bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 4472: Plitidepsin shows antitumor activity in patient-derived tumor xenografts and hematologic malignancies
Authors: Maier Armin , Kelter Gerhard , Vuaroquaux Vincent , Avilés Marin Pablo M. , Cuevas Carmen , Galmarini Carlos M. , Fiebig Heinz H. 
Published: August 2015

Abstract
Plitidepsin is a new marine-derived anti-tumor agent, originally isolated from the tunicate Aplidium albicans that is now fully obtained by total chemical synthesis. The compound is currently being evaluated in a pivotal phase III trial in patients with refractory/relapsed multiple myeloma. Previous in vitro studies in 26 hematological cell lines demonstrated that plitidepsin was more active in multiple myeloma and non-Hodgkin lymphoma compared to CML, AML and ALL derived cell lines as determined in a 4 day proliferation assay in suspension cultures. We have recently shown that plitidepsin interacts selectively with eEF1A2 (eukaryotic translation elongation factor 1 alpha 2) in tumor cells, which results in apoptotic cell death. To identify target tumor types for future clinical studies, the inhibition of colony formation of plitidepsin was assessed in vitro in 116 established patient derived xenografts tumor models from 23 different tumor types, including solid tumors and hematological malignancies such as myeloma, leukemia and lymphoma. The anti-tumor activity of plitidepsin varied depending on the concentration used, achieving a mean IC70 (inhibitory concentration of 70%) value of 3 nM (range between 0.03 nM and &gt;1 μM), which can be also achieved in patients treated using the clinical recommended dose or less. 39 out of 116 tumors showed above average sensitivity (IC70 &lt; 1nM) and IC70 values in these tumors were about 9-fold lower than the mean of all tumors as tested. Sensitive tumor types were seen among different tumor types, such as hematological malignancies, pleuramesothelioma, melanoma, small cell and non-small cell lung cancer (both adeno and large cell), as well as renal cancer. In conclusion plitidepsin showed a broad differential antitumor activity in vitro in hematological malignancies and in solid tumors. Bioinformatic analyses are currently underway to identify biomarkers and/or gene signatures that can predict sensitivity or resistance to plitidepsin for selecting patients being responsive to the drug.
Citation Format: Armin Maier, Gerhard Kelter, Vincent Vuaroquaux, Pablo M. Avilés Marin, Carmen Cuevas, Carlos M. Galmarini, Heinz H. Fiebig. Plitidepsin shows antitumor activity in patient-derived tumor xenografts and hematologic malignancies. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 4472. doi:10.1158/1538-7445.AM2015-4472
Abstract 448: The role of the Nanog transcription factor in tumor immune escape
Authors: Robitschek Emily , Mao Chih-Ping , Peng Shiwen , Hung Chien-Fu , Wu TC 
Published: August 2015

Abstract
The emergence of cancer stem cells and escape from immune surveillance play major roles in the progression of many cancer types. We recently established a link between these two “hallmarks” of cancer by demonstrating that they are both driven by overexpression of Nanog, a pivotal transcription factor in the self-renewal of pluripotent stem cells. In particular, we found that tumor cells acquire Nanog expression in the course of immune selection, and that Nanog confers a stem-like and immune-resistant phenotype to these cells. However, the way in which Nanog causes this to occur remains largely unknown. We reasoned that Nanog-driven immune escape may be in part due to the effect of this transcription factor on the tumor microenvironment. Therefore, here we investigated the relationship between Nanog, immune selection, and the properties of the tumor microenvironment.
We found that mice bearing tumor cells that underwent immune selection, compared to those bearing parental tumor cells (without immune selection), had markedly elevated levels of the cytokine IL-6 as well as of myeloid-derived suppressor cells (MDSCs) in the tumor microenvironment; both IL-6 and MDSCs have been well-documented to promote cancer immune escape. We further investigated the role of Nanog in setting up this microenvironment. To this end, we have devised an in vivo system that enables us to examine the relationship between Nanog expression in the tumor microenvironment and tumor growth in real-time.
Taken together, we infer from these data that not only is Nanog induction a consequence of immune selection, but Nanog also plays an essential role in tumor immune escape. In fact, we found in multiple mouse and human tumor models that Nanog is necessary and sufficient for immune escape. Additionally, these results suggest that Nanog mediates immune escape by converting the tumor microenvironment into an immune-inhibitory site, through the induction of IL-6 and MDSCs. These studies authenticate the role of Nanog in cancer progression as a central instigator of tumor immune escape, and demonstrate its potential both as an important diagnostic/prognostic index and as a therapeutic target.
Citation Format: Emily Robitschek, Chih-Ping Mao, Shiwen Peng, Chien-Fu Hung, TC Wu. The role of the Nanog transcription factor in tumor immune escape. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 448. doi:10.1158/1538-7445.AM2015-448
Abstract 4486: Antiangiogenic platinum through glycan targeting
Authors: Peterson Erica J. , Berners-Price Susan J. , Bezos Anna , Bohlman Lisa , Katner Samantha J. , Daniel A. Gerard , Chang Chih-Wei , von Itzstein Mark , Parish Christopher R. , Farrell Nicholas P. 
Published: August 2015

Abstract
Heparanase is an endo-β-D-glucuronidase that cleaves heparan sulfate glycosaminoglycans (HS-GAGs) in the extracellular matrix and basement membrane. Cancer cells that aberrantly express heparanase potentiate tumor progression, invasion and metastasis in two distinct ways; (1) cleavage of HS-GAGs releases growth-factors to directly activate growth receptors and (2) degradation of the heparan sulfate structural component of the extracellular matrix (ECM) allows metastatic spread of cancer cells. Recently, we determined that accumulation and cytotoxicity of polynuclear platinum compounds (PPCs), including the Phase II clinical trial compound, BBR3464 (+4), are dependent on the presence of cell-surface GAGs. Here, we demonstrate that high affinity PPC-GAG binding provides a new approach to glycan-based targeting by protection against enzymatic cleavage by heparanase. It was determined by NMR spectroscopy, that PPCs, especially the higher charged compound, TriplatinNC (+8), inhibit heparanase cleavage of the oligosaccharide, Fondaparineaux. Further, using the human umbilical primary cell line, HUVEC, it was determined that PPCs reduce heparanase cleavage of the GAG-bound growth factor, bFGF, from ECM. The end result of inhibition of heparanase cleavage is a reduction in tumor invasion and angiogenesis. Using the matrigel invasion assay, we show that sub-cytotoxic doses of PPCs, but not cisplatin, reduces serum-induced invasion of HCT116 cells through basement membrane. In an ex vivo rat aorta model, PPCs exhibit antiangiogenesis activity, measured by the inhibition of new blood vessel growth sprouting from the original aortic ring. Together, these encouraging results support the potential to combine anti-metastatic and cytotoxic activity in the development of dual-function platinum-based drugs.
Citation Format: Erica J. Peterson, Susan J. Berners-Price, Anna Bezos, Lisa Bohlman, Samantha J. Katner, A. Gerard Daniel, Chih-Wei Chang, Mark von Itzstein, Christopher R. Parish, Nicholas P. Farrell. Antiangiogenic platinum through glycan targeting. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 4486. doi:10.1158/1538-7445.AM2015-4486
Abstract 4494: Physical and metabolic stability of SH7139, a new drug candidate for non-Hodgkin's lymphoma targeting HLA-DR10
Authors: Balhorn Rod , Hok Saphon , Balhorn Monique Cosman 
Published: August 2015

Abstract
Oncology drugs must remain sufficiently stable during storage, following formulation, after introduction into the bloodstream and during their entry into cells to ensure accurate dosing. After uptake by cells, the biologically active form of the drug also needs to remain stable long enough to achieve an optimal anti-tumor response. SH7139, our most advanced small molecule therapeutic for non-Hodgkin's lymphoma, was designed to target and bind to a unique site on HLA-DR10, a cell surface receptor found on B-cell lymphocytes and over-expressed on many B-cell derived malignancies. Previous studies conducted with lymphoma and other cell lines have shown that SH7139 binds selectively and is highly cytotoxic only to tumor cells expressing HLA-DR10. SH7139 has also been shown to be highly effective in treating human Burkitt's lymphoma (Raji) in a mouse xenograft model. All of the studies performed to date suggest SH7139 meets the necessary stability requirements. No degradation of the drug has been observed during storage at -20°C over a period of 30 months. SH7139 is also stable when dissolved in water or saline over a wide range of pH (pH 2 to 9). Instability is only observed at a highly alkaline pH. At pH 12, a slow auto-catalytic cleavage reaction releases a fragment of one of the recognition elements. The amide bonds linking the three recognition elements to the lysine and miniPEG scaffold of SH7139 remain stable in plasma. Hepatocytes metabolize SH7139 at a moderate rate and produce two primary metabolites. The same metabolites are produced by both canine and human hepatocytes, and the smaller product, 2-[3-chloro-5-(trifluoromethyl)pyridin-2-yl]oxyaniline, is rapidly glucuronidated to facilitate its excretion. Both the physical and metabolic stability of SH7139 are consistent with the drug's observed anti-lymphoma activity. This research was supported by the National Cancer Institute Phase II SBIR award R44CA159843-02 to SHAL Technologies Inc. Part of this work was performed under the auspices of the U.S. Department of Energy by Lawrence Livermore National Laboratory under Contract DE-AC52-07NA27344.
Citation Format: Rod Balhorn, Saphon Hok, Monique Cosman Balhorn. Physical and metabolic stability of SH7139, a new drug candidate for non-Hodgkin's lymphoma targeting HLA-DR10. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 4494. doi:10.1158/1538-7445.AM2015-4494
Abstract 4515: A phase 1 randomized, open-label, fixed-sequence, 2-period study of the effect of multiple doses of rifampin on palbociclib (PD-0332991) pharmacokinetics in healthy volunteers
Authors: Hoffman Justin T. , Plotka Anna , O'Gorman Melissa , Chang Andrew , Kosa Maha , Loi Cho-Ming , Gallo-Stampino Corrado , Wang Diane D. 
Published: August 2015

Abstract
Background
Rifampin is a strong inducer of multiple Phase 1 and Phase 2 metabolic enzymes including cytochrome (CYP) P450 3A4 and sulfotransferases (SULT). In vitro, the metabolism of palbociclib occurs primarily through CYP3A4 and SULT2A1; thus, coadministration of rifampin and palbociclib could result in decreased exposure of palbociclib.
Methods
This open-label, 2-period, fixed-sequence study assessed the effect of multiple oral doses of rifampin on single-dose palbociclib pharmacokinetics (PK) in 15 healthy volunteers (ClinicalTrials.gov; NCT01953731). Each subject received the following treatments: Period 1, oral palbociclib 125 mg on day 1; Period 2, oral rifampin 600 mg for 12 days and oral palbociclib 125 mg on day 8 (washout of ≥12 days between the 2 palbociclib doses). Serial blood sampling for palbociclib PK was performed predose and up to 120 hours post-palbociclib dose in both periods. Plasma concentrations of palbociclib were measured using validated high-performance liquid chromatography tandem mass spectrometry methods. Palbociclib plasma PK parameters were estimated using standard non-compartmental methods.
Results
Median time to maximum plasma concentration (Tmax) and mean half-life (t1/2) were shorter with palbociclib plus rifampin relative to palbociclib alone. Adjusted geometric mean palbociclib AUCinf (area under the curve from time zero to infinity) and Cmax (maximal plasma concentration) following treatment with rifampin (242.5 ng•h/mL and 15.52 ng/mL, respectively) were considerably lower relative to palbociclib administered alone (1568 ng•h/mL and 51.42 ng/mL). Generally, study treatments were well tolerated with no reported serious adverse events; 1 subject discontinued due to liver function test abnormalities after receiving rifampin alone for 7 days in Period 2.
Conclusions
Treatment with multiple doses of rifampin with palbociclib decreased total (AUCinf) and peak (Cmax) palbociclib exposure by approximately 85% and 70%, respectively, versus palbociclib alone. Palbociclib was well tolerated when administered alone or in combination with rifampin. Based on these results, concurrent administration of palbociclib with strong CYP3A inducers should be avoided.
Citation Format: Justin T. Hoffman, Anna Plotka, Melissa O'Gorman, Andrew Chang, Maha Kosa, Cho-Ming Loi, Corrado Gallo-Stampino, Diane D. Wang. A phase 1 randomized, open-label, fixed-sequence, 2-period study of the effect of multiple doses of rifampin on palbociclib (PD-0332991) pharmacokinetics in healthy volunteers. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 4515. doi:10.1158/1538-7445.AM2015-4515
Abstract 4529: Pharmacokinetics (PK) of LOXO-101 during the first-in-human Phase I study in patients with advanced solid tumors: Interim update
Authors: Burris Howard A. , Shaw Alice T. , Bauer Todd M. , Farago Anna F. , Doebele Robert C. , Smith Steven , Nanda Nisha , Cruickshank Scott , Low Jennifer A. , Brose Marcia S. 
Published: August 2015

Abstract
Background
LOXO-101 is the first highly selective and potent small-molecule inhibitor of TRKA, TRKB, and TRKC to be dosed clinically. It has approximately 100-fold selectivity over other kinase and non-kinase targets. We report here the interim results of the first-in-man Phase I study which evaluates the safety, maximum-tolerated dose (MTD), and PK of LOXO-101 in patients with advanced solid tumors.
Methods
This is an ongoing open-label, multicenter, 3+3 dose escalation Phase I study of LOXO-101. Patients with solid tumors refractory to standard therapy, with normal hematopoietic and major organ function were eligible for study. LOXO-101 was administered orally as a single dose, followed by QD or BID doses for continuous 28-day cycles. Receptor occupancy was determined with an Emax model based on unbound LOXO-101 plasma concentrations.
Results
To date, data are available for 8 patients including patients treated at each of the first two dose levels, 50 mg QD and 100 mg QD. LOXO-101 has been well tolerated; the MTD has not been reached and no adverse events have been reported more than once other than fatigue (two patients; related but not serious) and syncope (two patients; unrelated and serious).
Maximum plasma concentrations of LOXO-101 were reached 30-60 minutes following dosing and exposure increased in approximate proportion with dose. Mean values of Cl/F, V/F, and half-life were 0.5 L/h/kg, 2 L/kg, and 3.5 h, respectively, and were independent of dose. Exposure was similar following the single dose and on Day 1 and Day 8 of repeated dosing in all subjects. The unbound drug levels of LOXO-101 appear sufficient for approximately 98% inhibition of TRKA/B/C at peak concentrations with once-daily dosing of 50 or 100 mg.
Conclusions
LOXO-101 has been well tolerated and has sufficient systemic exposure for robust inhibition of the TRKA, TRKB, and TRKC kinases without inhibition of other kinases. With dose escalation continuing, additional data and follow up will be provided at time of presentation.
Citation Format: Howard A. Burris, Alice T. Shaw, Todd M. Bauer, Anna F. Farago, Robert C. Doebele, Steven Smith, Nisha Nanda, Scott Cruickshank, Jennifer A. Low, Marcia S. Brose. Pharmacokinetics (PK) of LOXO-101 during the first-in-human Phase I study in patients with advanced solid tumors: Interim update. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 4529. doi:10.1158/1538-7445.AM2015-4529
Abstract 4556: Identification of novel agent for HCC treatment by GNMT-promoter orientated cell-based drug screening platform
Authors: Kant Rajni , Tung Lucas , Lu Chung-Kuang , Chen Yi-Ming , Yen Chia-Hung 
Published: August 2015

Abstract
Glycine N-methyltransferase (GNMT) a tumor suppressor gene for hepatocellular carcinoma (HCC) plays very important role in liver detoxification and tumorigenisis. GNMT expression is highly down-regulated in HCC. Recent studies have shown that overexpression of GNMT reduce tumor growth and sensitize HuH-7 cells to rapamycin treatment in vitro and in vivo. Therefore, enhancing GNMT expression is an attractive approach for HCC therapy. In present study we developed a GNMT-promoter driven luciferase reporter assay as a drug screen platform for the identification of novel drugs for prevention and treatment of HCC. We identified crude extract 317 as highest activator of GNMT promoter activity from a Chinese medicine library containing 472 herbal extracts. Partial purified fraction “F2-6” was isolated by bioassay-guided fractionation from crude extract 317 and validated for enhancement of endogenous GNMT expression at both mRNA and protein levels. Fraction F2-6 inhibited growth of liver cancer cell lines in vitro. Moreover, orally administrated F2-6 can delay and reduce growth of HCC xenograft tumor in vivo. Next, we identified the active component in fraction F2-6 named as compound P. Furthermore, we demonstrated that combination of sorafenib with compound P led to additive toxicity on HCC cells in vitro and in vivo. The cDNA microarray and real time PCR analysis showed that compound P altered cell cycle-associated genes such as CDK6, CCND1, CDKN1C, MYC and PLK1. Finally, Compound P treatment induced apoptosis in huh7 cells were confirmed by increased sub-G1 population and caspase 3/7 activity. Collectively, our results suggest that compound P has potential to be a novel agent for prevention and treatment of HCC.
Citation Format: Rajni Kant, Lucas Tung, Chung-Kuang Lu, Yi-Ming Chen, Chia-Hung Yen. Identification of novel agent for HCC treatment by GNMT-promoter orientated cell-based drug screening platform. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 4556. doi:10.1158/1538-7445.AM2015-4556
Abstract 4568: Inhibition of autophagy in EBV-positive Burkitt's lymphoma cells enhances EBV lytic genes expression and replication
Authors: De Leo Alessandra , Colavita Francesca , Ciccosanti Fabiola , Fimia Gian Maria , Lieberman Paul , Mattia Elena 
Published: August 2015

Abstract
Autophagy, an important degradation system involved in maintaining cellular homeostasis, serves also to eliminate pathogens and process their fragments for presentation to the immune system. Several viruses have been shown to interact with the host autophagic machinery to suppress or make use of this cellular catabolic pathway to enhance their survival and replication. Epstein Barr virus (EBV) is a γ-herpes virus associated with a number of malignancies of epithelial and lymphoid origin in which establishes a predominantly latent infection. EBV lytic cycle characterized by the sequential expression of immediate early (IE), early and late antigens results in the production of infectious particles which allow the virus to spread. In this study we analyzed the relationship between EBV and autophagy after inducing the virus productive cycle in Burkitt's lymphoma (BL) cells. By monitoring autophagy markers and EBV lytic genes expression, we demonstrate that autophagy is enhanced in the early phases of EBV lytic activation but decreases thereafter concomitantly with increased levels of EBV lytic proteins. In a cell line defective for late antigens expression, we found an inverse correlation between EBV early antigens expression and autophagosomes formation indicating that early after activation, the virus is able to suppress autophagy. We report that inhibition of autophagy by Bafilomycin A1 or shRNA knockdown of beclin1 gene, enhance EBV lytic genes expression as well as intracellular viral DNA and viral progeny yield. Taken together, these findings indicate that viral replication induces an autophagic response which can inhibit the further expression of EBV early lytic products. Moreover, our findings open the possibility to utilize pharmacological modulators of autophagy to control EBV infection and treat EBV-related lymphomas.
Citation Format: Alessandra De Leo, Francesca Colavita, Fabiola Ciccosanti, Gian Maria Fimia, Paul Lieberman, Elena Mattia. Inhibition of autophagy in EBV-positive Burkitt's lymphoma cells enhances EBV lytic genes expression and replication. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 4568. doi:10.1158/1538-7445.AM2015-4568