tbuckley/cabot-search huggingface dataset:
Abstract 3245: Preclinical evaluation of the imipridone family of small molecules, including analogues of clinical-stage anti-cancer small molecule ONC201, reveals potent anti-cancer effects of ONC212
Authors: Jessica Wagner, C. Leah Kline, Gary Olson, Bhaskara Nallaganchu, Richard Pottorf, Varun Prabhu, Martin Stogniew, Joshua Allen, Wafik El-Deiry
Journal: Cancer Research (2017)

Abstract We previously identified a novel, potent anti-cancer small molecule ONC201, which upregulates the integrated stress response (ISR) through ATF4/CHOP/DR5 and acts as a dual inactivator of Akt and ERK, leading to TRAIL gene activation. After completing a first-in-human phase I clinical trial that revealed exceptional safety, therapeutic pharmacokinetic (PK) profile and tumor engagement, ONC201 is under investigation in several advanced cancer Phase I/II trials. Given the unique imipridone core chemical structure of ONC201, we synthesized a family of analogues in an effort to identify additional chemical family members with distinct therapeutic properties. Based on in vitro potency improvements in human cancer cell lines and therapeutic window approximations with normal human fibroblasts, select analogues were investigated in animals for toxicity, maximum tolerated dose (MTD), and antitumor efficacy. ONC212 is one of the most promising new imipridones that was further evaluated to establish the PK profile, oral bioavailability, and efficacy in tumor types that are less sensitive to ONC201. Compared to ONC201, we noted distinct and more rapid kinetics of activity as well as improved potency in multiple human cancer cell lines in vitro. ONC212 has a broad therapeutic window, an acceptable PK profile, and is orally well-tolerated in mice. With no evidence of toxicity at efficacious doses in both colon and triple negative breast cancer, we have begun further evaluation of antitumor efficacy studies in ONC201-resistant tumor types. Efficacy studies with ONC212 are ongoing in melanoma models that are sensitive to ONC212 but less sensitive to ONC201 in vitro. Preliminary data indicates potent tumor growth reduction by ONC212 in vivo in ONC201-resistant melanoma xenografts. With a wide safety margin, potent antitumor activity in ONC201-insenstive tumors, and drug-like characteristics, ONC212 is being further developed as a drug candidate from the new imipridone class of compounds that complements the spectrum of activity of ONC201. Citation Format: Jessica Wagner, C. Leah Kline, Gary Olson, Bhaskara Nallaganchu, Richard Pottorf, Varun Prabhu, Martin Stogniew, Joshua Allen, Wafik El-Deiry. Preclinical evaluation of the imipridone family of small molecules, including analogues of clinical-stage anti-cancer small molecule ONC201, reveals potent anti-cancer effects of ONC212 [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 3245. doi:10.1158/1538-7445.AM2017-3245
Abstract 4153: CRISPR/Cas9-based oncogene editing enables characterization of rare mutations in cancer cells
Authors: Dennis Plenker, Martin L. Sos
Journal: Cancer Research (2017)

Abstract In the past decade new insights into key oncogenic pathways and the development of targeted therapies enabled the success of precision medicine. However, only a small part of the cancer genome can be targeted effectively. This is in part due to the fact that the number of cancer cell models for a given oncogenic mutation is limited. We hypothesized that CRISPR/Cas9-mediated genome editing may enhance the ability to functionally study rare genomic lesions or resistance mutations that arise in patients under therapy. As a proof of concept we established, genetically modified PC9 lung cancer cells that harbor an activating EGFR ex19 deletion (EGFRdel E746-A750) into double mutated (EGFRdel E746-A750+T790M) or triple mutated (EGFRdel E746-A750+T790M+C797S) EGFR in order to induce resistance against known EGFR inhibitors. These cell lines fully recapitulated the phenotypic response pattern to first and third generation EGFR inhibitors that have been observed in patients harboring these clinically relevant resistance mutations. In a next step we switched the dependency of PC9 cells from the intrinsic oncogenic EGFR mutation into a rare ex20 SVDins mutation (EGFRD770_N771insSVD) that is typically associated with resistance towards all known EGFR inhibitors. Again, we observed a shift in the response to targeted inhibition of EGFR when compared to parental cells. Since the methodological principles can be applied to an array on known oncogenic mutations our approach may serve as a versatile platform for the functional study of oncogenic mutations that are found in patients. We envision that such reprogrammed cells may be of use for the screening of novel targeted therapeutics and therefore may enable the development of mutation specific drugs that are currently lacking for the majority of patients. Citation Format: Dennis Plenker, Martin L. Sos. CRISPR/Cas9-based oncogene editing enables characterization of rare mutations in cancer cells [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 4153. doi:10.1158/1538-7445.AM2017-4153
Abstract 4496: Dissecting cellular heterogeneity using single cell RNA sequencing in human lung tumors
Authors: Elise T. Courtois, Huipeng Li, Yuliana Tan, Daniel Tan, Shyam Prabhakar, Paul Robson
Journal: Cancer Research (2017)

Abstract Intra-tumor heterogeneity is a key determinant of tumor biology, treatment response and patient survival. It is therefore essential to comprehensively characterize the phenotypes and interactions of the diverse cells within the tumor ecosystem. However, traditional molecular profiling studies have largely relied on bulk-tissue analysis, which obscures the signatures of distinct cell populations. We present here an unbiased analysis of functional heterogeneity in NSCLC (Non Small Cell Lung Cancer) cancers (Lung Adenocarcinoma and Squamous Cell Carcinoma) and their microenvironment using RNA-seq profiling of unsorted single cells from 20 primary tumors and matched normal lung tissue (NL). Using a new clustering algorithm RCA (Reference Component Analysis), we identified the major cell types composing the normal lung tissue as well as the tumor ecosystem such as epithelial, fibroblast, endothelial and immune cells. Notably, we were able to identify resident alveolar macrophages, in tumor and normal tissue and their single-cell differential expression analysis revealed substantial differences in their gene expression. Similarly, we identified blood-vessel endothelial cells in matched normal and tumor tissue, and identified the differentially expressed genes in both cell types. Our unbiased approach allowed us to study the diversity of the epithelial malignant cells present in different tumors, highlighting the tumor and patient specific variability. Together, the unbiased study of the NSCLC at the single cell level by sc-RNAseq offers a powerful tool to provide insights into the transcriptomic variability within the key cellular players of the tumorigenesis. Citation Format: Elise T. Courtois, Huipeng Li, Yuliana Tan, Daniel Tan, Shyam Prabhakar, Paul Robson. Dissecting cellular heterogeneity using single cell RNA sequencing in human lung tumors [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 4496. doi:10.1158/1538-7445.AM2017-4496
Abstract 1681A: Overcoming pd1 targeting antibody resistance using combination strategies
Authors: Jean-François Mirjolet, Maxime Ramelet, Damien France
Journal: Cancer Research (2017)

Abstract PD-1 targeting antibodies (nivolumab, pembrolizumab) are now approved in various tumor types either as second line treatment (locally advanced or metastatic urothelial carcinoma, advanced renal cell carcinoma, recurrent or metastatic head and neck squamous cell carcinoma, classical Hodgkin lymphoma) or even as first line therapy (metastatic melanoma, metastatic non-small cell lung cancer). Despite an increase in response rate as well as survival, there is still issue with resistance to PD-1 targeting therapies. Selection biomarkers as well as response biomarkers are still under intensive research. In addition, combination strategies are needed to increase response rate and overcome resistance. Combination strategies were therefore tested in one well characterized syngeneic mouse model, i.e. EMT-6 breast carcinoma. The model is known to be highly sensitive to CTLA-4 targeting antibody (optimum tumor to control ratio (T/C) of 3%), a moderate responder to PD-1 targeting treatment (best T/C of 54%) and a well immune infiltrated tumor. Antibodies targeting co-stimulatory receptor such as OX40, GITR and 4-1BB as well as co-inhibitory receptor such as Tim3 were combined to anti-PD-1 antibody. In all cases, combination arm produces better therapeutic activity when compared to single treatment alone. Moreover, both strategies, meaning combination of two antibodies targeting co-inhibitory receptors (PD-1 + Tim3) and combination targeting one co-inhibitory (i.e. PD-1) and one co-stimulatory receptors (OX40, GITR or 4-1BB) worked. Detailed results will be presented including response rate, immune infiltrates and cytokines profiles in order to rationally choose the best therapeutic treatment. Citation Format: Jean-François Mirjolet, Maxime Ramelet, Damien France. Overcoming pd1 targeting antibody resistance using combination strategies [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 1681A. doi:10.1158/1538-7445.AM2017-1681A
Abstract 3496: Long non-coding RNAs in colorectal cancer
Authors: Alena Opattova, Fábio Miguel Ferreira, Jozef Horak, Sona Vodenkova, Pavel Vodicka
Journal: Cancer Research (2017)

Abstract Colorectal cancer (CRC) is the third most common type of cancer worldwide and the second most common cause of cancer related deaths in Europe. Since Countries of Central Europe (Czech Republic, Slovakia, Hungary) have one of the highest rates both for incidence and mortality of CRC, CRC became a serious health, social and economic problem. CRC pathogenesis involves multiple genetic events. On behalf of a strong experimental work, there is still lack of predictive, prognostic and treatment-response related biomarkers. Long non-coding RNAs (lncRNA) are non-protein coding transcripts longer than 200 nucleotides. Deregulation of lncRNAs is often seen in a variety of human diseases, including cancer. Taken together, this makes lncRNAs the potential regulators of cancer progression, therapeutic targets or markers of treatment efficacy. The main aim of our present study was to define expression patterns of lncRNAs in colorectal tumor tissue and define their role in cancer cell proliferation, survival and DNA damage response (DDR). In the first part of our study, we analyzed the expression profile of 83 lncRNA known to be associated with cancer progression in cohort of CRC tumor tissues and adjacent mucosa. We found 12 upregulated lncRNAs (p&amp;lt;0.05) and 10 downregulated lncRNAs (p&amp;lt;0.05). Our results have been replicated on larger set of patients (100 CRC patients) and those lncRNAs associated with cell proliferation, survival and DNA damage response are functionally tested on colorectal cell lines (HCT116, HCT116 p53-/-) in vitro. Definition of role of lncRNA as a tumor suppressors or oncogenes in CRC etiology may lead to better understanding of regulation of CRC carcinogenesis. Furthermore, understanding the role of lncRNA in DDR may contribute to better treatment response of CRC patients and to define markers of individual treatment response. Acknowledgement: GACR 15-14789S, AZV 15-27580A, GAUK800216, AZV 15-26535A, SUSCEPTCOST LD14050 Citation Format: Alena Opattova, Fábio Miguel Ferreira, Jozef Horak, Sona Vodenkova, Pavel Vodicka. Long non-coding RNAs in colorectal cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 3496. doi:10.1158/1538-7445.AM2017-3496
Abstract 148: A dual and selective small molecule inhibitor of EGFR and PI3 kinase shows promising preclinical activity against KRAS and BRAF mutant colorectal tumors
Authors: Joel D. Maust, Elizabeth K. Ziemke, Christy L. Frankowski-McGregor, Jun Beom Ku, Rachel Mumby, Karin M. Hardiman, Christopher E. Whitehead, Judith S. Sebolt-Leopold
Journal: Cancer Research (2017)

Abstract Agents targeting epidermal growth factor receptor (EGFR) have met with limited success in the clinical management of colorectal cancer (CRC). Mutations in KRAS, BRAF, and PIK3CA are important drivers of resistance to EGFR-targeted therapy. Conversely, EGFR-mediated feedback mechanisms serve to mediate resistance to MEK inhibitor-based treatment of CRC by reactivating MAP kinase signaling. Our central hypothesis is that a dual small molecule inhibitor that potently and selectively targets only EGFR and PI3KA, when combined with a MEK inhibitor, will be highly efficacious against subpopulations of BRAF mutant or KRAS mutant colorectal cancers that are dependent upon these kinase molecules to drive tumor progression. Employing a computational modeling approach, we exploited the known binding modes of structurally related ATP binding site inhibitors of EGFR and PI3K to design small molecules that simultaneously inhibit both kinases in a selective manner. To the best of our knowledge, the lead compound MTX-211, whose binding mode is flipped in PI3K compared to EGFR, represents a first in class selective inhibitor of these two critical oncogenic kinases. MTX-211 exhibits a favorable pharmaceutical and selectivity profile, possessing sub- to low nanomolar potency against both targets, &amp;gt;70% oral bioavailability, strong pharmacodynamic modulation of both EGFR and PI3K signaling, and strong in vivo single agent efficacy against multiple BRAFmt and KRASmt colorectal cancer models, as evidenced by T/C values of 29 to 36% after 10-14 days of oral dosing of 50 mg/kg. A significantly higher degree of in vivo activity is seen when MTX-211 is co-administered with the MEK inhibitor trametinib (&amp;gt;400% increase in survival compared to single agent arms), lending support for this polypharmacology approach over triple drug combination strategies. Based on its promising therapeutic profile, MTX-211 is the focus of an ongoing mouse trial of a large panel of patient-derived xenograft BRAFmt and KRASmt CRC models to inform the design of future human clinical trials. Citation Format: Joel D. Maust, Elizabeth K. Ziemke, Christy L. Frankowski-McGregor, Jun Beom Ku, Rachel Mumby, Karin M. Hardiman, Christopher E. Whitehead, Judith S. Sebolt-Leopold. A dual and selective small molecule inhibitor of EGFR and PI3 kinase shows promising preclinical activity against KRAS and BRAF mutant colorectal tumors [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 148. doi:10.1158/1538-7445.AM2017-148
Abstract 5370: Examination of DNA looping near oncogenes reveals variable patterns of epigenetic landscapes in cancer
Authors: Monika Perez, Ty Johannes
Journal: Cancer Research (2017)

Abstract INTRODUCTION: The compaction of chromatin in the nucleus into hierarchical three-dimensional (3D) structures plays a key role in the regulation of gene expression. Advancements in high-throughput chromatin conformation capture assays have enabled the determination of this hierarchical structure in a variety of cell states, including cancer. Of note, recent studies have implicated pathogenic alterations in 3D topology of the genome with the activation of proto-oncogenes in a multitude of cancers. METHODS: To characterize the topological changes associated with different cancer phenotypes, we examine publically available epigenetic profiles from the ENCODE Project, including 3D data from Chromatin Interaction Analysis by Paired-End Tag Sequencing (ChIA-PET) from breast cancer and leukemia cell lines. Integrating the chromatin topology data with transcription factor binding, DNase accessibility, and histone modification data, we uncover variable epigenetic landscapes associated with differentially active oncogenes in these cancer cell lines. RESULTS: We provide evidence of topological variability influencing differentially expressed oncogenes and tie these observations to other epigenetic changes. In particular, we show insulated-neighborhoods mediated by CTCF looping partition segments of the genome containing active oncogenes away from repressive markings like H3K4me3. Additionally, we show that variation in topology differentially localizes H3K27ac in distal regulatory regions to promoters of oncogenes, providing a means for gene activation in non-coding regions. CONCLUSIONS: Variable patterns of chromatin topology provide a unique signature and mechanism of oncogenes for cancerous phenotypes. We use publically available data to show mechanisms of activity associated with chromatin topology variation. Citation Format: Monika Perez, Ty Johannes. Examination of DNA looping near oncogenes reveals variable patterns of epigenetic landscapes in cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 5370. doi:10.1158/1538-7445.AM2017-5370
Abstract 4467: ETV6 is a tumor suppressor regulated by EGFR-miR-96 pathway in prostate cancer
Authors: Yen-Nien Liu, Yuan-Chin Tsai, Wei-Yu Chen, Man Kit Siu, Hsiu-Lien Yeh
Journal: Cancer Research (2017)

Abstract ETV6 is an ETS transcription factor and a putative tumor suppressor in prostate cancer according to several genomic analyses. However, its cellular functions and upstream regulating signaling remain unclear. We demonstrated that ETV6 suppresses the prostate cancer progression and that ETV6 levels are negatively associated with advanced prostate cancer, supporting the idea that ETV6 acts as a tumor suppressor. Furthermore, ETV6 can be regulated by epidermal growth factor receptor (EGFR) signaling through microRNA (miR)-mediated downregulation. One of the miRs, miR-96, can be transcriptionally-regulated by nuclear EGFR. The association patterns connecting miR-96, EGFR activation, and ETV6 were further validated in the clinical tissue samples. We proposed an EGFR-miR-96-ETV6 signaling pathway in promoting prostate cancer. Note: This abstract was not presented at the meeting. Citation Format: Yen-Nien Liu, Yuan-Chin Tsai, Wei-Yu Chen, Man Kit Siu, Hsiu-Lien Yeh. ETV6 is a tumor suppressor regulated by EGFR-miR-96 pathway in prostate cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 4467. doi:10.1158/1538-7445.AM2017-4467
Abstract 1053: Synergistic anticancer effects of combined γ-tocotrienol and pterostilbene is associated with a suppression in Rac1/WAVE 2 signaling in highly malignant breast cancer cells
Authors: Ibrahim G. Algayadh, Paul William Sylvester
Journal: Cancer Research (2017)

Abstract Breast cancer is the most common cancer and the second leading cause of cancer death in American women. Rho GTPases play a crucial role in regulating different cellular functions, including cell proliferation, gene expression, cell morphology, actin polymerization, cell motility, metastasis and apoptosis. Wiskott-Aldrich syndrome protein family verprolin-homologous protein2 (WAVE2) is a member within the Wiskott-Aldrich syndrome protein (WASP) family displays a significant role in actin polymerization and cytoskeletal organization which, are essential for cellular migration and invasion. γ-Tocotrienol is a natural isoform within the vitamin E family that displays anticancer activity against a variety of cancer cell types. Pterostilbene is a natural dimethyl ether analog of resveratrol that has several beneficial effects such as anticancer activity. Studies were conducted to examine the effects of combined γ-tocotrienol and pterostilbene on Rac1/WAVE 2 signaling in mouse +SA and human MDA-MB231 breast cancer cells and cellular migration. Results show that combined treatment of γ-tocotrienol and pterostilbene caused a synergistic inhibition of both mouse +SA and human MDA-MB231 breast cancer cells growth, and corresponding reduction in Rac1/WAVE2 signaling as characterized by a significant inhibition in the levels of phospho-Rac1/cdc42, WAVE2, Arp2, and Arp3 expression. Additional studies indicated that this combination resulted in a significant inhibition in mammary cancer cell migration. In summary, these findings strongly suggest that combined treatment of γ-tocotrienol with pterostilbene may provide great benefit as a therapeutic approach in the treatment of metastatic breast cancer. Supported by a grant from the Louisiana Cancer Foundation. Citation Format: Ibrahim G. Algayadh, Paul William Sylvester. Synergistic anticancer effects of combined γ-tocotrienol and pterostilbene is associated with a suppression in Rac1/WAVE 2 signaling in highly malignant breast cancer cells [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 1053. doi:10.1158/1538-7445.AM2017-1053
Abstract 4415: Fatty acid synthase-mediated palmitate production impacts epidermal growth factor receptor signaling to regulate specificity protein 1 in breast cancer cells
Authors: Lincoln J. Barlow, Jian-Ting Zhang
Journal: Cancer Research (2017)

Abstract Fatty acid synthase (FASN), the sole cytosolic enzyme responsible for de novo palmitate synthesis, is critical for cancer cell survival and is a marker of poor prognosis. FASN overexpression has been shown to confer resistance to both drug and radiation resistance by inhibiting drug-induced ceramide production and by increasing DNA repair activities. Recently, it was found that FASN upregulation of non-homologous end joining (NHEJ) repair of double strand DNA breaks was due to FASN up-regulation of Poly (ADP-ribose) polymerase 1 (PARP1) by increasing expression of specificity protein 1 (SP1). However, how FASN regulates the expression of SP1 remains unknown. In this study, we tested the hypothesis that, palmitate, the end product of FASN catalysis, plays an important role in regulating SP1 expression by posttranslationally modifying epidermal growth factor receptor (EGFR) and affecting its activity. Using paired isogenic cell lines with FASN overexpression and FASN knockdown as well as exogenous supplementation of palmitate, we found that depleting palmitate in culture reduced SP1 expression while supplementing palmitate rescues this effect. Furthermore, FASN overexpression and knockdown increased and decreased, respectively, phosphorylation and activation of EGFR. Treatment with EGFR inhibitor, Erlotinib, reduced SP1 expression. These findings suggest that FASN regulation of SP1 and NHEJ repair may be via regulating EGFR activity. We are in the process of determining the potential effect of palmitoylation of EGFR on its activation and regulation of SP1 expression. Citation Format: Lincoln J. Barlow, Jian-Ting Zhang. Fatty acid synthase-mediated palmitate production impacts epidermal growth factor receptor signaling to regulate specificity protein 1 in breast cancer cells [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 4415. doi:10.1158/1538-7445.AM2017-4415