bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 4783: Selective antitumor activity of NSC311152 toward medullary thyroid cancer by downregulating the transcription of RET oncogene
Authors: Sun Daekyu , Kumarasamy Vishnu Muthuraj , Alqahtani Tariq 
Published: August 2018

Abstract
The RET (REarranged during Transfection) proto-oncogene encodes a tyrosine-kinase receptor specifically expressed in tissues originated from neuroectodermal tissues. Dominant-activating mutations in this RET proto-oncogene is often associated with Multiple Endocrine Neoplasia type 2A and 2B and Familial Medullary Thyroid Carcinoma syndromes, characterized by the occurrence of medullary thyroid carcinomas. Human medullary thyroid carcinoma cell line TT cell line harbours a MEN2A-type mutation, so this cell line could be a useful cell system to investigate the antitumor activity of new agents interfering with the function of RET oncogene in medually thyroid cancer. Recently, ellipticine and its derivatives were identified as excellent RET G-quadruplex stabilizing agents. Furthermore, these compounds also interfered with the transcriptional mechanism of the RET gene in TT cells, subsequently decreasing the endogenous RET protein expression. In present study, we demonstrated the specificity of NSC311152 by using papillary thyroid carcinoma (PTC) cells, the K1, which carry BRAF and PIK3CA mutations but lacks the dominant-activating mutations in this RET proto-oncogene. NSC311152 selectively suppresses cell proliferation by inhibiting the intracellular Raf/MEK/ERK and PI3K/Akt/mTOR signaling pathways in the TT cells. The systemic administration of NSC311152 in a mouse MTC xenograft model significantly inhibited the tumor growth through RET downregulation, whereas NSC31152 only showed a moderate antitumor activity against K1 xenograft tumors.
Citation Format: Daekyu Sun, Vishnu Muthuraj Kumarasamy, Tariq Alqahtani. Selective antitumor activity of NSC311152 toward medullary thyroid cancer by downregulating the transcription of RET oncogene [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 4783.
Abstract 479: miR-372 enhances tumorigenesis and drug resistance in oral carcinoma by targeting ZBTB7A transcription factor
Authors: Yeh Li-Yin , Chou Chung-Hsien , Liu Chung-Ji , Lin Shu-Chun , Chang Kuo-Wei 
Published: August 2018

Abstract
miRNA-mediated post-transcriptional regulation of targeted genes plays crucial roles in neoplastic process. miR-372 has been shown an oncogenic miRNA which is hypoxia-inducible and is conspicuously up-regulated in oral squamous cell carcinoma (OSCC). Zinc finger and BTB domain containing 7A (ZBTB7A) is a transcriptional repressor modulating a great diversities of physiological or oncogenic regulation. This study identified that ZBTB7A was a direct target of miR-372. ZBTB7A was down-regulated in 75% of OSCC tumors relative to adjacent oral mucosa. Reverse correlation across miR-372 expression and ZBTB7A expression was found in tumor samples. In OSCC cells with the stable knockdown of ZBTB7A, the oncogenic potential and drug resistance increased. Whereas, such increase was attenuated by ZBTB7A expression. High throughput screening and validation assay confirmed that ZBTB7A was able to repress multiple oncogenic factors and activate the expression of Trail-R1, Trail-R2 and Fas to increase the drug sensitivity in OSCC cells. miR-372 induction drastically repressed the expression of apoptosis genes by inhibiting ZBTB7A. This was accompany with the enrichment of oncogenicity and the increased tolerance to the toxicity of cisplatin and taxol. This study signifies the importance of miR-372-ZBTB7A-downstream effectors in mediating pathogenesis and drug resistance of OSCC. Interception of this pathogenic cascade would confer therapeutic benefits against oral carcinoma.
Citation Format: Li-Yin Yeh, Chung-Hsien Chou, Chung-Ji Liu, Shu-Chun Lin, Kuo-Wei Chang. miR-372 enhances tumorigenesis and drug resistance in oral carcinoma by targeting ZBTB7A transcription factor [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 479.
Abstract 4790: YH25448, an irreversible 3rd generation EGFR TKI, exhibits superior anticancer effects with potent brain BBB penetration in NSCLC
Authors: Yun Jiyeon , Hong Min Hee , Kim Seok-Young , Park Chae Won , Kim So-Young , Yun Mi Ran , Kang Han Na , Pyo Kyoung-Ho , Koh Jong Sung , Song Ho-Juhn , Lee Young- Sung , Oh Se-Woong , Choi Soongyu , Cho Byoung-Chul 
Published: August 2018

Abstract
EGFR mutated lung cancer shows approximately 10-15% of non-small cell lung cancer (NSCLC). Although the best therapeutic EGFR tyrosine kinase inhibitors (TKIs) targeting mutant EGFR, such as gefitinib and erlotinib, are used in the first line treatment of patients with advanced EGFR mutated NSCLC, the acquired resistance to the drugs usually appears in 10-12 months of therapy by the occurrence of a second EGFR mutation T790M. YH25448, a highly mutant-selective and irreversible 3rd generation EGFR TKI potently penetrating blood-brain barrier (BBB) penetration, targets both activating EGFR mutations Del19, L858R and T790M mutation while sparing wild type. In NSCLC cell lines and primary cancer cells from patients harboring EGFR mutations, YH25448 showed more potent inhibition of cancer cell growth and significantly increased tumor cell apoptosis compared to osimertinibs, which is one of 3rd generation EGFR TKIs. In vivo mouse model implanted with H1975 cells, YH25448 treatment at the once-daily showed a dramatic dose-dependent tumor regression in both subcutaneous and intracranial lesions with no abnormal signs such as skin keratosis shown in osimertinib-treated mice. Plasma half life of YH25448 was 5.9-6.8 hr and tumor to plasma AUC0-last ratio was 3.0-5.1 in tumor bearing mice. YH25448 also showed excellent penetration of the BBB, achieving CSF concentrations exceeding the IC50 value for pEGFR inhibition in the tumor-bearing mice. Taken together, these findings suggest important role for the further development of YH25448 as a novel therapeutic for the treatment of EGFR mutant-positive NSCLC patients with brain metastases.
Citation Format: Jiyeon Yun, Min Hee Hong, Seok-Young Kim, Chae Won Park, So-Young Kim, Mi Ran Yun, Han Na Kang, Kyoung-Ho Pyo, Jong Sung Koh, Ho-Juhn Song, Young- Sung Lee, Se-Woong Oh, Soongyu Choi, Byoung-Chul Cho. YH25448, an irreversible 3rd generation EGFR TKI, exhibits superior anticancer effects with potent brain BBB penetration in NSCLC [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 4790.
Abstract 4791: OMO-1, a potent, highly selective, orally bioavailable, MET kinase inhibitor with a favorable preclinical toxicity profile, shows both monotherapy activity, against MET pathway-driven tumors, and EGFR TKI combination activity in acquired resistance models
Authors: Libouban Marion , Jovcehva Eleonora , Lange Desiree De , Janssens Boudewijn , Verhulst Tinne , Ogata Souichi , Wroblowski Berthold , Mevellec Laurence , Lu Tianbao , Clack Glen , Perera Timothy 
Published: August 2018

Abstract
Activation of the MET/HGF pathway has been linked to tumor initiation, metastasis, angiogenesis and resistance to therapeutic agents. Here we present pharmacological characterization of OMO-1 (formerly JNJ-38877618), a potent, highly selective, orally bioavailable MET kinase inhibitor with nM binding affinity (Kd=1.4 nM) and enzyme inhibitory activity against wt and M1268T mutant MET (2 and 3 nM IC50). MET inhibitory effects were assessed in proliferation, colony formation and motility assays. OMO-1 displayed nM potency against MET Ampl/mutant and therapy resistant models. In vivo, OMO-1 induced complete inhibition of tumor growth in 3 models: the SNU5 MET amp gastric, U87-MG HGF autocrine glioblastoma and Hs746T MET exon 14 skipping mutant gastric cancer. OMO-1 induced regression of large MET amplified EBC-1 SqNSCLC where OMO-1 led to dose- and time-dependent inhibition of MET kinase activation, with the duration of target shut down considerably exceeding plasma exposure times. Combination treatments were well tolerated and improved EGFR targeted therapy. Although single agent OMO-1 had no effect on NSCLC HCC827 EGFR, combination with Erlotinib led to delayed onset of tumor recurrence. The acquired EGFR inhibitor resistant model HCC827-ER1 was determined to be MET amplified. OMO-1 and erlotinib both inhibited tumor growth of this model whilst combination induced tumor regression. In an EGFR inhibitor resistant PDX having MET amplification, single agent OMO-1 caused tumour stasis whereas MetMab/erlotinib only led to tumor growth delay. The potent preclinical activity we have observed, supports ongoing clinical development of OMO-1 in patients with MET pathway-driven tumors.
Citation Format: Marion Libouban, Eleonora Jovcehva, Desiree De Lange, Boudewijn Janssens, Tinne Verhulst, Souichi Ogata, Berthold Wroblowski, Laurence Mevellec, Tianbao Lu, Glen Clack, Timothy Perera. OMO-1, a potent, highly selective, orally bioavailable, MET kinase inhibitor with a favorable preclinical toxicity profile, shows both monotherapy activity, against MET pathway-driven tumors, and EGFR TKI combination activity in acquired resistance models [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 4791.
Abstract 4797: In vitro and in vivo effect of ARQ 531 on Trk family kinases
Authors: Yu Yi , Schwartz Gabi , Schamber Pascal , Savage Ron E. , Eathiraj Sudharshan , Hall Terence , Schwartz Brian 
Published: August 2018

Abstract
The tropomycin kinase (Trk) receptor family contain Trk A, B and C that are encoded by the NTRK1, NTRK2, and NTRK3 genes respectively. Trk family kinases have been shown to play a very important role in the development and physiological functions of the nervous system. Recently, chimeric Trk kinases resulted from gene fusions of NTRK genes are involved in initiation and progression of various cancers such as sarcoma, thyroid, salivary gland cancers, etc. Targeting such alteration of Trk family kinases becomes a new avenue for the therapeutic intervention. ARQ 531 has biochemical IC50 values of 1.3 nM, 1.8 nM and 1.8 nM for Trk A, B and C, respectively with targeting a unique set of other kinases. In a cell based assay, ARQ 531 inhibits kinase activity of Trk A, B and C in UOS2 cells overexpressing Trk family kinases with IC50 values of 50.5 nM, 28.0 nM and 4.1 nM respectively. Pathway analysis shows that ARQ 531 abolished autophosphorylation of TMP3-Trk A in colon cancer KM-12 cells after 2-hour treatment, concomitant with marked inhibition of pAKT, pERK and pPLCγ1. Moreover, in Trk A-overexpressing K562 cells, ARQ 531 suppressed phosphorylation of Trk A and its downstream targets AKT and MAPK. Anti-proliferative activity of ARQ 531 has been demonstrated in Ba/F3 system over-expressing fusion Tel-Trk family kinases (ETV6-NTRK1, 2 or 3), exhibiting IC50 value of 300, 481, and 341 nM for Tel-Trk A, B or C respectively. In TMP3-TrkA(TMP3-NTRK1) fusion-driven KM12 cells driven by ARQ 531 strongly suppressed cell proliferation with an IC50 value of 130 nM. Subsequently, apoptotic response was observed in KM-12 cells after treatment of ARQ 531 for 24 hours, which was demonstrated by the increase in cleaved PARP1 and cleaved caspase 3. Significant anti-tumor activity of ARQ 531 was observed in KM-12 xenograft mouse model. In conclusion, ARQ 531 is a potent Trk family kinase inhibitor and the results from preclinical study provides rationale for testing ARQ 531 in a clinical setting, particularly in cancers driven by Trk fusion kinases.
Citation Format: Yi Yu, Gabi Schwartz, Pascal Schamber, Ron E. Savage, Sudharshan Eathiraj, Terence Hall, Brian Schwartz. In vitro and in vivo effect of ARQ 531 on Trk family kinases [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 4797.
Abstract 4799: Nef-M1 peptide inhibits CXCR4 driven Wnt/β-catenin signaling in breast cancer
Authors: Katkoori Venkat R. , Manne Upender , Bumpers Harvey L. 
Published: August 2018

Abstract
Introduction: The Nef-M1 peptide (Nef-M1) competes effectively with the natural ligand of CXCR4, SDF-1α, and exhibits anti-tumorigenic activity in breast cancer (BC). However, the molecular mechanisms of action of Nef-M1 on BC remain unclear. In this study, we evaluated the Nef-M1 inhibition of CXCR4 driven Wnt/β-catenin pathway in BC. Experimental Design: Cell line derived xenografts (CDX), patient derived explant (PDE) and in vitro cell based models were used to examine the mechanisms of action of Nef-M1. The severe combined immunodeficient mice with tumor were treated intraperitoneally either with Nef-M1 or sNef-M1 (control). Preparation of BC tissue, explant complete media, and cultures and treatment for 48 hours was performed for the PDE study. Sections from tumors were evaluated by immunostaining (IHC) for signaling proteins implicating BC progression. Western blot (WB) analyses were also performed on lysates of both cell lines and tumors to assess the effect of Nef-M1 on the Wnt/β-catenin, stem cell or mitogen-activated protein kinase (MAPK) pathways. Results: The present study revealed that PDE recapitulate multiple biological features of the disease and these were found to be very similar to the corresponding original tumors. IHC analysis for Ub-H2B, a stem cell signaling protein that correlates with advanced disease and metastasis indicated that Nef-M1 treated CDX or PDE tumors had low expression of Ub-H2B. However, sNef-M1 treated tumors had high expression of Ub-H2B. WB analyses indicated that Nef-M1 not only suppressed the expression of Ub-H2B, but also significantly suppressed the activation of MAPK (e.g. p38, ERK) and Akt proteins in BC. Nef-M1 treated BC displayed inhibition of Wnt/β-catenin signaling as demonstrated by an increased expression of p21 and decreased expression of beta-catenin, cyclin D1, Axin 2 and survivin. Cells expressing CXCR4 became susceptible to Nef-M1-induced inhibition of MAPK, Akt, Wnt/beta-catenin and stem cell signaling pathways. Conclusions: These results indicate that Nef-M1 suppresses CXCR4 mediated activation of Wnt/β-catenin and MAPK pathways. Therefore, Nef-M1 inhibition of these signaling pathways may be a promising therapeutic strategy for BC. This work was supported by NIH/NCI Workforce Diversity Grant R21-CA171251.
Citation Format: Venkat R. Katkoori, Upender Manne, Harvey L. Bumpers. Nef-M1 peptide inhibits CXCR4 driven Wnt/β-catenin signaling in breast cancer [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 4799.
Abstract 4800: Targeting the polyamine pathway as a novel therapeutic treatment against diffuse intrinsic pontine glioma
Authors: Khan Aaminah , Tsoli Maria , Yu Denise , Joshi Swapna , Gamble Laura , Franshaw Laura , Haber Michelle , Ziegler David S. 
Published: August 2018

Abstract
Diffuse intrinsic pontine glioma (DIPG) is a highly aggressive paediatric brainstem tumour, with a peak incidence in middle childhood and a median survival of less than 1 year in the majority of cases. The dismal prognosis associated with DIPG is exacerbated by the repeated failure of over 250 clinical trials to improve survival over standard radiotherapy. Therefore novel and innovative therapeutic approaches are urgently needed to needed to treat this devastating disease. Polyamines are small intracellular polycations that control key aspects of cell biology, such as cell replication/growth, differentiation and survival and can be found up-regulated in many cancers. Difluoromethylornithine (DFMO) is an FDA-approved inhibitor of the enzyme ornithine decarboxylase (ODC1) which is involved in polyamine synthesis. The aim of this study was to investigate the efficacy of polyamine pathway inhibitors such as DFMO as a therapeutic strategy against DIPG. By RT-qPCR and western blotting, we observed high expression levels of key players of the polyamine pathway in a panel of DIPG samples. Through alamar blue cytotoxicity assays and soft-agar clonogenic assays, DFMO was found to be effective against a panel of neurosphere-forming DIPG cells. The activity of DFMO was synergistically enhanced when combined with a polyamine transport inhibitor, AMXT-1501. Increased apoptotic activity following either DFMO or AMXT-1501 treatment, alone or in combination, was observed by western blotting and flow cytometric analysis of Annexin V/7AAD stained cells. In addition, reduced uptake of the radiolabelled polyamine, spermidine, in the presence of AMXT-1501 confirmed polyamine transport inhibition in DIPG cells. Consistent with the in vitro results, the combination of DFMO and AMXT-1501 significantly prolonged the survival of mice bearing DIPG orthografts, and the combination therapy represents the most effective combination treatment we have tested to date in our DIPG animal model. Our results suggest that the polyamine pathway is a potential therapeutic target for this highly aggressive paediatric brain tumour while a number of clinical trials based on this approach are currently underway in a variety of malignancies.
Citation Format: Aaminah Khan, Maria Tsoli, Denise Yu, Swapna Joshi, Laura Gamble, Laura Franshaw, Michelle Haber, David S. Ziegler. Targeting the polyamine pathway as a novel therapeutic treatment against diffuse intrinsic pontine glioma [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 4800.
Abstract 4810: Targeting androgen receptor in combination with cisplatin: Effective treatment strategy for muscle invasive bladder cancer
Authors: Tyagi Ashish , Chandersekaran Balaji , Rai Samarpit , Alatassi Houda , Haddad Ahmed Q. , Ankem Murali K. , Damodaran Chendil 
Published: August 2018

Abstract
Background: Bladder cancer is one of the major causes of cancer death in US and worldwide. Cisplatin is a key component of chemotherapeutic regimens employed in the treatment of advanced bladder cancer. The role of androgen and androgen receptor (AR) signaling in bladder cancer remains uncharacterized.
Aim: The aim of the study is to delineate the role of AR in bladder cancer and to determine whether combination of AR inhibitor, enzalutamide (Enz) and cisplatin-based therapies effectively inhibit the growth of muscle invasive bladder cancer (MIBC).
Methods: AR expression was determined in 75 human bladder cancer specimens and in a panel of bladder cancer cell lines. Cells grown in charcoal stripped media supplemented with dihydrotestosterone (DHT) were treated with cisplatin, enzalutamide (AR inhibitor), or a combination of both. Cellular/phenotypic analysis including MTT assay, apoptotic assay, migration as well as invasion assays and molecular analysis including western blotting, real time PCR analysis were performed. Isobologram analysis for the combination was performed and analyzed with CompuSyn. Experiments were repeated in triplicates and analyzed with unpaired Student's t-test and one way ANOVA *p≤0.05, **p≤0.01, ***p≤0.001.
Results: AR expression was seen in around 40% of bladder cancer patients. Inhibition of AR signaling by enzalutamide effectively inhibited the growth of AR+ MIBC cells. Interestingly, enzalutamide in combination with cisplatin (Enz + Cis) synergistically inhibited the proliferation of MIBC cells, TCCSUP (CI: 0.42, 1.25 + 5 μM) and J82 (CI: 0.79, 2.5 + 5 μM) at low concentrations of enzalutamide and cisplatin resp.. The molecular studies revealed the induction of DNA damage markers (pATM, pATR, pChk1, pHis) and enhanced expression of the pro-apoptotic genes (Bax, caspases-3 and PARP) in Enz+Cis treated AR+ MIBC cells. In addition, we demonstrated abrogation of invasive and migratory potential with Enz+Cis treatment, by downregulation of the mesenchymal markers (N-cadherin, slug, β-catenin, and vimentin) in both cell lines. Our studies suggest combination of Enz + Cis may be effective in patients with AR+ MIBC.
Conclusion: Combination of cisplatin and AR inhibition effectively inhibit bladder tumor growth and migration, and hold promise as synergetic therapies for AR+ bladder cancer patients.
Citation Format: Ashish Tyagi, Balaji Chandersekaran, Samarpit Rai, Houda Alatassi, Ahmed Q. Haddad, Murali K. Ankem, Chendil Damodaran. Targeting androgen receptor in combination with cisplatin: Effective treatment strategy for muscle invasive bladder cancer [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 4810.
Abstract 4811: Inhibition of PLK1 abrogates side population and increases radiation-induced DNA damage in human glioblastoma
Authors: Pandey Arvind , Mai Junhua , Tripathi Satyendra C. , Hanash Samir M. , Shen Haifa , Mitra Sankar 
Published: August 2018

Abstract
Glioblastoma multiforme (GBM), a highly malignant form of brain tumor has limited treatment modalities with poor patient survival. Expression of CD133, a marker of cancer stem cells (CSCs), has been linked to GBM recurrence, metastasis and radiation/drug resistance. The GBM CSCs exhibit high level of ABC transporters, DNA repair enzymes and anti-apoptotic proteins. The side population (SP) phenotype of CSCs with high levels of ABC transporters is associated with chemo-resistance. Overexpression of Polo-like kinase-1 (PLK1), a key cell cycle regulator, has been linked to poor prognosis of various cancers. However, the role of PLK1 in radio/chemo-resistance of GBM is poorly understood. In this study, we explored the use of PLK1 inhibitor Volasertib in combination with temozolomide (TMZ) followed by radiation to overcome resistance in GBM, both in vitro and in vivo.
Our results revealed that Volasertib and TMZ act synergistically at a sub-lethal dose to inhibit cell proliferation and induce apoptosis. Both Volasertib and TMZ strongly induce reactive oxygen species (ROS) which may cause cell death by reducing repair capacity. Combined treatment with TMZ and Volasertib followed by radiation showed persistent DNA damage after removal of drugs for 24 hrs. In contrast to earlier reports, significant decrease in the side population was also observed, even after radiation treatment.
We also observed that Volasertib alone or in combination with TMZ activated STAT1 pathways and inhibited MAPK/AKT activation. As the latter pathway promotes apoptosis, our results suggest higher tumor growth inhibitory effect of combinatorial treatment compared to single agents in xenograft mouse model.
In summary, while Volasertib can be used alone or in the combination with radiation, Volasertib combined with TMZ may be useful to inhibit recurrence of GBM after radiation therapy. Furthermore, increased STAT1 expression may modulate the tumor-microenvironment and improve immunotherapy by MHC class 1 upregulation.
Citation Format: Arvind Pandey, Junhua Mai, Satyendra C. Tripathi, Samir M. Hanash, Haifa Shen, Sankar Mitra. Inhibition of PLK1 abrogates side population and increases radiation-induced DNA damage in human 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 4811.