bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract C41: A phase 1 study of OMN54 in patients with advanced malignancies
Authors: Renouf Daniel , Kollmannsberger Christian , Chi Kim , Chia Stephen , Tinker Anna , Mitchell Teresa , Lam Stephen , Joshi Teresa , Kwok David , Ostrem John , Sutcliffe Simon , Gelmon Karen A. 
Published: May 2016

Abstract
Purpose: With the increasing interest in natural products as therapeutics, we performed a Phase I open label study of OMN54 in patients with advanced malignancies to determine toxicity, maximum tolerated dose (MTD), dose limiting toxicities (DLT), and pharmacokinetics (PK). OMN54 is a multitargeted agent prepared from three Chinese botanical sources: Ganoderma lucidum, Salvia miltiorrhiza, and Scutellaria barbata, each with long histories of use as single agents.
Methods: Eligible patients (pts) were ≥ 18 years with advanced solid tumor malignancies, able to swallow oral capsules, ECOG performance status ≤ 2, measurable disease as defined by RECIST 1.0, and adequate organ function.
Results: 22 pts were enrolled in 6 dose levels, 2 at daily and 4 with twice daily dosing ranging from 1 to 5 gm orally per day; all evaluable for toxicity and 20 for response. Most common cancers included colorectal (13 pts), non small cell lung (3 pts), and ovarian (2 pts). 5 pts patients completed Cycle 1, 9 pts Cycle 2, 3 pts Cycle 3 and 1 pt each completed Cycles 4, 5, and 8. 2 pt had &lt; 1 cycle. Only 7 AEs in 5 pts were reported as possibly related to study drug; 6 were gastrointestinal disorders, 1 a skin disorder. One GR 2 AE of vomiting was probably related to study drug. All other AEs were Grade 1. There were no treatment-related SAEs or DLTs. A recommended phase II dose (RP2D) is 2.5 g orally twice daily. PK data revealed evidence of detectable plasma total OMN54 in cohorts 1 to 6 with all 4 parent drug chemical markers with plasma half-lives of 1- 2 hours and no evidence of accumulation. Preliminary evidence of biological activity was seen with stable disease for 8 months in 1 pt and 4 pts with dose responsive reductions in TGF-β, EGF & Rantes, biomarkers of immune suppression. Significant TGF-β decreases were seen for 4 pts at doses of 2gm daily to 2.5 gm bid including an ovarian, colorectal, fallopian tube and esophageal cancer.
Conclusion: OMN54 was well tolerated with no DLTs observed. Further studies at RP2D of 2.5 g bid orally should be done to assess activity.
Citation Format: Daniel Renouf, Christian Kollmannsberger, Kim Chi, Stephen Chia, Anna Tinker, Teresa Mitchell, Stephen Lam, Teresa Joshi, David Kwok, John Ostrem, Simon Sutcliffe, Karen A. Gelmon. A phase 1 study of OMN54 in patients with advanced malignancies. [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2015 Nov 5-9; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2015;14(12 Suppl 2):Abstract nr C41.
Abstract C67: Mitochondrial dysfunction confers therapy resistance in Hep3B hepatocellular carcinoma cell line
Authors: Han YuSeon , Je Gal MyeongEun , Yi EuiYeun , Kim YungJin 
Published: May 2016

Abstract
Mitochondria dysfunctional cells are useful models in studies for mitochondrial diseases, apoptosis, cancer and aging, but their functional aspects have not been fully understood. Mitochondrial dysfunction (MD) is found in many type of cancer such as colorectal, liver, pancreatic, breast, prostate, ovarian cancer etc. MD has also been known to be associated with cancer malignancy, especially apoptosis resistance (therapy resistance). Using mitochondrial-depleted P0 derived from Hep3B, we have tested the effects of mitochondrial dysfunction on the chemical and radiation resistance. When compared to parental cells, Hep3B/P0 cells were much less sensitive to doxorubicin and sorafenib and irradiation. Hep3B/P0 cells also showed increased efflux, decreased target molecules, rapid repair and DNA protection. These results suggest that mitochondrial dysfunction confers therapy resistance on the cancer cells, which could be a novel therapeutic target for cancer therapy.
Citation Format: YuSeon Han, MyeongEun Je Gal, EuiYeun Yi, YungJin Kim. Mitochondrial dysfunction confers therapy resistance in Hep3B hepatocellular carcinoma cell line. [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2015 Nov 5-9; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2015;14(12 Suppl 2):Abstract nr C67.
Abstract CN08-04: Targeting super-enhancer driven transcriptional dependencies in cancer
Authors: George Rani E. 
Published: May 2016

Abstract
Super-enhancers are acquired by cancer cells through gene amplification, translocation or transcription factor overexpression and facilitate high-level expression of genes including MYC, whose protein products are critical for the control of cell identity, growth and proliferation, and which are especially sensitive to perturbation. We demonstrate that the genomically amplified MYCN oncogene, by promoting the development of super-enhancers, leads to upregulation of the active transcriptional program of neuroblastoma cells. Using THZ1, a novel covalent inhibitor of cyclin-dependent kinase 7 (CDK7), a widely expressed regulator of transcription and cell cycle progression, we demonstrate selective targeting of MYCN-amplified neuroblastoma cells, leading to global repression of MYCN-dependent transcriptional amplification. This response translated to significant tumor regression in a mouse model of high-risk neuroblastoma, without toxicity to normal cells. The selectivity of THZ1 for MYCN-amplified cells was associated with preferential downregulation of super-enhancer-associated genes, including MYCN and other known lineage-specifying genes in neuroblastoma. These results indicate that CDK7 inhibition, by selectively targeting the mechanisms that promote transcriptional amplification in tumor cells, may be useful therapy for cancers that are driven by oncogenic transcription factors such as MYC.
Citation Format: Rani E. George. Targeting super-enhancer driven transcriptional dependencies in cancer. [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2015 Nov 5-9; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2015;14(12 Suppl 2):Abstract nr CN08-04.
Abstract LB-A02: trans,trans-Conjugated linoleic acid induces apoptosis by enhancing gap junctional intercellular communication inhuman breast cancer MCF-7 cells
Authors: Ha Yeong Lae , Rakib Abdur , Kim Jeong O. 
Published: May 2016

Abstract
t,t-Conjugated linoleic acid (CLA) isomers reported to exert antitumor effects by inducing apoptosis. However, the precise mechanism underlying remains unclear. Restoration of reduced gap junctional intercellular communication (GJIC) in cancer cells inhibits cell growth by apoptosis. We hypothesized, t,t-CLA might cause apoptosis with enhanced GJIC in MCF-7 cells. Growth inhibitory effects of t9,t11-and t10,t12-CLA were investigated with reference to t10,c12-CLA,which is equally effective with c9,t11-CLA. Results demonstrated, t,t-CLA inhibited cell growth with cell shrinkage, nuclear condensation, increased cell population in sub-G1 phase in cell cycle and elevated caspase-3 which indicate apoptosis. It enhanced GJIC with increased connexin43 (Cx43) at the mRNA and protein levels with higher efficacy as compared to t10,c12-CLA but t9,t11-CLA is superior to t10,t12-CLA. Findings suggest, the growth inhibitory effect of t,t-CLA isomers might be associated with the up-regulation of Cx43, which enhances GJIC in MCF-7 cells. t,t-CLAs inhibited nuclear factor- κB (NF-κB) translocation and increased reactive oxygen species (ROS) generation which might trigger up-regulation of Cx43 and restore GJIC.
Keywords: t,t-CLA, Apoptosis,Cx43, GJIC, ROS.
Citation Format: Yeong Lae Ha, Abdur Rakib, Jeong O. Kim. trans,trans-Conjugated linoleic acid induces apoptosis by enhancing gap junctional intercellular communication inhuman breast cancer MCF-7 cells. [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2015 Nov 5-9; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2015;14(12 Suppl 2):Abstract nr LB-A02.
Abstract LB-A19: Ceramide-Rubusoside, an Ultrasmall Nanomicells Effectively Restores p53 Expression in the Missense Mutant Cancer Cells
Authors: Liu Yong-Yu , Liu Zhijun , Khiste Sachin K. , Hosain Salman B. 
Published: May 2016

Abstract
Mutation of tumor suppressor p53, which exhibits oncogenic gain-of-function (GOF) and promotes tumor progression, emerges as a therapeutic target for approximately 50% of all cancer cases. However, it is still unclear whether it is possible to restore GOF of p53 mutants without heterotetramer effect, as this often eliminates the efficacy of current approaches used to restore p53 function in p53 mutant cancers. Ceramide, an active sphingolipid metabolite, has pro-apoptotic effects on cancer cells but the hydrophobicity it has limits to develop ceramide as therapeutic agents. Here, we report that the ceramide-rubusoside (Cer-RUB), an ultrasmall nanomicelles enhances the bioavailability of C6-ceramide in vivo and restores wild-type p53 expression and its function in tumor suppression. We found that Cer-RUB nanomicelles enhanced the aqueous solubility of ceramide by 2,000-folds (2 mg/ml vs. &lt;1.0 μg/ml), presented mono-disperse with an average particle sizes of 4 nm in cell culture medium, and elongated ceramide activity, due to a decrease in Cer-RUB glycosylation, compared to the C6-ceramide. More interestingly, Cer-RUB treatments (0.6 μM; 1 mg/kg) restored wild-type p53 expression documented in protein levels of phosphor-p53 and p53 responsive genes (p21, Bax) in cancer cell lines carrying R248G and R273H missense mutants and in heterozygous transgenic mice of 129S4-Trp53tm2.1Tyj. Cer-RUB significantly sensitized the resistance of these cells to anticancer drugs and eliminated cancer stem cells in cell culture and in tumor-bearing mice. This study indicates that Cer-RUB is a new approach to effectively target p53 mutant cancers.
Citation Format: Yong-Yu Liu, Zhijun Liu, Sachin K. Khiste, Salman B. Hosain. Ceramide-Rubusoside, an Ultrasmall Nanomicells Effectively Restores p53 Expression in the Missense Mutant Cancer Cells. [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2015 Nov 5-9; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2015;14(12 Suppl 2):Abstract nr LB-A19.
Abstract LB-A21: Single-agent activity and favorable pharmaceutical properties of orally bioavailable next-generation CDK4/6 inhibitor, ON 123300
Authors: Hoffman Benjamin , Reddy Ramana , Mallireddigari Muralidhar , Fox Daniel , Ren Chen , Maniar Manoj 
Published: May 2016

Abstract
Introduction: Recent proof-of-concept for targeting cyclin dependent kinases 4 and 6 (CDK4/6) culminated in the approval for breast cancer of the first-in-class CDK4/6 inhibitor, palbociclib (Ibrance®). Palbociclib and other potent but narrowly targeted CDK4/6 inhibitors are cytostatic rather than cytotoxic (Leonard et al, 2012), and require combination therapy for optimal activity. ON 123300 is a next-generation CDK4/6 inhibitor with improved single-agent cytotoxicity. This novel compound is a potent CDK4 and CDK6 inhibitor (IC50 = 3.9 nM and 9.8 nM, respectively) that is cytotoxic against breast and other cancer cell lines (Reddy et al, 2014). We present pre-IND profiling pharmacology, physicochemical and ADME studies to support ON 123300 as a clinical candidate and next-generation CDK4/6 inhibitor.
Methods and Results: Non-clinical studies were conducted in order to assess the drug-like properties of ON 123300 and its pharmaceutical salts. Physicochemical parameters were determined for the compound. ON 123300 was highly soluble below pH 4.0, with reduced solubility in more basic conditions. Predicted intestinal absorption, as measured by Caco-2 permeability, was 1.95×10-5 cm/s with a low efflux ratio. Based on these characteristics, the compound was advanced to lead profiling against 68 primary molecular targets. Radioligand binding studies revealed limited receptor inhibition (11/68 targets) with 10 μM of ON 123300. Human Ether-a-go-go (hERG) inhibition testing revealed no significant effect (IC50 &gt; 25 μM). In vitro metabolism studies indicated metabolism through CYP3A4 and CYP2C8. Finally, in silico based modeling (Cloe® PK) integrating all key non-clinical parameters was carried out in order to estimate the potential for oral absorption in humans. Preliminary analysis suggests good oral bioavailability and the potential to establish an acceptable therapeutic window.
Conclusions: The well differentiated biochemical, anticancer and pharmaceutical properties of ON 123300 provide the basis for pre-clinical toxicology testing, leading to an investigational new drug (IND) filing and clinical exploration of this compound across tumor types that share targets accessed by this next-generation CDK inhibitor.
Citation Format: Benjamin Hoffman, Ramana Reddy, Muralidhar Mallireddigari, Daniel Fox, Chen Ren, Manoj Maniar. Single-agent activity and favorable pharmaceutical properties of orally bioavailable next-generation CDK4/6 inhibitor, ON 123300. [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2015 Nov 5-9; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2015;14(12 Suppl 2):Abstract nr LB-A21.
Abstract LB-B05: MM-151 overcomes acquired resistance to cetuximab and panitumumab in colorectal cancer cells harboring EGFR extracellular domain mutations
Authors: Arena Sabrina , Siravegna Giulia , Mussolin Benedetta , Kearns Jeffrey D. , Wolf Beni B. , Misale Sandra , Lazzari Luca , Bertotti Andrea , Trusolino Livio , Adjei Alex A. , Montagut Clara , Di Nicolantonio Federica , Nering Rachel , Bardelli Alberto 
Published: May 2016

Abstract
Cetuximab and panitumumab are monoclonal anti-EGFR antibodies (moAbs) currently used for the treatment of ‘RAS’ wild type colorectal cancers (CRC). Development of acquired resistance almost invariably limits the efficacy of these agents. At relapse, about 20% of tumors treated with cetuximab and panitumumab carry EGFR extracellular domain (ECD) mutations (S492R, R451C, S464L, G465R, G465E, K467T, I491M), which impair antibody binding. We postulated that mCRC patients who become resistant to cetuximab or panitumumab due to the emergence of EGFR ECD mutations may still benefit from further line of treatment with EGFR blockade. We observed that the EGFR ECD variants are effectively targeted by the oligoclonal anti-EGFR antibody MM-151. MM-151 inhibits EGFR signaling and cell growth in preclinical models, including patient-derived cells carrying mutant EGFR.
We have analyzed liquid biopsies of 11 CRC patients that developed resistance to previous treatment with cetuximab and were then enrolled in the first MM-151 phase I study. Longitudinal profiling of circulating cell-free tumor DNA (ctDNA) samples collected during MM-151 treatment revealed a decrease of EGFR ECD mutant levels that paralleled the response as measured by radiological methods.In conclusion, we provide mechanistic evidence for the efficacy and use of MM-151 as a therapeutic opportunity for patients whose tumors develop EGFR ECD mutations as the prevalent mechanism of acquired resistance to cetuximab or panitumumab treatment.
Citation Format: Sabrina Arena, Giulia Siravegna, Benedetta Mussolin, Jeffrey D. Kearns, Beni B. Wolf, Sandra Misale, Luca Lazzari, Andrea Bertotti, Livio Trusolino, Alex A. Adjei, Clara Montagut, Federica Di Nicolantonio, Rachel Nering, Alberto Bardelli. MM-151 overcomes acquired resistance to cetuximab and panitumumab in colorectal cancer cells harboring EGFR extracellular domain mutations. [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2015 Nov 5-9; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2015;14(12 Suppl 2):Abstract nr LB-B05.
Abstract LB-B21: BI-69A11 inhibits Epithelial to Mesenchymal Transition exploiting β-catenin pathway in colon carcinoma
Authors: Pal Ipsita , Mandal Mahitosh 
Published: May 2016

Abstract
EMT is a potential biological phenomena required for metastatic dissemination. Although targeting EMT for therapeutic implication has been gaining interest to the scientific community, only few molecules have succeeded to employ their anti-metastatic effect so far. BI-69A11 has been earlier proved for its anti-tumor activity in prostate and colon carcinoma. This study aims to elucidate the biological consequence of BI-69A11 on EMT in colon carcinoma in vitro and in vivo. Our findings showed that BI-69A11 increased epithelial signature marker E-cadherin and reciprocally decreased the mesenchymal markers snail, slug and vimentin. Moreover, cellular migration, invasion and adhesion were potentially hampered by BI-69A11 through β-catenin dependent pathway. The underlying molecular mechanism behind BI-69A11 induced inhibition of EMT includes suppression of nuclear transport of β-catenin, diminished phosphorylation of β-catenin accompanied with enhanced E-cadherin- β-catenin complex formation at the membrane. Moreover, BI-69A11 controlled the transcriptional activity and reversed nuclear translocation by decrease in the phosphorylation at ser552 and ser45/Thr41 residue. The growing interaction between E-cadherin and β-catenin complex also promoted the E-cadherin transcription leading to the reversal of EMT. BI-69A11 caused increasing accumulation of vinculin in the membrane that in turn strengthened the focal adhesion junction leading to the inhibition of metastasis. Overall, these evidences present a thoughtful insight towards underlying molecular mechanism of BI-69A11 induced reversal of EMT in colorecteal carcinoma in vitro and in vivo.
Citation Format: Ipsita Pal, Mahitosh Mandal. BI-69A11 inhibits Epithelial to Mesenchymal Transition exploiting β-catenin pathway in colon carcinoma. [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2015 Nov 5-9; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2015;14(12 Suppl 2):Abstract nr LB-B21.
Abstract LB-C01: Patient-derived tumor xenografts in humanized NSG-SGM3 mice: A new immuno-oncology platform
Authors: Yao Li-Chin , Cheng Mingshan , Wang Minan , Banchereau Jacques , Shultz Leonard , Palucka Karolina , Keck James G. 
Published: May 2016

Abstract
Humanized mice engrafted with tumors enable in vivo investigation of the interactions between the human immune system and human cancer. We have recently found that humanized NOD-scid IL2Rγnull (NSG) mice bearing patient-derived xenografts (PDX) allow efficacy studies of check-point inhibitors. Next generation NSG strains include triple transgenic NSG mice expressing human cytokines KITLG, CSF2, and IL-3 (NSG-SGM3). Here we provide a direct comparison of check-point inhibitors evaluation in NSG and NSG-SGM3 mice engrafted with CD34+ human hematopoietic progenitor cells (HPCs) from the same donor and implanted with PDX tumors. Corroborating earlier studies, reconstitution of human immune system in the blood was faster and more robust in NSG-SGM3 compared to NSG recipients throughout the course of the study (18 weeks). Human CD45+ cells reached 25% of total blood cells at week 4 in hu-NSG-SGM3 mice and at week 9 in hu-NSG mice. A majority of blood hCD45+ cells in hu-NSG-SGM3 at week 4 were CD33+ myeloid cells. Circulating hCD3+ T cells reached 10% at week 9 and included regulatory T cells (Tregs), consistent with earlier studies. Hu-NSG mice displayed comparable hCD3+ T cells in the blood only at 12-15 weeks and did not contain Tregs. PDX tumors were then engrafted into partially HLA-matched hu-NSG-SGM3 mice at 9 weeks post engraftment. Two PDX models previously shown to respond to anti-PD1 therapy in hu-NSG mice, BR1126 and LG1306, were used. Treatment with the anti-PD-1 receptor antibody pembrolizumab (Keytruda) significantly reduced tumor growth in both models. Thus, PDX-bearing hu-NSG-SGM3 mice might serve as a new and improved platform for preclinical immuno-oncology efficacy studies.
Citation Format: Li-Chin Yao, Mingshan Cheng, Minan Wang, Jacques Banchereau, Leonard Shultz, Karolina Palucka, James G. Keck. Patient-derived tumor xenografts in humanized NSG-SGM3 mice: A new immuno-oncology platform. [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2015 Nov 5-9; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2015;14(12 Suppl 2):Abstract nr LB-C01.
Abstract LB-C03: Lovastatin induced anti-proliferation through multi-pathways in human intrahepatic cholangiocarcinoma
Authors: Yang Yu-Chen , Lin Hung-Yun 
Published: May 2016

Abstract
Lovastatin induced anti-proliferation through multi-pathways in human intrahepatic cholangiocarcinoma.
Yu-Chen Yang1, Hung-Yun Lin1, Chun A Changou1,2,3, Chun-Han Chen1, Yun-Ru Liu4, Jinghan Wang5, Xiaoqing Jiang5, Yun Yen1*
1PhD Program for Cancer Biology and Drug Discovery, College of Medical Science and Technology, Taipei Medical University, Taipei, Taiwan.2Integrated Laboratory, Center of Translational Medicine, Taipei Medical University, Taipei, Taiwan.3Core Facility, Taipei Medical University, Taipei, Taiwan. 4Office of Human Research, Taipei Medical University, Taipei, Taiwan and 5The First Department of Biliary Surgery, Eastern Hepatobiliary Surgical Hospital, Second Military Medical University, Shanghai, China.
Abstract
Human intrahepatic cholangiocarcinomas are one of the most difficult cancers to treat. Lovastatin, a 3-hydroxy-3-methylglutaryl-coenzyme-CoA (HMG-CoA) reductase inhibitor, exhibits anticancer properties. In this study, lovastatin inhibited cell proliferation, cell migration and cell adhesion. Results showed lovastatin inhibited the gene expressions of integrin β1 and integrin β3 but not integrin αv or integrin β5. Furthermore, gene expressions of transforming growth factor (TGF)-β1, cyclooxygenase (COX)-2 and intercellular adhesion molecule (ICAM)-1 were inhibited by lovastatin. Also, the cholesterol-depleting agent, methyl-beta-cyclodextrin (MβCD), reduced the expression of β3 integrin, but not that of the other genes in either cancer cell line. The lovastatin-induced inhibitory effects on expressions of TGFβ1, COX2, and ICAM-1 were positively controlled by the tumor suppressor, LKB1; however, the inhibition of integrin β3 by lovastatin was negatively affected by LKB1. The inhibitory effect of lovastatin on cell adhesion was associated with decreased expression of integrin β3 and the presentation of cell surface heterodimer integrin αvβ3. Furthermore, lovastatin strongly inhibited integrin αvβ3 downstream FAK activation, and the expression of β-catenin, vimentin, ZO-1, and β-actin. Therefore, in addition to the cholesterol-depleting effect, lovastatin modified the expressions of cell adhesion molecules leading to reduced tumor cell proliferation and migration. These advantageous effects of lovastatin may be mediated by blocking integrin β3 signaling suggesting a novel treatment option for cholangiocarcinomas.
Keywords: Bile duct cancer, HMG-CoA reductase inhibitor, Integrin, LKB1, TGF-β1
Citation Format: Yu-Chen Yang, Hung-Yun Lin. Lovastatin induced anti-proliferation through multi-pathways in human intrahepatic cholangiocarcinoma. [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2015 Nov 5-9; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2015;14(12 Suppl 2):Abstract nr LB-C03.