bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 1104: Novel specific RTK targeting of EGFR/FAK axis in glioblastoma invasion
Authors: Vengoji Raghupathy , Rachagani Satyanarayana , Gupta Suprit , Mallya Kavita , Jain Maneesh , Ponnusamy Moorthy , Batra Surinder , Shonka Nicole 
Published: July 2017

Abstract
Background: Glioblastoma (GBM) is the most aggressive primary brain tumor with a median survival rate of 14.6 months. Currently, the first-line treatment includes surgical resection, chemoradiation, and adjuvant chemotherapy with temozolomide. However, GBM recurs most often within 6.9 months. Receptor tyrosine kinases are dysregulated in GBM, with epidermal growth factor receptor (EGFR) representing 57.4% of the deleted/mutated GBM. In addition, 30 - 40% of GBM patients with EGFR amplification carry an oncogenic gene rearrangement EGFR variant III (EGFRvIII) which is constitutively active. Yet most EGFR inhibitors have shown very little clinical efficacy in GBM.
Methods: Afatinib, blood-brain barrier penetrant pan-EGFR inhibitor, covalently binds and irreversibly inhibits signaling from EGFR. Afatinib also persistently inhibits ErbB homo and hetero-dimers. Using GBM cell lines U87MG and U87MG transfected with wild type EGFR, EGFRvIII and EGFRvIII with dead kinase domain, we evaluated the efficacy of afatinib alone and in combination with temozolomide.
Results: Afatinib treatment resulted in a dose dependent decrease in the proliferation of U87MG cells transfected with EGFRvIII. The IC50 value for this cell line is 2µM (afatinib). 50µM temozolomide inhibited cell proliferation by 50%. We evaluated the combinational efficacy of IC25 of both. Afatinib effectively blocked EGFR signaling even 72 hours after treatment in the U87MG cell line transfected with either wild type EGFR or EGFRvIII. This was evidenced by decreased phosphorylation of EGFR (Tyr 1068) and its downstream signaling. Focal adhesion kinase (FAK) signaling in EGFRvIII expressing cells, largely responsible for the invasiveness of GBM, was abolished by afatinib. Furthermore, treatment with afatinib and temozolomide significantly decreased the in vitro tumorigenicity (anchorage dependent growth - colony formation assay as well as anchorage independent growth - soft agar assay) of EGFRvIII expressing GBM cells.
Conclusion: Altogether, these results support synergistic efficacy of afatinib and temozolomide in EGFRvIII expressing GBM.
Citation Format: Raghupathy Vengoji, Satyanarayana Rachagani, Suprit Gupta, Kavita Mallya, Maneesh Jain, Moorthy Ponnusamy, Surinder Batra, Nicole Shonka. Novel specific RTK targeting of EGFR/FAK axis in glioblastoma invasion [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 1104. doi:10.1158/1538-7445.AM2017-1104
Abstract 111: Targeting STAT3 and telomerase for the treatment of colorectal cancer
Authors: Chung Seyung , Okobi Quincy , Adekoya Debbie , Vadgama Jaydutt 
Published: July 2017

Abstract
There is an increasing evidence of pro-inflammatory cytokines involvement in cancer development. Here, we found that two cytokines, IL-6 and TNF-α, induced colorectal cancer cells more active and invasive. Combined treatments of IL-6 and TNF-α phosphorylated transcription factors STAT3 in a synergistic manner. STAT3 and NF-κB physically interacted upon cytokine stimulation. Similarly, STAT1 hetero-dimerized with STAT3 and the binding affinity was enhanced with cytokine treatments. STAT3 bound the promoter region of human telomerase reverse transcriptase (hTERT), and IL-6 and TNF-α stimulation further enhanced this STAT3 binding affinity. Withaferin A, an anti-inflammatory steroidal lactone, inhibited the IL-6 and TNF-α induced cancer cell invasiveness and decreased colonosphere formation. Notably, withaferin A inhibited STAT3 phosphorylation and abolished the STAT3 and NF-κB interactions. STAT3 binding to hTERT promoter was inhibited and telomerase activity was decreased with the withaferin A treatments. Taken together, pro-inflammatory cytokines induced-cancer cell invasiveness is mediated by STAT3 regulated mechanism in colorectal cancer cells. Our study suggests the novel natural compound therapy for the metastatic colorectal cancer in clinical settings.
Citation Format: Seyung Chung, Quincy Okobi, Debbie Adekoya, Jaydutt Vadgama. Targeting STAT3 and telomerase for the treatment of 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 111. doi:10.1158/1538-7445.AM2017-111
Abstract 1112: Forced reduction of DSS1, a member of TREX2 complex, highly sensitizes chemotherapy to breast cancer cells in a BRCA2-independent manner
Authors: Kuwahara Kazuhiko , Gondo Naomi , Rezano Andri , Zhang Zhenhuan , Hato Yukari , Kuzushima Kiyotaka , Iwata Hiroji , Toyama Tatsuya , Kondo Eisaku 
Published: July 2017

Abstract
[Introduction] DSS1 (deleted in split-hand/split-foot malformation 1) was originally identified as a BRCA2-associated/stabilizing protein. By comparison of DSS1 mRNA level, we reported that the high DSS1 expression groups in breast cancer patients showed worse prognosis in relapse-free survival (RFS); however, DSS1 expression per se was not correlated with other clinical parameters including cellular proliferation or tumor grade, suggesting that the level of DSS1 affected the sensitivity of DNA-damage agents in breast cancer cells (Rezano et al., 2013). It still remains unclear why the expression level of DSS1 is associated with chemosensitivity, because DSS1 has multifunctional properties regulating homologous recombination and RNA-mediated genomic stability. In this study, we investigated if the effect of DSS1 in chemosensitivity is influenced by two representative DSS1-associated molecules, BRCA2 and PCID2.
[Methods] We established MCF7 overexpressing DSS1 (MCF7/DSS1) by retroviral transfection. DSS1, BRCA2, or PCID2 knockdown in MCF7 was performed using siRNA transfection. The susceptibility to the cytotoxic chemotherapy such as doxorubicin and paclitaxel in breast cancer cells was evaluated by flow cytometry to detect apoptosis and colony assay. In addition, we compared patient survival by dividing patients into high or low expression group of BRCA2 or PCID2 using cohort studies.
[Results] BRCA2 depletion in MCF7/DSS1 did not alter the chemoresistance. Although DSS1 knockdown induced the downregulation of BRCA2, direct depletion of BRCA2 did not show marginal effect to chemosensitivity, suggesting that the enhancement of chemosensitivity by DSS1 knockdown was not related to BRCA2 expression. Importantly, over- and under-expression of PCID2 induced similar effect to chemosensitivity compared to those of DSS1. There was a trend that high PCID2 expression group in breast cancer patients showed worse prognosis in RFS.
[Conclusion] DSS1 could be a molecular target to increase chemosensitivity, which is independent of BRCA2 expression. Rather, the transcription-coupled DNA damage induced by impaired TREX2 complex might be associated with induction of chemosensitivity.
Citation Format: Kazuhiko Kuwahara, Naomi Gondo, Andri Rezano, Zhenhuan Zhang, Yukari Hato, Kiyotaka Kuzushima, Hiroji Iwata, Tatsuya Toyama, Eisaku Kondo. Forced reduction of DSS1, a member of TREX2 complex, highly sensitizes chemotherapy to breast cancer cells in a BRCA2-independent manner [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 1112. doi:10.1158/1538-7445.AM2017-1112
Abstract 1118: Synthetic lethality of CDK12 inhibition in tumors with EWS/FLI rearrangements
Authors: Balboni Amanda L. , Stolte Bjorn , Conway Amy Saur , Alexe Gabriela , Wang Emily Jue , Kwiatkowski Nicholas , Zhang Tinghu , Abraham Brian J. , Kalev Peter , Chowdhury Dipanjan , Benes Cyril H. , Young Richard A. , Gray Nathanael S. , Stegmaier Kimberly 
Published: July 2017

Abstract
THZ1 is a potent, covalent inhibitor of the transcriptional CDKs, CDK7/12/13. Chemical genomic profiling of THZ1 across &gt;1,000 diverse cancer cell lines revealed that EWS/FLI- rearranged Ewing sarcoma cells were remarkably sensitive to this molecule. We demonstrated that THZ1 inhibits the phosphorylation of the C-terminal domain of RNA Polymerase II, decreased colony formation capacity, and induced apoptosis in a dose-dependent manner in Ewing sarcoma cell lines. Using selective CDK7 and CDK12/13 inhibitors, we revealed that the primary target of THZ1 in Ewing sarcoma is CDK12/13. Genetic suppression of CDK12, but not CDK13, induced strong anti-viability effects, confirming CDK12 as the primary target. Treatment of Ewing sarcoma cell lines with THZ531, a novel CDK12/13 selective inhibitor, preferentially repressed genes involved in DNA damage repair. Additionally, suppression of EWS/FLI rendered Ewing sarcoma cells resistant to THZ531 and partially rescued the anti-viability effects of CDK12 knockdown. These results suggest that EWS/FLI imparts vulnerability to DNA damage repair inhibition and implicate a synthetic lethal relationship between the tumor-specific expression of EWS/FLI and CDK12 inhibition. Furthermore, we demonstrated that CDK12 and PARP inhibitors are highly synergistic in vitro, inducing widespread yH2AX foci formation. Interestingly, THZ531 impairs the ability of the PARP inhibitor, olaparib, to induce RAD51 foci formation, suggesting that THZ531 specifically causes a defect in homologous recombination repair. Moreover, we observed striking synergy of THZ1 and olaparib in two mouse models of Ewing sarcoma with limited toxicity observed. These findings have important translational significance as clinical trials with PARP inhibitors as single agents in Ewing sarcoma failed to demonstrate efficacy, highlighting the need to identify combination therapies that will enhance the activity of PARP inhibition. We anticipate that CDK12 and PARP inhibitor combinations will be of therapeutic interest in other ETS-rearranged tumors, as well as tumors with defects in DNA repair.
Citation Format: Amanda L. Balboni, Bjorn Stolte, Amy Saur Conway, Gabriela Alexe, Emily Jue Wang, Nicholas Kwiatkowski, Tinghu Zhang, Brian J. Abraham, Peter Kalev, Dipanjan Chowdhury, Cyril H. Benes, Richard A. Young, Nathanael S. Gray, Kimberly Stegmaier. Synthetic lethality of CDK12 inhibition in tumors with EWS/FLI rearrangements [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 1118. doi:10.1158/1538-7445.AM2017-1118
Abstract 1125A: β-hydroxybutyrate inhibits histone deacetylase activity and radiosensitizes malignant glioma cells
Authors: Woolf Eric C. , Rossi Alex P. , Silva-Nichols Helena B. , Gardner Kara D. , Syed Nelofer , Scheck Adrienne C. 
Published: July 2017

Abstract
Several preclinical studies support the use of the therapeutic ketogenic diet (KD) and/or caloric restriction (CR) as an adjuvant to cancer therapy. This data not only suggests that this approach alters multiple hallmarks of cancer growth, but that it may also enhance other therapeutic modalities. We have demonstrated that the unrestricted KD greatly increases survival in a mouse model of malignant glioma when administered in combination with radiation, yet the underlying mechanisms are not fully elucidated. Mounting evidence suggests that the abnormal epigenetic landscape in tumors may, among other things, impact radiosensitivity. Specifically, many cancers exhibit increased histone deacetylase (HDAC) activity which contributes to the epigenetic milieu found in tumors and alters DNA damage repair. It was recently demonstrated that the ketone body β-hydroxybutyrate (BHB) inhibits HDAC activity in normal mouse tissue. As the use of HDAC inhibitors as anti-cancer agents has generated great interest, we examined the effect of BHB on HDAC activity and radiosensitivity in the context of malignant glioma. We found that BHB radiosensitizes mouse glioma, human glioma and human glioma stem-like cells in vitro. We also demonstrate that BHB inhibits HDAC activity in a dose dependent manner and alters key components of DNA damage repair. Taken together this data opens up another avenue for understanding the mechanisms underlying the KD and its impact on radiation therapy, ultimately helping us better understand how to implement it for clinical use in oncology.
Citation Format: Eric C. Woolf, Alex P. Rossi, Helena B. Silva-Nichols, Kara D. Gardner, Nelofer Syed, Adrienne C. Scheck. β-hydroxybutyrate inhibits histone deacetylase activity and radiosensitizes malignant glioma 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 1125A. doi:10.1158/1538-7445.AM2017-1125A
Abstract 1126: Potent inhibition of HCMV by modulating the cellular SNARE syntaxin 5
Authors: Desai Dhimant H. , Cruz Linda , Streck Nicholas T. , Desai Trisha D. , Lukacher Aron , Amin Shantu G. , Buchkovich Nicholas J. 
Published: July 2017

Abstract
Human cytomegalovirus (HCMV), also referred to as human herpesvirus-5 (HHV-5), can cause serious and even fatal disease in immunocompromised individuals and newborns, namely individuals with AIDS, solid organ transplant recipients, chemotherapy patients and recipients of bone marrow and stem cell transplants. HCMV is a ubiquitous virus found throughout all geographic regions and socioeconomic groups, infecting greater than 50% of adults in industrialized countries and as many as 100% in developing countries. Although current therapeutics improves clinical outcomes, they are limited by toxicity, intravenous infusion and the development of resistance by the virus. Thus, there is a pressing need to develop novel therapeutics to prevent HCMV infections with concomitant organ toxicity. Formation of the cytoplasmic viral assembly compartment (cVAC) is an important step for efficient HCMV assembly. To do this, the virus must alter and repurpose the normal cellular balance of membrane and protein flux, a process that is not well understood. We have identified a compound Retro94, which potently inhibits production of infectious HCMV virions in cells by operating against a host cell process, rather than directly targeting the virus. The presence of Retro94 results in the severely impaired production of infectious virions, as great as 5 logs (99-99.99%). Here we discuss in vitro, in vivo, stability, and binding study of Retro94. Overall, our findings have identified Retro94, as novel agent that affects key cellular trafficking factors important for supporting HCMV infection.
Citation Format: Dhimant H. Desai, Linda Cruz, Nicholas T. Streck, Trisha D. Desai, Aron Lukacher, Shantu G. Amin, Nicholas J. Buchkovich. Potent inhibition of HCMV by modulating the cellular SNARE syntaxin 5 [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 1126. doi:10.1158/1538-7445.AM2017-1126
Abstract 1131: O-GlcNAc transferase inhibition in breast cancer cells
Authors: Barkovskaya Anna , Prasmickaite Lina , Duveau Damien Y. , Mills Ian G. , Mælandsmo Gunhild M. , Moestue Siver A. , Itkonen Harri M. 
Published: July 2017

Abstract
O-linked-N-acetylglucosamination (O-GlcNAcylation) is a post-translational modification that occurs on serine and threonine amino acid residues of the intracellular proteins. O-GlcNAcylation of numerous targets is catalyzed by a single enzyme - O-GlcNAc-transferase (OGT). O-GlcNAcylation impacts protein activation and stability thereby regulating several key biological functions, and is heavily involved in cancer development and progression. OGT expression and total protein O-GlcNAcylation are elevated in many cancers compared to non-malignant adjacent tissues. In breast cancer, this increase also has a positive correlation with the tumor grade suggesting a possible link to metastasis and disease progression. Here we investigated the effects of OGT inhibition in two triple-negative (TNBC) and two receptor-positive luminal breast cancer cell lines. Treatment of cells with an OGT inhibitor as well as OGT knockdown led to a strong decrease in viability and proliferation of the TNBC cells, but significantly less so in the luminal receptor-positive cell lines. This differential response was evaluated using analysis of apoptosis, cell cycle, gene expression and a reverse-phase antibody-based protein array (RPPA). We found that cell cycle progression was affected by OGT inhibition. In addition, proteomics data pointed towards the transcription factor hairy and enhancer of split-1 (HES1) as a possible mediator of the cytotoxicity observed in the TNBC cell lines. We currently work to elucidate the molecular mechanisms of HES1 regulation by OGT and its effect on TNBC cell survival and apoptosis. In conclusion, OGT inhibition has a pronounced cytotoxic effect on the TNBC cells and may have some potential for therapeutic use in the future.
Citation Format: Anna Barkovskaya, Lina Prasmickaite, Damien Y. Duveau, Ian G. Mills, Gunhild M. Mælandsmo, Siver A. Moestue, Harri M. Itkonen. O-GlcNAc transferase inhibition 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 1131. doi:10.1158/1538-7445.AM2017-1131
Abstract 1138: The protein disulfide isomerase inhibitor XCE853 inhibits in vitro, ex-vivo and in vivo growth of human tumors
Authors: Prevost Gregoire Pierre , Chauchereau Anne , Ladam Patrick , Seigneuric Renaud , Carniato Denis , Pitty Marc-Henry , Foster Paul 
Published: July 2017

Abstract
Protein disulfide isomerase (PDI) is a chaperone protein that regulates oxidative protein folding as well as cell viability. Increased PDI levels have been documented in a variety of human cancers associated with a poor overall survival, including ovarian, prostate, brain and lung cancers. Inhibition of PDI activity leads to apoptosis in cancer, suggesting that PDI is a promising druggable target. XCE853 is a synthetic small molecule displaying an excellent docking with the catalytic domain of the human PDI. XCE853 inhibits in vitro recombinant PDI enzymatic activity. In addition, the proliferation of a large panel of human tumor cells is blocked by XCE853 with IC50s in the nanomolar range through an irreversible cytolysis leading to a tumor cell death by autophagy and particles release (vesicles or protein aggregates). XCE853 is also active on a large panel of drug resistant human cancer cells. XCE853 induced an irreversible cytolysis of human tumor cells after a short in vitro exposure independently of efflux pumps. In addition, the ex-vivo approach using fresh human tumor explants cultivated in 3 dimensions with low concentrations of XCE853 has shown a strong decrease of the proliferation (KI-67 labeling) in several tumor types. Finally, XCE853 displayed excellent oral bioavailability in mice and was able to block the growth of several human cancers using in vivo xenograft models leading to a complete tumor growth arrest even after the cessation of the treatment. Altogether, these data strongly support further efforts to move this drug candidate to the preclinical studies to access advanced cancer patients.
Citation Format: Gregoire Pierre Prevost, Anne Chauchereau, Patrick Ladam, Renaud Seigneuric, Denis Carniato, Marc-Henry Pitty, Paul Foster. The protein disulfide isomerase inhibitor XCE853 inhibits in vitro, ex-vivo and in vivo growth of human 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 1138. doi:10.1158/1538-7445.AM2017-1138
Abstract 1142: Novel target discovery for glioblastoma using chemical biology fingerprinting
Authors: Finlay Darren , Aza-Blanc Pedro , Dhruv Harshil , Eroshkin Alexey , Hauser Craig , Kiefer Jeff , Kim Seungchan , Long Tao , Oshima Robert G. , Peng Sen , Speyer Gil , Berens Michael , Vuori Kristiina 
Published: July 2017

Abstract
The most common adult brain tumor is Glioblastoma Multiforme (GBM), an extremely aggressive cancer with only scant treatment options. Even with standard of care most patients present with a recurrence and the median survival is only circa 15 months. The need, therefore, for new therapeutic targets and treatment options is pressing. Here we describe here a multipronged approach to identifying said targets. We present an established methodology for the isolation and culture of patient derived GBM samples that retain the “stem-like” fraction thought to underlie resistance and recurrence. Furthermore we show genomically that these samples represent specific subtypes of the disease yet still form distinct groups in unbiased clustering analysis. Thus we have multiple representative patient derived cultures that are suitable for our drug discovery and chemical biology analyses. Using a process we term Chemical Biology Fingerprinting (CBF) we utilize small focused, and clinically relevant, chemical collections in order to identify patterns of chemovulnerabilities across multiple samples. This allows an unbiased yet cancer relevant sub-stratification and the identification of agents, and therefore targets, which may be relevant for GBM patient subtypes. Indeed our use of the highly annotated NCI CTD2 Informer Set of chemicals allows ready drug-to-target mapping and facilitates data sharing across the CTD2 network. Moreover, already defined subgroups can be clustered to find agents, or groups of agents, that show selective activity against traditional classifications (e.g. proneural, mesenchymal etc.). Finally our strategy is permissive for the identification of “exceptional responders”. That is, individual patient samples that respond to a specific drug whilst most samples are refractory. In sum we demonstrate generation of patient derived models and identify specific, and novel, drugs that may be relevant for specific GBM subtypes. Supported by NIH U01CA168397
Citation Format: Darren Finlay, Pedro Aza-Blanc, Harshil Dhruv, Alexey Eroshkin, Craig Hauser, Jeff Kiefer, Seungchan Kim, Tao Long, Robert G. Oshima, Sen Peng, Gil Speyer, Michael Berens, Kristiina Vuori. Novel target discovery for glioblastoma using chemical biology fingerprinting [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 1142. doi:10.1158/1538-7445.AM2017-1142