric pocket of MEK1. The kinetics study and kinase profiler analysis confirmed the allosteric character of SMK-17. SMK-17 inhibited MEK1 kinase activity by a non-ATP-competitive manner and it was highly selective to MEK1 and 2. SMK-17 inhibited the growth of tumor cell lines in vitro. Especially, it seemed that cell lines harboring highly phosphorylated MEK1/2 and ERK1/2 were highly sensitive to SMK-17. Moreover, unlike previously reported MEK inhibitors, PD184352 or U0126, SMK-17 did not inhibit phosphorylation of ERK5. In vivo, SMK-17 exhibited potent antitumor activity in animal models by oral administration. SMK-17 selectively blocked the MAPK pathway signaling without affecting other signal pathways, which resulted in significant antitumor efficacy without notable side effects.
In conclusion, we found very potent MEK inhibitor SMK-17 from our structure-activity correlation study of new derivative series of diphenyl amine sulfonamide. Kinase profiler and kinetics study revealed that SMK-17 is a non-ATP-competitive and highly selective MEK1/2 inhibitor. Moreover, SMK-17 exhibited potent antitumor activity in animal models by oral administration. SMK-17 selectively blocked the MAPK pathway signaling without affecting other signal pathways both in vitro and in vivo. These findings suggest that SMK-17 is a useful chemical biology tool for characterizing the function of MEK/MAPK signaling.
Furthermore, we are now investigating the combination effects of SMK-17 with several drugs, and studying about prediction marker of this compound.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2011 Nov 12-16; San Francisco, CA. Philadelphia (PA): AACR; Mol Cancer Ther 2011;10(11 Suppl):Abstract nr B133.
Abstract B152: Modulating the activity of nerve growth factor (NGF) and its receptors tropomyosin-related kinase A (TRKA) and p75 neurotrophin receptor (p75NTR) in perineural invasion (PNI) in pancreatic cancer.
Authors: Bapat Aditi A. , Munoz Ruben M. , Maredia Saaiqa , Von Hoff Daniel D. , Han Haiyong 
Published: June 2012

Abstract
Pancreatic cancer is the fourth leading cause of cancer-related death in the US with a 5-year survival rate of less than 5%. Even after surgery and chemotherapy, prognosis is dismal due to tumor re-occurrence. Perineural Invasion (PNI) is a process where surrounding pancreatic nerves are invaded by pancreatic cancer cells. This invasive and proliferative ability of pancreatic cancer cells is indicative of their aggressiveness and is shown to be associated with poor prognosis and pain in pancreatic cancer patients. The nerve growth factor (NGF) signaling pathway is implicated in PNI and NGF binds to a high-affinity receptor, tropomyosin kinase A (TRKA), which is differentially expressed in pancreatic tumor tissues and a low-affinity receptor, p75 neurotrophin receptor (p75NTR), whose role in PNI in pancreatic cancer is unclear. In this study, we seek to understand the molecular mechanisms of NGF regulation of PNI in pancreatic cancer. Whether NGF regulates PNI via an autocrine or paracrine manner is not well understood. Signaling via NGF-TRKA pathway induces neurites in the PC-12 neurite extension assay and conditioned media (CM) from several pancreatic cancer cell lines including BxPC3 induced neurites in this assay. Addition of an antibody to neutralize NGF in the CM or an azaoxindole inhibitor (GW441756) of TRKA resulted approximately in a 50% and 40% decrease in neurites respectively in the PC-12 assay. These results could indicate a paracrine action of NGF in promoting neurite extension in the PC-12 assay and perhaps nerve growth as related to PNI. Furthermore, knocking down the expression of NGF, p75NTR, TRKA using siRNA or inhibitor GW441756 of TRKA decreased migration of BxPC3 pancreatic cancer cells in the Boyden chamber assay by 45 − 60%. A similar inhibitory effect was observed in the movement of pancreatic cancer cells towards dorsal root ganglia (DRG) in a DRG-pancreatic cancer cell co-culture assay. Thus, NGF may function in an autocrine manner to increase proliferation and invasiveness of pancreatic cancer cells in PNI. Currently, we are working to further optimize our assays to delineate the interplay between NGF and TrkA (autocrine or paracrine) in PNI and understand the involvement of p75NTR (low-affinity NGF receptor) in NGF signaling and consequently in PNI. Understanding the molecular mechanisms involved in PNI will aid in designing novel therapeutics that prevent PNI and alleviate pain associated with PNI in patients with pancreatic cancer.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2011 Nov 12-16; San Francisco, CA. Philadelphia (PA): AACR; Mol Cancer Ther 2011;10(11 Suppl):Abstract nr B152.
Abstract B234: LY2835219, a potent oral inhibitor of the cyclin-dependent kinases 4 and 6 (CDK4/6) that crosses the blood-brain barrier and demonstrates in vivo activity against intracranial human brain tumor xenografts.
Authors: Sanchez-Martinez Concepcion , Gelbert Lawrence M. , Shannon Harlan , De Dios Alfonso , Staton Brian A. , Ajamie Rose T. , Sawada Geri , Wishart Graham N. , Raub Thomas J. 
Published: June 2012

Abstract
Effective treatments for primary brain tumors and brain metastases represent a major unmet medical need. The blood-brain barrier (BBB) arises from both a structural barrier and drug efflux transporters that prevent most anti-cancer drugs from efficiently reaching brain tumors or metastases. The CDK4/6 pathway (CDK4/6-cyclin D1-Rb-CDKN2) plays a key role in regulating cellular proliferation. The importance of this pathway is highlighted by its inactivation in a majority of human tumors including glioblastoma multiforme. We have identified and characterized a potent and selective dual cdk4/6 inhibitor, LY2835219. Preclinical characterization was performed with the monomesylate salt (LY2835219-MsOH), which inhibits these kinases with IC50 values of 2 and 10 nM for CDK4 and CDK6, respectively. LY2835219-MsOH is a potent inhibitor of Rb phosphorylation in vitro and in vivo that induces G1 specific arrest and inhibition of tumor growth. To determine the potential of LY2835219-MsOH for the treatment of brain tumors and metastases, we assessed the ability of LY2835219-MsOH to cross the BBB and its interaction with the P-gp and BCRP efflux pumps that are expressed at the BBB. Using MDCK cells over-expressing either human ABCB1 (P-gp) or mouse abcg2 (Bcrp), LY2835219-MsOH and a second CDK4/6 inhibitor (PD0332991) are substrates for these two pumps, but each cross the murine BBB in vivo to a different degree. Unlike PD0332991, LY2835219-MsOH saturates BBB efflux with an unbound plasma IC50 of ∼95 nM (1.8 uM total plasma). The percent of dose in brain for LY2835219-MsOH is 0.5–3.9% and is comparable to that for temozolomide (1.9% plasma). In both a subcutaneous and intracranial human glioblastoma model (U87MG), LY2835219-MsOH suppressed tumor growth in a dose-dependent manner both as a single agent, and in combination with temozolomide. In summary, LY2835219-MsOH is a potent and selective oral CDK4/6 inhibitor that crosses the BBB and inhibits the growth of intracranial tumors alone or in combination with other agents.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2011 Nov 12-16; San Francisco, CA. Philadelphia (PA): AACR; Mol Cancer Ther 2011;10(11 Suppl):Abstract nr B234.
Abstract B36: Exploring potential clinical application of cetuximab in NSCLC: Efficacy study in a large panel patient derived xenograft (PDX) model.
Authors: Yang Mengmeng , Chen Dawei , Yang Jie , Deng Jiangyun , Song Xiaoming , Cai Jie , Chen Taiping , Chen Yiyou , Li Henry 
Published: June 2012

Abstract
NSCLC is a common cancer with one of the highest mortality numbers and few effective treatment options, except those with EGFR and ALK activating mutations. Cetuximab has been approved for CRC and H&N, but not yet for NSCLC. In this study, we set out to explore potential clinical utilities by testing cetuximab in a large cohort of patient derived xenograft (PDX) models (over established 60 models).
Among the 12 NSCLC models tested so far, 5 out of 12 were found to be sensitive (42%), with all of which have wild-type KRAS and EGFR except for 1 model that carries an EGFR exon-20 a short in-frame insertion. These data suggest that cetuximab could potentially benefit a subgroup of patients, although it remains to be seen whether cetuximab can offer additional benefit besides standard chemotherapy regimens through combinational therapies. Among the 7 resistant models, two of them have L858R mutation in EGFR, a known driver mutation for non-smoking Asian female patients who are sensitive to gefitinib treatment. This data suggests that although both cetuximab and gefitinib can block EGFR signaling, the mechanism of action may also play an important role in tumor response to drugs. Analysis of genomic analysis did not reveal obvious relationship between cetuximab sensitivity and EGFR expression level, nor EGFR copy number. This could be attributed the relative small cohort size so far.
Although the current study suggests that EGFR L858R mutation might be negatively correlated with response to cetuximab, additional studies with more PDX models are needed to further substantiate this observation, and for uncovering other biomarkers which could potentially predict patient populations who can benefit from cetuximab treatment.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2011 Nov 12-16; San Francisco, CA. Philadelphia (PA): AACR; Mol Cancer Ther 2011;10(11 Suppl):Abstract nr B36.