International Cancer Study & Therapy Conference
April 4-6, 2016   Baltimore, USA
Day 1 : 04:04:2016

Keynote Forum

Gregory Hess

University of Pennsylvania & 2Symphony Health Solutions Horsham, USA
Keynote:
Improving patient data quality by integrating oncology practice and state cancer registry tumor staging information: Feasibility and future value

Biography :

Gregory Hess currently serves as EVP & Chief Medical Officer (CMO) at Symphony Health Solutions – formerly Chief of Clinical Informatics. He also practices clinically at the CVIM Clinic in West Chester and teaches at the Drexel University College of Medicine Philadelphia. His academic appointments include Senior Fellow at the University of Pennsylvania Leonard Davis Institute for Health Economics. He also serves as Chair of ASCO’s CancerLinQ Data Advisory Committee.

Previously Dr. Hess was CMO, Global Health Economics & Outcomes Research and for the US Business at IMS Health, VP for Health Economics & Outcomes Research and Chief Medical Officer at SDI (acquired by IMS). Additional positions have included SVP of CareScience, Inc., worldwide VP and Managing Director of Market Economics for SmithKline Beecham Pharmaceuticals, and Director for clinical research at the Sandoz Research Institute. Before joining the private sector, Dr. Hess was a member of the Bush Sr. administration. In addition to a White House Fellowship, successive positions included various senior advisory roles, and serving with the President’s Council on Competitiveness. Working as Liaison for FDA, EPA, and other Departments, his work focused on environmental issues, health affairs, health care delivery, and human health risk assessment.

Abstract :

Background: The transition in oncology to electronic charting offers the potential to improve the quality of patient care and value of observational research. Data fields that are more complete, have common standards, and are searchable are critical to help meet these goals. As a key data field, and proof-of-concept we studied the additional gain in recorded stage and agreement in cancer staging by adding ‘missing’ stage information into an oncology practice’s electronic medical records (EMR) from a state cancer registry.

Methods: In this observational study, patient records were matched and compared between a practice-based (EMR) database (Georgia Cancer Specialists [GCS]) and a state cancer registry (Georgia Comprehensive Cancer Registry [GCCR]). Impact on recorded cancer stage following a merge of the EMR and registry data was assessed. Eligible patients had 1 visit to any GCS practice site during the study period (1/1/200512/31/2008) and had a diagnosis of a primary, malignant solid neoplasm (except brain or spine).

Results: The final sample included 38,248 patients from GCS files, with 13,486 matched to patients with a solid malignant tumor in the GCCR files. There were 3,424 (25%) patients without staging information prior to GCCR integration, which was reduced to 12% after GCCR integration - a relative gain of 52%. Differences between initial GCS stage and initial GCCR stage occurred in 45% of the sample, and varied by cancer type.

Conclusions: Adding information from external data sources can help create more complete patient records. The concept is feasible and has the potential to improve data quality. Patient data collected in different systems for different reasons will often be discordant.

Keynote Forum

Mahin Khatami

Aging and Cancer Research; National Cancer Institute, NIH, USA
Keynote:
Multistep ‘accidental’ discoveries: Role of inflammation in altering immune responses toward tumorigenesis and angiogenesis

Biography :

Professor Mahin Khatami received her PhD on Molecular Biology from University of Pennsylvania (UPA) in 1980. She was a researcher and faculty of medicine at UPA involved in cell/molecular biology of diabetic retinopathy/maculopathy and ocular inflammatory diseases. In 1998, at National Cancer Institute (NCI)/NIH she was program director, involved in concept development for molecular diagnosis and prevention of cancer for large clinical trials (PLCO). At NCI, extension and promotion of her earlier discoveries initially met with severe opposition and denial. However, she awakened the cancer community to the importance of inflammation in cancer research and immunotherapy. In the last decade numerous funded programs have focused on the topic that she promoted. In 2009, she retired from NCI, as director of IMAT program and assistant director of technology program development, OTIR/OD/NCI, at professor level.  Since her retirement, Dr. Khatami continued extension of her pioneering studies in several articles, edited 2 books on inflammatory diseases and cancer; involved in editorial activities; international lectures and collaborations.

Abstract :

Factors involved in failed cancer targeted therapies include lack of systematic and logical understanding of the loss of immune surveillance that control growth of cancer or other chronic diseases. In 1980’s we established models of acute and chronic inflammatory diseases that included tumorigenesis and angiogenesis. We demonstrated multistep interactions and synergies between host immune cells (e.g., mast, goblet & B cells) and recruiting cells (e.g., eosinophils, TAMs) during altered immune dynamics and induction of tumors in conjunctival-associated lymphoid tissues.  Results of these studies became ‘accidental’ discoveries in cancer research and therapy.  Without being in cancer research in 1980’s, we presented systematic evidence on multiple first findings of early and late immune response dynamics toward tissue growth and angiogenesis.  In 2008, acute inflammation was defined as balance between two biologically opposing arms, Yin (tumoricidal) and Yang (tumorigenic) of immunity.  Chronic inflammation is loss of Yin-Yang and a common denominator in genesis of all age-associated diseases or cancer. Future research efforts should focus on systematic understanding of host-pathogen interactions that lead to carcinogenesis and to promote the Yin -Yang balance for effective immunity.  Outcomes are expected to hold real promise in our understanding of how cancer cells become threat to body and for translation of cancer biology into cost-effective drug designs and clinical trials.

Keynote Forum

Charles Streckfus

University of Texas School of Dentistry at Houston, USA
Keynote:
Salivary protein profiles for determining the efficacy of mantel cell lymphoma therapy

Biography :

Dr. Streckfus has over 100 peer-reviewed journal articles and has been invited to speak at numerous national and international conferences. He has received many honors and awards which include the prestigious President’s Award for Scientific Excellence, Presented by the International Society for Preventive Oncology, awarded atthe Pasteur Institute, Paris, France, the NIH Award of Merit for his statistical analysis of the NHANES III Study, the ADA recognition award for services on the Council of Scientific Affairs, the American Academy of Oral Medicine Service Award and the Mayor of Baltimore City Baltimore’s Best Award for rendering dental services to the underserved citizens of Baltimore. He was granted 4 patents for his work in breast cancer biomarker research all which were assigned to the University of Mississippi Medical Center and the University of Texas Health Science Center. He is the first dentist to ever receive funding from the Komen Breast Cancer Foundation.

Abstract :

Objective: The objective of this study was to compare the salivary protein profiles from an individual diagnosed with Mantel Cell Lymphoma (MCL) before, during, and after chemotherapy.

Methods: Saliva specimens were serially acquired from a volunteer patient prior, during, and after chemotherapy. Experimentally, the specimens were trypsinized and the peptide digests labeled with the appropriate iTRAQ reagent. Labeled peptides from each of the digests were combined and analyzed by reverse phase (C18) capillary chromatography on an LC-MS/MS mass spectrometer equipped with an LC-Packings HPLC. The Swiss-Proteome database was employed for protein identification.

Results: The results yielded 258 comparative salivary proteins between the baseline and post-treatment samples. Among the total number of proteins, 26 were significantly differentially expressed between the evaluations. The results of the study suggest salivary protein alterations secondary to MCL and that a number of the proteins were changed as a result of chemotherapeutic intervention implying that the treatment, from a proteomic perspective, was efficacious. However, there were protein signatures that were unchanged and remained differentially expressed.

Conclusions: The results of the study suggest that salivary protein alterations are altered secondary to MCL and may be useful in monitoring the efficacy of treatment. It is also interesting to observe that a number of the proteins were changed as a result of chemotherapeutic intervention; however, there were a number of proteins that were unaffected by the intervention implying that a patient may be in clinical remission, but not molecular remission leaving the patient vulnerable to future disease recurrence. The study proposes that salivary secretions may be used as a “real-time” in vivo model for studying MCL progression and treatment efficacy.

Session 1 : Cancer Etiology and Epidemiology & Vaccines and Cancer Prevention Mechanisms

Session Introduction

Aikaterini Kontrogianni-Konstantopoulos

University of Maryland School of Medicine, USA
Title: Giant obscurins: Novel tumor and metastasis suppressors in breast cancer

Biography :

Aikaterini Kontrogianni-Konstantopoulos received her Ph.D. from the Department of Cell Biology at Baylor College of Medicine in Houston, TX. After graduating from Baylor, she joined the laboratory of Dr. E.J. Benz, Jr., in the Division of Hematology, at Johns Hopkins University, School of Medicine as a post-doctoral fellow.  In  2007,  she  joined  the  Department  of  Biochemistry  and  Molecular  Biology  in  the University of Maryland School of Medicine as Assistant Professor, and in 2012 was promoted to Associated Professor.  Her research focuses on the elucidation of the roles of cytoskeletal and membrane-associated proteins as structural and signaling mediators. Using the muscle and epithelial cell as model systems, my laboratory has pioneered the molecular and functional characterization of the obscurin subfamily and its binding partner Myosin Binding Protein-C slow in health and disease. Her research has been funded by several organizations, including NIH, Muscular Dystrophy Association and American Heart Association.

Abstract :

Obscurins, encoded by the single OBSCN gene, are giant cytoskeletal proteins containing tandem adhesion and signaling domains, including an active RhoGEF motif that directly binds and activates RhoA. The OBSCN gene is highly mutated in breast cancer resulting in a 2-fold reduction of its mRNA levels. Consistent with this, obscurin proteins are nearly lost from breast cancer cell lines and human biopsies, independently of their hormonal status or molecular differentiation. Loss of giant obscurins from breast epithelial cells confers them with a survival and growth advantage following exposure to common chemotherapies. Obscurin-depleted breast epithelial cells fail to form adhesion junctions, undergo epithelial-to-mesenchymal transition and generate primary and secondary mammospheres bearing markers of cancer-initiating cells. Moreover, obscurin-deficient breast epithelial cells display markedly increased motility as a sheet in 2-dimensional (2D) substrata and individually in confined spaces, increased invasion in 3D matrices, and extend microtentacles mediating the attachment of circulating tumor cells to the endothelium, an advantage that persists even after paclitaxel treatment. More importantly, loss of giant obscurins from breast epithelial cells promotes primary tumor formation and lung colonization in vivo. These major phenotypic alterations appear to be the result of reduced RhoA activity and increased PI3K/Akt activity. Collectively, our findings reveal that loss of giant obscurins from breast epithelium results in disruption of cellcell contacts and acquisition of a mesenchymal phenotype that leads to enhanced tumorigenesis, migration and invasiveness in vitro and in vivo by affecting RhoA- and PI3K/Akt-mediated processes. In addition, our data suggest that loss of obscurins may represent a selective advantage for breast cancer cells during metastasis, and that treatment with paclitaxel may exacerbate this advantage by preferentially allowing obscurin-deficient stem-like cells to attach to the endothelium at distant sites, a first step towards colonizing metastatic tumors. To the contrary, treatment of obscurin-depleted breast cancer cells with PI3K inhibitors, currently in phase III clinical trials, appears to be highly beneficial by reducing their survival, growth, motility and invasive capabilities.

XiangLin Tan

Rutgers Cancer Institute of New Jersey, USA
Title: Targeting RET signaling pathway: a novel molecular mechanism of action of metformin in pancreatic cancer prevention and treatment

Biography :

Dr. Xiang-Lin Tan received a M.D. degree from Tongji Medical College, and a Ph.D in Epidemiology from German Cancer Research Center at Heidelberg University. He was a Postdoctoral fellow at Wadsworth Center and Albert-Einstein College of Medicine, and a Senior Research Fellow at Mayo Clinic. He is currently an Assistant Professor of Medicine and Epidemiology at Rutgers Cancer Institute of New Jersey. Dr. Tan’s current research is focusing on repurposing exiting drugs for prostate and pancreatic cancer prevention and treatment. He is an Editorial Reviewer Board member of several international journals, and reviewed articles for more than 10 peer-reviewed journals.

Abstract :

Pancreatic cancer (PaCA) is one of the most lethal human cancers and is the fourth leading cause of cancer-related deaths in the United States. However, there are currently no established recommendations for prevention of PaCA using pharmacological agents. Metformin has recently gained attention as an anti-cancer drug and/or a chemoprevention agent because of its effects on inhibiting mTOR, lowering hyperinsulinemia, modulating inflammatory responses, and selectively killing cancer stem cells. However, the key underlying molecular mechanisms for the inhibitory effects of metformin on PaCA progression remain largely unknown. Using RNA sequencing followed by the confirmation of RT-PCR and Western blotting, we found that metformin significantly decreased the mRNA and protein levels of RET (REarranged during Transfection), a single-pass transmembrane receptor tyrosine kinase (RTK). RET and its ligand, glial cell-derived neurotrophic factor (GDNF), are strongly expressed in PaCA and correlated to invasion and reduced survival after surgical resection. GDNF, as a chemoattractant for PaCA cells, can activate RET to induce tumor progression, migration and invasion in vitro and in vivo. We further demonstrated that metformin significantly inhibited GDNF-induced migration and invasion of PANC-1 cells. These data indicate that targeting RET with metformin or the combination of metformin and RET inhibitors may be an attractive and novel strategy for the prevention and treatment of PaCA progression and metastasis. To further examine the inhibitory effects of metformin on the growth and spread of PaCA tumors in humans, further in vitro and in vivo studies are warranted to investigate how metformin modulates RET signaling to inhibit the progression and metastasis of PaCA. Such studies have potential clinical significance using metformin as adjuvant preventive and therapeutic options for PaCA prevention and treatment.

Jiandi Zhang

Zestern Biotechnique LLC and Yantai Zestern Biotechnique Co. LTD, USA
Title: Zestern Analysis, from theory into practice in high throughput immunoblot analysis

Biography :

Jiandi Zhang received his Doctorate from Department of Cell Biology, Duke University with Drs. Yusuf Hannun and Lina Obeid on the lipid mediators and chemotherapeutic agent-induced apoptosis.  He went on to complete his postdoc training with Nobel Laureates Drs. Mike Brown and Joe Goldstein at UT Southwestern Medical Center working on IRS-2 and insulin signaling pathway.  Dr. Zhang continued to work on insulin signaling pathway and regulatory effect of SirT1 on this pathway with several independent publications.  In 2012, he patented Zestern technique as the improved immunoblot technique of Western blot and Dot blot analyses. Right now, he serves as the Founder and CEO of Zestern Biotechnique LLC to promote this technique in the field of protein analysis.  He believes the adoption of this technique in basic research and clinical studies would significantly improve the efficiency and accuracy of protein analysis over existing immunoblot methods.

Abstract :

The completion of the human genome projects marks the arrival of genomic research era, where genetic information is accumulated and analyzed in an unprecedentedly speed in the last decadesto significantly change the world of Cancer research.  In contrast, proteomic research in Cancer Research is clearly lagging behinddue to lacking of high throughput method in immunoblot analysis.  While antigen-antibody interaction serves as the basis of immunoblot research, it faces a long-lasting challenge of cross-reactivity of antibodies. In this talk, a novel method, Zestern analysis, is demonstrated to address this issue with clear advantages of simple, fast, specific and quantifiable, suitable for high throughput analysis of protein samples.  The method follows a standard dot blot protocol until the formation of immunocomplexon the membrane.  An elution step is added in Zestern analysis where a competing molecule based on the epitope of detecting antibody is used to liberate the detection antibody from the immunocomplex into elution solution for direct quantification.  A working system of Zestern analysis is shown in this talk where both the tagged and endogenous proteins were analyzed using this method under various experimental conditions.  Continuing exploration of this method may revolutionize the field of proteomic research with direct impact on high throughput immunoblot analysis to move the field of Cancer Research forward.

Alvaro Macieira

French National Institute of Health (INSERM), France
Title: The suppressive effect of organism senescence on cancers

Biography :

Dr. Alvaro Macieira-Coelho completed an MD at the University of Lisbon, Portugal, was an intern at the University Hospital, and completed a PhD at the University of Uppsala, Sweden. He was appointed Head of the Department of Cell Pathology, Cancer Institute, Villejuif, France and Research Director at the French National Institute of Health. He has authored 150 peer-reviewed articles and published nine books.
Awards: Fritz Verzar prize, University of Vienna; Doctor Honoris Causa, University of Linköping; Johananof International visiting professor, Mario Negri Institute, Milan; Seeds of Science Career prize, Lisbon.

Abstract :

Most scientific literature reports that aging favors the development of cancers. Each type of cancer, however, initiates and evolves differently, and their natural history can start much earlier in life before their clinical manifestations. The incidence of cancers is spread throughout human life span, and is the result of pre- and post-natal aggressions, individual susceptibility, developmental changes that evolve continuously throughout an individual's life, and time of exposure to carcinogens. Finally, during human senescence, the incidence declines for all cancers. Frequently, the progression of cancers is also slower in aged individuals. There are several possible explanations for this decline at the tissue, cell, and molecular levels, which will be described. It is time to ask why some tumors are characteristic of either the young, the aged, or during the time of a decline in the reproductive period, and finally, why the incidence of cancers declines late during senescence of human beings. These questions need to be addressed before the origin of cancers can be understood.

Waseem Khaliq

Johns Hopkins University, USA
Title: Prevalence and predictors of non-adherent to breast cancer screening: Perspective and preferences of hospitalized women

Biography :

Dr. Waseem Khaliq M.D, M.P.H is faculty at Johns Hopkins University School of Medicine, Baltimore. He earned his medical degree at King Edward Medical College, Pakistan and Master's in Public Health (MPH) from University of Minnesota, Minneapolis. He completed his medical training in medicine at University of Illinois, Urbana. His research interest includes breast cancer screening and treatment disparities, breast cancer risk stratification, and breast cancer chemoprevention. He has published several manuscripts and serves as an editorial board member and reviewer for many medical journals.

Abstract :

Disparities in screening mammography use persist among low-income women, even those who are insured, despite the proven mortality benefit. We evaluated the prevalence of breast cancer screening non-adherence among hospitalized women and their receptivity to inpatient screening mammography as a novel approach to increase breast cancer screening rate. A cross sectional study was conducted among 250 hospitalized women age 50-75 years, admitted to medicine service at Johns Hopkins Bayview Medical Center in early 2012. Approximately one-third of women enrolled were African American, and 61% of the study population reported an annual household income of < $20,000. 41% were overdue for screening, of which, 13% never had a mammogram. Thirty-two percent of the women were at high risk for breast cancer (Gail score ≥1.7%). The most commonly reported barriers to screening mammograms were failure to remember appointments, and lack of transportation. We also evaluated the socio-demographic and clinical comorbidities risk factors associated with non-adherence. After adjustment of all these predictors, three variables were found to be independently associated with non-adherence to breast cancer screening: low income (OR=3.81, 95%CI; 1.84–7.89), current or ex-smoker (OR=2.29, 95%CI; 1.12–4.67), and history of stroke (OR=2.83, 95%CI; 1.21–6.60). Although most women believed that it is important for healthcare providers to discuss breast cancer screening while patients are in the hospital, 72% were willing to pay out of pocket a mean of $83.41 (95% CI, $71.51-$95.31) in advance towards inpatient screening mammogram.

Conclusions: A significant number of hospitalized women from lower socioeconomic class are non-adherent and at high risk of developing breast cancer. Because hospitalization creates the scenario wherein patients are in close proximity to healthcare resources, at a time when they may be reflecting upon their health status, strategies could be employed to counsel, educate, and motivate these patients towards health maintenance.

Mohammad Obaidul Hoque

Johns Hopkins University, USA
Title: Targeting the YAP1/COX2/SOX2 signaling axis eliminates cancer stem cells in urothelial carcinoma

Biography :

Dr. Hoque is an Associate Professor of Otolaryngology-Head & Neck Surgery, Urology and Oncology at Johns Hopkins University School of Medicine. His major research interests includes:  a) To understand molecular biologic basis of head and neck, lung and genitourinary cancer b) To develop and validate genetic and epigenetic approach for early cancer diagnosis, cancer risk assessment and cancer prognosis and c) To identify molecular alterations due to environmental exposures such as active smoking, passive smoking and arsenic. He has published over 95 papers in reputed journals and has been serving as an editor and/or editorial board member of several bio-medical journals.

Abstract :

Bladder cancer stem/progenitor cells (CSC) contribute to tumor maintenance and resistance to therapy and accumulated evidence suggest that chronic carcinogen exposure induce “stemness” in different in vitro and in vivo models. Therapeutic targeting of CSCs could improve treatment response and prolong patient survival. Here we used our recently published in vitro chronic arsenic (As) exposed models to characterize the property of bladder CSC due to As exposure.  We hypothesized that urothelial stem cells have a survival selection advantage during carcinogen exposure such as As, and it facilitates their malignant transformation and in acquiring selective phenotypes similar to CSC.

As-exposed cells displayed more aggressive phenotype than As unexposed cells in a time dependent manner. In gene set enrichment analysis of expression array of chronic As exposed and unexposed cells; EGFR, COX2 and YAP1 were top-ranked oncogenic signature based on enrichment score in As-exposed cells. Further analysis indicated that several known basal cell markers were overexpressed in As exposed cells in comparison with As unexposed cells. Because the presence of urothelial CSCs in basal-type provides a biological explanation for their aggressive behaviors, we assessed the influence of As on generating CSC phenotypes. Our results showed that As exposure was associated with overabundance of potential CSCs characterized by sphere formation, self-renewal capacity, redifferentiation, and chemotherapy resistance. To explore global association of As exposure and CSC generation, we used the Human Stem Cell RT² Profiler™ PCR Array and found that SOX2 has been gradually overexpressed in line with acquired spheroid formation and self-renewal capacities. Moreover, SOX2 mRNA expression was significantly higher UC cell lines and As exposed cells, especially in the spheroid cells; and in urine from As exposed normal than from controls. Stable silencing of SOX2 reduces in vitro CSCs properties and also in vivo tumorigenicity. COX2 and YAP1 are also frequently overexpressed in UC cell lines, and inhibition of COX2 or YAP1 reduced SOX2 expression. Interestingly, the inhibition of COX2 and YAP1 expression inversely induced YAP1 and COX2 expression, respectively which also reflect in primary UC tumors. Combination treatment with COX2 and YAP1 inhibitors reduced SOX2 expression and suppressed spheroid formation significantly than single agent. In conclusion, chronic As exposure induces CSCs with SOX2 overexpression, an important CSC factor for UC. COX2 and YAP1 coordinately regulate SOX2 expression, and mutually compensate for the reduction of expression of SOX2 to maintain CSCs. Thus targeting the COX2/YAP/SOX2 signaling axis eliminates urothelial CSCs. 

Ashok Jain

Albany State University, USA
Title: Diet and breast cancer: Understanding molecular interaction of phytochemicals and PhIP induced cytotoxicityin breast epithelial cells

Biography :

Dr. Ashok Jain is a professor of biology at Albany State University, Albany, GA and program coordinator for Biotechnology program. Dr. Jain has received research funding from NIH, DOD and USDA. Dr. Jain is also serving as MARC U*STAR project director.  His research focuses on prevention of breast cancerHe has published more than 35 papers in reputed journals and has been serving as reviewer for six journals of international repute.

Abstract :

Cooking of meat at high temperature such as frying or barbeque causes production of heterocyclic amines (HCAs). At least a dozen of HCAs are found in cooked meat. The 2-amino-1-methyl-6-phenylimidazo[4-5-b]pyridine (PhIP) is abundant and most potent HCA.Several studies have shown that PhIP can induce tumors in breast, prostate and colon cells and in rodent models. It is shown that PhIP causes DNA mutation, promote tumor growth and promote invasiveness of cancer cells. Metabolism of PhIP results in the formation of free radicals (ROS) and PhIP metabolites are known to produce DNA adduct and DNA strand breaks. Phytochemicals are known to inhibit cytotoxic and genotoxic effects. Therefore, we hypothesized that the right combination of antioxidants and or phytochemical (naturally present in fruits, vegetables and spices) along with grilled meat should be capable of suppressing the PhIP induced cytotoxicity and breast cancer. Therefore, a model system using human breast epithelial cells (MCF 10A) was developed to test various antioxidants in presence or absence of PhIP. We have tested four vitamin (C, K3, D3, and E), Gingerol (6 and 10), N-acetyl cysteine, glutathione and curcumin at varying concentrations. The protective effect of these compounds was evaluated using cell viability assay, DCF assay to quantify ROS production, Comet assay to quantify the DNA damage and DNA adduct formation by immunofluorescence method. Results indicate that presence of these compounds improves cell viability as compared to PhIP treated group. However, curcumin co-treated cells showed significant differences and PhIP induced cell cytotoxicity was consistently reverted to normal. Gene expression analysis indicates that curcumin interact via multiple molecular targets, suggesting that curcumin appears to be an effective anti-PhIP food additive.

Jiang Cao

The 2nd Affiliated Hospital, Zhejiang University School of Medicine, China
Title: Non-translation initiation functions of eIF3g in breast cancer

Biography :

Jiang Cao obtained his PhD degree from Zhejiang Medical University (now Zhejiang University School of Medicine). He is currently working in Clinical Research Center, the 2nd Affiliated Hospital, Zhejiang University School of Medicine. His research focuses on the molecular mechanisms involved in development and progression of cancer and has published more than 40 papers in reputed journals.

Abstract :

Translation Eukaryotic translation initiation factors (eIFs) are important for protein synthesis of both normal and malignant cells. Deregulated protein synthesis may promote cell growth, proliferation, invasion and metastasis which lead to the development and progression of cancer. As the largest and the most complicate eIF, eIF3 is the core protein complex which cooperates with other eIFs and plays an important role in the initiation of protein synthesis. EIF3is composed of 13 subunits, and only subunits eIF3a, 3b, 3c, 3e, 3f and 3h are indispensable for the core function of eIF3, while other subunits may possess other functions than translation initiation. Aberrant expressions of eIF3 subunits in various tumors have been observed and nuclear localization of eIF3a, 3e and 3k have been reported. Recent studies showed that eIF3g also plays roles in the cytoskeleton network and caspase-mediated apoptosis. We previously found that eIF3g was significantly up-regulated in the multidrug resistant K562 leukemia cells (K562/ADR).In our current work, we found that eIF3g is also up-regulated in breast cancer cell that are multidrug resistant. We further investigated the nuclear distribution of eIF3g and identified nuclear proteins that may interact with eIF3g in breast cancer cells by co-immuno precipitation and mass spectrometry, and confirmed by cross linking and confocal co-localization observation. These findings indicate that eIF3g also has non-translation initiation functions in breast cancer. (Sponsored by grant from National Natural Science Foundation of China 81172516)

Patrik Andersson

Karolinska Institute, Sweden
Title: VEGF-B promotes cancer metastasis through a VEGF-A– independent mechanism and serves as a marker of poor prognosis for cancer patients

Biography :

Patrik Andersson received his B.Sc. at the age of 21 within biomedical sciences and is now pursuing his Ph.D. studies on the topic of tumor lymph- and heme angiogenesis in promoting metastasis. He is receiving his training at the Karolinska Institutet, Sweden under the supervision of Professor Yihai Cao. He was invited as a speaker at the prestigious Gordon Conference in angiogenesis (2013) and at the International Cancer and Prevention methods conference (2015). He has obtained several research and travel grants, and has co-authored ten peer-reviewed articles either published or under current revision.

Abstract :

The biological functions of VEGF-B in cancer progression remain poorly understood. Here, we report that VEGF-B promotes cancer metastasis through the remodeling of tumor microvasculature. Knockdown of VEGF-B in tumors resulted in increased perivascular cell coverage and impaired pulmonary metastasis of human melanomas. In contrast, the gain of VEGF-B function in tumors led to pseudonormalized tumor vasculatures that were highly leaky and poorly perfused. Tumors expressing high levels of VEGF-B were more metastatic, although primary tumor growth was largely impaired. Similarly, VEGF-B in a VEGF-A–null tumor resulted in attenuated primary tumor growth but substantial pulmonary metastases. VEGF-B also led to highly metastatic phenotypes in Vegfr1 tk−/− mice and mice treated with anti–VEGF-A. These data indicate that VEGF-B promotes cancer metastasis through a VEGF-A–independent mechanism. High expression levels of VEGF-B in two large-cohort studies of human patients with lung squamous cell carcinoma and melanoma correlated with poor survival. Taken together, our findings demonstrate that VEGF-B is a vascular remodeling factor promoting cancer metastasis and that targeting VEGF-B may be an important therapeutic approach for cancer metastasis.

Session 2 : Cancer Drug Discovery and Development

Session Introduction

Mine Yarim

Yeditepe University, Turkey
Title: Novel benzothiazole-piperazine derivatives with anticancer activity

Biography :

Professor Yarim has completed his Ph.D from Hacettepe University and postdoctoral studies from ETH-Zürich. Professor Yarim has studied anticancer drug design and she has authored several peer-reviewed reports. She has served on numerous review committees for the National Science Foundation in Turkey. She has served on the editorial boards for the Pharmacologia. She is a member of the QSAR Society.

Abstract :

New series of benzothiazole-piperazine derivatives are synthesized and their cytotoxic activities are evaluated on colorectal (HCT-116), breast (MCF-7) and hepatocellular (HUH-7) cancer cell lines by sulforhodamine B assay. Results are compared with 5-fluorouracil as reference compound.
Dihalo substituted compounds BTP-2 (N-(6-ethoxybenzothiazole-2-yl)-2-[4-(2,6-dichlorobenzyl)piperazinyl]acetamide) (HCT-116:GI50 =0.4 µM; HUH-7: GI50 =0.7 µM; MCF-7: GI50 =2.6 µM) and BTP-7 (N-(6-ethoxybenzothiazole-2-yl)-2-[4-(4-bromo-2-fluorobenzyl)piperazinyl]acetamide)(HCT-116:GI50 =0.9 µM; HUH-7: GI50 =0.3 µM; MCF-7: GI50 =12.2 µM) are found to have highest cytotoxic activities in all studied cancer cell lines.

Hiroshi Kobayashi

Chiba University, Japan
Title: Superiority of anti-cancer drugs specific to acidic cancer nests

Biography :

Hiroshi Kobayashi received his Ph.D. in Biochemistry from University of Tokyo in 1974. After his postdoctoral training at Colorado University Medical Center, he started to study adaptation strategies of microorganisms to acidic environments at Chiba University in 1978. His recent research is focused on mammalian cell functions under acidic conditions from 1996 at Graduate School of Pharmaceutical Sciences, Chiba University. He retired in March 2012 and is now Professor Emeritus at Chiba University. He works as an associate editor of International Immunopharmacology published by Elsevier B.V. from 2014.

Abstract :

Solid cancer nests are acidified below pH 6.5, although normal tissues and blood are usually maintained at pH around 7.4 in mammals. Such acidification of cancer nests may change the efficacy of anti-cancer drugs when their target molecules are enzymes whose activity is dependent on pH. We measured the inhibitory effect of approximately 300 compounds at pH 6.7 and 7.5, and five compounds, lovastatin, cantharidin, manumycin A, doxorubicin, and ionomycin, showed a high activity to inhibit cancer cell proliferation at pH 6.7, while their inhibitory effect was very low at pH 7.5. We focused our work on statins because clinical investigations had already revealed the therapeutic effect of statins on human cancers. It has been reported recently that statins inhibit cancer growth in mice. Statins have been used as a drug against hyperlipidemia because statins inhibit cholesterol synthesis and no effect on cancer cell proliferation had been reported in vitro until our study. Our further investigations have revealed that the inhibition of cell proliferation by statins is caused by the decrease in the synthesis of geranylgeranyl diphosphate used for protein prenylation but not in cholesterol synthesis. Statins are generally accepted to be a safe drug without serious side effects, such as immune system dysfunction. Our data showed that the inhibitory effect of statins on immune cells is negligible in medium whose pH is close to blood pH. These results suggest that anti-cancer drugs specific to acidic areas are useful for cancer chemotherapy with low side effects. We found that the expression of approximately 700 genes was elevated at acidic pH, suggesting that many other anti-cancer drugs whose efficacy increases in acidic cancer nests could be found besides statins. Our in vitro assay method may promote exploitation of new anti-cancer drugs specific to acidic areas, which improves cancer chemotherapy.

Andrei L. Gartel

University of Illinois at Chicago, USA
Title: Targeting FOXM1 in cancer

Biography :

Andrei L. Gartel, PhD, is an Associate Professor in the Department of Medicine at the University of Illinois at Chicago, and is the academic editor of PLOS ONE. He is the author of 86 peer-review publications that include more than 20 reviews. He has more than 8500 citations and his h-index is 36. His scientific interests include cancer, cell cycle, protein-protein interactions, regulation of CDK inhibitor p21 and regulation of oncogenic transcription factors FOXM1, and c-Myc.  Specifically his lab is interested in identification of new FOXM1 inhibitors. He received his funding from NIH, DOD and private companies/foundations.

Abstract :

FOXM1 is an oncogenic transcription factor that is overexpressed in majority of human cancers and it is a potential target for anticancer drugs.  We identified proteasome inhibitors as the first type of drugs that target FOXM1 in cancer cells. Moreover, we found that HSP90 inhibitor PF-4942847 that does not act as proteasome inhibitor also suppresses FOXM1. Chaperone HSP70 is induced after treatment with both proteasome/HSP90 inhibitors and after heat-shock stress and we identified this chaperone as a novel negative regulator of FOXM1 after proteotoxic stress. We showed that FOXM1 and HSP70 interact in cancer cells following proteotoxic stress and FOXM1/HSP70 interaction led to inhibition of FOXM1 binding to target gene promoters, including its own (auto-regulation loop).  Inhibition of FOXM1 transcriptional auto-regulation by HSP70 leads to suppression of FOXM1 protein expression because of its auto-regulation. Therefore, we propose here that HSP70 is the universal negative regulator of FOXM1 after proteotoxic stress. In contrast, HSP70 inhibition increased FOXM1 expression and simultaneous inhibition of FOXM1, and HSP70 dramatically augmented the sensitivity of human cancer cells to apoptosis induced by different anticancer drugs.  Our study advocates exploring the combination of FOXM1 and HSP70 inhibitors as potential therapeutics for cancer treatment.  Overall, our results suggest that HSP70 chaperone induced by proteotoxic stress inhibits FOXM1 oncogene by previously unknown mechanism.

Miral Dizdaroglu

The National Institute of Standards and Technology (NIST), USA
Title: Inhibitors of DNA glycosylases as potential therapeutic drugs in cancer

Biography :

Dr. Dizdaroglu has obtained his PhD at the Karlsruhe Technical University, Germany, and subsequently worked for seven years at the Max-Planck-Institute for Radiation Chemistry, Germany, before moving to US in 1978. He has been at the National Institute of Standards and Technology (NIST) for more 30 years. In 2006, Dr. Dizdaroglu was conferred upon the rank of NIST Fellow. He published more than highly cited 230 papers. Dr. Dizdaroglu received numerous scientific awards including the Hillebrand Prize of the American Chemical Society and the Gold Medal Award of the US Department of Commerce. He was also awarded two Honorary Doctorates.

Abstract :

Ionizing radiation and most chemotherapeutic agents kill tumor cells by damaging DNA. The efficacy of DNA-damaging agents may be influenced by increased DNA repair capacity in tumors that results from overexpression of DNA repair proteins. Inhibition of activities of these proteins in tumors is a promising approach to enhance the efficacy of DNA damage-based therapy. Intense efforts are underway worldwide to find inhibitors of DNA repair proteins.Of these proteins, DNA glycosylases are involved in the first step of base excision repair mechanism by removing modified DNA bases. Despite the successes with other proteins of this repair pathway, the development of inhibitors has been lagging for DNA glycosylases. Recently, several DNA glycosylases including NEIL1, OGG1 and NTH1 were identified as potential targets in combination therapeutic strategies. We designed experiments to discover small molecule inhibitors of NEIL1 as the proof-of-principle glycosylase. A fluorescence-based assay was developed to detect both glycosylase and AP lyase activities of NEIL1.We screened small molecule libraries for inhibitors of NEIL1 activities. Several purine analogs were found, whose postulated presence in the active site of NEIL1 fits with the paradigm of NEIL1 action on damaged purines. We also applied gas chromatography/isotope-dilution tandem mass spectrometry to measure the effect of small molecule inhibitors on glycosylase activities of NEIL1, OGG1 and NTH1. The release of modified DNA bases known as substrates of these enzymes was measured in the presence and absence of the inhibitors. These data revealed that several of the purine analogs were general glycosylase inhibitors with one compound being the most effective inhibitor for all three enzymes. However, there were significance differences in inhibition of enzymatic activities among these DNA glycosylases. Overall, this work forms the foundation for the future discovery of DNA repair inhibitors as drugs in cancer therapy for the entire family of DNA glycosylases.

Juan Jose Marugan

National Center for Advancing Translational Sciences, NIH, USA
Title: Metarrestin blocks metastasis by impairing a new function of EEF1A involved in modulation of ribosomal biogenesis

Biography :

Dr. Juan Marugan has been involved for more than 20 years in translational sciences, with extensive experience as a team leader of programs at lead optimization stage, many of which have been licensed to pharmaceutical companies, producing also several molecules that advanced toward pre-clinical development and clinical trials. His job responsibilities include lead discovery and optimization with early ADME and pharmacokinetics profiling, managing internal and external resources, structure-activity relationship optimization, chiral separation, and in vivo studies. He is also very familiar in other areas of translation such as structure-based drug design, high-throughput screening, enzymatic and cell assays, and in vivodisease models.
Dr. Marugan serves since 2008 as team leader within the division of preclinical innovation of NCATS. Previously he held positions of increase responsibilities in several pharmaceutical companies from research scientist to head of pre-clinical drug research.

Abstract :

In the last decade a number of studies have indicated the importance of ribosomal biogenesis as a fundamental process controlling epithelial to mesenchymal transition (EMT) both during embryogenesis and cancer development. Studies toward understanding the underlying mechanisms responsible of neurocristopathies and metastasis have shown that the up-regulation of ribosomal biogenesis is important for promoting efficient EMT, migration and invasion. One cellular marker of metastatic potential is the perinuclear compartment (PNC), a unique structure adjacent to the nucleolus which indicates an elevated state of transcription and assembly of ribosomal components, and correlates clinically with metastasis of solid tumors.Screening and optimizing for disassemblers of the PNC, we identified metarrestin, a well-tolerated orally-bioavailable small molecule able to block metastasis in three different mouse cancer xenograft models of breast, prostate and pancreatic human cancers. In vitro, Mearrestin blocks migration and invasion of metastatic tumoral cells at nontoxic doses. Pull down studies identified EEF1A (EEF1A1 and EEF1A2) as the main binding partner of metarrestin. We then sought to validate this target by through siRNA treatments, evaluation of the levels of nascent pre-rRNA, visualization of nucleolar structure changes by immunofluorescence of key proteins. The results indicated that metarrestin blocks a previously unknown function of EEF1Ainvolved inthe up-regulation of the transcriptional activity of RNA Polymerase I. Metarrestin’s modulation of Pol I-EEF1A-dependent function impacts ribosome synthesis and nucleolar structure without affecting other classical functions of this protein such as its role in translation elongation and protein synthesis. Our studies represent a broad and novel way to block the progression of tumorgenesis toward metastasis and open the door to the development of a new generation of nontoxic anticancer agents specifically blocking metastasis.

Audrey Claing

Université de Montréal, Canada
Title: ARF proteins are key molecular switch controlling breast cancer invasiveness

Biography :

Dr. Claing received her PhD in Pharmacology from the Université de Sherbrooke, in Canada. She then joined the laboratory of Robert J Lefkowitz at Duke University as a post-doctoral fellow where she began to be interested in the function ARF proteins plays in mediating receptor-mediated cellular responses. She is currently professor of Pharmacology at the Université de Montréal. Her research team studies the molecular basis of cell migration and proliferation, with emphasis on the basic mechanism by which ARF proteins controls intracellular signaling. She is recognized for her pioneering research aimed at unraveling the function of ARF1 in breast cancer.

Abstract :

Triple-negative breast cancers (TNBC) are a highly invasive type of breast cancer and associated with poor prognostic. The Epidermal Growth Factor Receptor (EGFR)is overexpressed and regulates cellular proliferation as well as invasiveness. Drugs inhibiting its activity have however shown limited effects mainly due to the development of resistance. There is therefore a need to identify new therapeutic targets for the design of alternative therapies.We and others have shown that the Ras-related ADP-ribosylation factors (ARF) are another class of small GTPases regulating key features of cancer cells. Here, we report that ARF1 is highly expressed in cells and tumor tissue of the most aggressive and advanced subtypes of breast cancers. Knock down of ARF1 expression impairs the ability of breast cancer cells to proliferate, migrate and degrade the extracellular matrix. Furthermore, growth of primary tumors as well as lung metastasis is reduced in a murine xenograft model when expression of the GTPase is inhibited. To understand how ARF1 contributes to invasiveness, we used a poorly invasive breast cancer cell line, MCF7 (ER+), and examined the effects of overexpressing ARF1 to levels similar to that found in invasive cell lines. Our findings demonstrate that increased levels of ARF1 lead to the epithelial-mesenchymal transition (EMT). Mechanistically,ARF1 controls cell–cell adhesion through ß-catenin and E-cadherin. In addition, this GTPase promotes oncogenic Ras activation and expression of EMT inducers such as snail and slug. We further show that ARF1 overexpression enhances MCF7 cell invasion, proliferation and even resistance to treatment with the chemotherapeutic agent, etoposide. In vivo, ARF1 overexpressing MCF7 cells are able to form more metastases to the lung. Overall, our results identify ARF1 as a molecular switch of cancer progression and thus suggest that limiting the expression/activation of this GTPase could help improve outcome for breast cancer patients.

Zhibin Wang

Johns Hopkins University, USA
Title: Synergistic and coordinated actions of three DNMT enzymes for the establishment and maintenance of DNA methylation patterns

Biography :

Dr. Zhibin Wang obtained his Ph.D from the Ohio State University. He started his biomedical research with the development of chromatin immunoprecipitation plus deep sequencing (ChIP-seq) method in the National Heart, Lung, and Blood Institute. His pioneering reports shed lights on what kind of “histone code” in the human genome and revealed the binding of corepressor histone deacetylase (HDAC) for active genes instead of broadly accepted silent genes. The resulting concept changes are important for the understanding/development/application of HDAC inhibitors in the treatment of cancers. New model for the establishment and maintenance of DNA methylation patterns also helps the application of the DNMT inhibitor drugs for cancers.

Abstract :

Abnormal DNA methylation patterns including global hypomethylation and focal promoter hypermethylation are hallmarks of cancer cells. Global hypomethylation and promoter hypermethylation of tumor suppressor genes contribute to the cancer biogenesis. However, it remains to be determined how cancer cells obtain these abnormal methylation patterns and how such patterns exactly contribute to oncogenesis. Currently, it has been broadly accepted that de novo DNA methyltransferases 3a/3b (DNMT3a/3b) methylate the unmethylated cytosines to initiate the methylation patterns in the genome of early embryos, and subsequently, these patterns are faithfully copied from parental strands to daughter strands during DNA replication by maintenance DNMT1. This ‘two-step’ model highlights the importance of DNMT1 maintenance in transmitting epigenetic information to next generations of cells. Because of this importance, inhibitor drugs specifically targeting DNMT1 have been developed and used in clinical trials. Despite promising results against hematologic malignancies, the efficacy of DNMT1 inhibitors in solid tumors has been “disappointing”, raising the concern of the guiding ‘two-step’ model.

To determine the mechanism of the establishment and maintenance of DNA methylation patterns, we have examined genome-wide DNA methylation patterns in mouse embryonic stem (ES) cells and DNMT-deficient ES cells. Indeed, investigations suggest that both maintenance DNMT1 and de novo DNMT3a/3b function complementarily and simultaneously to establish and maintain methylation patterns. These results partially explain the limitations of inhibiting only one DNMT1 enzyme in current trials, because DNMT3a/3b still methylate CpGs. Furthermore, data demonstrate that even complete demethylation in the genome surprisingly only de-silenced a minority of genes in the genome. Only genes with low CpG density tend to be re-activated. Lastly, we demonstrate that maintenance DNMT1 activity is crucial for inhibition of retrotransposon long terminal repeats (LTRs), whereas de novo DNMT3a/3b activities are for suppressing retrotransposon long interspersed nuclear elements (LINEs). Our novel mechanistic insights of the establishment and maintenance of DNA methylation patterns help to develop next-generation DNMT inhibitor drugs.

Young-Kyoon Kim

Kookmin University, Korea
Title: Pinoradiol®, the plant derived polyphenolics targets growth inhibition of human breast cancer cells through induction of oxidative stress mediated lysosomal membrane permeabilization (LMP)

Biography :

Dr. Young-Kyoon Kim is from the Department of Forest Products and Biotechnology and he is the Dean of College of forest Science. He has served as a professor in Kookmin University since 1994. He is also the Principal Investigator of Forest material Bioindustrialization Research Center, Forest Science & Technology, Korea.He worked as a Research Scientist in the US Department of Agriculture, Agricultural Research Service (USDA-ARS),Western Regional Research Center (WRRC), Albany, California (2011-2012). He also worked in Scripps Institution of Oceanography, University of California, San Diego, La Jolla (1992-1994). He received a B.A. from the Kangweon National University in 1985, and M.A. from Seoul National University in 1987, and a Ph.D. in Natural Products from University of California at Berkeley in 1992.

Abstract :

Polyphenols are abundant non-nutrients in our diet as they are present in the fruits, vegetables, cereals, beverages and tea. Several epidemiological studies have repeatedly shown an inverse relationship between the risk of cancer development and the consumption of polyphenols rich diet. Polyphenols targets cancer cells by various mechanisms such as estrogenic or antiestrogenic activity, antiproliferation, induction of cell cycle arrest or apoptosis, suppression angiogenesis, regulation of the host immune system and cellular signalling pathways. In the present study, we report a novel mechanism of action of the polyphenolic mixtures,Pinoradiol® studied against breast cancer which is one of the most prevalent cancer types among women worldwide at present, using human cancer cell lines. First, we observed that Pinoradiol® induced an extensive cytoplasmic vacuolation in breast cancer cells, MCF-7. Those vacuoles were mostly caused by lysosomal dilation evidenced by reduced acridine orange red and lysotracker green fluorescence intensity, and cytosolic distribution of lysosomal aspartyl protease, cathepsin-D. Mechanistic investigations revealed that Pinoradiol® induced increased production of ROS was responsible for the loss of lysosomal membrane integrity evidenced from improved lysosomal function in the presence of an antioxidant, n-acetylcysteine. Next we found that Pinoradiol® induced breast cancer cell death was independent of caspases. Moreover, Pinoradiol® caused an accumulation of LC-3 and its associated protein, p62, confirming the blockade of autophagic flux at the maturation stage, which might be the loss of lysosomal function. Collectively, our study reveal a novel mechanism underlying Pinoradiol® induced breast cancer cell death involving ROS mediated lysosomal membrane permeabilization.

Acknowledgement:

The financial support of the present study was from Forest Science & Technology projects (Project No. S211315L010110), Forest Service, Republic of Korea.

Yanmin Zhang

Xi’an Jiaotong University, PR China
Title: Taspine derivatives inhibited tumor angiogenesis by targeting EphrinB2 and regulating its signaling players

Biography :

Dr. Yanmin Zhang is a professor of School of Pharmacy, Health Science Center, Xi'an Jiaotong University of China, member of Chinese Pharmaceutical Association. Yanmin Zhang received his B.S. in chemistry and Ph.D. in pharmaceutical analysis. He began his independent career in 1999. He is currently the director of molecular pharmacology program and a full professor at school of Pharmacy of Xi'an Jiaotong University, and assistant research scientist in the Biodesign Institute of Arizona State University, USA. Research interests in the Yanmin Zhang Group are at the interface of pharmacy and biology focused on screening and activity evaluation of small molecular drug for antitumor, studies of molecular mechanism of bioactive natural products and drug process analysis in vivo. He has published more than 100 papers including CDDs, Sci Rep, JCMM, Cancer Lett, et al. and holden 21 patents.

Abstract :

Introduction: The Eph receptor tyrosine kinases and their plasma-membrane-anchored Ephrin ligands play a pivotal role in angiogenesis, cell proliferation and migration in many different cell types and tissues[1]. EphrinB2 ligand expressed in various tumor cells is related to its high vascularity.EphrinB2 is a transmembrane subclass ligand and its reverse signaling is mediated by the EphrinB2 cytoplasmic domain, which contains a PDZ binding motif that can interact with signaling molecules [2,3]. So, regulation of EphrinB2 signaling might be useful to simultaneously interfere with the function of VEGFR2 and VEGFR3 which act together during angiogenesis[4].Taspine isolated from Radix et RhizomaLeonticis was a kind of aporphines alkaloid. The aim of this study is to investigate the action of taspine derivatives which inhibit tumor angiogenesis by targeting EphrinB2 and regulating its pathway.

Methods: Over-expressed Ephrin B2 cells, non-small lung carcinoma cell line A549, NCI-H1299 and NCI-H460 were used to study the cell proliferation, which was used to screen active compounds from taspine derivatives. The cell membrane chromatography (CMC) and binging assay were used to confirm the target. The biological activities of screened active compound were evaluated by cell assays and angiogenesis model of CAM in vivo and TMA in vitro. In addition, EphrinB2 expression and signaling players were investigated by Western Blotting.

Results: The cell proliferation results indicated that No.1822, No.T27 and No.T9among the taspine derivatives showed good inhibition on over-expressed EphrinB2 cells and lung cancer cells. At the same time, No.1822could act on EphrinB2 cell membrane stationary phase and interact on EphrinB2. The cell binging assay exerted the consistent result of No.1822 with CMC. Angiogenesis models in intro and in vivo showed the obvious inhibition on the angiogenesis treated by No.1822.The obtained data of western blotting indicated No.1822inhibitedEphrinB2expression and PDZ protein PICK1. Accordingly, it was associated with the down-regulation of PI3K/AKT/mTOR and MAPK signal pathway molecules, such as Akt, mTOR, Erk1/2, PLCγ, etc.

Conclusions: No.1822, a taspine derivative, showed good retention activity on EphrinB2CMC stationary phase and could target EphrinB2, and regulate PI3K/AKT/mTOR and MAPK signal pathway, which contributed to its inhibition on tumor angiogenesis.

Acknowledgements: This work was supported by the National Natural Science Foundation of China (Grant no. 81370088), the Fundamental Research Funds for the Central Universities of Zhuizong, and the Supporting Plan of Education Ministry's New Century Excellent Talents (Grant no. NCET-13-0467).