bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 794: The ATR inhibitor VE-821 in combination with the novel topoisomerase I inhibitor LMP-400 selectively kills cancer cells by disabling DNA replication initiation and fork elongation
Authors: Jossé Rozenn , Martin Scott E. , Guha Rajarshi , Ormanoglu Pinar , Pfister Thomas , Morris Joel , Doroshow James H. , Pommier Yves 
Published: May 2015

Abstract
Camptothecin, a specific topoisomerase I inhibitor is a potent anticancer drug, especially against solid tumors. This agent produces well-characterized double-strand breaks upon collision of replication forks with topoisomerase I cleavage complexes. In an attempt to improve its efficacy, we conducted a synthetic lethal siRNA screening using a library that targets nearly 7000 human genes. Depletion of ATR, the main transducer of replication stress-induced DNA damage response exacerbated cytotoxic response to both camptothecin and the indenoisoquinoline LMP-400, a novel class of topoisomerase inhibitors in clinical trial. Inhibition of ATR by the recently developed specific inhibitor VE-821 induced synergistic antiproliferative activity when combined with either topoisomerase inhibitor. Cytotoxicity induced by the combination with LMP-400 was greater than with camptothecin. Using single cell analysis and DNA fiber spread, we show that VE-821 abrogated the S-phase checkpoint, restored origin firing and replication fork progression. Moreover, the combination of a topoisomerase inhibitor with VE-821 inhibited the phosphorylation of ATR and ATR-mediated Chk1 phosphorylation but strongly induced γH2AX. Single cell analysis revealed that γH2AX pattern changed overtime from well-defined focus to a pan-nuclear staining. The change in γH2AX pattern can be useful as a predictive biomarker to evaluate the efficacy of therapy. The key implication of our work is the clinical rationale it provides to evaluate the combination of indenoisoquinoline topoisomerase I inhibitors with ATR inhibitors.
Citation Format: Rozenn Jossé, Scott E. Martin, Rajarshi Guha, Pinar Ormanoglu, Thomas Pfister, Joel Morris, James H. Doroshow, Yves Pommier. The ATR inhibitor VE-821 in combination with the novel topoisomerase I inhibitor LMP-400 selectively kills cancer cells by disabling DNA replication initiation and fork elongation. [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 794. doi:10.1158/1538-7445.AM2014-794
Abstract 806: Selective killing of cancer cells with mitochondrial respiratory dysfunction induced by activation of oncogenic Ras
Authors: Lu Weiqin , Yang Yaying , Logsdon Craig , Huang Peng 
Published: May 2015

Abstract
Mitochondrial dysfunction is an important mechanism by which cancer cells become resistant to chemotherapeutic agents. Oncogenic Ras activation is often observed in human cancer and was reported to cause mitochondrial dysfunction by compromising mitochondrial electron transport chain. Therefore, identification of new agents capable of effectively killing mitochondrial defective cancer cells would have important therapeutic implications. Our previous work has discovered that mitochondrial respiratory dysfunction could cause increased NADPH oxidase (NOX) activity to support cell survival in the metabolic switch from mitochondrial oxidative phosphorylation to glycolysis. Mitochondrial respiratory dysfunction can also cause profound redox alteration to adapt ROS stress. Here, we report that targeted inhibition of NOX and glutathione synthesis has synergy effect in killing mitochondrial respiratory dysfunction cells, including cancer cells harboring oncogenic Ras activation. Activation of NOX and increased glutathione antioxidants are always observed in Ras activated cells. Treatment of these cancer cells with DPI and BSO to inhibit NOX activity and antioxidant adaptation function resulted in an elevated ROS stress, increased gamma-H2AX expression, leading to massive death of the cancer cells, such as Panc-1 and HCT116 cells. Antioxidant NAC and catalase attenuated the BSO and DPI induced cell death in mitochondrial respiratory dysfunction cells. The synergistic effect of BSO and DPI to kill oncogenic Ras bearing HCT116 cells was further confirmed using colony formation assay. Our results suggest that DPI, in synergy with BSO, is a promising compound capable of killing cancer cells bearing oncogenic Ras mutations through a ROS-mediated mechanism and warrants further investigations.
Citation Format: Weiqin Lu, Yaying Yang, Craig Logsdon, Peng Huang. Selective killing of cancer cells with mitochondrial respiratory dysfunction induced by activation of oncogenic Ras. [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 806. doi:10.1158/1538-7445.AM2014-806
Abstract 823: Water-soluble ureidomustine (BO-1055) potently suppresses orthotopic 22Rv/HL2 prostate tumor xenografts: early preclinical studies
Authors: Su Tsann-Long , Chen Yi-Ren , Shieh Jae-Hung , Tsai Tung-Hu , Moore Malcolm A.S. , Lee Te-Chang 
Published: May 2015

Abstract
In developed countries, prostate cancer (PCa) is one of the leading causes of death in men. PCa often recurs and metastasizes after an initial response to hormone therapy. Once PCa progresses to the castration-resistant stage, it becomes incurable. New and effective agents against PCa are therefore urgently needed. The objective of this study is to evaluate the antitumor activity of ureidomustine (BO-1055), which is a chemically stable and water-soluble phenyl N-mustard-benzamide conjugate previously synthesized from our laboratory. We previously demonstrated that ureidomustine exhibited potent therapeutic efficacy in nude mice bearing various human tumor xenografts, such as human colon cancer HCT-116 and prostate adenocarcinoma PC-3 xenografts (subcutaneous implantation), inhibiting growth by &gt;95% and &gt;99%, respectively. To broaden the antitumor spectrum of this agent, we evaluated the therapeutic efficacy of ureidomustine in nude mice bearing 22Rv/HL2 human PCa tumors implanted at an orthotopic site. The results showed that ureidomustine was as efficacious as docetaxel (&gt;92% tumor suppression) and more potent than carboplatin (62% suppression) against 22Rv/HL2 PCa tumors in an orthotopic xenograft model. It revealed that ureidomustine exhibited low toxicity in mice, with no apparent pathological changes. We also studied the cytotoxicity of ureidomustine against normal murine cells and human hematopoietic stem cells (cord blood CD34+). The results showed that this agent exhibited low cytotoxicity against human hematopoietic stem cells (cord blood CD34+), primary human endothelial cells, and mesenchymal stem cells (BSC). Moreover, we performed the early preclinical studies including pharmacokinetics in rats, rat plasma protein binding, metabolic stability in rat liver microsomes, the 14 day intravenous acute toxicity in mice, and the biodistribution in rat, to determine whether this agent is a candidate for future clinical studies. The results indicate that ureidomustine is as potent as docetaxel against 22Rv/HL2 PCa cells in orthotopic xenograft models with low toxicity. In addition, this agent has low toxicity to human hematopoietic stem/progenitor cells and stromal cells such as BM-derived endothelial cells (BMEC) and MSC. Furthermore, early preclinical studies (ADME) suggest that ureidomustine has high potential for the treatment of advanced PCa in the clinic.
Citation Format: Tsann-Long Su, Yi-Ren Chen, Jae-Hung Shieh, Tung-Hu Tsai, Malcolm A.S. Moore, Te-Chang Lee. Water-soluble ureidomustine (BO-1055) potently suppresses orthotopic 22Rv/HL2 prostate tumor xenografts: early preclinical studies. [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 823. doi:10.1158/1538-7445.AM2014-823
Abstract 825: The development of a novel PARP inhibitor with potent antitumor activity in various tumor xenograft models
Authors: Park Ji-Seon , Kim Jang-Hyun , Cheon Kwang-Woo , Cho Bo-Young , Kim Kang-Jeon , Lee Han-Chang , Kim Young-Cheol , Oh Hyung-Chan , Lee Hyun-Ho , Kim Jeong-Min 
Published: May 2015

Abstract
Poly (ADP-ribose) Polymerase (PARP) plays a critical role in DNA repair processes. Small molecule inhibitors of PARP for the treatment of cancer are currently being investigated either single agents or in combination therapy with other DNA damaging agents. Based on recent published data, PARP inhibitors have shown promising results as a powerful therapeutic anticancer agents, especially in tumors deficient in BRCA-1or BRCA-2 function. In this study, we present a novel synthetic inhibitor of poly (ADP-ribose) polymerase (PARP) for their anti-tumor activity in various types of tumor xenograft model. Among new synthetic PARP inhibitors, JPI-283 shows synergistic effects in vitro cell cytotoxicity with DNA damaging agent such as Temozolomide(TMZ), SN-38, and CDDP. Also, JPI-283 represents a potential anticancer activity in BRCA-1 and BRCA-2 mutant cells as a single agent. In tumor xenograft model studies, the combination of JPI-283 with TMZ by oral dosing results in more than 60-70% tumor growth inhibition rate, compared to the control group in CAPAN-1, U87MG, MDA-MB-468 and SW620 tumor xenograft model. In addition, the combination of JPI-283 with CDDP shows superior antitumor activity compared to that of AZD2281 with CDDP in MDA-MB468 triple negative breast tumor xenograft model. The pharmacokinetics of JPI-283 in mouse and rat shows over 50% bioavailability. These findings suggest that JPI-283 would be an attractive therapeutic candidate for the treatment of cancer including DNA repair deficient cancer.
Citation Format: Ji-Seon Park, Jang-Hyun Kim, Kwang-Woo Cheon, Bo-Young Cho, Kang-Jeon Kim, Han-Chang Lee, Young-Cheol Kim, Hyung-Chan Oh, Hyun-Ho Lee, Jeong-Min Kim. The development of a novel PARP inhibitor with potent antitumor activity in various tumor 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 825. doi:10.1158/1538-7445.AM2014-825
Abstract 837: The unique profile of microtubule stability initiated by the taccalonolides leads to potent antitumor activities
Authors: Risinger April L. , Li Jing , Peng Jiangnan , Bennett Melissa J. , Rohena Cristina C. , Schriemer David C. , Mooberry Susan L. 
Published: May 2015

Abstract
The taccalonolides are structurally distinct microtubule stabilizers purified from the roots and rhizomes of plants of the genus Tacca. The taccalonolides impart a unique mechanism of microtubule stabilization through covalent attachment to the 212-230 peptide of β-tubulin. The profound interprotofilament stability conferred by taccalonolide binding, as demonstrated by hydrogen deuterium exchange mass spectrometry, occurs independent of changes in the H7 or M-loops, which makes their effects different from other classes of microtubule stabilizers. This remarkable stability results in the formation of microtubules that are highly resistant to cold induced depolymerization or mechanical disruption. The covalent attachment of the taccalonolides to microtubules is proposed to be directly responsible for their strong cellular persistence and ability to circumvent multiple mechanisms of clinically relevant drug resistance, including expression of P-glycoprotein.
We have isolated and characterized 66 new taccalonolides that range in potency from 0.37 nM to over 50 µM, allowing for detailed structure activity relationship studies. These studies demonstrate that epoxidation of the C22,23 double bond present in most naturally occurring taccalonolides is optimal for potency. A simple, one step oxidation reaction has been employed and increases the potency of 17 natural taccalonolides by as much as 700-fold. The new, potent taccalonolides show excellent antitumor activity against the MDA-MB-231 triple negative breast cancer xenograft model at cumulative doses as low as 0. 5 mg/kg. This exquisite in vivo potency facilitates antitumor evaluations from small quantities of material and allows administration in aqueous vehicles. Studies to further map the optimal interactions of the taccalonolide backbone with microtubules and identify a candidate for clinical development are in progress.
Citation Format: April L. Risinger, Jing Li, Jiangnan Peng, Melissa J. Bennett, Cristina C. Rohena, David C. Schriemer, Susan L. Mooberry. The unique profile of microtubule stability initiated by the taccalonolides leads to potent antitumor activities. [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 837. doi:10.1158/1538-7445.AM2014-837
Abstract 844: Contribution of dual oxidase 2 (DUOX2) to hyper radiosensitivity in human gastric cancer cells
Authors: Nguyen Duc , Chang Elizabeth , Sharma Navesh , Carrier France 
Published: May 2015

Abstract
Whole abdominal radiotherapy (WART) is a primary method for managing gastrointestinal cancers that have disseminated into intra-abdominal tissues. While effective, this approach is limited since combination of WART with full-dose chemotherapy regimens increase toxicity to normal tissue. Recent studies have demonstrated a survival advantage in a novel treatment paradigm that allows for the safe use of full-dose systemic chemotherapy in combination with Low Dose Fractionated Radiotherapy (LDFRT). Traditionally, radiotherapy used doses greater than 120 cGy because it was thought that lower radiation doses would be ineffective for tumor therapy. We now know that LDFRT can produce hyper-radiosensitivity (HRS), a phenomenon where cells undergo apoptosis at radiation doses as low as 15 cGy, in a number of proliferating cells. Here we aimed at determining whether LDFRT can induce HRS in gastrointestinal cancer cells and at identifying biomarkers of chemopotentiation by LDFRT. Our data indicate that three consecutive daily fractions of 15 cGy produced HRS in gastric cancer cells and potentiated a modified regimen of Docetaxel, Cisplatin, and 5’-fluorouracil (mDCF). Colony survival assays indicated that 15 cGy was sufficient to kill 90% of the cells when LDFRT was combined with mDCF whereas an almost ten times higher dose (135 cGy) was needed to achieve the same rate when using conventional radiotherapy alone. RT2 PCR Profiler Array analysis indicated that this combined regimen up-regulated dual oxidase 2 (DUOX2), an enzyme functioning in the production of hydrogen peroxide, without up-regulating genes involved in DNA repair. Moreover, down regulation of DUOX2 increased radiation resistance at every radiation doses tested. In addition, a subset of genes known to be activated by Reactive Oxygen Species were specifically upregulated by LDFRT when combined with mDCF. Taken together these data suggest that chemopotentiation by LDFRT in gastric cells may be due, at least in part, to increased ROS production (DUOX2) without upregulation of the DNA repair machinery. These data thus provide a rationale for further explorations of potential clinical applications of LDFRT, such as in WART, as chemopotentiator for advanced and metastatic gastric cancers.
Citation Format: Duc Nguyen, Elizabeth Chang, Navesh Sharma, France Carrier. Contribution of dual oxidase 2 (DUOX2) to hyper radiosensitivity in human gastric 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 844. doi:10.1158/1538-7445.AM2014-844
Abstract 851: Gold nanoparticle-mediated infrared hyperthermia reduces the radiotherapy dose required for tumor therapy
Authors: Hainfeld James F. , O'Connor Michael J. , Lin Lynn , Slatkin Daniel N. , Dilmanian F. Avraham , Smilowitz Henry M. 
Published: May 2015

Abstract
Gold nanoparticles (AuNPs) absorb light and can be used to heat and ablate tumors. The “tissue window” at ∼800 nm (near infrared, NIR) is optimal for best tissue penetration (∼2cm). Previously large, 50-150nm gold nanoshells and nanorods that absorb well in the NIR have been used. Here we show that small AuNPs, that may penetrate tumors better, barely absorb at 800nm. However, when conjugated to antitumor antibodies, they are taken up by tumor cells, which catalytically aggregate them by enzyme degradation and pH effects, thus shifting their absorption to the NIR region thereby amplifying their photonic absorption. The AuNPs are NIR transparent until they accumulate in tumor cells; this reduces background heating in blood and non-targeted tissues thereby increasing specificity in contrast to constructs that are always NIR absorbing. We show that treatment of subcutaneous EGFR overexpressing human squamous cell carcinoma (A431) tumor xenografts with 15nm AuNPs conjugated with anti-EGFR and NIR resulted in complete tumor ablation with virtually no normal tissue (skin) damage. Further, using radioresistant mouse squamous cell carcinoma SCCVII xenografts, we have combined AuNP-mediated infrared heating with x-ray therapy to take advantage of the well-known synergy of hyperthermia and radiotherapy. Lipoic Acid modified 15nm AuNPs were injected intratumorally by convection-enhanced delivery (CED) followed by NIR and X-ray therapy. It was found that the dose required for control of 50% the tumors, 55Gy, could be reduced to &lt;15Gy, a factor of 3.7 less. AuNPs therefore provide a method to use hyperthermia to reduce the x-radiation needed for tumor control, thereby sparing normal tissue, reducing side effects and making radiotherapy more effective.
Citation Format: James F. Hainfeld, Michael J. O'Connor, Lynn Lin, Daniel N. Slatkin, F. Avraham Dilmanian, Henry M. Smilowitz. Gold nanoparticle-mediated infrared hyperthermia reduces the radiotherapy dose required for tumor 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 851. doi:10.1158/1538-7445.AM2014-851
Abstract 858: Treatment resistance of colon cancer with low proteasome activity
Authors: Munakata Koji , Uemura Mamoru , Nishimura Junichi , Hata Taishi , Takemasa Ichiro , Mizushima Tsunekazu , Yamamoto Hirofumi , Doki Yuichiro , Mori Masaki 
Published: May 2015

Abstract
Background and aims:Emerging evidence indicates that cancer stem cells are resistant to chemotherapy and radiation therapy which result in recurrence after curative intent treatment for solid tumor. Recently, several reports have indicated that some cancer stem cells (CSCs) would be characterized by low proteasome activity. And cell of low proteasome activity could lead to new therapeutic targets.
Material and methods:
We engineered human colorectal adenocarcinoma cells (HCT116, KM12SM, SW480, LoVo, DLD1, HT29) to express a green fluorescent molecule fused to the degron of ornithine decarboxylase (Gdeg) from a retroviral vector; the fluorescent Gdeg supposed to be accumulated in CSC like cells as a result of low activity of the 26S proteasome. The feature of Gdeghigh cells were analyzed by sphere formation assay, surface marker analysis, reactive oxygen species (ROS) analysis and assessment of chemotherapy and radiation therapy sensitivity.
Results:
Population of Gdeghigh was up-regurated by chemotherapy (5-FU and oxaliplatin) and radiation therapy. Furthermore CSC markers were increased by chemotherapy and radiation therapy. ROS activity of Gdeghigh was lower than Gdeglow.
Conclusions:
Low proteasome activity cells suggested eatures of CSCs. Mechanisms of chemotherapy and radiation therapy resistance should be revealed to establish new therapeutic approach based on CSCs hypothesis.
Citation Format: Koji Munakata, Mamoru Uemura, Junichi Nishimura, Taishi Hata, Ichiro Takemasa, Tsunekazu Mizushima, Hirofumi Yamamoto, Yuichiro Doki, Masaki Mori. Treatment resistance of colon cancer with low proteasome activity. [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 858. doi:10.1158/1538-7445.AM2014-858
Abstract 877: Detection of colorectal cancer-associated genetic alterations in urine of patients with CRC
Authors: Clemens Adam W. , Lin Selena , Jain Surbhi , Chen Sitong , Su Ying-Hsiu , Song Wei 
Published: May 2015

Abstract
Colorectal cancer (CRC) has been the second leading cause of cancer-related deaths due in part to a low compliance rate (&lt;50%) of the current screening method, an invasive colonoscopy, resulting in failure of detecting cancer early in its curative stages. 20% of CRCs are only detected once the cancer has spread to a distant site, drastically reducing the 5-year survival rate from 90% to 12%. In order to improve the success of early detection methods of CRC, we have focused on developing non-invasive, multi-biomarker detection assays designed to identify CRC-associated genetic alterations. The genetic alterations of four genes, (mutations of the KRAS (muKras) and BRAF V600E (muBRAF) genes and aberrant hypermethylation of the Vimentin (mVIM) and Septin9 (mSEPT9) genes, have shown to be potential biomarkers of CRC through stool or serum-derived DNA. We set out to show that these four biomarkers could be used as a panel for a non-invasive urine test of CRC in a highly specific and sensitive manner. We have previously demonstrated that urine contains circulation-derived low molecular weight (LMW) DNA (&lt;300 bp), which suggests that LMW urine DNA could be used to detect CRC-associated genetic alterations. A blinded concordance study was used to validate mVIM as a biomarker for CRC between 20 urine samples and the corresponding tissue sample. We have developed a locked nucleic acid (LNA) clamp and a Simple Probe to distinguish mVIM from normal VIM suitable for fragmented short DNA templates. By using this assay, we indicated that mVIM can be detected from LMW urine DNA, and it has the potential to serve as a CRC-specific biomarker (Song et al., 2012). This LNA-clamp short-qPCR assay has been adapted for quantitation of muBRAF, muKRAS, and mSEPT9, for testing these biomarkers with open-labeled CRC samples. In addition, a prevalidation study is in progress with blinded CRC samples to confirm the specificity and sensitivity of these genetic biomarkers.
References
Song, B. P., Jain, S., Lin, S. Y., Chen, Q., Block, T. M., Song, W., ... & Su, Y. H. (2012). Detection of hypermethylated vimentin in urine of patients with colorectal cancer. The Journal of Molecular Diagnostics, 14(2), 112-119.
Citation Format: Adam W. Clemens, Selena Lin, Surbhi Jain, Sitong Chen, Ying-Hsiu Su, Wei Song. Detection of colorectal cancer-associated genetic alterations in urine of patients with CRC. [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 877. doi:10.1158/1538-7445.AM2014-877