bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract A23: Oncogenic Ras induces inflammatory cytokine production by upregulating squamous cell carcinoma antigen (SerpinB3)
Authors: Catanzaro Joseph , Sheshadri Namratha , Pan Ji-An , Sun Yu , Shi Chanjuan , Li Jinyu , Powers Scott , Crawford Howard , Zong Wei-Xing 
Published: May 2015

Abstract
Mounting evidence indicates that oncogenic Ras can modulate cell autonomous inflammatory cytokine production, although the underlying mechanism remains unclear. Here we show that squamous cell carcinoma antigen (SCCA), a member of the Serpin family of serine/cysteine protease inhibitors, is transcriptionally up-regulated by oncogenic Ras via MAPK and the ETS family transcription factor PEA3. Increased SCCA expression leads to inhibition of protein turnover, unfolded protein response (UPR), activation of NF-κB, and is essential for Ras-mediated cytokine production and tumor growth. Analysis of human colorectal and pancreatic tumor samples reveals a positive correlation between Ras mutation, enhanced SCCA expression, and IL-6 expression. These results indicate that SCCA is a Ras-responsive factor that plays an essential role in Ras-associated cytokine production and tumorigenesis.
Citation Format: Joseph Catanzaro, Namratha Sheshadri, Ji-An Pan, Yu Sun, Chanjuan Shi, Jinyu Li, Scott Powers, Howard Crawford, Wei-Xing Zong. Oncogenic Ras induces inflammatory cytokine production by upregulating squamous cell carcinoma antigen (SerpinB3). [abstract]. In: Proceedings of the AACR Special Conference on RAS Oncogenes: From Biology to Therapy; Feb 24-27, 2014; Lake Buena Vista, FL. Philadelphia (PA): AACR; Mol Cancer Res 2014;12(12 Suppl):Abstract nr A23. doi: 10.1158/1557-3125.RASONC14-A23
Abstract A39: Repurposing of AP-102 and AP-103 in the treatment of breast cancer via inhibiting the RAF/ERK pathway
Authors: Tsai Pei-Yi , Ding Yu-Sian , Hung Le-Mei , Ho Yueh-Feng , Peng Ling-Chiu , Liou Chiung-Wen , Chang Jia-Ming 
Published: May 2015

Abstract
Breast cancer is a serious health care issue with millions of women being diagnosed worldwide. Although RAS is mutated in only a minor fraction of breast cancers, the Ras signaling pathway is hyperactivated in half of these tumors. Tamoxifen is most commonly used as hormone therapy for breast cancer, which usually accompanied not serious but bothersome side effects. AP-102 and AP-103 are approved drugs in treating diabetes and antipyretic and analgesic, respectively. Repurposing approved drugs for cancer represents an opportunity to improve advance patients therapies based on the new findings and clinical treatment experience via new proposed signaling pathway. In this study, the antitumor efficacy of two drugs was evaluated on the estrogen-dependent ZR-75-1 human breast cancer xenograft model. The tumor-bearing mice were randomly divided into 5 groups and administrated with vehicle, AP-102, AP-103, AP-102 plus AP-103, and paclitaxel, respectively. Results showed that the tumor inhibition rate of AP-102, AP-103, AP-102/AP-103, and paclitaxel were 27.25%, 17.3%, 43.42%, and 14.25%, respectively. Mechanistic analyses revealed that combination of AP-102 and AP-103 is deduced by inhibiting RAF/ERK activation. Moreover, the mice treated with AP-102/AP-103 showed an increase of 36.5% in white blood cell count compared with the mice treated with vehicle. These data posed an apparent anticancer effect in combination of AP-102 and AP-103 with significant difference, which might be associated with innate immunity evidenced by increased WBC number. For in vitro cytotoxicity, ZR-75-1 cells showed more resistant to paclitaxel than MDA-MB-231 cells. This study provides the important information that combination of two drugs, AP-102 and AP-103, might have potential therapeutic use for tumor cells with highly expressed estrogen receptors or breast tumor resistance to chemo drugs.
Citation Format: Pei-Yi Tsai, Yu-Sian Ding, Le-Mei Hung, Yueh-Feng Ho, Ling-Chiu Peng, Chiung-Wen Liou, Jia-Ming Chang. Repurposing of AP-102 and AP-103 in the treatment of breast cancer via inhibiting the RAF/ERK pathway. [abstract]. In: Proceedings of the AACR Special Conference on RAS Oncogenes: From Biology to Therapy; Feb 24-27, 2014; Lake Buena Vista, FL. Philadelphia (PA): AACR; Mol Cancer Res 2014;12(12 Suppl):Abstract nr A39. doi: 10.1158/1557-3125.RASONC14-A39
Abstract A47: Targeting Ras - is there Ras-specific palmitoylation in human cells that can be targeted for cancer treatment?
Authors: Young Evelin C. , Zheng Ze-Yi , Wilkins Angela D. , Jeong Hee-Tae , Li Min , Olivier Lichtarge , Chang Eric C. 
Published: May 2015

Abstract
Ras GTPases act on the plasma membrane (PM) to mediate extracellular signaling and tumorigenesis. PM association for many Ras proteins depends on palmitoylation, which in budding yeast is catalyzed by the Erf2-Erf4 palmitoyl transferase. Despite this, there was no evidence that its human ortholog DHHC9 can similarly control Ras in vivo, and some studies even proclaimed that there was no Ras-specific palmitoylation. We performed an unbiased screen to seek fission yeast (Schizosaccharomyces pombe, sp) mutants with reduced PM Ras. Mutations affecting sp-erf2 to varying degrees were isolated 5 times; in contrast, deleting several other S. pombe palmitoyl transferases did not affect Ras. Sp-Erf2 localizes to the trans-Golgi, mediated by its third transmembrane domain and the Erf4 cofactor. In fission yeast, the human ortholog zDHHC9 fully rescues the phenotypes of sp-erf2 null cells, while expressing zDHHC14, another sp-Erf2-like human protein, did not rescue Ras1 mislocalization in these cells. Importantly, ZDHHC9 is widely overexpressed in human cancers, including several types that do not contain frequent oncogenic RAS mutations. Overexpressing ZDHHC9 in mammalian cells promotes, while repressing it diminishes, Ras PM localization, as well as transformation. These data strongly demonstrate that sp-Erf2/zDHHC9 palmitoylates Ras proteins in a highly selective manner in the trans-Golgi to facilitate PM targeting via the trans Golgi network. zDHHC9 overexpression can apparently increase Ras signaling outputs at the PM, such that tumor formation can occur in many tissues with no oncogenic mutations in RAS genes themselves. zDHHC9 may thus be a good drug target for the treatment of a wide range of cancers.
Citation Format: Evelin C. Young, Ze-Yi Zheng, Angela D. Wilkins, Hee-Tae Jeong, Min Li, Lichtarge Olivier, Eric C. Chang. Targeting Ras - is there Ras-specific palmitoylation in human cells that can be targeted for cancer treatment? [abstract]. In: Proceedings of the AACR Special Conference on RAS Oncogenes: From Biology to Therapy; Feb 24-27, 2014; Lake Buena Vista, FL. Philadelphia (PA): AACR; Mol Cancer Res 2014;12(12 Suppl):Abstract nr A47. doi: 10.1158/1557-3125.RASONC14-A47
Abstract B12: Using Lrig1CreERT2/+ stem cell driver mice to model colorectal cancer
Authors: Poulin Emily 
Published: May 2015

Abstract
Genetically engineered mouse (GEM) models of human cancer provide important insights into mechanisms of disease development. Colorectal cancer is a common malignancy, whereas small intestinal cancer is much less frequent. We recently developed a mouse model of colonic neoplasia, using the highly efficient inducible stem cell driver, leucine-rich repeats and immunoglobulin-like domains protein 1 (Lrig1CreERT2), and a floxed allele of the tumor suppressor gene, adenomatous polyposis coli (Apcfl/+) (Cell 149: 146-158, 2012). Lrig1CreERT2/+;Apcfl/+ mice develop multiple, large highly dysplastic adenomas in the distal colon within 50 days of tamoxifen induction; the proximal colon is spared and smaller tumors are detected in the small intestine. We hypothesized an additional oncogenic event would advance tumorigenesis in this model. To investigate this hypothesis, using a Kras mutation (G12D) as the second event, we developed a new inducible mouse model: Lrig1CreERT2/+;Apcfl/+;KrasLSL-G12D/+. Due to broad Lrig1 expression, systemic Kras activation through intraperitoneal tamoxifen injection results in debilitating oral and facial tumors within three to five weeks, precluding longer-term intestinal studies. To overcome the rapid onset of this phenotype, we administered 4-hydroxytamoxifen (4-OHT) enemas to achieve local tamoxifen delivery. This method delayed onset of oral tumor development, even preventing it in some mice. However, we noted Lrig1CreERT2/+;Apcfl/+;KrasLSL-G12D/+ mice rarely developed colonic tumors, compared to Lrig1CreERT2/+;Apcfl/+ control mice. We hypothesized Kras activation before complete Apc loss of heterozygosity provides a barrier to tumor formation. Therefore, we administered 4-OHT enemas to Lrig1CreERT2/+;Apcfl/fl;KrasLSL-G12D/+ mice to determine whether Kras activation could advance tumorigenesis in the setting of loss of both Apc alleles. In a preliminary experiment, we observed that Kras activation caused a more severe phenotype in the colonic epithelium of Lrig1CreERT2/+;Apcfl/fl mice compared to Lrig1CreERT2/+;Apcfl/fl control mice. Both genotypes developed skin lesions that affected the health of animals, requiring sacrifice as early as 28 days after tamoxifen administration. Further characterization of this model will determine whether invasion in the colonic lesions can occur under these genetic conditions.
Citation Format: Emily Poulin. Using Lrig1CreERT2/+ stem cell driver mice to model colorectal cancer. [abstract]. In: Proceedings of the AACR Special Conference on RAS Oncogenes: From Biology to Therapy; Feb 24-27, 2014; Lake Buena Vista, FL. Philadelphia (PA): AACR; Mol Cancer Res 2014;12(12 Suppl):Abstract nr B12. doi: 10.1158/1557-3125.RASONC14-B12
Abstract B14: Human Mut T homolog 1 (MTH1) as a novel facilitator of KRAS-driven lung cancer
Authors: Patel Asmita , Halvorsen Katherine , Balkan Wayne , Cohen Alexander , Reiner Teresita , Robbins David , Nguyen Dao , Rai Priyamvada 
Published: May 2015

Abstract
Non-small cell lung carcinoma (NSCLC), a chemoresistant form of lung cancer, is characterized by oncogenic KRAS mutations that confer multiple tumor-promoting traits. Several of these traits are mediated by oncogene-induced reactive oxygen species (ROS). However, oncogenic ROS also produce DNA damage, a major effector of tumor suppressor mechanisms. We previously reported overexpression of the mammalian 8-oxo-dGTP triphosphatase, human MutT Homolog 1 (MTH1), inhibits RAS oncogene-induced senescence (OIS) and any associated DNA damage without substantially affecting ROS levels. Here we report that MTH1 expression is elevated in NSCLC tumors relative to adjacent normal tissue, particularly in tumors with high KRAS expression. We show that MTH1 overexpression facilitates transformation of lung epithelial cells by oncogenic KRAS. We further report that MTH1 suppression in NSCLC cell lines reduces proliferation and tumorigenicity either via DNA strand break-induced elevation of the p53/p21 pathway or by inhibition of Akt activation in p53-nonfunctional tumor cells. Collectively our results indicate MTH1 as a novel potential chemotherapeutic target in NSCLC with activating KRAS mutations.
Citation Format: Asmita Patel, Katherine Halvorsen, Wayne Balkan, Alexander Cohen, Teresita Reiner, David Robbins, Dao Nguyen, Priyamvada Rai. Human Mut T homolog 1 (MTH1) as a novel facilitator of KRAS-driven lung cancer. [abstract]. In: Proceedings of the AACR Special Conference on RAS Oncogenes: From Biology to Therapy; Feb 24-27, 2014; Lake Buena Vista, FL. Philadelphia (PA): AACR; Mol Cancer Res 2014;12(12 Suppl):Abstract nr B14. doi: 10.1158/1557-3125.RASONC14-B14
Abstract B40: Blocking Ras chaperons for cancer therapy
Authors: Kloog Yoel , Haklai Roni , Elad-Sfadia Galit 
Published: May 2015

Abstract
We have previously developed a new concept and a new class of Ras inhibitors that affect specifically the active forms of Ras. This concept is based on the knowledge that the farnesyl moiety common to all Ras proteins might not only serve as a lipophilic lipid anchor but also confer functional specificity on Ras. This raised the possibility that the farnesyl group may act as part of a recognition unit for specific anchorage lipids or protein(s) that interact with Ras in the cell membrane. Such binding partners of Ras have been identified where it was shown that galectin-1 and galectin-3 discovered first as lectin binding proteins, act respectively as specific binding partners of farnesylated active H-Ras and K-Ras. Recently Nucleoline was identified as a specific chaperon of active N-Ras. The galectins possess a putative hydrophobic binding pocket-the putative farnesyl binding site. Galectin-1 was shown to drive H-Ras.GTP nanocluster formation and to be an integral component of the H-Ras-GTP nanocluster, a site at which Raf is activated. Similarly, galectin-3 drives K-Ras.GTP nanoclustring and robust K-Ras signaling. Ras signaling to ERK is strongly diminished in Galectin -3 knockout MEFS and in thyroid cancer cells that lack Galectin - 3. Together these findings mark the farnesyl-binding pockets as outstanding targets for Ras directed therapy, assuming that compounds that would block such sites will act as Ras inhibitors. The Ras inhibitor, S-trans-trans farnesylthiosalicylic acid (Salirasib, FTS) was indeed designed to mimic the farnesyl moiety in the carboxy terminal of Ras and was found to induce accelerated dislodgement of Ras from the cell membrane and subsequently degradation of the protein. FTS was also found to be highly efficient in inhibiting growth of many types of cancer cell lines that exhibit high Ras.GTP levels both, in vitro and in vivo. More recent phase 2 clinical trials showed that oral Salirasib treatment of pancreatic and of non-small-lung cancer patients increased significantly survival of the patients with no toxic effects. We propose to use Salirasib for the treatment of pancreatic and of non-small-lung carcinoma.
Note: This abstract was not presented at the conference.
Citation Format: Yoel Kloog, Roni Haklai, Galit Elad-Sfadia. Blocking Ras chaperons for cancer therapy. [abstract]. In: Proceedings of the AACR Special Conference on RAS Oncogenes: From Biology to Therapy; Feb 24-27, 2014; Lake Buena Vista, FL. Philadelphia (PA): AACR; Mol Cancer Res 2014;12(12 Suppl):Abstract nr B40. doi: 10.1158/1557-3125.RASONC14-B40
Abstract B53: Utilizing bimolecular fluorescent complementation to identify inhibitors of RAL and KRAS
Authors: Ifediba Marytheresa , Burnett David , Hovda Nicholas , Burnett William , VanBrocklin Matthew 
Published: May 2015

Abstract
We have identified RAL activity to be vital for NSCLC survival independent of KRAS or EGFR mutation status in a large panel of adenocarcinomas and have developed a novel high throughput screening assay based on Bimolecular Fluorescent Complementation (BiFC) in order to identify small molecules that impair RAL function. By coupling RALA and RALB to the C-terminus of the Venus protein (VC) and coexpressing either with direct binding effector RALBP1 fused to the N-terminus of the Venus protein (VN) results in a fluorescent signal when RAL-RALBP1 binding occurs in cells. This allows for the interrogation of small molecules to disrupt RAL-RALBP1 binding interactions (resulting in loss of fluorescence) in a real time, high throughput manner. Our preliminary screen with a natural compound library identified 14 small molecules that demonstrated high activity in disrupting both RALA- and RALB-RALBP1 binding and fluorescence. We are currently investigating these compounds' mode of action and have recently expanded our assay to screen for molecules that impair mutant KRAS activity (VC-KRAS / RAF1-VN). BiFC provides a rapid, more physiologic method to identify molecules that can disrupt protein-protein interactions of targets considered ‘undruggable’ including membrane bound small GTPases such as RAL and KRAS.
Citation Format: Marytheresa Ifediba, David Burnett, Nicholas Hovda, William Burnett, Matthew VanBrocklin. Utilizing bimolecular fluorescent complementation to identify inhibitors of RAL and KRAS. [abstract]. In: Proceedings of the AACR Special Conference on RAS Oncogenes: From Biology to Therapy; Feb 24-27, 2014; Lake Buena Vista, FL. Philadelphia (PA): AACR; Mol Cancer Res 2014;12(12 Suppl):Abstract nr B53. doi: 10.1158/1557-3125.RASONC14-B53
Abstract IA06: Discovery of a first-in-class ERK 1,2 inhibitor
Authors: Samatar Ahmed A. 
Published: May 2015

Abstract
The RAS /RAF /MEK / ERK signal transduction pathway is frequently activated in several human cancers, due to a gain of function mutations in KRAS, NRAS, or BRAF. Because of the high frequency of activating mutations, this pathway has become a focus for targeted therapy. A wide spectrum of MEK and RAF inhibitors have been developed to inhibit components of the pathway. Vemurafenib and dabrafenib, selective BRAF inhibitors, and trametinib, an allosteric MEK inhibitor, have shown clinical efficacy in melanoma patients. However, the majority of responses to RAF inhibitors are transient and acquired resistance is often associated with pathway reactivation involving the downstream extracellular-signal-regulated kinases 1 and 2 (ERK1/2). Pathway blockade at ERK, the last signaling node prior to MAPK transcriptional programming, may not only be efficacious in MAPK-activated tumors but might also have utility in RAF or MEK inhibitor resistant settings. This abstract describes the identification and characterization of SCH772984, a potent and selective ATP competitive inhibitor of ERK1/2 which displays behaviors of both type I and type II kinase inhibitors. SCH772984 has nanomolar cellular potency on tumor cells with mutations in RAF, NRAS, or KRAS and induces tumor regressions in xenograft models at tolerated doses. SCH772984 effectively inhibited MAPK signaling and cell proliferation in RAF or MEK inhibitor resistant models as well as in the context of RAF/MEK combination resistance. Together these data support the clinical development of ERK inhibitors, not only in patients with MAPK activated tumors, but also in patients who have developed acquired resistance to RAF or MEK inhibitors or resistance to the recently described combination of these agents. Strategies to overcome acquired resistance to pathway inhibitors will be also described.
Citation Format: Ahmed A. Samatar. Discovery of a first-in-class ERK 1,2 inhibitor. [abstract]. In: Proceedings of the AACR Special Conference on RAS Oncogenes: From Biology to Therapy; Feb 24-27, 2014; Lake Buena Vista, FL. Philadelphia (PA): AACR; Mol Cancer Res 2014;12(12 Suppl):Abstract nr IA06. doi: 10.1158/1557-3125.RASONC14-IA06
Abstract PR04: Cooperation between Ras network mutations in cancer
Authors: Stites Edward C. , Trampont Paul C. , Haney Lisa B. , Walk Scott F. , Ravichandran Kodi S. 
Published: May 2015

Abstract
Cancer genome sequencing often identifies mutations within the Ras signaling network other than the well-established KRAS, NRAS, and BRAF oncogene mutations and NF1 tumor suppressor gene mutations. The extent to which a novel mutation in a commonly mutated pathway can be assumed to have cancer promoting potential, and whether or not certain contextual conditions are required for the mutation to have cancer promoting effects, is not well understood. We investigated this problem with a computational model of the Ras signaling network, with focused cell-based experiments, and with statistical analysis of large cancer genomic data sets. We first applied our previously developed computational model of the Ras signaling network to identify potential synergistic combinations within the Ras network. For example, our modeling suggested that mutations to the tumor suppressor gene NF1 can amplify the effects of other Ras pathway mutations, including the effects of weakly-activating, noncanonical, Ras mutants. Experiments comparing the strength of signal produced by noncanonical Ras mutants expressed in neurofibromin deficient and wild-type cells confirmed this prediction. If such synergistic effects contribute to the development of cancer, we reasoned that there should be an increased rate of co-occurrence between the mutations that the model predicted to have cooperative potential. Analysis of large cancer genomic data sets from the Cancer Cell Line Encyclopedia and The Cancer Genome Atlas identified increased rates of co-occurrence between mutations predicted to display synergy. Overall, our study suggests that there may be combinations of Ras pathway mutations that serve the role of cancer “driver”.
This abstract is also presented as Poster B33.
Citation Format: Edward C. Stites, Paul C. Trampont, Lisa B. Haney, Scott F. Walk, Kodi S. Ravichandran. Cooperation between Ras network mutations in cancer. [abstract]. In: Proceedings of the AACR Special Conference on RAS Oncogenes: From Biology to Therapy; Feb 24-27, 2014; Lake Buena Vista, FL. Philadelphia (PA): AACR; Mol Cancer Res 2014;12(12 Suppl):Abstract nr PR04. doi: 10.1158/1557-3125.RASONC14-PR04
Abstract A24: Network-based inference of resistance mechanisms to estrogen inhibitors in ER+ breast cancer
Authors: Alvarez Mariano Javier , Shen Yao , Bisikirska Brygida , Realubit Ronald , Pampou Sergey , Karan Charles , Califano Andrea 
Published: May 2015

Abstract
Anti-estrogen therapy is the standard of adjuvant care for luminal breast cancer. However, more than 30% of the cases either do not respond to the therapy or develop resistance and progress to metastatic disease. In this work we use a network-based approach to identify the regulatory motifs driving resistance to estrogen inhibitors and to predict small molecule compounds that can abrogate the activity of such regulatory modules, thus reverting the resistance phenotype. This is similar to what we have accomplished in glucocorticoid resistance in T-ALL (Piovan et.al (2013) Cancer Cell 24(6):766). To accomplish this goal, we established genome-wide expression signatures characteristic of the resistant phenotype (ER-GES) both from patients' data and cell lines. Then, we used the VIPER algorithm to interrogate a breast carcinoma-specific transcriptional network (BRCAnet) assembled from 844 TCGA tumor samples with these signatures, to infer master regulators of resistance. Finally we leveraged the connectivity map (CMAP) dataset, containing expression profiles from MCF7 cells exposed to 1,300 small molecule compounds, to identify the effectors of each profiled compounds. By comparing drug effectors with master regulators of ER-inhibitors chemoresistance, we identified small molecule compounds predicted to revert resistant cells to a sensitive state.
We reasoned that a compound able to reverse such resistance should induce synergistic activity when combined with anti-estrogen agents, like tamoxifen. To validate our prediction in an unbiased way, we assessed the synergistic nature of the interaction between tamoxifen and 100 compounds (sensitizer set) selected to have the most orthogonal mechanism of action, using 4 x 4 dilutions assays, with cell viability as readout. Synergistic interactors were identified by combination index (CI &lt; 0.9) and Excess over BLISS (EOB &gt; 10%). Interestingly, compounds predicted to rescue sensitivity to ER inhibitors in cell lines were highly enriched in those that were experimentally validated to be synergistic with tamoxifen. Taken together, these results suggest that network-based analysis is effective in capturing drivers of chemoresistance to estrogen deprivation, as well as the specific compounds that can rescue sensitivity by inhibiting them.
Citation Format: Mariano Javier Alvarez, Yao Shen, Brygida Bisikirska, Ronald Realubit, Sergey Pampou, Charles Karan, Andrea Califano. Network-based inference of resistance mechanisms to estrogen inhibitors in ER+ breast cancer. [abstract]. In: Proceedings of the AACR Precision Medicine Series: Drug Sensitivity and Resistance: Improving Cancer Therapy; Jun 18-21, 2014; Orlando, FL. Philadelphia (PA): AACR; Clin Cancer Res 2015;21(4 Suppl): Abstract nr A24.