bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 2795: Screening and characterization of drugs that inhibit the ubiquitin-proteasome system
Authors: Selvaraju Karthik , Mofers Arjan , Pellegrini Paola , Hillert Ellin-Kristina , D'Arcy Padraig , Linder Stig 
Published: August 2018

Abstract
Pharmacological inhibition of proteasomal cysteine deubiquitinase (DUB) activity (i.e., USP14 and UCHL5 DUBs) has been shown to be particularly cytotoxic to cancer cells and to result in inhibition of tumor growth in several in vivo models. Most proteasome DUB inhibitors contain α, β-unsaturated ketones with the potential to covalently bind DUB active site cysteines. We here performed a screen of 5000 compounds containing α, β-unsaturated ketones in order to identify novel proteasome DUB inhibitors and to examine the question of the specificity of such compounds. Surprisingly, only ~3% of 5000 compounds containing α, β-unsaturated ketones showed anti proliferative activity at 5 uM. Almost one third of these cytotoxic compounds were found to block proteasome processing. Treatment of cells with the hit compounds induced the accumulation of proteasome bound high molecular weight polyubiquitin conjugates, induction of the chaperone HSP70B' and the oxidative stress marker heme oxygenase-1 (HO-1) and to induce an apoptotic response. A subset of 10 compounds were studied in detail and found to inhibit proteasome DUB activity in vitro. Importantly, hit compounds did not show inhibitory activity on a panel of recombinant non-proteasome DUBs. Inhibition of proteasome processing by hit compounds was not due to inhibition of 20S proteasome enzymatic activity. Exposure of multiple myeloma cells to the hit compounds resulted in thermostabilization of USP14 at the relevant concentrations using CETSA. These results suggest that α, β-carbonyls-containing compounds are promising candidates for development of drugs targeting proteasome DUBs and that drugs showing unexpected selectivity can be identified.
Citation Format: Karthik Selvaraju, Arjan Mofers, Paola Pellegrini, Ellin-Kristina Hillert, Padraig D'Arcy, Stig Linder. Screening and characterization of drugs that inhibit the ubiquitin-proteasome system [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 2795.
Abstract 2801: Novel selenodiazoles as antitumor and radical scavenging agents
Authors: Ruberte Ana Carolina , Plano Daniel , Encio Ignacio , Sharma Arun K. , Sanmartin Carmen 
Published: August 2018

Abstract
Heterocyclic compounds with selenium atom in endo position, such as ebselen (EBS), have achieved very promising activity against cancer and hold an excellent pharmacological profile. In fact, EBS is currently under Phase II clinical trial for the evaluation of its therapeutic safety and efficacy. The purpose of this study was to make structural modifications over this scaffold to improve its anticancer and antioxidant characteristics.
Twenty-eight novel benzo[c][1,2,5]selenodiazole-5-carboxamide derivatives were designed and synthesized. Cytotoxicity of these structures, using the MTT assay, was tested in vitro against a panel of five human cancer cell lines, including prostate (PC-3), colon (HT-29), leukemia (CCRF-CEM), lung (HTB-54) and breast (MCF-7). The selectivity of all the compounds was further examined in two non-malignant cell lines derived from breast (184B5) and lung (BEAS-2B). For MCF-7 cells, the apoptotic status and cell cycle analysis of the cells were based on the TUNEL technique. Likewise, their radical scavenging activity was determined using the DPPH assay.
Interestingly, three compounds exhibited higher cytotoxic activity than EBS in solid tumors, along with higher selectivity indexes. The cytotoxic activity of lead compound 8 was remarkable in MCF-7 cells. The antioxidant capacity of four compounds was greater than EBS.
The toxicity of derivative 8 in the non-tumoral cell line 184B5 was low (lethal dose (LD50) &gt; 100 µM) and it exhibited promising antiproliferative values in MCF-7 cells with a growth inhibition of 50% (GI50) of 3.7 µM. The radical scavenging capacity of four compounds was greater than EBS.
Given the low toxicity and moderate antioxidant activity, these compounds can serve as an excellent scaffolds to achieve new and potent antioxidant compounds useful for several diseases such as cancer, neurodegenerative and heart diseases.
Citation Format: Ana Carolina Ruberte, Daniel Plano, Ignacio Encio, Arun K. Sharma, Carmen Sanmartin. Novel selenodiazoles as antitumor and radical scavenging agents [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 2801.
Abstract 2804: Identifying an optimal site for linker conjugation of the taccalonolides, novel microtubule stabilizing drugs
Authors: Risinger April L. , Du Lin , Ola Antonius , Cichewicz Robert H. , Mooberry Susan L. 
Published: August 2018

Abstract
The taccalonolides are a structurally distinct class of microtubule stabilizers purified from the roots and rhizomes of plants of the genus Tacca. The covalent binding of taccalonolides bearing a C-22,23 epoxide to β-tubulin generates a distinct profile of microtubule stabilization that results in a high level of cellular persistence and the ability to circumvent multiple mechanisms of clinically relevant drug resistance, including expression of P-glycoprotein. The biological effects of 121 structurally distinct taccalonolides, including 23 isolated natural products and 98 semi-synthetic derivatives have been evaluated. These compounds range in potency from 0.6 nM to over 50 µM, allowing for detailed structure activity relationship studies.
Some of the most potent taccalonolide derivatives include semi-synthetic modifications at C-6, C-7, or C-15 in combination with C-22,23 epoxidation. While these compounds did not have an acceptable therapeutic window for in vivo antitumor activity by systemic administration, they demonstrated highly effective and exquisitely persistent antitumor activity in a drug-resistant tumor model when delivered directly into the tumor. Additional studies were undertaken to see whether large chemical moieties could be added at these sites to facilitate targeted delivery of these compounds. In contrast to C-7 and C-15 derivatives, which are cleaved, C-6 modifications are stable and retain microtubule stabilizing and cytotoxic activities. In particular, fluorescent C-6 taccalonolide conjugates allowed, for the first time, direct visualization of these compounds in live cells, which co-localized with bundled microtubules. Further probing of the functionality at taccalonolide C-6 will allow for more detailed mechanistic studies of drug transport and distribution as well as optimization of a linker that could be used for antibody-based drug delivery.
Citation Format: April L. Risinger, Lin Du, Antonius Ola, Robert H. Cichewicz, Susan L. Mooberry. Identifying an optimal site for linker conjugation of the taccalonolides, novel microtubule stabilizing drugs [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 2804.
Abstract 2809: Novel 2,5,8-trihydro-6,7-disubstituted-4-(3'-alkylsulfonamidoanilino) quinazoline derivatives as RAF inhibitor
Authors: Yen Shih Chieh , Peng Shao-Zheng , Huang Hung-Jyun , Yang Ju-Ying , Liu Yen-Hsi , Ciou Sian-Yi , Kuo Mann-Yan , Liao Chu-Bin 
Published: August 2018

Abstract
The oncogenic mutations of BRAF which occur most frequently in V600E, leading to constitutive activation of the MAPK signaling pathway, are common in a variety of human cancers. Recently, drugs targeting RAF kinase have been approved as an effective treatment for human malignancies that rely on this target for their growth. Thus, suppressing RAF kinase activity is a clinically meaningful approach to treat cancer patients harboring RAF driven oncogene. In this study, a series of 2,5,8-trihydro-6,7-disubstituted-4-(3'-alkylsulfonamidoanilino)quinazoline was synthesized and evaluated for their RAF kinases inhibition activity. Several potent compounds displayed double-digit nanomolar IC50 values for RAF kinases including CRAF, BRAF, and BRAFV600E. Preliminary profiling of one of the most active compounds in a panel of protein kinases revealed its selectivity for RAF kinases. In cells, this compound exhibited selective cytotoxicity against cancer cells harboring BRAF V600E mutation and dose-dependent inhibition of phosphorylation of RAF downstream effectors MEK and ERK. Moreover, the compound was oral active in mice bearing A375 BRAFV600E-mutant melanoma xenograft. Therefore, the novel quinazoline derivative proved to be active as RAF inhibitor.
Citation Format: Shih Chieh Yen, Shao-Zheng Peng, Hung-Jyun Huang, Ju-Ying Yang, Yen-Hsi Liu, Sian-Yi Ciou, Mann-Yan Kuo, Chu-Bin Liao. Novel 2,5,8-trihydro-6,7-disubstituted-4-(3'-alkylsulfonamidoanilino) quinazoline derivatives as RAF inhibitor [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 2809.
Abstract 2828: MMR status affects efficiency of homologous recombination repair of F10-induced DNA DSBs
Authors: Gmeiner William H. , Mani Chinnadurai , Palle Komaraiah 
Published: August 2018

Abstract
Background: DNA mismatch repair (MMR) is an important stratification factor in colorectal cancer (CRC). 10-20% of sporadic CRC cases display high microsatellite instability (MSI-H) due to DNA mismatch repair (MMR) deficiency, and these are refractory to current fluoropyrimidine (FP) chemotherapy. Our studies with DNA-directed FP polymers, such as F10, indicate they are highly effective regardless of MMR-deficiency consistent with inducing MMR-independent cell death. We investigate the role of MMR-status on potency of F10 and induction of DNA damage and activation of the DNA damage response as part of an overall effort to determine if fluoropyrimidine polymers can be used effectively in the treatment of MMR-deficient CRC.
Methods: Studies were conducted using MMR-deficient HCT-116 CRC cells and HCT-116 3-6 cells. Potency was assessed by cell-titer glo and clonogenic assays. Replication stress was evaluated by DNA fiber combing. DNA damage and activation of the DNA damage response was evaluated by Western blots for gH2AX, Chk1 activation, and proteins important for homologous recombination repair.
Results: F10 is highly potent to CRC cells regardless of MMR status and is ~1,000-fold more potent than 5-FU to MMR-deficient HCT-116 cells. The increased potency of F10 parallels increased efficiency at causing replication fork slowing as assessed by DNA fiber analysis. F10 causes DNA double strand breaks (DSBs) and activates Chk1 consistent with causing replication fork collapse. DNA DSBs, Chk1 activation, and upregulation of FANCD2, which mediates HR-repair of DNA DSBs all show a marked MMR-dependence consistent with hMLH1 being a factor in HR-mediated repair of F10-induced DNA DSBs.
Conclusions: F10 is highly potent to CRC cells regardless of MMR status via a mechanism involving replication fork slowing and increased replication stress. MMR status affects basal levels of proteins involved in HR and the upregulation of these proteins in response to F10 treatment. Our studies indicate FP polymers are likely to be generally effective in CRC regardless of MMR status however MMR status may be an important factor in a personalized medicine approach to their use as combination with Chk1 inhibitors and other drugs modulating the DNA damage response may depend on MMR status.
Citation Format: William H. Gmeiner, Chinnadurai Mani, Komaraiah Palle. MMR status affects efficiency of homologous recombination repair of F10-induced DNA DSBs [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 2828.
Abstract 2830: Understanding chemotherapy-induced replicative stress to identify rational combination therapies
Authors: Alkan Ozan , Schoeberl Birgit , Shah Millie , Koshkaryev Alexander , Heinemann Tim , Drummond Daryl , Yaffe Michael B. , Raue Andreas 
Published: August 2018

Abstract
Cells respond to DNA damage by activating complex signaling networks that decide cell fate, promoting not only DNA damage repair and survival but also cell death. We have developed a multi-scale computational model using the U2OS osteosarcoma cancer cell line that quantitatively links chemotherapy-induced DNA damage response signaling to cell fate. The computational model was trained and calibrated based on an extensive data set that comprises cell cycle distribution of the initial cell population, signaling data measured by western blot, and cell fate data in response to chemotherapy treatment measured by time-lapse microscopy. The resulting mechanistic model can predict the cellular responses to chemotherapy alone and in combination with targeted inhibitors of the DNA damage response pathway, which we were able to confirm experimentally. Computational models, like the one presented here, can be used to understand the molecular basis that defines the complex interplay between cell survival and cell death, as well as to rationally identify chemotherapy-potentiating drug combinations.
Citation Format: Ozan Alkan, Birgit Schoeberl, Millie Shah, Alexander Koshkaryev, Tim Heinemann, Daryl Drummond, Michael B. Yaffe, Andreas Raue. Understanding chemotherapy-induced replicative stress to identify rational combination therapies [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 2830.
Abstract 2845: The mechanisms of resistance to temozolomide in glioma cells
Authors: Ohba Shigeo , Hirose Yuichi 
Published: August 2018

Abstract
Glioblastoma is one of the most aggressive tumor in the central nervous system tumors, with 5-year survival rates of less than 10%. The standard therapy for glioblastomas is maximal safe resection, followed by radiation therapy and chemotherapy with temozolomide (TMZ). One of the reasons of the worse prognosis of the tumor is the acquisition of resistance to TMZ in glioma cells. TMZ is a DNA-methylating agent. TMZ-induced O6-methylguanine adducts, in the absence of repair by O6-methylguanine DNA methyltransferase (MGMT), mispair with thymine during the next DNA replication cycle, leading to futile DNA mismatch repair (MMR) by the MMR system, formation of double strand breaks (DSBs) and eventual cell death of glioma cells. Several mechanisms have been proposed about the acquisition of resistance to TMZ in glioblastomas, such as changes of expression of MGMT, MMR, nucleotide excision repair and homologous recombination (HR). To clarify the mechanisms of resistance to TMZ and to find the way to overcome the resistance to TMZ, several clones of U251 cells resistant to TMZ were obtained and analyzed. FACS analyses showed several patterns of cell cycle distributions of the cells treated with TMZ. #3 resistant clone showed G2 arrest at day3 after TMZ exposure and this arrest was abrogated sooner compared to the G2 arrest of parental U251. TMZ did not induce G2 arrest in #8 resistant clone. Consistent with the results, TMZ-induced DSBs in #3 resistant cells were rapidly disappeared compared to those in U251 cells, and the DSBs were least induced by TMZ in #8 resistant cells. The expression of MGMT was not found in U251 parental cells, #3 cells nor #8 cells, which mean MGMT was not associated with the resistance to TMZ in those cells. The protein levels of MSH6, which was associated with MMR, was reduced in #8 cells. The inhibitor of PLK1 or PARP reduced the cell growth independent of MMR. The ability of HR was increased in #3 resistant clone. By suppression of Rad51, which was major factor associated with HR, the resistant #3 clone was re-sensitized to TMZ, however #8 was not. These results suggested that inhibition of HR may be a viable means to resensitize some kinds of temozolomide-resistant gliomas to TMZ.
Citation Format: Shigeo Ohba, Yuichi Hirose. The mechanisms of resistance to temozolomide in glioma cells [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 2845.
Abstract 2848: Radiographic and genomic evolution of individual metastases during HER2 blockade in colorectal cancer
Authors: Siravegna Giulia , Lazzari Luca , Sartore-Bianchi Andrea , Crisafulli Giovanni , Mussolin Benedetta , Cassingena Andrea , Martino Cosimo , Lanman Richard , Nagy Rebecca , Corti Giorgio , Bartolini Alice , Arcella Pamela , Montone Monica , Lodi Francesca , Vanzati Alice , Valtorta Emanuele , Cappello Giovanni , Bertotti Andrea , Lonardi Sara , Zagonel Vittorina , Leone Francesco , Russo Mariangela , Balsamo Antonella , Truini Mauro , Nicolantonio Federica Di , Amatu Alessio , Bonazzina Erica , Ghezzi Silvia , Regge Daniele , Vanzulli Angelo , Trusolino Livio , Siena Salvatore , Marsoni Silvia , Bardelli Alberto 
Published: August 2018

Abstract
Targeting HER2 with trastuzumab and lapatinib is effective in ERBB2 amplified metastatic colorectal cancer (mCRC). Although at least 30% of the patients initially respond, secondary resistance occurs in most of the cases.
Since the drivers of secondary resistance to trastuzumab and lapatinib in ERBB2 amplified mCRC are unknown, we exploited longitudinal plasma collections and patient-derived cell models to define the molecular bases of resistance to HER2 blockade. Levels of ERBB2 amplification in plasma circulating tumor DNA (ctDNA) paralleled response and relapse. The emergence of EGFR, ERBB2, RAS, BRAF and PIK3CA variants in ctDNA was associated with resistance. Radiographic measurements of individual metastases coupled with longitudinal liquid biopsies unveiled lesion-specific patterns of heterogeneous response in several patients. Phylogenetic tracking and functional analyses on tissue samples and patient-derived cell models established from eight metastases of a single case revealed new druggable oncogenic dependencies and genomic evolution associated with resistance. These data highlight the relevance of coupling imaging and liquid biopsies analyses in precision oncology and provide the rationale for additional lines of therapies in HER2 positive mCRC relapsing upon HER2 blockade.
Citation Format: Giulia Siravegna, Luca Lazzari, Andrea Sartore-Bianchi, Giovanni Crisafulli, Benedetta Mussolin, Andrea Cassingena, Cosimo Martino, Richard Lanman, Rebecca Nagy, Giorgio Corti, Alice Bartolini, Pamela Arcella, Monica Montone, Francesca Lodi, Alice Vanzati, Emanuele Valtorta, Giovanni Cappello, Andrea Bertotti, Sara Lonardi, Vittorina Zagonel, Francesco Leone, Mariangela Russo, Antonella Balsamo, Mauro Truini, Federica Di Nicolantonio, Alessio Amatu, Erica Bonazzina, Silvia Ghezzi, Daniele Regge, Angelo Vanzulli, Livio Trusolino, Salvatore Siena, Silvia Marsoni, Alberto Bardelli. Radiographic and genomic evolution of individual metastases during HER2 blockade in colorectal cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 2848.
Abstract 2849: Biodynamic imaging predicts response of breast cancer patients to neoadjuvant chemotherapy
Authors: Turek John J. , Nolte David D. , An Ran 
Published: August 2018

Abstract
The goal of this research was to determine if biodynamic imaging (BDI) and frozen breast cancer tumors from tissue banks could be used to retrospectively assess response to chemotherapy and identify the more chemoresistant patients. Neoadjuvant chemotherapy (NAC) is a common protocol for breast cancer patients prior to surgery. Many patients will respond to initial chemotherapy, but there is a significant percentage of patients that do not receive a benefit from NAC due to chemoresistance. Accurate prediction of chemoresistance prior to therapy, could enhance the effectiveness of NAC by allowing for better drug selection. BDI uses Doppler detection of light scattered by intracellular motion in living tissue, and several xenograft, and clinical studies have shown that this phenotypic profiling method is a highly accurate predictor of resistance to chemotherapy. Frozen, clinically annotated breast cancer samples were obtained from several tissue banks. All of the patients received adriamycin-cyclophosphamide and paclitaxel (AC-T) neoadjuvant chemotherapy prior to surgery. The samples were rapidly thawed and 1mm3 pieces were placed in tissue culture medium in a 96 well plate, sealed with a gas permeable membrane, and 6 replicates for each drug treatment assayed over an 18 hour period. Drugs tested were the AC combination, and also the individual drugs (adriamycin, 4-hydroxycyclophosphamide, and paclitaxel). A negative drug vehicle control was 0.1% DMSO in growth medium, and vincristine was used as a positive control. For the analysis, patients were classified as sensitive or resistant based upon the clinically annotated pathology reports. The BDI spectral data for each drug treatment was analyzed using a machine learning algorithm to identify patterns in the frequency vector biomarkers for each patient using a combination of a similarity matrix and a linear separability analysis using a neural net perceptron. The neural net perceptron and hold-out cross validation of BDI spectral data correctly identified all patients as sensitive or resistant. Frozen samples from tissue banks contain enough viable cells to evaluate drug response using BDI. This makes it possible to conduct retrospective studies on chemoresistance using frozen banked tissue samples and also makes it possible to study the relationship between genotype to chemo-phenotype. Supported by Animated Dynamics, Inc.
Citation Format: John J. Turek, David D. Nolte, Ran An. Biodynamic imaging predicts response of breast cancer patients to neoadjuvant chemotherapy [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 2849.