bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract PL04-01: Developing therapies for Ras driven cancers.
Authors: Cichowski Karen 
Published: August 2014

Abstract
The Ras pathway is one of the most commonly deregulated pathways in cancer. However Ras-driven tumors are often refractory to conventional therapies and a clinically effective targeted therapy has not yet been developed. Moreover, in some cancers KRAS mutations are used to exclude patients from being treated with specific targeted agents. As such, developing an effective targeted therapy for Ras-driven tumors is an important endeavor. We have been focusing on developing therapies for distinct Ras-driven cancers: Nf1-mutant cancers (nervous system malignancies and melanoma) as well KRas/p53-mutant non-small cell lung cancer (NSCLC). We have been using PI3K/mTOR inhibitors as a platform to develop novel combination therapies and have identified several new combinations, a subset of which are being evaluated in the clinic. We have also been deconstructing the mechanism by which these agents cooperate, which is providing insight into developing useful biomarkers and additional drug combinations.
Citation Information: Mol Cancer Ther 2013;12(11 Suppl):PL04-01.
Citation Format: Karen Cichowski. Developing therapies for Ras driven cancers. [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 PL04-01.
Abstract PL04-03: Selective inhibition of K-Ras G12C through allosteric control of GTP affinity and effector interactions.
Authors: Ostrem Jonathan M. , Peters Ulf , Sos Martin L. , Wells James A. , Shokat Kevan M. 
Published: August 2014

Abstract
Somatic mutations in the small GTPase K-Ras are the most common activating lesions found in human cancer, and are generally associated with poor response to standard therapies1-3. Efforts to directly target this oncogene have faced difficulties due to its picomolar affinity for GTP/GDP4 and the absence of known allosteric regulatory sites.Oncogenic mutations result in functional activation of Ras family proteins by impairing GTP hydrolysis5,6. With diminished regulation by GTPase activity, the nucleotide state of Ras becomes more dependent upon relative nucleotide affinity and concentration. This gives GTP an advantage over GDP7 and increases the proportion of active GTP-bound Ras. Here, we report the development of small molecules that irreversibly bind to a common oncogenic mutant, K-Ras G12C.These compounds rely on the mutant cysteine for binding and therefore do not affect the wild type protein (WT). Crystallographic studies reveal the formation of a new pocket that is not apparent in previous structures of Ras, beneath the effector binding switch-II region. Binding of these inhibitors to K-Ras G12C disrupts both switch-I and switch-II, subverting the native nucleotide preference to favor GDP over GTP and impairing binding to Raf. Our data provide structure-based validation of a novel allosteric regulatory site on Ras that is targetable in a mutant specific manner.
Citation Information: Mol Cancer Ther 2013;12(11 Suppl):PL04-03.
Citation Format: Jonathan M. Ostrem, Ulf Peters, Martin L. Sos, James A. Wells, Kevan M. Shokat. Selective inhibition of K-Ras G12C through allosteric control of GTP affinity and effector interactions. [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 PL04-03.
Abstract PR03: Selective sensitization of mutant K-Ras cancer cells to DNA damage based therapies by targeting wild type H- and N-Ras.
Authors: Grabocka Elda , Pylayeva-Gupta Yuliya , Yemanaberhan Eyoel , Lubkov Veronica , Taylor Laura , Bar-Sagi Dafna 
Published: August 2014

Abstract
Mutations in Kras are highly prevalent in human cancers and are strongly predictive of resistance to chemotherapy. As the constitutive activation of K-Ras has been believed to confer functional autonomy and dominance over the wild type Ras forms, it has been thought that wild type Ras forms are dispensable to the mutant K-Ras driven tumorigenic phenotype. Here we demonstrate a functional dependence of mutant K-Ras driven tumors on wild type Ras for the activation of the DNA damage response, and that this dependence can be exploited to specifically sensitize K-Ras cancers to DNA[[Unable to Display Character: &#8211;]]damage-inducing agents. We show that in mutant K-Ras cancer cells, wild type H-Ras and N-Ras are required for the activation of Chk1, the G2 DNA damage checkpoint, and the cellular response to DNA-damage-inducing chemotherapy. Specifically, we show that targeted depletion of wild type H- and N-Ras in mutant K-Ras cancer cells leads to the hyperactivation of the Erk/p90RSK and PI3K/Akt pathways, and as a consequence, the phosphorylation of Chk1 at an inhibitory site, Ser 280. The resulting inhibition of ATR/Chk1 signaling abrogates the activation of the G2 DNA damage checkpoint, and confers a specific sensitization of mutant K-Ras cancer cells to DNA damage therapeutic agents both in vitro and in vivo. Our results demonstrate a previously unappreciated role for wild type Ras in the DNA damage response of mutant K-Ras cancer cells and reveal a promising approach for targeting K-Ras-driven tumors.
Citation Information: Mol Cancer Ther 2013;12(11 Suppl):PR03.
Citation Format: Elda Grabocka, Yuliya Pylayeva-Gupta, Eyoel Yemanaberhan, Veronica Lubkov, Laura Taylor, Dafna Bar-Sagi. Selective sensitization of mutant K-Ras cancer cells to DNA damage based therapies by targeting wild type H- and N-Ras. [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 PR03.
Abstract LB-204: Highly potent and optimized small-molecule inhibitors of MDM2 achieve complete tumor regression in animal models of solid tumors and leukemia.
Authors: Wang Shaomeng , Sun Wei , Yu Shanghai , Zhao Yu-jun , Kumar Sanjeev , McEachern Donna , Liu Liu , Bernard Denzil , Sun Duxin , Zou Peng , Li Xiaqin , Yi Han , Stuckey Jeanne , Long Jianting , Malek Sami , Yang Dajun , Kang Snmao , Guo Ming , Wood Brian , Leopold Lance , Sorensen Mel , Barriere Cedric , Meaux Isabelle , Dos-Santos Odette , Carry Jean-christophe , Abecassis Pierre-yves , Charlier Anne , Ferey Vincent , Garciaecheverria Carlos , Lengauer Christophe , Debussche Laurent 
Published: August 2014

Abstract
Activation of p53 by blocking the interaction of MDM2-p53 using non-peptide small-molecule inhibitors is being pursued as a promising new cancer therapeutic strategy. Although genetic activation of p53 has been shown to achieve complete tumor eradication in mice, the best small-molecule inhibitors of the MDM2-p53 interaction reported to date (Nutlins including RG7112 or first generation spiro-oxindoles such as AT219) can only inhibit tumor growth but fail to achieve significant tumor regression in animal models of human cancer. In the present study, we demonstrate, for the first time, that 2 highly optimized spiro-oxindole compounds, Compound A and Compound B, are capable of achieving complete tumor regression or even permanent cure in multiple xenograft models of human cancer (sarcoma, leukemia, prostate) without causing any significant signs of toxicity to animals. They bind to human MDM2 protein with Ki values of &lt;1 nM, 5000-times more potent than the wild-type p53 peptide. These potent MDM2 inhibitors are capable of activating p53 at concentrations as low as 30–100 nM and induce robust p53-dependent cell cycle arrest and apoptosis against tumor cells with wild-type p53. Both compounds display good pharmacokinetic and pharmacodynamic profiles in animals. For instance, clearance is low in mice and moderate in dog representing 4 and 15 % of hepatic blood flow respectively. Importantly, excellent oral bioavailability was shown with 25–60 % F in dogs and 75 % F in mice and both compounds trigger rapid and sustained activation of pharmacodynamic biomarkers such as p53, p21, MDM2 and PUMA. Molecular profiling using large number of primary AML leukemia samples have identified that AML cells with wild-type p53 and FLT3-ITD mutation are exquisitely sensitive to apoptosis induction by our MDM2 inhibitors, suggesting an interesting clinical trial rationale. Toxicology studies are ongoing.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr LB-204. doi:10.1158/1538-7445.AM2011-LB-204
Abstract 1027: EGFR targeting antibody SYM004 causes radiosensitization in tumor cells expressing wild-type K-Ras via modulation of MAPK signaling.
Authors: Saker Jarob , Huang Shyhmin , Park Lindsey , Pedersen Mikkel , Kragh Michael , Harari Paul 
Published: August 2014

Abstract
SYM004 is a promising new cancer therapeutic agent containing a mixture of two antibodies that target distinct epitopes on domain III of the EGFR. Treatment of tumor cells with SYM004 leads to clustering of EGFR followed by rapid internalization and degradation. We have recently shown that the combination of SYM004 and radiation therapy (RT) induces potent anti-tumor effects in head and neck (H&N) and lung cancer cell lines.
In this study we demonstrate that radiosensitization via SYM004 correlates with inhibition of DNA double strand break repair and induction of apoptosis. These effects are promoted by down regulation of the MAPK pathway. Treatment of SCC6 and H226 cell lines with SYM004 for 30min or 24h prior to irradiation leads to a 1.2 - 1.7 fold increase in unrepaired DNA double strand breaks (DSB) 24h after 2 Gy RT (detected via DNA repair foci formation). The fraction of early (1.8 -1.9 fold) and late (1.3 - 1.7 fold) apoptotic cells increased in both cell lines. However, these effects were reversible by treating the cells with 12-O-tetradecanoylphorbol-13-acetate (TPA), an activator of Raf, for 30 min before RT at concentrations as low as 0.1 μM. In addition, mutant K-Ras cells lines A549 and H358 showed no radiosensitization after treatment with SYM004 for 24h prior to RT via DNA repair or apoptosis. Furthermore, transfection of SCC6 cell lines with a K-Ras version carrying an activating SNP (G12V) reversed the inhibitory effect on DNA repair induced by SYM004 in wild type K-Ras cells. These data suggest that the superior impact of combination therapy with SYM004 and RT on wild type K-Ras tumor cell lines reflects alterations in DNA repair and apoptosis via modulation of the MAPK pathway.
Citation Format: Jarob Saker, Shyhmin Huang, Lindsey Park, Mikkel Pedersen, Michael Kragh, Paul Harari. EGFR targeting antibody SYM004 causes radiosensitization in tumor cells expressing wild-type K-Ras via modulation of MAPK signaling. [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 1027. doi:10.1158/1538-7445.AM2013-1027
Abstract 1281: POLD3 is required for DNA damage response to endogenous and exogenous DNA damage in human cells.
Authors: Tian Xu , Swenberg James , Nakamura Jun 
Published: August 2014

Abstract
Methyl methanesulfonate (MMS) induces mutations in a nonlinear (hockey-stick-shaped) dose-response curve in DT40 cells, about 55% of which are located at A:T sites with a high frequency of A to T mutations. We hypothesized that these transversion mutations are due to base excision repair (BER) intermediates, such as abasic sites and single strand breaks derived from N3-methyladenine. One candidate polymerase to bypass abasic sites is polymerase delta (POLD). POLD is responsible for the lagging strand during DNA replication. POLD is referred to as a high fidelity DNA polymerase because of its ability to discriminate deoxynucleotides and its 3’-&gt;5’ exo-nuclease activity. One of the POLD subunits, POLD3, is important to recruit PCNA binding to the POLD core enzyme and is implied to have critical roles for translesion DNA synthesis. In yeast, cells deficient in POLD3 homologous gene POL32 are sensitive to DNA damaging agents and resistant to mutations caused by mutagens, such as MMS and UV. Here we generated POLD3 knock-down (KD) cells via lentivirus based shRNA in three different human cell lines. All POLD3 KD cells grow slower than the control cells, suggesting POLD3 function tolerates endogenous DNA lesions. Furthermore, we found that POLD3 KD cells were sensitive to various genotoxic agents including MMS and potassium chromate. To further investigate the role of POLD3 in the DNA damage response, we introduced a series of deletion mutations of POLD3 in POLD3 deficient cells. We found that both the POLD2 binding domain and the middle linker domain are critical for the activity of POLD3 while the C-terminal PCNA binding domain is dispensable. While there is little homology between human POLD3 and yeast POL32, function of these two proteins appears to be quite similar in structure biology analysis. Our results also suggest that POLD3 plays important roles to bypass DNA lesions caused by endogenous and various exogenous genotoxic agents.
Citation Format: Xu Tian, James Swenberg, Jun Nakamura. POLD3 is required for DNA damage response to endogenous and exogenous DNA damage in human 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 1281. doi:10.1158/1538-7445.AM2013-1281
Abstract 1320: Effects of selective androgen-receptor and estrogen-receptor modulators on telomerase activity in melanoma and prostate cancer cells.
Authors: Lu Yan , Narayanan Ramesh , Wang Jin , Li Wei , Yepuru Murali , Liu Lingling , Loveless Vivian S. , Miller Duane D. 
Published: August 2014

Abstract
Male hormones and the androgen receptor (AR) are well-known key targets for prostate cancer therapy. The potential cause of a gender-based disparity in melanoma has been suspected for many years. A recent analysis suggests that female patients have a 30% survival advantage in cutaneous melanoma. Telomerase has been shown to add protective telomere repeats to chromosome endings and cause cancer cells to become immortal. We have recently discovered that the AR is expressed in melanoma cell lines. In current report, we tested the telomerase activity in lysates of both melanoma and prostate cancer cell lines. Telomeric repeat amplification protocol (TRAP) was carried out to test the activity of telomerase in melanoma A375, androgen-sensitive prostatic cancer LNCap and androgen-insensitive prostatic cancer PC-3 cell lines under treatments of steroid hormones, SARM and SERM compounds. The effects of sex hormones, selective androgen-receptor modulators (SARMs), and estrogen-receptor modulators (SERMs) on telomerase activity in both melanoma and prostate cells were investigated.
Citation Format: Yan Lu, Ramesh Narayanan, Jin Wang, Wei Li, Murali Yepuru, Lingling Liu, Vivian S. Loveless, Duane D. Miller. Effects of selective androgen-receptor and estrogen-receptor modulators on telomerase activity in melanoma and prostate 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 1320. doi:10.1158/1538-7445.AM2013-1320
Abstract 1826: A critical role of LincRNA-Up6 in Bcr-Abl-induced tumorigenesis.
Authors: Chen Jilong , Guo Guijie , Kang Qingzheng 
Published: August 2014

Abstract
Long noncoding RNAs (lncRNAs) have been implicated in numerous human malignancies, including leukemia. Philadelphia-positive (Ph+) chronic myeloid leukemia (CML) is a stem cell disease induced by Bcr-Abl hybrid gene. In an attempt to provide better understanding of the mechanisms by which Bcr-Abl mediates cellular transformation, lncRNA microarray was used to determine the differentially expressed non protein-coding genes in K562 human leukemic cells in response to disruption of Bcr-Abl expression. All the lncRNA genes whose expressions were altered by at least 2-fold were clustered and displayed. We further investigated the functional involvement of selected lncRNA genes in regulating cell proliferation, cell survival and tumor formation. Interestingly, expression of a long intergenic noncoding RNA which we named as lincRNA-Up6 was found to be greatly up-regulated by silencing the Bcr-Abl expression in K562 cells. We showed that forced over-expression of lincRNA-Up6 sensitized imatinib-induced apoptosis in Bcr-Abl transformed cells. In addition, we observed that over-expression of lincRNA-Up6 significantly inhibited K562 xenograft growth in nude mice. Furthermore, we found that lincRNA-Up6 was involved in negative regulation of STAT5-dependent expression of anti-apoptotic Bcl-XL protein. Importantly, our experiments showed that expression of lincRNA-Up6 had profound effects on signaling pathways associated with development of leukemia stem cells of CML, resulting in inhibition of Bcr-Abl-mediated tumor formation. Together, these results suggest that lincRNA-Up6 suppresses Bcr-Abl-induced tumorigenesis, and the tumor suppressor function of lincRNA-Up6 may be of significance for the development of novel therapeutic strategies for treating CML.
Citation Format: Jilong Chen, Guijie Guo, Qingzheng Kang. A critical role of LincRNA-Up6 in Bcr-Abl-induced tumorigenesis. [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 1826. doi:10.1158/1538-7445.AM2013-1826
Note: This abstract was not presented at the AACR Annual Meeting 2013 because the presenter was unable to attend.
Abstract 1855: Regulation of proliferation of colon cancer cells by compounds affecting glycolysis including 3-bromopyruvate, 2-deoxyglucose and biguanides.
Authors: Lea Michael A. , Qureshi Mehreen , Buxhoeveden Michael , Gengel Nicolette , Kleinschmit Jessica , desBordes Charles 
Published: August 2014

Abstract
In earlier work we found that incubation of colon cancer cells with 2-deoxyglucose had an additive inhibitory effect on proliferation with the biguanides, metformin and phenformin, and blocked the acidification of the medium caused by incubation of cells with biguanides. In the present work, studies were performed with Caco-2, HCT116, HT29 and SW1116 colon cancer cells. Metabolism of glucose and acidification of the medium was greater with the more rapidly proliferating cells being greatest with HCT116 cells and least with SW1116 cells. We have seen that, as with 2-deoxyglucose, 3-bromopyruvate can also prevent the lowering of medium pH caused by biguanide treatment. . Inhibition of glucose metabolism paralleled the decrease in acidification of the medium. 3-bromopyruvate inhibited colon cancer cell proliferation. Additive effects with metformin and 3-bromopyruvate were not observed in any of the four colon cancer cell lines but some additive effects were seen with phenformin and 3-bromopyruvate. An additive effect was more notable in combined treatment with 3-bromopyruvate and 2-deoxyglucose. Induction of alkaline phosphatase activity serves as a marker of differentiation in colon cancer cells. The induction of alkaline phosphatase activity by butyrate was not consistently affected by combination with other agents that modified glucose metabolism. The drug combinations that were examined inhibited proliferation in wild type and P53 null HCT116 cells and affected colon cancer lines with different growth rates. Although metformin and phenformin increase glucose metabolism by colon cancer cells while 3-bromopyruvate and 2-deoxyglucose inhibit glucose metabolism, all these compounds have potential inhibitory action on the proliferation of colon cancer cells.
Citation Format: Michael A. Lea, Mehreen Qureshi, Michael Buxhoeveden, Nicolette Gengel, Jessica Kleinschmit, Charles desBordes. Regulation of proliferation of colon cancer cells by compounds affecting glycolysis including 3-bromopyruvate, 2-deoxyglucose and biguanides. [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 1855. doi:10.1158/1538-7445.AM2013-1855
Abstract 2145: PSMA-specific anti-tumor activity of the targeted-tubulysin conjugate, EC1169.
Authors: Reddy Joseph A. , Bloomfield Alicia , Dorton Ryan , Nelson Melissa , Vetzel Marilynn , Hahn Spencer , Vlahov Iontcho , Leamon Christopher 
Published: August 2014

Abstract
Prostate-specific membrane antigen (PSMA) is a biomarker that is overexpressed on prostate cancer, and it's also present on the neovasculature within many non-prostate solid tumors. We previously reported on EC0652, a 99mTc-labeled small molecule that specifically binds to PSMA-positive tumors and is currently being clinically evaluated for diagnostic imaging applications. Herein, we report on the construction and biological testing of novel tubulysin B-containing, companion therapeutic agents for the treatment of PSMA-expressing cancer. One of these compounds, EC1169, recently emerged as a lead candidate for preclinical development. This water-soluble conjugate was shown to have high affinity for PSMA-positive cells. When tested in vitro, EC1169 was found to inhibit the growth of PSMA-positive cells, but it displayed no activity against PSMA-negative cells. Brief treatment of nude mice bearing PSMA-positive LNCaP human xenografts with EC1169 led to complete remissions in 5/7 mice, and cures (i.e. tumor free &gt;90 days post implantation) in 2/7 mice. Furthermore, this activity occurred in the absence of weight loss or major organ tissue degeneration. In contrast, the non-targeted tubulysin B drug proved to be inactive against the LNCaP tumor model when administered at doses near to or greater than the maximum tolerated level. PSMA-negative KB tumors did not appreciably respond to EC1169 therapy, thereby confirming this compound's targeted specificity for PSMA-expressing cells. Finally, treatment of LNCaP-bearing mice with docetaxel (the most active chemotherapeutic agent approved for prostate cancer), was found to produce only modest anti-tumor activity (2/4 partial responses, 1/4 cures), and this outcome was also associated with severe weight loss (18%). Taken together, these results strongly indicate that PSMA-positive tumors may be more effectively treated using highly potent, PSMA-targeted small-molecule drug conjugates using regimens that do not cause unwanted toxicity.
Citation Format: Joseph A. Reddy, Alicia Bloomfield, Ryan Dorton, Melissa Nelson, Marilynn Vetzel, Spencer Hahn, Iontcho Vlahov, Christopher Leamon. PSMA-specific anti-tumor activity of the targeted-tubulysin conjugate, EC1169. [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 2145. doi:10.1158/1538-7445.AM2013-2145