bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 3322: GW4716 selectively targets multiple p53 mutant cancer models.
Authors: Heckler Mary , Albanese Christopher , Riggins Rebecca 
Published: August 2014

Abstract
The TP53 gene is the most commonly mutated gene in all cancers, with over 50% of human cancers harboring an inactivating mutation. Most frequently when p53 is mutated, the mutation occurs as a single nucleotide substitution within the DNA-binding domain. The selective advantage for retaining mutant p53 varies between cancer cells. Mutant p53 can have both gain-of-function and loss-of-function properties. Given the high frequency of p53 mutations in human cancers, understanding mutant p53 function and identifying novel therapies is a clinically relevant and important area of research.
We have identified a novel pharmacological approach that selectively targets p53 mutant cancer cells across multiple cancer models using the acyl hydrazone GW4716. We have found cancer cells harboring a mutation in p53, treated with GW4716 for 24h, exhibit significantly greater cell death measured by DNA fragmentation (subG1) than p53 wild-type cells in both breast cancer and glioblastoma models. In contrast, GW4716 has little/no effect on normal (non-transformed) cells Furthermore, the mode of cell death induced by GW4716 differs between p53 wild-type and mutant cells. p53 mutants undergo a G2/M arrest, exhibit characteristics of mitotic catastrophe and ultimately apoptose in response to GW4716. MAPK signaling proteins (p38 and MK2) involved in G2/M checkpoint control, progression through mitosis, and cell death are induced by GW4716 treatment in p53 mutant cells. In contrast, p53 wild-type cells exhibit an induction of cell cycle regulatory proteins (p53 and p21) and the p53-specific autophagy marker DRAM, with a concomitant inhibition of p62 (SQSTM1).
This leads us to hypothesize that the cytotoxic effects of GW4716 treatment occur in a p53-dependent manner, and the mode of cell death caused by GW4716 differs depending on p53 status. We hypothesize the loss of functional p53 leads to aberrant mitosis and ultimately apoptosis. We also hypothesize that p53 wild-type cells, which are less sensitive to GW4716, undergo autophagy. With the increasing emphasis on personalized medicine, these data suggest a clinically relevant role for GW4716 in the treatment of multiple p53 mutant cancers.
Citation Format: Mary Heckler, Christopher Albanese, Rebecca Riggins. GW4716 selectively targets multiple p53 mutant cancer models. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 3322. doi:10.1158/1538-7445.AM2013-3322
Note: This abstract was not presented at the AACR Annual Meeting 2013 because the presenter was unable to attend.
Abstract 3335: Ouabain, a cardiac glycoside, inhibits the Fanconi Anemia-BRCA pathway activated by DNA crosslinking agents.
Authors: Hwang Mihwa , Jun Dong Wha , Kim Hyun Jung , Hwang Soo Kyung , Lee Chang-Hun , Kim Sunshin 
Published: August 2014

Abstract
Most cancer therapies, including conventional chemotherapy and radiotherapy, are based on DNA damage-induced tumor cell death. In tumor cells, cellular DNA repair machinery can decrease anticancer drug efficacy and induce drug resistance. The DNA repair pathway has been an emerging target for development of anticancer drugs. DNA intercrosslinking, one of the most severe forms of DNA damage which are caused by anticancer drugs, such as cisplatin and mitomycin C (MMC), could activate the Fanconi anemia (FA)-BRCA DNA repair pathway. Inhibition of the FA-BRCA pathway can enhance the cytotoxic effects of anticancer drugs which induce DNA crosslinking and can reduce anticancer drug resistance. To find FA-BRCA pathway inhibitory small molecules, we established a cell-based high-content screening method for detecting the FA-BRCA pathway by measuring ubiquitinated FANCD2 foci on DNA lesions after immunofluorescence staining and then we applied our method to chemical screening. Using commercial LOPAC1280 chemical library screening, ouabain was identified as a competent FA-BRCA pathway inhibitory molecule. Ouabain, a member of the cardiac glycoside family and an endogenous mammalian hormone, binds to and inhibits the plasma membrane protein Na+/K+-ATPase and has been used for the treatment of heart disease for many years. We observed that ouabain, as well as its cardiac glycoside family members―digitoxin and digoxin―reduced monoubiquitination of FANCD2, inhibited ubiquitinated FANCD2 foci formation on DNA lesions and abrogated cell cycle arrest induced by MMC treatment. These inhibitory activities of the FA-BRCA pathway were independent of the cellular Ca++ ion increase or the drug uptake-inhibition effect which is known to be a function of ouabain. Furthermore, we found that ouabain potentiated cytotoxic effects of MMC in tumor cells. Taken together, we identified an additional role of ouabain as a FA-BRCA pathway inhibitor which has chemosensitization activity. The results of this study suggest that ouabain may serve as a chemosensitizer to anticancer drugs which induce DNA crosslinking.
Citation Format: Mihwa Hwang, Dong Wha Jun, Hyun Jung Kim, Soo Kyung Hwang, Chang-Hun Lee, Sunshin Kim. Ouabain, a cardiac glycoside, inhibits the Fanconi Anemia-BRCA pathway activated by DNA crosslinking agents. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 3335. doi:10.1158/1538-7445.AM2013-3335
Abstract 3339: HSP90 inhibitor 17-allylamino-geldanamycin enhances sensitivity to double-strand DNA break-inducing agents (platinum and PARP inhibitors) in epithelial ovarian cancer.
Authors: Battelli Chiara , Morse Alexander , Hu Hai , Levantini Elena , Wulf Gerburg , Konstantinopoulos Panagiotis A. 
Published: August 2014

Abstract
Double-strand DNA break (DSB)-inducing agents such as platinum analogues and poly (ADP-ribose) polymerase inhibitors (PARPis) exhibit significant antitumor activity in epithelial ovarian cancer (EOC). Approximately 50% of patients with EOC harbor genetic or epigenetic alterations of the homologous recombination (HR) DNA repair pathway and are highly responsive to these agents. However, resistance to DSB-inducing agents develops in the majority of patients and represents a major limitation for successful treatment of EOC. We recently defined a gene expression profile of “BRCAness” that correlates with responsiveness to double-strand DNA break-inducing agents (platinum and PARPis) in EOC. We applied this profile to the Connectivity Map to identify candidate compounds that might be able to enhance sensitivity to these agents. This analysis showed that the top-performing compound was the heat shock protein 90 (HSP90) inhibitor 17-allylamino-geldanamycin (17-AAG) with very high connectivity scores (&gt;0.8) across several cell lines and concentrations (permutation p value &lt; 0.00001). We then evaluated the ability of 17-AAG to enhance sensitivity to double-strand DNA break-inducing agents in a panel of ovarian cancer cell lines. Exposure to increasing concentrations of 17-AAG (0.02-0.1uM) was associated with increased sensitivity of 36M2 and OVCAR5 cells to carboplatin in a dose response manner. Similarly, exposure to increasing concentrations of 17-AAG (0.02-0.1uM) was associated with increased sensitivity of 36M2 and OVCAR5 cells to PARPi olaparib in a dose response manner. Exposure of these cell lines to combination of 17-AAG with carboplatin induced increased phosphorylation of H2AX (gamma H2AX) - a surrogate of DNA double-strand breaks - compared to carboplatin alone, as assessed by Western blotting. In conclusion, the HSP90 inhibitor 17-AAG enhances sensitivity of ovarian cancer cell lines to carboplatin and olaparib. The mechanism of this previously unknown, off-target effect, seems to be due to increasing DNA double strand breaks.
Citation Format: Chiara Battelli, Alexander Morse, Hai Hu, Elena Levantini, Gerburg Wulf, Panagiotis A. Konstantinopoulos. HSP90 inhibitor 17-allylamino-geldanamycin enhances sensitivity to double-strand DNA break-inducing agents (platinum and PARP inhibitors) in epithelial ovarian cancer. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 3339. doi:10.1158/1538-7445.AM2013-3339
Abstract 3373: Clinical trial simulation for the individualization of docetaxel dosing.
Authors: Perez-Ruixo Carlos , Valenzuela Belen , González-Sales Mario , Calvo Emiliano 
Published: August 2014

Abstract
Background and objective: To evaluate if docetaxel severe neutropenia can be reduced by pharmacokinetic (PK) and absolute neutrophils counts (ANC) guided dose individualization.
Methods: The incidence of Grade 4 neutropenia following docetaxel 75 mg/m2 every 3 weeks (Arm A) or docetaxel individualized dose (Arm B) was predicted on the basis of the model proposed by Bruno [1] and Quartino [2]. Optimal sampling times for PK and ANC assessments after an initial test dose were determined. The individual model parameters estimated using the maximum a posteriori estimation in NONMEM 7 were used to determine the individualized docetaxel dose, defined as the maximum dose that yields a probability of neutropenia Grade 4 lower than 30%.
Results: An initial dose of 50 mg/m2 at least 2 weeks earlier, plasma concentrations collected at 1, 3 and 7 h after the start of the infusion, and ANC measurements determine at 0, 7, 14, and 21 days were adequate to determine the individualized dose, without any carry-over effect. The neutropenia Grade 4 incidence was 55% and 45% in arms A and B, respectively. A sample size of 154 patients per arm was need to have a 82% power of detecting the effect of dose individualization. The average docetaxel individualized dose was 55 mg/m2.
Conclusions: Docetaxel PKPD guided dose individualization is potentially useful in controlling the PKPD variability and decreasing the incidence of neutropenia Grade 4.
1.Bruno R, Vivier N, Vergniol JC, De Phillips SL, Montay G, Sheiner LB.A population pharmacokinetic model for docetaxel (Taxotere): model building and validation. J Pharmacokinet Biopharm. 1996; 24: 153-172.
2.Quartino AL, Friberg LE, Karlsson MO. A simultaneous analysis of the time-course of leukocytes and neutrophils following docetaxel administration using a semi-mechanistic myelosuppression model. Invest New Drugs. 2012; 30: 833-845.
Citation Format: Carlos Perez-Ruixo, Belen Valenzuela, Mario González-Sales, Emiliano Calvo. Clinical trial simulation for the individualization of docetaxel dosing. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 3373. doi:10.1158/1538-7445.AM2013-3373
Abstract 3384: Depletion of NEDD9 destabilizes Aurora A kinase and augments efficacy of inhibitors.
Authors: Ice Ryan J. , McLaughlin Sarah , Culp Mark , Eddy Erik , Livengood Ryan , Pugacheva Elena 
Published: August 2014

Abstract
Aurora A Kinase (AURKA) is overexpressed in 96% of human cancers and is considered an independent marker of poor prognosis. While the majority of tumors have elevated levels of
AURKA protein, only few have AURKA gene amplification; therefore, posttranscriptional mechanism regulating AURKA protein levels are significant. In this study, we show that the known activator and binding partner of AURKA, NEDD9, is directly involved in AURKA stability. Analysis of comprehensive breast cancer tissue microarray revealed a tight correlation between expression of both proteins and significantly increased prognostic value. A decrease in AURKA proteins, concomitant with increased ubiquitination and proteasome-dependent degradation, occurs due to depletion or knockout of NEDD9 proteins. Re-expression of wild type (WT) NEDD9 was sufficient to rescue the observed phenomenon. Binding of NEDD9 to AURKA is critical for AURKA stabilization. Mutation of S296E was sufficient to disrupt the binding and reduce the level of AURKA protein. Mechanistically, NEDD9 stabilizes AURKA by limiting the binding of cdh1-substrate recognition subunit of APC/C Ubiquitin Ligase to AURKA. Moreover, depletion of NEDD9 in tumor cells increased their sensitivity to AURKA inhibitors. Combinational therapy using NEDD9 shRNAs and AURKA inhibitors had a profound inhibitory effect on tumor initiation and later, metastasis in lungs of human tumor xenografts. Our findings provide evidence for successful application of AURKA inhibitors for treatment of solid tumors, which often overexpress NEDD9.
Citation Format: Ryan J. Ice, Sarah McLaughlin, Mark Culp, Erik Eddy, Ryan Livengood, Elena Pugacheva. Depletion of NEDD9 destabilizes Aurora A kinase and augments efficacy of inhibitors. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 3384. doi:10.1158/1538-7445.AM2013-3384
Abstract 3398: Overexpression of ATP-binding cassette transporter ABCG2 as a potential mechanism of acquired resistance to vemurafenib in BRAF(V600E) mutant cancer cells.
Authors: Wu Chung-Pu , Sim Hong-May , Huang Yang-Hui , Liu Yen-Chen , Hsiao Sung-Han , Cheng Hsing-Wen , Li Yan-Qing , Ambudkar Suresh , Hsu Sheng-Chieh 
Published: August 2014

Abstract
Melanoma is the most serious type of skin cancer with a high potential for metastasis and very low survival rates. The discovery of constitutive activation of the BRAF kinase caused by activating BRAF(V600E) kinase mutation in most melanoma patients led to the discovery of the first potent BRAF(V600E) signaling inhibitor, vemurafenib. Vemurafenib was effective in treating advanced melanoma patients and was proposed for the treatment of other BRAF(V600E) mutant cancers as well. Unfortunately, the success of vemurafenib was hampered by the rapid development of acquired resistance in different types of BRAF(V600E) mutant cancer cells. It becomes important to identify and evaluate all of the potential mechanisms of cellular resistance to vemurafenib. In this study, we characterized the interactions of vemurafenib with three major ATP-binding cassette (ABC) transporters, ABCB1, ABCC1 and ABCG2. We found that vemurafenib stimulated the ATPase activity and potently inhibited drug efflux mediated by ABCB1 and ABCG2. Vemurafenib also restored drug sensitivity in ABCG2-overexpressing cells. Moreover, we revealed that in the presence of functional ABCG2, BRAF kinase inhibition by vemurafenib is reduced in BRAF(V600E) mutant A375 cells. Taken together, our findings indicate that ABCG2 confers resistance to vemurafenib in A375 cells, suggesting involvement of this transporter in acquired resistance to vemurafenib. Thus, combination chemotherapy targeting multiple pathways could be an effective therapeutic strategy to overcome acquired resistance to vemurafenib for cancers harboring the BRAF(V600E) mutation.
Citation Format: Chung-Pu Wu, Hong-May Sim, Yang-Hui Huang, Yen-Chen Liu, Sung-Han Hsiao, Hsing-Wen Cheng, Yan-Qing Li, Suresh Ambudkar, Sheng-Chieh Hsu. Overexpression of ATP-binding cassette transporter ABCG2 as a potential mechanism of acquired resistance to vemurafenib in BRAF(V600E) mutant cancer cells. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 3398. doi:10.1158/1538-7445.AM2013-3398
Abstract 3402: Relief of feedback inhibition of HER3 transcription by RAF and MEK inhibitors attenuates their antitumor effects in BRAF mutant thyroid carcinomas.
Authors: Montero-Conde Cristina , Ruiz-Llorente Sergio , Dominguez Jose M. , Knauf Jeffrey A. , Viale Agnes , Sherman Eric J. , Ryder Mabel , Ghossein Ronald A. , Rosen Neal , Fagin James A. 
Published: August 2014

Abstract
The RAF inhibitor vemurafenib (PLX4032) increases survival in patients with BRAF-mutant metastatic melanoma, but has limited efficacy in patients with colorectal cancers. A trial with vemurafenib for thyroid cancer patients is now in progress.
We compared the response of thyroid and melanoma cell lines harboring BRAFV600E to vemurafenib and found that the majority of thyroid cancer cells were refractory to the inhibitor (IC50 &gt; 1.5 μM). In addition, thyroid cancer cell lines showed a rebound in pERK beginning 6h post-treatment and a transient activation of pAKT. Expression profiling and pRTK array screens of PLX4032-treated cells showed higher expression and activation of HER family receptors, particularly HER2 and HER3. Phosphorylation of HER3 represented the most consistent PLX4032-dependent RTK activated across thyroid cancer cell lines (5/6 lines tested) and was not detectable in any of the melanoma or colorectal cancer cells we investigated. HER3 phosphorylation was also induced by the allosteric MEK inhibitor PD0325901 in thyroid cancers of TPO-Cre/LSL-BrafV600E mice. We identified HER2 as the main HER3 heterodimerization partner, which was activated via a neuregulin-dependent autocrine loop, which was specific to the thyroid cancer lineage, as it was not observed in either melanoma or colorectal BRAF-mutant lines. HER3 transcription was induced by MAPK inhibition, via dissociation of the CTBP1/2 transcriptional repressors from the HER3 gene promoter. Finally, the HER2/HER3 kinase inhibitor lapatinib sensitized BRAF-mutant thyroid cancer cells to growth inhibition by RAF or MEK inhibitors in vitro and in vivo, providing rationale for combination therapies in this disease. Hence, the early response of BRAF-mutant cancers to selective MAPK pathway inhibitors is marked by the relaxation of oncoprotein-driven negative feedback events, which differ between tumors of various lineages, and which predict a requirement for distinct therapeutic strategies.
Citation Format: Cristina Montero-Conde, Sergio Ruiz-Llorente, Jose M. Dominguez, Jeffrey A. Knauf, Agnes Viale, Eric J. Sherman, Mabel Ryder, Ronald A. Ghossein, Neal Rosen, James A. Fagin. Relief of feedback inhibition of HER3 transcription by RAF and MEK inhibitors attenuates their antitumor effects in BRAF mutant thyroid carcinomas. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 3402. doi:10.1158/1538-7445.AM2013-3402
Abstract 3408: The anticancer mechanisms of ciclopirox olamine.
Authors: Shen Tao , Zhou Hongyu , Huang Shile 
Published: August 2014

Abstract
Ciclopirox olamine (CPX), a synthetic fungicide clinically used to treat mycoses of the skin and nails, has been demonstrated as a novel anticancer agent. However, the underlying anticancer mechanisms are not well understood. Here we show that CPX suppressed cell proliferation, induced cell death (apoptosis and autophagy), and inhibited cell motility in breast cancer (MDA-MB-231) and rhabdomyosarcoma (Rh30) cells. We observed that CPX induced inhibitory phosphorylation of CDK2 and inhibited cyclin D1 expression, resulting in dephosphorylation of Rb in the tumor cells, which was correlated to cell cycle arrest at G1 phase. Furthermore, we found that CPX caused DNA damage and activated ATR-Chk1 axis, increasing phosphorylation and degradation of Cdc25A, a critical protein involved in the regulation of cell cycle progression and apoptosis. CPX also activated JNK cascade, associated with apoptosis. Moreover, CPX downregulated cellular protein expression of small GTPases (RhoA, Cdc42 and Rac1) and induced inhibitory phosphorylation of FAK, related to cell migration. In addition, we found that CPX inhibited the signaling of mTOR, a central controller of cell proliferation, survival (apoptosis and autophagy) and motility. The results suggest that CPX exerts its anticancer activity by targeting multiple signaling molecules.
Citation Format: Tao Shen, Hongyu Zhou, Shile Huang. The anticancer mechanisms of ciclopirox olamine. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 3408. doi:10.1158/1538-7445.AM2013-3408
Abstract 3421: Differential potentiation of temozolomide and camptothecin by the PARP inhibitors olaparib and veliparib in relationship with their PARP-DNA trapping abilities, and lack of impact of PARP inhibitors on cisplatin activity.
Authors: Pommier Yves G. , Murai Junko 
Published: August 2014

Abstract
We recently showed that poly(ADP-ribose) polymerase (PARP) inhibitors act by a novel allosteric mechanism of action that involves the trapping of PARP-DNA complexes in addition to their previously established NAD-competitive catalytic inhibitory mechanism). We also demonstrated that PARP inhibitors differ in their ability to trap PARP-DNA complexes, with olaparib being more effective than veliparib in spite of their comparable potency as catalytic PARP inhibitors). Here, by using PARP knockout cells, olaparib and veliparib, we tested the role of PARP trapping in the potentiating effect of PARP inhibitors with the alkylating agent temozolomide and the topoisomerase I inhibitor, camptothecin. Using isogenic chicken DT40 cells, we show that PARP-dependent potentiation of temozolomide is markedly greater for olaparib than veliparib, and goes beyond knocking out PARP-1. On the other hand, in the case of camptothecin, knocking out PARP-1 has a greater effect than veliparib or olaparib. In human DU145 prostate cancer and SF295 glioblastoma cells, olaparib is markedly more potent than veliparib in potentiating the cytotoxicity of temozolomide whereas both olaparib and veliparib are almost comparable in the case of camptothecin. By measuring cellular PARP-DNA complexes), we find that in the case of temozolomide, olaparib is a least 10-fold more potent than veliparib at trapping PARP-DNA complexes. On the other hand, in the case of camptothecin, neither olaparib nor veliparib produced detectable trapping of PARP-DNA complexes. Finally, olaparib fails to sensitize DT40, DU145 or SF295 cells to cisplatin and does not induce detectable PARP-DNA complexes in cisplatin-treated cells. These results suggest that, in the case of temozolomide, olaparib trapping of PARP-DNA complexes is more toxic than inactivating PARP catalytic activity, which is not the case for topoisomerase I-induced DNA damage, where catalytic inactivation of PARP appears to be the sole enhancing mechanism.
Citation Format: Yves G. Pommier, Junko Murai. Differential potentiation of temozolomide and camptothecin by the PARP inhibitors olaparib and veliparib in relationship with their PARP-DNA trapping abilities, and lack of impact of PARP inhibitors on cisplatin activity. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 3421. doi:10.1158/1538-7445.AM2013-3421