Surgical and Medical oncology
An investigation in the role of MicroRNA146a and novel Rhenium compounds on prostate cancer cell lines derived from African Americans and Caucasian patients--an in vitro study of racial disparity in morbidity and mortality from prostate cancer
Dr. HirendraNath Banerjee received his BS with honors and MD degree from Calcutta University, India, MS in Molecular Biology from Conolly College of Pharmacy and Health Sciences at Long Island University, NY and Ph.D. in Molecular Biology from Howard University Cancer Center, Washington, D.C. Dr. Banerjee did his post doctoral training at Yale University Medical School and Medical University of South Carolina before joining Elizabeth City campus of the University of North Carolina where he is now a tenured Professor in the department of Natural, Pharmacy and Health Sciences. Dr. Banerjee did a sabbatical at Rockefeller University under the mentorship of nobel laureate Dr. Gunter Blobel in studying the cell biology of nuclear pore complex's. Dr. Banerjee's current research involves cancer biology and Efferocytosis.
African American men have disproportionately high incidence and mortality rates of prostate cancer when compared to other ethnic groups in the United States. The identification of molecular factors that contribute to this disparity could improve diagnosis and therapeutic intervention. MicroRNA-146a suppresses prostate cancer transformation from androgen-dependent to -independent cells, suppresses a kinase coding gene which reduces cell proliferation, invasion, and metastasis to human bone marrow endothelial cell monolayers, and is dysregulated by latent membrane protein 1 (LMP1) which contributes substantially to the oncogenic potential of Epstein-Barr virus. It is projected that microRNA-146a and other microRNAs may one day become biomarkers for clinical diagnosis and prognosis of several types of cancer including prostate. Novel rhenium compounds have shown anti cancer properties specially in prostate cancer. Therefore, the purpose of this study was to determine the miRNA 146a expression profile in novel African American and Caucasian prostate cell lines at each clinical stage of prostate cancer progression and also to study the anti cancer properties of two novel organorheniumpentylcarbonate (RPC) compounds. The miR-146a expression profile was investigated using novel African American and Caucasian prostate cell lines representing each pathological stage: benign, androgen dependent and independent tumors. Relative miRNA expression was determined by qRT-PCR,miRNA plate assay and smart flare technology after isolating total RNA from the cells and the exosomes from the tumor microenvironment. Cytotoxicity studies of the RPC compounds were done by using MTT and Trypan Blue assay. Our initial data showed a several fold increase for miR-146a in African American prostate cancer cell line in comparison to the benign and Caucasian prostate cancer cell lines. The RPC compounds showed bioactivity in all the lines and significant anti cancer effects. To date, we are unaware of any studies that compare the miRNA146a profile of prostate cancer among two racial groups. Our study suggests that miRNA146a is upregulated in prostate cancer cell line derived from African American(AA) patient than Caucasians(CA) and could possibly contribute to the aggressiveness associated in African American patients with prostate cancer. We also found out that the novel organorhenium compounds are bioactive and have anti prostate cancer properties. Farther studies are currently getting conducted in our laboratory on the anti cancer role of these rhenium compounds and investigations on miR146a expression in other prostate cancer cell lines derived from AA and CA patients.
Acknowledgement: This research is supported by a grant from the BorroughsWellcomeFund,NSF-LSAMP,NIH-MARC and a Disability Supplement from NIH-NCI.
Adhip P. N. Majumdar
Title: Gut microbiome: A potential regulator of cancer stem cells and colon carcinogenesis
Dr. Adhip P.N. Majumdar, received his MS and Ph.D. degrees from the University of London, England, and D.Sc (Doctor of Science) degree in Gastroenterology from the University of Aarhus, Denmark. Dr. Majumdar has been a Professor at Wayne State University since 1992. He also holds the post of Senior Research Career Scientist at the Detroit VA Medical Center. Over the past several years Dr. Majumdar’s work has been streamlined to uncover the biochemical and physiological pathways governing the growth of gastrointestinal (GI) tract. He has published over 196 original scientific articles in peer-review journals and a multitude of book chapters and review articles. As reflected by the literature published from Dr. Majumdar's lab, he is particularly interested in elucidating the patho-physiology of age-related changes in the GI mucosa specifically those that lead to malignancy. To this end, Dr. Majumdar has begun to investigate the role of pluripotent, self-renewing CSCs in the development and progression of GI malignancies. Dr. Majumdar has been continually funded by the VA and NIH and is considered one of the nation’s leading investigators in gastrointestinal aging and cancer.
The concept that pluripotent cancer stem cells (CSCs) are involved in the development and progression of many types of malignancies, including colorectal cancer (CRC), is now well accepted. Earlier, we reported that patients with ≥3 adenomas (High-risk for CRC) exhibit a marked increase in CSCs in the colon than those without adenomas. Although the regulatory mechanisms for this increase in CCSs are poorly understood, we have suggested a role for secondary bile acids in the intestine, specifically deoxycholic (DCA) and lithocholic (LCA) acids, bio-transformed by gut microbiota, in regulating this process. Indeed, we observed a marked rise in Fusobacterium nucleatum and Enterobacterium (both are associated with CRC) in High-risk CRC patients. An opposite phenomenon was noted for the anti-inflammatory Bifidobacteria and also for the probiotic Lactobacillus acidophilus. Among the secondary bile acids, DCA and LCA are thought to be the most significant with respect to the development of CRC. Interestingly, we found the levels of DCA and LCA in the colon of High-risk CRC patients to be markedly higher than those at lower risk for CRC. We also found DCA and LCA to induce stemness in normal human colonic epithelial cells, as evidenced by increased colonosphere formation and elevated expression of several CSC markers as well as p-EGFR, c-myc and MMP-2, accompanied by a marked rise in lncRNAs, specifically CCAT2 and HOTAIR, which are known to be upregulated in CRC. Our observations suggest that alterations in specific gut micro-organisms resulting in increase in DCA and LCA that induce stemness in colon mucosal cells could partly be responsible for the development of sporadic CRC.
Title: Understanding how distinct tumor cell clones communicate in glioblastoma
Monica Nistér is a professor of pathology since 2002 at the Department of Oncology – Pathology, Karolinska Institutet, Karolinska University Hospital, Sweden. Her major research interests are to characterize the cancer cell heterogeneity and cancer stem cells in brain cancer, and to study the involvement of growth factor stimulation and p53 loss of function as well as epigenetic mechanisms and mitochondrial dynamics in cancer. Dr. Nistér has authored 120 peer-reviewed articles, a majority of whichin the cancer field, especially onbrain cancer. She has a PhD degree in Pathology (Tumor Biology) from Uppsala University in 1987 and became professor of experimental pathology at the same university in 1999.
Tumor cell heterogeneity constitutes a major challenge in cancer treatment. It has been shown thatinteractions between genetically different tumor cell subclonesin glioblastomacan affect the overall tumor growth.
To identify further signaling pathways and factors that contribute to interclonal effects we have usedthe U343 cell culture system, which consists of a panel of cell clones derived from a single glioblastomatumor, including U343MG, U343MGa, U343MGa31L and U343MGaCl2:6.
Here we show that U343MG cells have invasive capacity in vitro and express elevated mRNA levels of mesenchymal genes, including SNAI2, LAMC1 and FN1. In contrary, the other clones are less invasive and express high mRNA levels of the stem cell factor SOX2 and the astrocytic marker GFAP. By genomic copy number analysis a set of common gains and losses indicated a common ancestor, while specific alterations illustrated how the different clones had evolved. By co-culture and conditioned media experiments we found that U343MG elicited differentiation and growth inhibitory effects on U343MGaCl2:6 in co-culture via Notch signaling, and inhibited the proliferation of U343MGa31L via secreted factors. Gene-expression,proteomicand functional genomic approaches will pinpointthe specific pathways that elicit these inter-clonal effects.
Our studies show that different tumor cell subclones in a single glioblastomamay affect each other´s growth and differentiation via secreted and cell-associated factors. Massive single-cell analyses and further studies of fresh tumor samples will tell what combinations of interacting cell types may prevail in glioblastoma. Knowledge about cell-to-cellcommunicationin glioblastomamayprovidenovel therapeutic targets.
Title: A randomized phase 2 trial of ascorbic acid in combination with Docetaxel in men with metastatic prostate cancer
Channing J. Paller, M.D, is Assistant Professor of Oncology at the Johns Hopkins University School of Medicine. Dr. Paller earned her M.D. at Harvard Medical School and completed her medical residency at the Johns Hopkins Hospital, where she was a member of the Osler Housestaff Program, and her Fellowship in Medical Oncology at the Johns Hopkins Kimmel Cancer Center.
As an investigator, Dr. Paller is focused on translational research and clinical trials of developmental therapeutics in prostate and other solid tumors. Dr. Paller actively participates in the Johns Hopkins Kimmel Cancer Center Phase I program, with a concentration on the rigorous evaluation of natural products. She focuses on novel clinical trials of immunotherapy (TGFBR inhibitor) and natural products in men with prostate cancer or other solid tumors including pomegranate, muscadine grape skin, vitamin C, and mistletoe.
Ascorbic acid is being used by complementary medicine practitioners to treat cancer, infections, and other conditions. Annual administration of more than 355,000 doses of intravenous (IV) ascorbic acid for more than 10,000 patients has been documented, although total industry sales are more than double that amount. The average prescribed dose is 28 grams every 4 days. Complications reported have been minimal, with fatigue reported in 1.2% of patients overall and rare reports of phlebitis and kidney stones.
A long period of controversy over the efficacy of ascorbic acid in cancer patients began in 1976. Ewan Cameron with Linus Pauling published a retrospective study of untreatable cancer patients that demonstrated a survival benefit of 321 days with IV and oral ascorbic acid vs. 38 days for controls. In contrast, a 1979 Mayo Clinic study did not replicate this finding, although ascorbic acid was delivered only orally instead of IV. Phase 1 and 2 clinical trials in 2012, 2013, and 2014 demonstrated safety and anti-tumor activity for high dose IV ascorbic acid. These studies warranted testing the efficacy of IV ascorbic acid in randomized, placebo-controlled clinical trials. At high doses, ascorbic acid is very poorly bioavailable when delivery orally. Maximal oral administration has been shown to result in concentrations of no more than 0.2 mM, far below therapeutic levels.The effective therapeutic concentration of ascorbic acid is high, and can only be achieved with intravenous dosing. Thus the findings of the 1979 Mayo Clinic study, which used oral administration only, do not conflict with Cameron and Pauling’s findings that used IV plus oral administration.
A recent study of high dose IV ascorbic acid in ovarian cancer patients indicated that ascorbic acid treatment combined with standard chemotherapy (paclitaxel) reduces certain toxicities associated chemotherapy and might increase survival.
Dr. Channing Paller is conducting a randomized phase 2 clinical trial comparing docetaxel plus IV ascorbic acid (1g/kg, 3 times per week) versus docetaxel plus IV fluid (placebo) in mCRPC patients. The primary outcomes will be PSA response and reduction of chemotherapy-related toxicities.Key secondary outcomes include radiographic progression free survival, safety, quality of life, and the need for dose reductions of docetaxel.Laboratory correlates including pharmacokinetics of ascorbic acid and docetaxel and oxidative stress levels. Biomarkers of resistance to docetaxel will also be investigated.This clinical trial activates in spring 2016 and will be conducted at Johns Hopkins University and partnering sites.
In vitro treatment of mesothelioma with cell cycle inhibition and pemetrexed
Mark Klein, M.D. is an Assistant Professor of Medicine at the University of Minnesota and a staff physician at the Minneapolis VA Healthcare System. He earned his M.D. from the University of Iowa and did internal medicine residency and hematology/oncology fellowship training at the University of Minnesota. His laboratory research interests include identifying new treatment strategies against mesothelioma and small cell lung cancer and therapeutic peptide design and development.
Introduction: Mesothelioma therapy is a highly fatal disease with limited therapeutic options. Pemetrexed forms the backbone of first line chemotherapy in mesothelioma. The major mechanism of action of pemetrexed is thought to be via inhibition of the folic acid synthesis pathway via inhibition of thymidylate synthase, dihydrofolate reductase, and glycinamide ribonucleotide formyltransferase. Low expression of the endogenous CDK4/CDK6 inhibitor and tumor suppressor p16INK4A has been demonstrated in up to 50-90% of mesothelioma tumors.Inhibition of CDK4 has been shown to be associated with decreased levels of thymidylate synthase and cell cycle arrest at the G1/S transition. Decreased levels of thymidylate synthase have been associated with increased response to pemetrexed in some studies.
Hypothesis: Palbociclib will sensitizemesothelioma cells to pemetrexed-based therapy.
Results: Previously, we have demonstrated that palbociclib inhibits mesothelioma cell proliferation, inhibits retinoblastoma protein phosphorylation, and results in cell cycle arrest. Mesothelioma cells in culture were treated with palbociclib and pemetrexed alone and in combination. At concentrations at 100 mM or greater, single agent palbociclib was associated with decreased cell proliferation versus single agent pemetrexed. At higher concentrations of palbociclib and pemetrexed (> 100 nM), no additive or synergistic effects were observed for the combination therapy against mesothelioma cell lines. Preliminary results are consistent with at least an additive effect on cell proliferation in H2373 and H2461 mesothelioma cells at 1 mM palbociclib plus 10 nM pemetrexed. In H2373 cells treatment with palbociclib at 10 mM results in complete inhibition of phosphorylation of site T826 in Rb, while treatment with 1 mM palbociclib results in partial inhibition of phosphorylation at the same site. Treatment with 100 nM pemetrexed plus 1 mM palbociclib resulted in complete inhibition of phosphorylation at T826.
Conclusion: Pemetrexed affects Rb phosphorylation and may sensitize mesothelioma cells to treatment with CDK4/6 inhibitor palbociclib. Further investigation of this combination approach may be useful for mesothelioma treatment.
Stem cell models in ovarian cancer
Dr. Dinulescu is an Assistant Professor at Harvard Medical School. She received her Ph.D. from Oregon Health and Science University and completed her postdoctoral studies in the field of Cancer Genetics at MIT. Dr. Dinulescu’s research interests focus on cancer biology, malignancies of the gonads and reproductive tract, with a special emphasis on ovarian cancer research and endometriosis. Our laboratory is actively investigating the key contribution of cancer stem cells (CSCs) to tumor chemoresistance. Our current studies focus on better understanding the mechanism of stem cell signaling in the maintenance of the CSC niche and ovarian tumorigenesis. The aim is to harness the power of nanotechnology to develop improved “homing” technologies for the delivery of therapeutic agents specifically targeting and sensitizing ovarian cancer cells, including CSCs, in a spatio-temporal fashion.
Ovarian cancer has a high mortality rate and despite initially robust clinical responses to platinum and taxane-based chemotherapy, most patients will relapse within 2 years following diagnosis. Drug-resistant self-renewing cancer stem cells, which evade the anti-cancer effects of systemic chemotherapy, have emerged as a key player responsible for tumor recurrence. Identifying the chemoresistance signatures of cancer stem cells is an important step for designing new strategies for therapeutic intervention in recurrent tumors. Multiple studies have now defined cancer stem cells (CSCs) as having an increased tumorigenic ability in serial transplantation experiments conducted in tumor xenografts. This assay, however, may not be entirely accurate in clearly identifying CSCs. Nevertheless, there is enough evidence to support the idea that CSCs are necessary to initiate and propagate tumor diversity. In addition, CSCs are studied in multiple solid tumors, including ovarian cancer, due to their intrinsic chemoresistance properties. Thus, while non-CSCs have been shown to be sensitive to available therapies, CSCs are enriched in response to treatment and regenerate an increasingly platinum resistant tumor. Furthermore, similar to normal stem cells, CSCs are likely shielded from damage and injury by the tumor niche microenvironment, which makes it difficult to target them therapeutically.
The cellular origin of ovarian cancer stem cells has been difficult to identify. Multiple stem cell models have been proposed. One model proposes that CSCs can originate either from somatic adult stem cells or from progenitor non-stem cells. The ovarian surface epithelium and distal fallopian tube, which are tumor initiation sites, consist of both adult stem cells and also progenitor cells that are relatively undifferentiated and capable of differentiating into distinct morphological subtypes. We have recently found that ovarian cancer and somatic stem cells share common molecular pathways and markers, which is consistent with the model that some cancer stem cells may either arise from adult stem cells or most likely evolve to mimic somatic stem cell properties. Clearly, the identification of key CSC markers and pathways and their efficient use in the design of targeted therapies are necessary before such treatments can be meaningfully implemented in the clinic. Our research presentation will detail key aspects of CSC-driven tumor chemoresistance in ovarian cancer, outline methods of efficiently targeting CSCs, and discuss the implications of using these novel therapies in the clinical setting.
Metformin may reduce oral cancer risk in patients with type 2 diabetes
Dr. Chin-Hsiao Tseng is a senior attending physician at the Department of Internal Medicine, National Taiwan University Hospital, a full professor at the Department of Internal Medicine, National Taiwan University College of Medicine and an adjunct research fellow at the National Health Research Institutes in Taiwan. He had been appointed as the directors of the Division of Endocrinology and Metabolism, and the Department of Medical Research and Development at the National Taiwan University Hospital Yun-Lin Branch from August 2006 to July 2008. He has published more than 200 refereed papers and more than 10 book chapters in either English or Chinese on arsenic-related health problems and the relationship between diabetes mellitus and cancer. He has been invited to write an article entitled “Arsenic-induced diabetes mellitus” for “Encyclopedia of Metalloproteins”; and invited as a consultant to the “Workshop on the Potential Role of Environmental Chemicals in the Development of Diabetes and Obesity” organized by the National Institute of Environmental Health Sciences/National Toxicology Program, US Department of Health and Human Services, which was held in North Carolina on January 10-13, 2011. Prof. Tseng has also been invited by the International Agency for Research on Cancer/ World Health Organization to serve as an expert in the working group for the monograph volume 108 on “Carcinogenicity of some drugs and herbal medicines” held in Lyon, France in 2013. Prof. Tseng has been invited as a Lead Guest Editor for a Special Issue on “Diabetes and Cancer: Epidemiological, Clinical, and Experimental Perspectives” for Experimental Diabetes Research, which has been published in 2012. He has gained more than 20 research awards and has been invited to referee for scientific papers for more than 200 times by more than 100 international medical journals and to give lectures for several hundred times. He is currently serving as a member of the editorial advisory board of several medical journals including Current Diabetes Reviews, World Journal of Pharmacology, World Journal of Cardiology, World Journal of Diabetes, Open Diabetes Journal and Journal of Environmental Science and Health, Part C.
Purpose: To evaluate the risk of oral cancer associated with metformin use.
Methods: The reimbursement database of the National Health Insurance in Taiwan was used. Patients with type 2 diabetes mellitus at an onset age of 25-74 years during 1999-2005 and newly treated with either metformin (n=288198, “ever users of metformin”) or other antidiabetic drugs (n=16263, “never users of metformin”) were followed for at least 6 months for oral cancer until December 31, 2011. The treatment effect of metformin (for ever versus never users, and for tertiles of cumulative duration of therapy) was estimated by Cox regression adjusted for propensity score (PS) or incorporated with the inverse probability of treatment weighting (IPTW) using PS.
Results: The respective numbers of incident oral cancer in ever users and never users were 1273 (0.44%) and 119 (0.73%), with respective incidences of 92.7 and 163.6 per 100,000 person-years. The overall hazard ratios (95% confidence intervals) suggested a significantly lower risk [0.584 (0.483-0.707) for PS-adjusted model, and 0.562 (0.465-0.678) for IPTW model]. In tertile analyses, the PS-adjusted hazard ratios (95% confidence intervals) for the first (＜21.5 months), second (21.5-45.9 months) and third (＞45.9 months) tertile of cumulative duration were 1.403 (1.152-1.708), 0.557 (0.453-0.684) and 0.152 (0.119-0.194), respectively; and were 1.244 (1.024-1.511), 0.526 (0.429-0.645) and 0.138 (0.108-0.176), respectively, for IPTW.
Conclusions: Metformin may significantly reduce the risk of oral cancer, especially when the cumulative duration is more than 21.5 months.
Title: Crocin (saffron’s biomolecule) is a potent preventive agent against liver cancer
Amr Amin has completed his PhD at University of Illinois at Chicago, and received a post-doctoral training in the field of molecular genetics at the University of Pennsylvania School of Medicine. He started his academic career at UAE University where he serves now as a Full Professor of Cell Biology. Amr’s research focuses on ways to control cancer, particularly liver cancer. He published many research articles and reviews and serves as reviewer and as an editorial member of many specialized peer-reviewed journals. He is also a member of many specialized societies and the sole recipient of many scientific awards.
Hepatocellular carcinoma (HCC) is the second most common cause of cancer-related death worldwide. The prognosis of patients with HCC is usually poor; hence, a novel approach against HCC is essential for a better therapeutic outcome. Saffron and its active constituents were reported to have antioxidant, anti-inflammatory, and anti-tumor properties. The aim of this study was to investigate chemopreventive action of crocin, one of the promising active constituents of saffron, against diethylnitrosamine (DEN)-induced liver cancer in rats, and the possible mechanisms by which crocin exerts its anti-tumor effects. Findings reported herein demonstrated the anti-proliferative and pro-apoptotic properties of crocin when administrated in DEN-treated rats. Additionally, crocin exhibited anti-inflammatory properties that inhibited NF-kB, among other inflammatory markers. According to our network analysis, NF-kB was identified as a regulatory hub, and therefore, a candidate therapeutic drug target. Together, these findings nominates crocin as a candidate chemopreventive and therapeutic agent against HCC.
Title: Dissecting molecular networks of leptin in breast cancer: Complexities and opportunities
Sharma attained her PhD in Oncology followed by postdoctoral training at University of Maryland and Johns Hopkins University. Dr. Sharma is an Associate Professor of Oncology at Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins. Her lab focuses on investigating the molecular links between obesity and cancer, emphasizing aspects that have potential clinical significance. They are exploring new strategies to disrupt obesity-cancer connection using a variety of approaches. Their overall goal is to understand the molecular networks by which obesity affects carcinogenesis and discover novel agents to effectively disrupt obesity-cancer axis.
Perturbations in the adipocytokines-profile, especially higher levels of leptin, are a major cause of breast tumor progression and metastasis. The focus of this talk is to discuss the impact of obesity on cancer with a special focus on breast cancer, discuss the underlying molecular mechanisms and discuss the potential therapeutic opportunities.
Using cystine knot proteins to retarget oncolytic measles virus for tumor-associated integrins
Sangeet Lal is a postdoctoral scholar in the lab of Corey Raffel at UCSF.He has createda modified oncolytic measles virus (MV) targeting tumor-specific receptors and is investigating the efficacy ofMV for the treatment of pediatric brain cancers using immune-competent murine models. At OHSU, he performed research of clinical interest showing that simultaneous expression of αv integrin and HER2, a tyrosine kinase receptor, is required for the invasion of Her2-positive breast cancer cells in brain microenvironment. The interaction between αv integrin and HER2 regulates the localization of HER2 on cell membrane.During Ph.D.,Sangeet studied the role of calpain2 protease in the invasion of glioblastoma tumor cellsand developed a novelin vivoorthotopicxenograftmodel of zebrafish tomonitor invasion of transplanted glioblastoma cells in the brain of living animals. Sangeet has published 6 papers with another 4 in peer-review or preparation stage and presented his research(oral and poster) at international meetings. His long-term goalis to develop as a notable scientist in the field of translational brain cancer research and therapy.
Introduction: Modified measles virus (MV) is an effective oncolytic virus and is currently being investigated in clinical trials for various cancer types. An advantage of using MV is the ease of retargetingthe virus to a receptor of choice. We investigated the use of cystineknot proteins (CKP) to direct MV activity. CKP are short polypeptides that bind their targets with high affinity. A library of these proteins has been made, and a CKP that binds αvβ3 and αvβ5integrins with single digit nanomolar affinity has been isolated. We have used this CKP to target MV to the integrins.
Methods: MV genome was modified to express the integrin-binding CKP at the C-terminus of a mutated H protein that does not bind to its normal receptor CD46. We tested the virus for specificity to integrinsby assessing cell killing and MV replication in vitro.
Results: MV-CKP killed and replicated in glioblastoma, medulloblastoma,DIPG and breast cancer cells, which express the target integrins. The virus did not kill and did not replicate in cells in which αvintregrin expression was knocked down with anαv-integrin antisense lentivirus. MV-CKP activity was competitively blocked by echistatin, an integrin binding peptide. When the CKP was cleaved from the virus at an inserted protease site, virus activity was abrogated.
Conclusions: These results indicate that CKP can be used to selectively target MV. Because the integrins of interest are expressed by tumor cells and tumor-associated endothelium and because the CKP used has been shown to localize to tumor when injected IV, MV-CKP may be potentially effective as IV therapy, a major step forward in the use of MV. In addition, the CKP library can be screened for other targeted CKPs of interest. Importantly, the use of CKP to target viruses is applicable to many viruses other than MV.
Expression pattern of ER/PR in 456 invasive breast cancer cases and rate of disease progression and recurrence in 174 breast cancer cases who are on treatment based on certain prognostic factors
Getamesay Kebede is an Assistant Professor of Clinical Pathology has been working professionally since 2010 at Haromaya University, Ethiopia. He has written a paper on breast cancer and has ongoing studies on tuberculosis and on infant mortality. Getamesay received his doctorate degree in medicine at Gondar University in Gondar, Ethiopia and speciality in Clinical Pathology at Addis Ababa University, Ethiopia.
Inorder to determine the rate of expression of ER/PR in invasive breast cancer we have reviewed the results of invasive breast cancer cases. A total of 456 breast cancer cases were tested for ER and PR at Tikur Anbessa specialized Hospital, Addis Ababa, from 2008 – sept.,2010G.C. 63.7% were ER positive and 49.2% were PR positive.
The expression of both ER and PR is seen in higher rates with male breast cancer than with female breast cancer. Disease progression was seen with higher frequency with lymph node involvement and it is statistically significant (p=0.118), increasing tumor stage statistically significant (p=0.018), invasive lobular carcinoma not statistically significant (p=0.211), surgical margin involvement not statistically significant (p=0.06), and higher tumor histologic grade statistically significant (p=0.045) and with ER positivity statistically significant (p=0.015). Large number of female breast cancer patients had history of hormonal contraceptive use. (42.6%)
Title: A new method of the initial dose of 120mg regorafenib for metastatic colorectal cancer as a salvage-line monotherapy
Dr. Hiroshi Osawa Medicine Doctor (Ph.D.-medicine) now is a chairman of department of Oncology and Hematology in Edogawa Hospital Tokyo, Japan. Dr. Hiroshi Osawa graduated the Teikyo university school of medicine, Tokyo, Japan, 1990. He got his Specialist in Oncology and Hematology, Medicine Doctor's degree (Ph.D.) at the Tokyo Jikei University, Tokyo. And Dr. Hiroshi Osawa had learned clinical research, molecular biology and cancer cell signaling at Cancer Institute Hospital(four years), Tokyo, Japan and he researched resistance in TGF-beta 1 correlates with aberrant expression of TGF-beta receptor Ⅱ in human B-cell lymphoma cell line at National Institute on Aging(three and half years) as a research fellow, Baltimore, USA. Currently Dr. Hiroshi Osawa has been focusing clinical phase studies and researches on gastrointestinal tract field include of these adverse events.
Regorafenib is an oral multikinese inhibitor with proven activity in metastatic colorectal cancer (mCRC) patients who have a benefit with salvage line chemotherapy for progression free and overall survival. We evaluated four patients who received initial dose of regorafenib 160mg once a daily which dose could not continue each cycles. However, severe toxicity of initial dose has resulted in the clinical use of a reduced dose of regorafenib 120mg as an initial dose for other patients. Best objective response of partial response (PR) was 17% and stable disease (SD) was 17% and disease control rate was 34%. These PR cases of medication terms were 9 (6.5 months) and 6 (5 months) cycles, respectively. The most common AEs of under grade 2 were HFSR (58.3%), fatigue (50%), liver dysfunction and anemia (33.3%), leukopenia (25%) and hypertension (16.7%). There was no chemotherapy-related death. Despite a reduced initial dose of regorafenib, we recognized to remarkable two PR cases and favorable SD cases. We suggest to initial dose of regorafenib which might be started 120mg, because of severe adverse events. If a patient of our method had a tolerable adverse event, regorafenib will be able to be a dose escalation or not.
Title: The ratio between distinct subsets dictates overall neutrophil contribution in cancer
Dr. Granot did his B.Sc, M.Sc and PhD at the Hebrew University in Jerusalem. His PhD thesis (2000-2005) dealt with the degradation pattern of StAR, a unique protein that is involved with steroid hormone synthesis. He then did a postdoctoral fellowship at the Hebrew University (2005-2007) where he focused on organ size control using pancreatic eta-cells as a model. Next, he did a postdoctoral fellowship at Memorial Sloan-Kettering, New-York, NY, USA (2007-2012). During this fellowship Dr. Granot focused on neutrophils, a subset of white blood cells that has the capacity to limit the metastatic spread. The understanding of this new role for neutrophils is very limited and requires further studies. Currently Dr. Granot is a PI at the Hebrew University in Israel, where he studies neutrophil versatility in cancer and the mechanisms that mediate tumor cell recognition and elimination by neutrophils.
In recent years it has become apparent that the non-malignant stroma surrounding tumors plays a critical role in the processes of tumor initiation, growth and metastatic progression. In this context the part neutrophils play has been a matter of debate. Neutrophils are the most abundant leukocytes in the human circulation and are usually associated with inflammation and with fighting infections. In cancer, neutrophils were shown to provide a variety of pro-tumor functions including secretion of tumor promoting cytokines, degradation of the ECM, immune suppression and more. In contrast, neutrophils were also shown to have the capacity to kill disseminated tumor cells either through direct cytotoxicity or via antibody dependent cytotoxicity. These conflicting reports suggest that although neutrophils are largely viewed as a homogeneous population they may consist of distinct subsets with significantly different properties. Indeed, we identified a heterogeneous subset of low-density neutrophils (LDN) that appears transiently in self-resolving inflammation but accumulates continuously with cancer progression. While high-density neutrophils (HDN) maintain a pro-inflammatory, anti-tumor phenotype, LDN present with a reduced inflammatory profile, impaired neutrophil function and acquire immunosuppressive properties. In early tumor development HDN are the predominant neutrophil subpopulation giving neutrophils, in general, an anti-tumor phenotype. However, with tumor progression, LDN are preferentially propagated to the extent that they become the dominant circulating neutrophil subpopulation. When this happens the overall neutrophil contribution switches from anti- to pro-tumor. Our observations identify dynamic changes in neutrophil subpopulations and provide a mechanistic explanation to mitigate the controversy surrounding neutrophil function in cancer.
Title: Tumorigenesis of NIH3T3 cells induced by the exogenously over-expression of the novel tumor antigen OVA66
Hailiang Ge is a professor of Department of Microbiology and Immunology, Shanghai Jiao Tong University School of Medicine. He graduated from Shanghai Second Medical University in 1977 majoring in medicine. Then he obtained the Master Degree in Nuclear Medicine of Ruijin Hospital, Shanghai Second Medical University in 1985 and got the Doctor Degree in Immunology of Shanghai Second Medical University in 1991. He worked on research as a postdoctoral fellow in the Department of Microbiology and Immunology, University of California, San Francisco, U.S.A. from 1992 to 1995. In 1998 and 2002, he studied in School of Medicine, University of Michigan and School of Medicine, University of Pittsburgh, U.S.A. as a visiting professor respectively.
The tumor associated antigen OVA66 which is firstly defined by serological analysis of human ovary cancer of recombinant cDNA expression library, has been demonstrated to be highly expressed in the majority of malignant tumors. We constructed a eukaryotic expression vector pFlag-OVA66 to establish an OVA66 stably over-expressed mouse fibroblast NIH3T3 cell line. The OVA66 over-expressed NIH3T3 cells exhibited several significantly malignant changes, the S and G2/M phage was markedly increased whereas the G1/G0 phage was decreased in the total cell cycle, indicating that the over-expression of OVA66 is able to promote cell cycling and proliferation. MTT and colony formation assay validated that OVA66 promotes the cell growth and colony formation in vitro. NIH3T3 cells with the over-expression of tumor antigen OVA66 displayed more resistance to the cell apoptosis induced by 5-FU. In vivo assay of the tumor xenograft studies in nude mice revealed the OVA66 over-expressed NIH3T3 cells were capable of forming tumors in the nude mice compared to the NIH3T3-mock cells with low expression of OVA66. Analysis of the phosphorylation of AKT and ERK1/2 stimulated with serum indicated a hyper activation of ERK1/2 MAPK and PI3K/AKT pathway in OVA66 stably over-expressed NIH3T3 cells. The results suggesting that OVA66 as a novel tumor antigen with its strong tumorigenic ability might be a novel target for the early detection, prevention and treatment of tumor in the future.
Title: MS17-38 mAb targeting of PODXL-v2 inhibits gastric cancer growth and metastasis
Dr. Zhang Dongqing is a professor in the Department of Microbiology and Immunology, Shanghai Institute of Immunology, Shanghai Jiao Tong University School of Medicine, China. He graduated from Shanghai Second Medical University in 1985 majoring in medicine. Then he obtained the Master Degree in Shanghai Institute of Immunology, Shanghai Second Medical University in 1991. He worked on research as a postdoctoral fellow in the Department of Nerve immunology research institute McGill University from 1997 to 1998; Also, in 2005 he studied in Yale University School of Medicine, as a visiting professor.
Gastric cancer is the primary cause of cancer-specific mortality worldwide. PODXL (podocalyxin-like protein or podocalyxin) is a cell-surface glycoprotein that belongs to CD34 family of sialomucins. PODXL-v1 is widely expressed on vascular endothelium, mesothelial cells, and platelets; in contrast, PODXL-v2, a truncated short form of PODXL is specifically expressed or up-regulated in numerous cancer cell types as well as in small blood vessels in tumor tissues. There remains considerable interest in generating monoclonal antibodies (mAbs) directed against specific tumor targets for antigen (Ag) discovery, diagnosis and therapy. MS17-38 mAb was generated by live cells HTS and was demonstrated to bind to a specific conformational epitope of PODXL-v2 on GC cells. PODXL-v2 expression inhibition by PODXL-v2 siRNA or the PODXL-v2-neutralizing antibody MS17-38 resulted in inhibition of GC cell growth and prevention of GC cell migration in vitro. Furthermore, in vivo studies demonstrated that MS17-38 mAb can potently inhibit tumor growth and prevent MKN-45 metastasis to the lungs in nu/nu mouse models. Finally, high expression of PODXL-v2 was associated with advanced GC stage and short survival time (P<0.01). Additional engineering of this mAb into chimeric or humanized forms could permit development of MS17-38 for diagnosis, staging or therapy of human malignancy. Our findings indicate that PODXL-v2 is specifically expressed in the extracellular matrix of GC, and MS17-38 mAb directed against a conformational epitope of PODXL-v2 identified through HTS can functionally inhibit GC cancer cell growth and migration/metastasis both in vitro and in vivo. MS17-38 is a promising functional antibody directed against GC that could potentially be developed into a therapeutic mAb for clinical application.
Title: Epigenetic silencing of microRNA in cancer associated fibroblasts mediates prostaglandin E2/interleukin 6 signaling in the tumor microenvironment
Tumor initiation andgrowth depend on its microenvironmentin which cancer associated fibroblasts (CAFs)in tumor stroma play an important role. Prostaglandin E2 (PGE2) and interleukin (IL)-6 signal pathways are involved in the crosstalk between tumor and stromal cells. However, how PGE2-mediated signaling modulates this crosstalk remains unclear. Here, we show that microRNA (miR)-149 links PGE2 and IL6 signaling mediating the crosstalk between tumor cellsand CAFs in gastric cancer (GC). miR-149 inhibited fibroblast activationby targeting IL6 and miR-149 expression was substantially suppressed in the CAFs of GC. miR-149 negatively regulated CAFs and their effect on GC development both in vitro and in vivo. CAFs enhanced epithelial to mesenchymal transition (EMT) and the stem-like properties of GC cells in a miR-149-IL6-dependent manner. In addition to IL6, PGE2 receptor2 (PTGER2/EP2) was revealed as another potential target of miR-149in fibroblasts. Furthermore, H. pylori infection, a leading cause of human gastric cancer, was able to inducecyclooxygenase-2 (COX-2)/PGE2 signaling and to enhance PGE2 production, resulting in thehypermethylation of miR-149 in CAFs and increasedIL6 secretion. Our findings indicate that miR-149 mediates the crosstalk between tumor cellsand CAFs in GC and highlight the potential of interfering miRNAs in stromal cells to improve cancer therapy.
Title: ERp19 contributes to tumorigenicity in human gastric cancer by promoting cell growth, migration and invasion
ERp19, a mammalian thioredoxin-like protein, plays a key role in defense against endoplasmic reticulum stress. It belongs to families of protein disulfide isomerase (PDI) whose members have been implicated in cancer development including breast cancer, ovarian cancer and gastrointestinal cancer. Recently, little is known regarding ERp19 function in gastric cancer (GC). Therefore, the aim of our study is to investigate the expression and prognostic value of ERp19 in GC patients and to explore the role of ERp19 in tumorigenicity. The expression of ERp19 in human GC tissues was detected by immunohistochemical staining and real-time PCR. Statistical analysis of clinical cases revealed that the expression levels of ERp19 were higher in tumor tissues compared with the non-tumor tissues. And the expression levels of ERp19 were correlated with tumor size, lymph node involvement and poor prognosis of GC patients. Furthermore, ERp19 knockdown dramatically suppressed gastric cancer cell growth, inhibited cell migration/invasion and downregulated the phosphorylation of FAK and paxillin. Whereas ERp19 over-expression did reversely. On the basis of these data, we indicated that ERp19 contributes to the tumorigenicity and metastasis via activation of the FAK signaling pathway, and may function as an oncogene in GC. In conclusion, ERp19 is expected to become a new diagnostic and prognostic marker and a novel target of the treatment of GC.
Clinical trials (CT) as an innovative way of medical institution development
Mohammad Hojouj is an Assistant Professor, MD, MSo, Oncologist, Master of medicine, a member of The National Comprehensive Cancer Network NCCN, a member of the European Association of Physicians in Germany (NGO), member of the international conference, Speaker of the international conference in the United Arab Emirates 2015, a member of the Association of Arab doctors in Ukraine. Actual Member of the American Association of Clinical Oncology (ASCO). Has experience of more than 9 international clinical researches as Sub investigator. He gives great attention to the educational process, organization and conduction of clinical trials in oncology practice.
Clinical trials are an important way of evaluating new treatment technologies and their effectiveness from the perspective of evidence-based medicine. Involvement of clinical trials in the hospital promotes the growth of its rating, significantly improves the quality of staff training and promotes innovative development of the facility. Clinical studies have become more successful in using the principles of effective management, and clinicaltrialssitemanagementsystem (СTSMS).
The purpose: To prove the feasibility and effectiveness of СTSMS in the management of clinical trials.
Materials and methods. The subject of the study was the experience of the organization and conduct of265 clinical trials for the period since 2002, whereabout 3,000 cancer patients were involved. During 2011-2015, the research center developed and implemented CTSMS «Investigator», which has proved its effectiveness.
1. Participation in clinical trials allowed signingagreements with 65 sponsor-companies and contract research organizations (CRO), which made it possible to investigate 200new pharmaceutical drugs.
In total, doctors of the hospital gained experience with about 400 cancer drugs and dose regimes. They have been trained in 35 countries on 280 investigator meetings.More than 120 scientific papers have been published in leading magazines of the world, which made us the most cited hospital of our country abroad.
2. CTSMS allowsplanning all kinds of activities in the research center,allows performing full control of all processes and gives analytical information about the quality of the data from each research center department. It allows remote control of all processes online from anywhere in the world. Combination of CTSMS and in-patient mode of treatmentallows increasing the number of patient in three times.
3. The patient receives a special card with barcodes for each procedure.Barcode scanning generates signal through a Wi-Fi network, which accurately registers the time of each procedure. Separating patients into three streams, depending on the kinds of research procedures, reduced the time for procedure waitingup to 3-5 minutes.
4. We have developed a system of medical records registration which allowed controlling the timeliness of doctors and data managers’ activities.Such system gives the opportunity to organize remote control monitoring and significantly reduces the cost of clinical trials.
5. Extremely important to consider the improvement of communication between the participants of clinical trials. For this purpose,research site set up a media center that includes: a web site www.sitetv.net, internet channel on YouTube, online radio-channel and newspaper “The Site News”.
1. Application of the principles of good management and CTSMS increases the number of clinical trials carried out simultaneouslyfrom 10-11 clinical trials(till the end of 2011) till 25-28 clinical trials (after 2011). The amount of treated patients per week increased from 120-150 patients till 310 patients.
2. High quality of the center work has been confirmed by the conclusions of the Food and Drug administration audit in 2013
3 Hospital received the highest status as a strategic partner for many pharmaceutical companies and increased its international standing and prestige.
4. We believe that described principles of site management may be useful for other hospitals willing to perform clinical trials.