bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract C55: Discovery and optimization of inhibitors of the KIFC1 motor protein.
Authors: Lamb Michelle L. , Wu Jiaquan , Mikule Keith , Wang Wendy , Su Nancy , Petteruti Philip , Gharahdaghi Farzin , Code Erin , Zhu Xiahui , Jacques Kelly , Lai Zhongwu , Zhang Tao , Boulay David , Grewal Gurmit , Keen Nicholas , Yang Bin , Chuaqui Claudio , Chuaqui Claudio , Chen Huawei 
Published: August 2014

Abstract
KIFC1, a kinesin-14 family protein, plays an essential role in centrosomal bundling, a strategy employed by cancer cells to avoid multipolar mitosis in the presence of amplified centrosomes. However, its function is not required for normal diploid cell division, suggesting that KIFC1 is an attractive therapeutic target for human cancers. We have recently reported the first small molecule inhibitor of KIFC1, AZ82 [1]. AZ82 binds specifically to the KIFC1/microtubule (MT) binary complex, and inhibits the MT-stimulated KIFC1 enzymatic activity with a KI of 0.043 µM. AZ82 effectively engaged with the minus-end directed KIFC1 motor in HeLa cells to reverse the monopolar spindle phenotype induced by the inhibition of the plus end-directed kinesin Eg5 by AZD4877, consistent with what was observed with genetic knock down of KiFC1 by siRNA. Additionally, treatment with AZ82 caused centrosome declustering in BT-549 breast cancer cells with amplified centrosomes. Here we further describe the chemistry approach and related structure-activity relationships that led to the discovery of AZ82.
[1] http://pubs.acs.org/doi/abs/10.1021/cb400186w
Citation Information: Mol Cancer Ther 2013;12(11 Suppl):C55.
Citation Format: Michelle L. Lamb, Jiaquan Wu, Keith Mikule, Wendy Wang, Nancy Su, Philip Petteruti, Farzin Gharahdaghi, Erin Code, Xiahui Zhu, Kelly Jacques, Zhongwu Lai, Tao Zhang, David Boulay, Gurmit Grewal, Nicholas Keen, Bin Yang, Claudio Chuaqui, Claudio Chuaqui, Huawei Chen. Discovery and optimization of inhibitors of the KIFC1 motor protein. [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2013 Oct 19-23; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2013;12(11 Suppl):Abstract nr C55.
Abstract C58: GS-19, a novel GSK inhibitor suppresses the growth of pancreatic cancer cells by inhibiting EGFR/AKT/STAT-3 signaling.
Authors: Ranjan Alok , Srivastava Sanjay K. , Gupta Parul , Birkenfeld Ashlee , Hua Duy , Lu Jianyu 
Published: August 2014

Abstract
The American Cancer Society estimates that over 43,000 new cases of pancreatic cancer are diagnosed each year in the United States, with a five-year survival rate below 6%. Conventional therapies are often of limited use because of the resistance development and cancer relapse. Therefore, identification of novel strategies to control and treat pancreatic cancer is of great importance. GS-19 is a novel compound designated as a GSK inhibitor and shown good activity in neural protective assay using MC65 cells. In this study, we determined the cytotoxic effects of GS-19 in pancreatic cancer cells. GS-19 treatment inhibited the growth of Panc-1 and BxPC-3 cells in a concentration-dependent manner. Both the cell lines treated with GS-19 exhibited G-1 cell cycle arrest as well as apoptosis. Western blot analysis of both BxPC-3 and Panc-1 cells treated with GS-19 inhibited the activation (phosphorylation) and expression of key survival signaling proteins such as EGFR, STAT3 and AKT. The apoptosis induced by GS-19 was associated with cleavage of caspase-3 and PARP. Taken together, our results suggest that GS-19 suppress pancreatic cancer cell growth by inhibiting EGFR/AKT/STAT-3 signaling. However, further mechanistic studies are in progress to establish the role of EGFR/AKT/STAT-3 signaling in pancreatic cancer cells and correlate it with G1 cell cycle arrest and apoptosis induced by GS-19. The studies in part were supported by R01 grant CA129038 awarded by NIH to S.K.S
Citation Information: Mol Cancer Ther 2013;12(11 Suppl):C58.
Citation Format: Alok Ranjan, Sanjay K. Srivastava, Parul Gupta, Ashlee Birkenfeld, Duy Hua, Jianyu Lu. GS-19, a novel GSK inhibitor suppresses the growth of pancreatic cancer cells by inhibiting EGFR/AKT/STAT-3 signaling. [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2013 Oct 19-23; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2013;12(11 Suppl):Abstract nr C58.
Abstract C60: Exposure of low doses of quercetin on DNA oxidation in Pectobacterium carotovorum KD 100 and Agrobacterium tumefaciens GV 3103.
Authors: Boadi William Y. , Johnson Damitea , Dumenyo Korsi 
Published: August 2014

Abstract
Oxidative stress may be a key factor in the onset of certain diseases, including cancer. Oxy-radicals play important roles in the initiation, promotion, and progression of carcinogenesis. During the course of DNA excision and repair of oxidized, deaminated or alkylated bases apurinic/apyrimidinic (AP) or abasic sites are formed. The flavonoid quercetin was investigated for its ability to inhibit the oxidation of plasmid from Pectobacterium carotovorum KD 100 and Agrobacterium tumefaciens GV 3103 using the Fenton's chemistry. Utilizing a Colorimetric Assay Kit (Oxford Biomedical Research #FR09, Oxford, MI) for DNA damage quantification, AP sites were measured for plasmid following incubation with low doses of quercetin (1, 2, 2.5, 3, 3.5 µM) or without for 12 or 24 hr. With the increasing concentrations of quercetin the number of AP sites in each sample significantly decreased more for Pectobacterium carotovorum KD 100 compared to Agrobacterium tumefaciens GV 3103 in a time- and dose-dependent manner in comparison to their respective controls for the 12 and 24 hr incubation periods. The differences in decrease in AP sites can be linked to structural differences between the two bacterial strains and/or decreased oxidation for each sample with increased quercetin aliquots.
Citation Information: Mol Cancer Ther 2013;12(11 Suppl):C60.
Citation Format: William Y. Boadi, Damitea Johnson, Korsi Dumenyo. Exposure of low doses of quercetin on DNA oxidation in Pectobacterium carotovorum KD 100 and Agrobacterium tumefaciens GV 3103. [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2013 Oct 19-23; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2013;12(11 Suppl):Abstract nr C60.
Abstract C71: Phase II study of maintenance therapy with pazopanib or pemetrexed in patients with advanced non-small cell lung cancer (NSCLC) who have not progressed following platinum-based chemotherapy.
Authors: Konduri Kartik , Smith David , Compton Natalie , Elmore Lockheed Denise , Chakrabarti Debasis , Bhatt Kamal 
Published: August 2014

Abstract
Background: Platinum-based chemotherapy combinations are the standard of care in first-line treatment of advanced NSCLC. Maintenance therapy with a chemotherapeutic agent (continuation maintenance) or a targeted agent (switch maintenance) has been explored to delay recurrence. The purpose of this trial (NCT01313663) was to evaluate the clinical activity and safety profile of pazopanib as switch maintenance in patients with stable disease or better as best response after induction therapy in advanced NSCLC.
Methods: Eligible patients had received 4-6 cycles of induction therapy with cisplatin/carboplatin plus pemetrexed and should have had best response of complete response, partial response, or stable disease before entering the study. In this 2-arm, open-label, phase II study, patients were randomized to receive either oral pazopanib 800 mg daily or intravenous pemetrexed 500 mg/m2 on Day 1 of a 21-day cycle. The primary endpoint was to estimate the hazard ratio (HR) for investigator-assessed progression-free survival; secondary endpoints included overall survival, best overall response, and safety.
Results: Planned enrollment was 200 patients. The trial was terminated due to evolving standards of care that resulted in a slow enrollment rate. Twenty patients were randomized and 19 received treatment (10 received pazopanib; 9 received pemetrexed). Progression-free survival was 10.3 weeks in the pemetrexed arm and 12.7 weeks in the pazopanib arm (HR = 0.92; 90% confidence interval: 0.32, 2.65). However, the number of evaluable patients was too small to draw conclusions for efficacy, as evidenced by the width of the 90% confidence interval for the HR. Best response was stable disease (2 patients in each arm). All patients experienced at least 1 adverse event (AE). Hepatic toxicities were more common with pazopanib, but low enrollment prevented a complete characterization of AE frequency. There were no fatal serious adverse events (SAEs) in the pazopanib arm and there were 2 fatal SAEs in the pemetrexed arm (respiratory failure and pneumonia).
Conclusions: Low accrual and early termination prevented evaluation of the primary endpoint. No new safety signals emerged.
Citation Information: Mol Cancer Ther 2013;12(11 Suppl):C71.
Citation Format: Kartik Konduri, David Smith, Natalie Compton, Denise Elmore Lockheed, Debasis Chakrabarti, Kamal Bhatt. Phase II study of maintenance therapy with pazopanib or pemetrexed in patients with advanced non-small cell lung cancer (NSCLC) who have not progressed following platinum-based chemotherapy. [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2013 Oct 19-23; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2013;12(11 Suppl):Abstract nr C71.
Abstract C75: Rucaparib (CO-338) accumulation and persistence of PARP inhibition in vitro and in vivo and efficacy of intermittent vs continuous schedules.
Authors: Murray James C. , Thomas Huw D. , Berry Philip , Kyle Suzanne , Jones Christopher , Plummer Ruth , Boddy Alan V. , Curtin Nicola J. 
Published: August 2014

Abstract
Background: Preclinical studies show that both duration and extent of PARP inhibition is critical for synthetically lethality in tumors with defects in homologous recombination repair (HRR). Rucaparib is undergoing clinical evaluation in HRR-defective tumors. Our aim was to determine whether multiple daily doses or an intermittent schedule will give the required “coverage” for anticancer activity.
Methods: The accumulation of 14C-rucaparib and duration of PARP inhibition was determined in SW620 and BRCA2 mutant Capan-1 cells after a 30 minute pulse. Rucaparib concentration in plasma brain and Capan-1 tumor xenografts and PARP inhibition in brain and tumor was determined at intervals up to 1 week after a single dose of rucaparib. The efficacy of continuous and discontinuous schedules of rucaparib was determined in mice bearing Capan-1 xenografts.
Results: Rucaparib accumulates in cells via a carrier-mediated transporter (Km of 8.4 ± 1.2 μM and Vmax of 469 ± 22 pmol/106cells/10 min) PARP activity in Capan-1 cells was suppressed by 80% for 72 hr after a pulse of 50 or 400 nM rucaparib, and still 40% reduced 7 days after 400 nM. Rucaparib was cleared rapidly from the plasma but it was detectable for up to 72 hr and suppressed PARP activity in the tumors for 7 days, being 25% and 10% of control after 10 mg/kg and 150 mg/kg, respectively. Peak levels in the brain were 2-10% of those in the tumor and only modest, transient PARP inhibition was observed in the brain. Tumor growth was suppressed by rucaparib at 150 mg/kg po on a weekly schedule as effectively as 10 mg/kg po on a daily x5 every week for 6 weeks.
Conclusion: Rucaparib accumulates in human tumor cells and PARP inhibition by rucaparib is durable after a 30 min pulse. PARP is inhibited in tumor xenografts for up to 1 week after a single dose and when the drug concentrations are no longer detectable. Weekly dosing with rucaparib inhibits tumor growth.
Citation Information: Mol Cancer Ther 2013;12(11 Suppl):C75.
Citation Format: James C. Murray, Huw D. Thomas, Philip Berry, Suzanne Kyle, Christopher Jones, Ruth Plummer, Alan V. Boddy, Nicola J. Curtin. Rucaparib (CO-338) accumulation and persistence of PARP inhibition in vitro and in vivo and efficacy of intermittent vs continuous schedules. [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2013 Oct 19-23; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2013;12(11 Suppl):Abstract nr C75.
Abstract C86: Tethered Hsp90 inhibitors carrying optical or radioiodinated probes reveal selective internalization of ectopic Hsp90 in malignant breast tumor cells.
Authors: Barrott Jared J. , Smith Aaron P. , Osada Takuya , Ramanujam Nimmi , Zalutsky Michael R. , Lyerly Kim , Haystead Timothy A. J. 
Published: August 2014

Abstract
Hsp90 inhibitors have demonstrated unusual selectivity for tumor cells despite its ubiquitous expression. This phenomenon has remained unexplained but could be influenced by ectopically expressed Hsp90 in tumors. We have synthesized novel Hsp90 inhibitors that can carry optical or radioiodinated probes via a PEG tether. We show that these tethered inhibitors selectively recognize cells expressing ectopic Hsp90 and become internalized. The internalization process is blocked by Hsp90 antibodies, suggesting that active cycling of the protein is occurring at the plasma membrane. In mice, we show exquisite accumulation of the fluor-tethered versions within breast tumors at very sensitive levels. Cell-based assays with the radiolabeled version showed picomolar detection in cells that express ectopic Hsp90. Our findings show that fluor-tethered or radiolabeled inhibitors targeting ectopic Hsp90 can be used to detect breast cancer malignancies through non-invasive imaging.
Citation Information: Mol Cancer Ther 2013;12(11 Suppl):C86.
Citation Format: Jared J. Barrott, Aaron P. Smith, Takuya Osada, Nimmi Ramanujam, Michael R. Zalutsky, Kim Lyerly, Timothy A. J. Haystead. Tethered Hsp90 inhibitors carrying optical or radioiodinated probes reveal selective internalization of ectopic Hsp90 in malignant breast tumor cells. [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2013 Oct 19-23; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2013;12(11 Suppl):Abstract nr C86.
Abstract C98: Quizartinib (AC220) potentiates the antineoplastic activity of wild-type ABCG2 and ABCB1 substrates.
Authors: Kumar Priyank , Kathawala Rishil J. , Zhang Hui , Anreddy Nagaraju , Chen Yanglu , Gupta Kanav , Trombetta Louis D. , Cheng Zhe S. 
Published: August 2014

Abstract
Quizartinib (AC220), a novel and potent class II receptor tyrosine kinase inhibitor that has better therapeutic and pharmacokinetic profile amongst its class. Quizartinib is currently under clinical trials for FLT3 ITD and wild-type AML and is tested in combination with chemotherapy. This study examined the effects of quizartinib on ABC transporter-mediated multidrug resistance (MDR). Cytotoxic studies showed that 0.75, 1.5, and 3 μM are the three less toxic concentrations for normal as well as cancer cells. Out of these three concentrations, quizartinib at 3 μM showed a significant reversal of MDR mediated by ABCG2 and ABCB1 in different MDR cell models, when compared to the positive controls, fumetrimorgin C and verapamil at 3 μM, respectively. Interestingly, quizartinib did not show a significant reversal of the MDR associated with the two mutants (R482T and R482G) ABCG2 overexpression. Results also showed that quzartinib at 3 μM significantly reversed wild-type ABCG2-mediated drug resistance by antagonizing the drug efflux function of wild-type ABCG2 and increasing the intracellular accumulation of [3H]-mitoxantrone in wild-type ABCG2-overexpressing cells. However, quizartinib at 3 μM did not reverse ABCC1- and ABCC10-mediated drug resistance in HEK/ABCC1 and HEK/ABCC10 cell lines. Hence these results conclude that quizartinib potentiates the antineoplastic activity of wild-type ABCG2 and ABCB1 substrates.
Citation Information: Mol Cancer Ther 2013;12(11 Suppl):C98.
Citation Format: Priyank Kumar, Rishil J. Kathawala, Hui Zhang, Nagaraju Anreddy, Yanglu Chen, Kanav Gupta, Louis D. Trombetta, Zhe S. Cheng. Quizartinib (AC220) potentiates the antineoplastic activity of wild-type ABCG2 and ABCB1 substrates. [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2013 Oct 19-23; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2013;12(11 Suppl):Abstract nr C98.
Abstract CN03-01: Drug testing in genetically engineered murine models.
Authors: Sharpless Norman E. 
Published: August 2014

Abstract
Traditional xenograft testing has a poor track record of predicting the efficacy in humans of a novel anticancer compound. Autochthonous tumors occurring in genetically engineered mice more faithfully recapitulate some aspects of human cancers, and therefore may have advantages for preclinical efficacy assessment. The UNC Lineberger Mouse Phase I Unit (MP1U) was founded to allow for medium-throughput testing of novel therapeutics in credentialed cancer GEMMs. The MP1U harnesses the power of murine genetics to produce multi-allelic cancer models featuring autochthonous tumors with physiological tumor-stroma interface and an intact immune response. Promising anticancer compounds are tested alone and in combination in these models, using cohort sizes comparable to human Phase II trials (15-50 subjects per treatment). Agents are considered "active" if they induce sustained and pronounced tumor regression, whereas tumor growth inhibition (TGI) is not considered predictive of human efficacy. Pharmacokinetic and pharmacodynamic assessment is included in efficacy trials, as is serial tumor imaging if needed. The goal is to make testing in the MP1U as close to human Phase I/II anticancer trials as possible, while still taking advantage of the powerful experimental features of murine tumor models. Results of testing with a variety of novel agents will be presented to illustrate the promise and power of GEMM testing.
Citation Information: Mol Cancer Ther 2013;12(11 Suppl):CN03-01.
Citation Format: Norman E. Sharpless. Drug testing in genetically engineered murine models. [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2013 Oct 19-23; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2013;12(11 Suppl):Abstract nr CN03-01.
Abstract CN04-04: Targeting death receptors and SMAC mimetics.
Authors: Fulda Simone 
Published: August 2014

Abstract
Evasion of apoptosis is a hallmark of human cancers and contributes to tumor formation and progression as well as resistance to current cancer therapies, which largely rely on intact cell death pathways in cancer cells. Apoptosis resistance can be caused by aberrant expression of antiapoptotic proteins, for example Inhibitor of Apoptosis (IAP) proteins, which are expressed at high levels in many human cancers. Since IAP proteins block apoptosis at the core of the apoptotic machinery by inhibiting effector caspases, they present promising therapeutic targets.
Smac mimetics are small-molecule inhibitors that mimick the IAP-binding motif of the endogenous IAP antagonist Smac and are among the most widely used strategies to antagonize IAP proteins. In addition to their use as single agents, Smac mimetics have been used in combination with various cytotoxic stimuli to trigger cell death in cancer cells, in particular together with death receptor ligands such as soluble TRAIL or TRAIL receptor agonists. For example in pancreatic cancer_ one of the most lethal types of cancer_ IAP antagonists were shown to synergize with TRAIL receptor agonists to induce apoptosis and suppress tumor growth in preclinical in vitro and in vivo models. Furthermore, Smac mimetics and TRAIL acted in concert to trigger apoptosis in CLL, even in patients with poor prognostic features such chemoresistant disease, p53 mutation or chromosome 17p deletion. Thus, Smac mimetics may open new perspectives to overcome resistance to death receptor-mediated apoptosis in various forms of human cancers.
Citation Information: Mol Cancer Ther 2013;12(11 Suppl):CN04-04.
Citation Format: Simone Fulda. Targeting death receptors and SMAC mimetics. [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2013 Oct 19-23; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2013;12(11 Suppl):Abstract nr CN04-04.
Abstract CN05-01: PARP inhibitors: Trapping of PARP and rational for combinations.
Authors: Pommier Yves G. , Murai Junko , Morris Joel , Doroshow James H. 
Published: August 2014

Abstract
Poly(ADPribose) polymerases (PARPs) are promising targets of several anticancer drugs in clinical development. We will review the genetic and biochemical evidence that PARP inhibitors act as cytotoxic anticancer agents by trapping PARP-DNA complexes (1). We will also show that PARP inhibitors differ from each other by their ability to trap PARP. They can be ranked by decreasing potency for PARP trapping: BMN-673 ≫ Niraparib &gt; Olaparib = Rucaparib ≫ Veliparib, while all the PARP inhibitors are relatively similar with respect to PARP catalytic inhibition. We propose that PARP trapping results from allosteric effect whereas catalytic inhibition results from competition with NAD+. We will also discuss the rationale for combining PARP inhibitors with topoisomerase I inhibitors, and its dependence on PARP catalytic inhibition, and the rationale for combination with temozolomide, which depends both on catalytic inhibition and PARP trapping.
1. Murai J, Huang S-yN, Das BB, Renaud A, Zhang Y, Doroshow JH, Ji J, Takeda S, Pommier Y. Trapping of PARP1 and PARP2 by Clinical PARP Inhibitors. Cancer Research 2012; 72: 5588-99.
Citation Information: Mol Cancer Ther 2013;12(11 Suppl):CN05-01.
Citation Format: Yves G. Pommier, Junko Murai, Joel Morris, James H. Doroshow. PARP inhibitors: Trapping of PARP and rational for combinations. [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2013 Oct 19-23; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2013;12(11 Suppl):Abstract nr CN05-01.