bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 2808: Simultaneous inhibition of SHP2 phosphatase at two allosteric sites
Authors: Fodor Michelle , Price Edmund , Wang Ping , Lu Hengyu , Argintaru Andreea , Chen Zhouliang , Glick Meir , Hao Huai-Xiang , Kato Mitsunori , Koenig Robert , LaRochelle Jonathan R. , Liu Gang , McNeill Eric , Majumdar Dyuti , Nishiguchi Gisele , Perez Lawrence , Paris Greg , Quinn Christopher , Ramsey Timothy , Sendzik Martin , Shultz Michael , Williams Sarah , Stams Travis , Blacklow Stephen C. , LaMarche Matthew J. , Acker Michael G. 
Published: August 2018

Abstract
SHP2 is a cytoplasmic non-receptor tyrosine phosphatase involved in the propagation of extracellular signaling through receptor tyrosine kinases. Aberrant SHP2 activity has been identified as a driver in multiple cancers and SHP2 has also been implicated in the PD-1/PD-L1-mediated exhaustion of effector T-cells, leading to immune system evasion of tumors. Recently, we reported the identification of SHP099, an allosteric inhibitor of SHP2 with in in vivo efficacy against multiple RTK-driven tumor xenograft models. Here we report the use of alternate screening paradigms to identify a novel allosteric inhibitor which binds to a previously uncharacterized pocket on SHP2. Like SHP099, the second allosteric inhibitor stabilizes a closed conformation of SHP2, which blocks access to the phosphatase active site. Structure based drug design led to improvements in potency, and combination studies in biochemical, biophysical and cellular assays confirm dual occupation of SHP099 and the second allosteric molecule, resulting in improved potency. This work highlights a rare opportunity for dual occupation of inhibitors for a single target and provides additional tools for the exploration of SHP2 biology.
Citation Format: Michelle Fodor, Edmund Price, Ping Wang, Hengyu Lu, Andreea Argintaru, Zhouliang Chen, Meir Glick, Huai-Xiang Hao, Mitsunori Kato, Robert Koenig, Jonathan R. LaRochelle, Gang Liu, Eric McNeill, Dyuti Majumdar, Gisele Nishiguchi, Lawrence Perez, Greg Paris, Christopher Quinn, Timothy Ramsey, Martin Sendzik, Michael Shultz, Sarah Williams, Travis Stams, Stephen C. Blacklow, Matthew J. LaMarche, Michael G. Acker. Simultaneous inhibition of SHP2 phosphatase at two allosteric sites [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 2808.
Abstract 282: Inferring transcriptional regulatory programs in gynecological cancers
Authors: Osmanbeyoglu Hatice U. , Jelinic Petar , Douglas Douglas , Leslie Christina 
Published: August 2018

Abstract
Cancer cells acquire genetic and epigenetic alterations that often lead to dysregulation of oncogenic signal transduction pathways, which in turn alter downstream transcriptional programs. Transcription factors (TFs) are the main link between signaling pathways and the transcriptional regulatory programs. The Cancer Genome Atlas (TCGA) has studied several of the most common and aggressive gynecologic tumors including high-grade serous ovarian carcinomas (HGSOC), uterine carcinosarcoma (UCS), and the serous-like subset of endometrial cancer (UCEC), together with basal breast cancer, which shares many genomic features with serous ovarian tumors. TFs impacts on gene regulation have not been well characterized in gynecological and basal breast cancers. The majority of these tumors lack accurate predictors of response and resistance and share an unmet need for adequate treatment of recurrent disease. We developed a multitask learning framework for integrating regulatory sequence from ATAC-mapped promoters and enhancers from cell line models with RNA-seq data from patient tumors in order to infer transcription factor (TF) regulatory activities and explore similarities and differences between uterine, ovarian, and basal breast tumors. We showed that our multitask learning framework enables us to selectively share the information across tumors and strongly improves the accuracy of gene expression prediction models for gynecological and basal breast tumors. Our analysis identified histologic type specific and common TF regulators of gene expression as well as predicted distinct dysregulated transcriptional regulators downstream of somatic alterations in these different cancers. Moreover, many of the identified TF regulators were significantly associated with survival outcome within the histological subtype. Computationally dissecting the role of TFs in these cancers may ultimately lead to new therapeutics tailored to groups of subtypes or individuals.
Citation Format: Hatice U. Osmanbeyoglu, Petar Jelinic, Douglas Douglas, Christina Leslie. Inferring transcriptional regulatory programs in gynecological cancers [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 282.
Abstract 2825: PIN1-SCFFBW7 proteolytic signaling regulates the Fanconi anemia pathway
Authors: Wang Jingming , Chan Bryan , Tong Michael , Seeliger Markus , Kim Hyungjin 
Published: August 2018

Abstract
Genome instability caused by defective DNA repair mechanisms is a hallmark of cancer and drives tumorigenesis. The Fanconi anemia (FA) DNA repair pathway contributes to the integrity of the genome by resolving DNA interstrand cross-links (ICLs) encountered during DNA replication. Deregulation of the FA pathway is associated with cancer predisposition and affects therapeutic outcomes against DNA-damaging cytotoxic chemotherapy. FANCD2 monoubiquitination by a multi-subunit ubiquitin E3 ligase, the FA core complex, is an essential gateway that connects the DNA damage response to enzymatic steps of DNA ICL repair. We have previously identified FAAP20 as a critical component of the FA pathway; and demonstrated that the phosphorylation of the Cdc4 phospho-degron (CPD) motif in FAAP20 by GSK3β is required for its proteasomal degradation mediated by the E3 ligase, SCFFBW7 complex. However, the upstream signaling that governs the FAAP20 phosphorylation status and its detailed mode of action for FAAP20 degradation remain elusive. Here, we show that PIN1, a phosphorylation-specific prolyl isomerase, is a key regulator of the integrity of the FA core complex and, therefore, FA pathway activity as a whole. By catalyzing a proline cis-trans isomerization of the phosphorylated backbone and thereby converting the substrate into a conformation that is favorable or refractory to downstream proteolytic signaling, PIN1 modulates the rate of protein turnover. We demonstrate that PIN1 interacts and catalyzes a phosphorylated Ser48-Pro49 motif of FAAP20 and by inducing a conformational change of FAAP20, PIN1 enhances the affinity of FAAP20 with PP2A (Protein phosphatase 2), the phosphatase of the CPD motif in FAAP20 and thereby prevents its degradation from the GSK3β-FBW7 mediated proteolytic signaling. Collectively, our studies uncover PIN1-dependent isomerization as a new regulatory mechanism for DNA ICL repair. Given that PIN1 overexpression is prevalent in diverse human cancers, identifying a way to regulate PIN1 activity in the FA pathway may help develop a PIN1 inhibitor as a chemosensitizer for cytotoxic chemotherapy to increase its therapeutic efficacy.
Citation Format: Jingming Wang, Bryan Chan, Michael Tong, Markus Seeliger, Hyungjin Kim. PIN1-SCFFBW7 proteolytic signaling regulates the Fanconi anemia pathway [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 2825.
Abstract 2831: Collateral lethality: A new target for personalized oncology
Authors: Lin Yu-Hsi , Hammoudi Naima , Satani Nikunj , Ackroyd Jeffrey , Khadka Sunada , Georgiou Dimitra , Marszalek Joe , Sun Yuting , Protopopova Marina , Francesco Maria E. Di , Czako Barbara , Wang Alan Y. , DePinho Ronald A. , Muller Florian L. 
Published: August 2018

Abstract
Large-scale genomic profiling efforts, such as The Cancer Genome Atlas (TCGA) have painted an unprecedentedly detailed picture of the genetic alterations that underlie carcinogenesis, yet the key challenge remains as to how to turn this information into actionable therapies. Genomic deletions are a frequent event in diverse cancers, which inactivate a limited number of tumor suppressor genes (“driver”-events) but frequently include many chromosomal neighbors as “passengers”, some of which play critical but redundant roles in normal cellular housekeeping. The overall hypothesis we propose to test is that collateral deletions of such “passenger” genes can be utilized as novel targets of synthetic lethality, an idea which we term “collateral lethality." The large number of passenger deleted genes, playing diverse functions in cell homeostasis, offers a rich repertoire of pharmacologically targetable vulnerabilities presenting novel opportunities for the development of personalized anti-neoplastic therapies. We have provided in vitro proof-of-principal of a collaterally deleted glycolytic gene Enolase 1 (ENO1) at the 1p36 tumor suppressor locus in glioblastoma (GBM), that leads to dramatic sensitization to inhibition of the redundant paralogue, ENO2. The next step is to take this concept to the clinic. Our overall goal is to generate a clinical candidate Enolase inhibitor for tumors with ENO1-deletions, like GBM for which there is no other treatment option and the therapeutic benefit could be quite substantial.
Citation Format: Yu-Hsi Lin, Naima Hammoudi, Nikunj Satani, Jeffrey Ackroyd, Sunada Khadka, Dimitra Georgiou, Joe Marszalek, Yuting Sun, Marina Protopopova, Maria E. Di Francesco, Barbara Czako, Alan Y. Wang, Ronald A. DePinho, Florian L. Muller. Collateral lethality: A new target for personalized oncology [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 2831.
Abstract 2837: Single-cell heterogeneity with transcriptional memory confers resistance to cancer therapy
Authors: Shaffer Sydney , Emert Benjamin , Raj Arjun 
Published: August 2018

Abstract
Targeted therapies for cancer are a promising class of drugs that inhibit the specific molecular alterations that underlie the uncontrolled proliferation seen in cancer. The primary shortcoming of targeted therapy is disease relapse, which is driven by a subpopulation of cells that are resistant to these drugs. This phenomenon is generally thought to be genetic in origin; however, our recent work on melanoma shows that nongenetic cellular plasticity may provide a mechanism of resistance to these therapies. Furthermore, we showed that through the addition of the drug itself, cells transition from this transient plasticity into a new, stably resistant cell state via cellular reprogramming, suggesting that the time an individual cell exists in a state is important for producing the divergent resistance phenotype. However, there are currently no methods available to quantify the timescale of these fluctuations for the whole transcriptome. Thus, broadly generalizing this concept of timescales for cellular plasticity, we developed a novel method for genome-wide quantification of the timescales of gene expression memory based on a modern version of the ingenious Luria-Delbrück fluctuation analysis. Specifically, we isolated individual cells, allowed them to expand, and then performed RNA sequencing on each of the samples. For genes with uniform expression, all the samples should have similar RNA sequencing counts; however, for genes that occasionally turn on in a subset of cells, the RNA sequencing counts across all samples should show high variance. In melanoma, this method revealed the gene expression state of rare cells resistant to targeted therapy. In a completely new model, triple-negative breast cancer, this method revealed a novel rare subpopulation of cells exhibiting resistance to chemotherapy. More generally, this method has the potential to reveal other new phenotypes associated with rare cell biology, including metastasis and the early stages of stem cell differentiation.
Citation Format: Sydney Shaffer, Benjamin Emert, Arjun Raj. Single-cell heterogeneity with transcriptional memory confers resistance to cancer therapy [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 2837.
Abstract 2846: Extracellular ATP induces different types of drug resistances in cancer cells through ATP internalization-mediated intracellular ATP level increase
Authors: Chen Xiaozhuo , Wang Xuan , Zhang Haiyun , Qian Yanrong , Li Yunsheng , Cao Yanyang , Shriwas Pratik 
Published: August 2018

Abstract
Cancer cells are able to uptake extracellular ATP (eATP) via macropinocytosis to elevate intracellular ATP (iATP) levels, enhancing their survival from drug treatment (1). However, the involved drug resistance mechanisms are unknown. Here we investigated the roles of eATP as either an energy or a phosphorylating molecule in general drug resistance mediated by ATP internalization and iATP elevation. We report that eATP increased iATP levels and promoted drug resistance to various tyrosine kinase inhibitors (TKIs) and chemo-drugs in human cancer cell lines of five cancer types, including non-small cell lung cancer, breast cancer, colon, liver cancer, and pancreatic cancer (2). In A549 lung cancer cells, the resistance was downregulated by macropinocytosis inhibition or siRNA knockdown of PAK1, an essential macropinocytosis enzyme, strongly suggesting that the resistance is mediated at least in part by micropinocytosis (and therefore ATP internalization) (2). The elevated iATP upregulated the efflux activity of ABC transporters in A549 and SK-Hep-1 cells, as well as phosphorylation of PDGFRα and proteins in the PDGFR-mediated Akt-mTOR and Raf-MEK signaling pathways in A549 cells, increasing cell cycle progression and decreasing drug-induced apoptosis. Similar phosphorylation upregulations were found in A549 tumors. The resistance was not significantly affected by purinergic receptor-mediated signaling. These results demonstrate, for the first time, that eATP induces different types of drug resistance by eATP internalization and iATP elevation, implicating the ATP-rich tumor microenvironment in cancer drug resistance, expanding our understanding of the roles of eATP in the Warburg effect and offering new anticancer drug resistance targets.
References
1.Qian, Y. et al. Mol Cancer Res 14(11); 1087-1096 (2016)
2.Wang, X. et al. Oncotarget 8, 87860-87877 (2017).
Citation Format: Xiaozhuo Chen, Xuan Wang, Haiyun Zhang, Yanrong Qian, Yunsheng Li, Yanyang Cao, Pratik Shriwas. Extracellular ATP induces different types of drug resistances in cancer cells through ATP internalization-mediated intracellular ATP level increase [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 2846.
Abstract 2847: Investigation of the combinatorial treatment strategy for BRAFmutant anaplastic thyroid cancer based on real time monitoring technology
Authors: Byeon Hyung Kwon , Ku Minhee , Choi Ji Hye , Kee Hyunjung , Kim Ji-Hoon , Koh Yoon Woo , Yang Jaemoon 
Published: August 2018

Abstract
Purpose Previously, we have identified that c-Met-mediated reactivation of PI3K/AKT pathway contributes to acquired resistance to BRAF inhibitor in BRAF mutant (BRAFm) anaplastic thyroid cancer (ATC). So dual inhibition of BRAF and c-Met led to sustained treatment response. However, previous RTK array result in 8505C cells following PLX4032 treatment revealed increased expression of Src together with c-Met. Therefore further in-depth investigation is required to elucidate the optimal combinatorial strategy to maximize the treatment effects in BRAFm ATC. Using non-invasive, real-time monitoring in vitro and in vivo technologies, the best treatment strategy was investigated with consideration of not only the specific treatment regimens but also the mode of combinatorial treatment.
Methods Real-time cell analysis (RTCA), a cell-based label-free technology using electronic impedance sensors was adopted as a strategy for real-time screening of cellular response to drugs. Live wound healing assays with supporting live cell microscopy and confocal microscopy were conducted for in vitro analyses and both ectopic xenograft and metastatic mouse models were utilized for in vivo analyses. Tumor characteristics were evaluated using 9.4T MR diffusion weighted imagings.
Results Dual inhibition of BRAF and c-Met was not fully effective in overcoming BRAF inhibitor resistance in BRAFm ATC. Src-mediated signal has a greater contribution than c-Met-mediated signaling in conferring BRAF inhibitor resistance. Inhibition of Src exerted a more potent effect than c-Met inhibition. Simultaneous drug treatment was more effective than sequential therapy. Combinatorial treatment of BRAF inhibitor (PLX4032) and Src inhibitor (dasatinib) presented the maximal therapeutic effect against BRAFm ATC.
Conclusions Real-time/non-invasive monitoring assays sensitively provides more accurate information regarding drug response.
Citation Format: Hyung Kwon Byeon, Minhee Ku, Ji Hye Choi, Hyunjung Kee, Ji-Hoon Kim, Yoon Woo Koh, Jaemoon Yang. Investigation of the combinatorial treatment strategy for BRAFmutant anaplastic thyroid cancer based on real time monitoring technology [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 2847.
Abstract 2860: The chemosensitizing and oncolytic effects of Dihydrotanshinone in glioblastoma
Authors: Kumar Varun , Leonardi Donna 
Published: August 2018

Abstract
Temozolomide is the primary chemotherapeutic agent used to treat glioblastoma. However, many tumors are initially resistant to or develop resistance to temozolomide, mainly due to high levels of O6-methylguanine DNA transferase (MGMT) which repairs DNA damage traditionally caused by temozolomide. Dihydrotanshinone (DHT) is extracted from Salvia miltiorrhiza, a Chinese medicinal plant, and has been shown to have antiproliferative effects on various cancer cell lines. DHT has also been to shown to induce apoptosis via induction endoplasmic reticulum stress, that can reportedly sensitize cells to temozolomide. MTS cellular proliferation assays or trypan blue viability assays were used to determine the effects of DHT/temozolomide combinatorial treatment. Enzyme-linked immunosorbent assay (ELISA) was used to determine effects on MGMT, P-glycoprotein, AKT, p65, and IlkB levels after singular and combinatorial treatment. DNA microarray was used to gauge gene expression and miRNA levels. Solute clearance of the blood-brain barrier was analyzed using a co-culture model system and confocal microscopy. DHT had a selectively cytotoxic synergistic oncolytic effect in a MGMT-deficient cell line and a sensitizing effect in a MGMT-expressing cell line. Cytotoxicity due to DHT was shown to be reactive oxygen species-dependent, while the combinatorial effect of DHT and temozolomide synergistically reduced MGMT and P-glycoprotein expression and protein levels. In addition, the NFkB complex was sensitive to combinatorial treatment, while AKT activity and gene expression was downregulated in response to treatment. DHT was shown to augment temozolomide efficacy, indicating that, since DHT can penetrate the blood–brain barrier, temozolomide in combination with DHT may represent a promising therapeutic option for glioblastoma.
Citation Format: Varun Kumar, Donna Leonardi. The chemosensitizing and oncolytic effects of Dihydrotanshinone in glioblastoma [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 2860.
Abstract 2862: Inhibition of DNA repair pathways in breast cancer is a potential mechanism of action of IT-139
Authors: Conde Isabel , Fallah Yassi , Demas Diane , Bakewell Suzanne , Lynce Filipa , Shajahan-Haq Ayesha N. 
Published: August 2018

Abstract
IT-139 is a novel small-molecule drug that demonstrated a manageable safety profile at the maximum tolerated dose and modest antitumor activity as a monotherapy in a phase I clinical trial. A high affinity for albumin and unique chemistry allow increased uptake and activation of IT-139 within tumor cells, respectively. To date, IT-139 has been reported to inhibit the endoplasmic reticulum stress-sensing protein GRP78. However, different cancer cells show disparate responses to IT-139 and the precise mechanism of action in high-response versus low-response cancer cells remains unclear. In vitro studies have indicated that IT-139 induces cytostatic rather than cytotoxic effects as a monotherapy. In this study, to understand IT-139 mediated signaling mechanism in breast cancer cells, we used estrogen receptor-positive (ER+) MCF7 breast cancer cells to obtain gene-metabolite integrated models following IT-139 treatment (10 or 100 μM for 72 h). Our data showed that IT-139 significantly reduced expression of genes involved in the DNA repair pathway, including BRCA1 and RAD51, following treatment with IT-139 in MCF7 cells. Validation of our findings in other breast cancer cell lines including MDA-MB-175 (ER+), MDA-MB-231 and MDA-MB-468 (both ER-) cells also showed increased phosphorylation of H2AX (Ser139) following IT-139 treatment, suggesting lack of proper DNA surveillance and subsequent accumulation of DNA double-stranded breaks (DSB). Consequently, we investigated the effects of combination treatment approaches with IT-139 and other clinical anticancer therapies that interfere with nucleotide synthesis or DNA damage repair pathways, particularly in ER- breast cancers. Our data showed additive effects of IT-139 in combination with capecitabine (5-FU prodrug) or olaparib (PARP inhibitor) and a synergistic effect with carboplatin in ER- breast cancer cell lines. Further analysis of IT-139 mediated signal transduction in breast cancer cells will reveal whether it can be combined with aforementioned chemotherapies to circumvent resistance.
Citation Format: Isabel Conde, Yassi Fallah, Diane Demas, Suzanne Bakewell, Filipa Lynce, Ayesha N. Shajahan-Haq. Inhibition of DNA repair pathways in breast cancer is a potential mechanism of action of IT-139 [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 2862.