Day 2 :
Keynote Forum
Paul J Davis
Albany Medical College, USA
Keynote: Anti-apoptotic and pro-angiogenic properties of thyroid hormone may oppose cancer chemotherapy
Time : 9:30-10:10
Biography:
Davis is a graduate of Harvard Medical School and had his postgraduate medical training at Albert Einstein College of Medicine and the NIH. His academic positions have included Chair, Department of Medicine, Albany Medical College. He has served as President, American Thyroid Association, as a member of the Board of Directors of thern American Board of Internal Medicine and he is Co-Head, Faculty of 1000 – Endocrinology. He serves on multiple Editorial Boards of His scientific interests include molecularrnmechanisms of actions of nonpeptide hormones, particularly, thyroid hormone. He and his colleagues described the cell surface receptor for thyroid hormone on integrinrnavb3 that underlies the pro-angiogenic activity of the hormone and the proliferative action of the hormone on cancer cells. He has co-authored more than 200 original research articles and 30 textbook chapters and he has edited three medical textbooks.
Abstract:
The principal secretory product of the thyroid gland, L-thyroxine (T4), is anti-apoptotic at physiological concentrations in a number of cancer cell lines. Among the mechanisms of anti-apoptosis activated by the hormone is interference with the Ser-15 phosphorylation (activation) of p53 and with TNFα/Fas-induced apoptosis. The hormone also decreases cellular abundance and activation of proteolytic caspases and of BAX and causes increased expression of X-linked inhibitor of apoptosis (XIAP). The antiapoptoticrn effects of thyroid hormone largely are initiated at a cell surface thyroid hormone receptor on the extracellular domain of integrin αvβ3 that is amply expressed and activated in cancer cells. Tetraiodothyroacetic acid (tetrac) is a T4 derivative that, in a modelrnof resveratrol-induced p53-dependent apoptosis in glioma cells, blocks the anti-apoptotic action of thyroid hormone, permitting specific serine phosphorylation of p53 and apoptosis to proceed. In a nanoparticulate formulation limiting its action to αvβ3, tetrac modulates integrin-dependent effects on gene expression in human cancer cell lines that include stimulation of expression of apanel of pro-apoptotic genes and downregulated transcription of defensive anti-apoptotic XIAP and MCL1 genes. By a variety ofrnmechanisms, thyroid hormone (T4) acts as an endogenous anti-apoptotic factor that may oppose chemotherapy-induced apoptosis in αvβ3-expressing cancer cells. It is possible to oppose this anti-apoptotic activity pharmacologically by reducing circulating levels of T4 or by blocking effects of T4 that are initiated at αvβ3.
- Steroids and Cancer
Session Introduction
Donald Poirier
Research Center and University Laval
Canada
Title: A new family of steroidal 17 beta-HSD type 1 inhibitors to treat hormone-dependent breast cancers
Time : 10:10-10:40
Biography:
Professor Donald Poirier received his training in chemistry (B.Sc., 1977-1980) and organic chemistry (PhD, 1980-1985) at Université Laval (Québec City, Canada). He subsequently specialized in medicinal chemistry (Post-doctoral training at CHUL - Research Center, 1986-1990) and more recently in solid phase synthesis of small molecules of therapeutic interest. He is especially interested in the development of inhibitors of steroidogenic enzymes (17b-hydroxysteroid dehydrogenases (types 1, 2, 3, 7, 10 and 12) and steroid sulfatase) and antitumor agents for the treatment of different cancers (breast, prostate, ovary, leukemia). In addition to the synthesis of small molecules by classical chemistry, he succeeded by developing solid-phase synthesis of C18-steroid (estrane), C19-steroid (androstane) and C21-steroid (pregnane) derivatives that enabled the generation of model libraries of targeted therapeutic compounds. Thus, he developed a new sulfamate linker for solid-phase synthesis that produces two classes (phenol and sulfamate) of relevant steroidal or nonsteroidal compounds according to the conditions of cleavage. He also developed a diethylsilylacetylene linker to generate libraries of acetylenic tertiary alcohols, which are well known to be biologically more stable than their corresponding secondary alcohols.
He is also interested to additional aspects of organic chemistry (synthesis, new methodologies, NMR analysis, etc.) and medicinal chemistry (structure-activity relationships, molecular modelisation, biological assays, etc.). He is professor at the Department of Molecular Medicine (Faculty of Medicine, Université Laval, Québec City, Canada) since July 1991, researcher at CHU de Québec - Research Center (Québec City) since 1991 and director of the Organic Synthesis Service (CHU de Québec) since 2008. Professor Poirier is member of professional organizations such as ACS, CIC, OCQ, ACFAS and CRCQ. He published 202 papers and 8 patents. He was also author or co-authors of 414 presentations (invited speaker, oral and poster presentations).
Abstract:
PBRM is steroid derivative recently developed in our research group as anticancer agents. PBRM, or 3-{[(16β,17β)-3- (2-bromoethyl)-17-hydroxyestra-1(10,2,4-trien-16-yl]methyl} benzamide, was synthesized from estrone (E1) using a sequence of eight steps in an overall yield of 11%. PBRM inactivated the transformation of E1 into estradiol (E2), the most potent estrogen, by the action of steroidogenic enzyme 17β-hydroxysteroid dehydrogenase type 1 (17β-HSD 1), which is thought to play a pivotal role in the progression of estrogen-dependent breast cancer. In fact, PBRM inhibited the 17β-HSD1 in T-47D cells (IC50 = 83 nM), in the pure enzyme (Ki = 381 nM, kinact = 0.084 min-1) and did not inhibit other key enzymes such as 17β-HSD2, 17β-HSD7, 17β-HSD12, CYP3A4 and CYP-2D6, suggesting a good selectivity of action. In the presence of microsomes, PBRM was gradually transformed into an oxidized form of PBRM (100% after 12h). This PBRM metabolite has proven almost as active as PBRM for the transformation of E1 to E2 by 17β-HSD1 (49 and 87% vs. 87 and 95% of inhibition at 0.1 and 1 μM, respectively). When injected subcutaneously (sc) in mouse, PBRM is the major product (660 ng/mL at 5h) found in blood and oxidized PBRM is present in small quantities (8.5 ng/mL at 5h). Most tissues reach their maximum level of PBRM 6h after sc injection. PBRM was observed mostly in digestive tract over the first 6h, but did not accumulate in any other organ. It was recuperated in feces (93%) and in urine (7%), with 68% of the elimination occurring in the first 24h. Interestingly, in the estrogen-sensitive breast cancer cell line T-47D and in ovariectomized mice (uterine and vagina weight), PBRM showed no estrogenic activity. When tested on the T-47D xenograft tumor model in female ovariectomized nude mice, PBRM (250 μg/mouse/day) fully blocked (100%) the tumor growth induced with exogenous E1 (0.1 μg/mouse/day). In summary, PBRM represent a new generation of 17β-HSD1 inhibitors that generated promising in vitro and in vivo results against breast cancer cells and tumor model.
Alan Prem Kumar
National University of Singapore
Singapore
Title: DEAD-box RNA Helicase DP103 as a Biomarker for Therapeutic Response to Docetaxel
Biography:
Dr. Alan Prem Kumar earned his Ph.D. from University of North Texas, USA. From his Ph.D. work, he discovered a novel regulatory protein, PyrR for the pyrimidine biosynthetic pathway in Pseudomonas. Dr. Kumar then pursued Postdoctoral training in Cancer Research at Sidney Kimmel Cancer Center, California, USA. He was awarded a Postdoctoral Fellowship for his work on the role of nuclear receptors in the transcriptional regulation of human myeloperoxidase, a leukocyte enzyme implicated as causative agent in atherosclerosis and Alzheimer’s disease. Dr. Kumar relocated back to Singapore to join the Faculty of Medicine, National University of Singapore as an independent Principal Investigator to continue on his expertise on nuclear receptor signaling in cancer biology. His current research focus in the areas of signaling by nuclear receptors and oncogenes in breast tumor cells as well as the development of molecular therapeutics and biomarkers of drug action in breast cancer.
Abstract:
Resistance to chemotherapy offers limitations to the treatment of breast cancer. This has generated an increased interest in identifying new biomarkers to better predict drug responses among patients. Gene expression analysis and immuno-histochemistry profiling of patient samples, randomized to a combination of docetaxel and doxorubicin, revealed a chemotherapy induced decrease in DP103 expression among responders, and an increase among non-responders. These clinical findings were also validated in-vitro, using representative cell lines to mimic responders, and their corresponding drug resistant subtypes as non-responders. Upon stratification by the receptor status, the predictive value of DP103 was only observed in patient samples and cell lines with ERα-positive status and not with ERα-negative status. The observed changes in DP103 expression was well correlated to a similar drug induced change in the expression of ERα; raising a possibility of a cross-talk between DP103 and ERα. ChIP-Seq analysis and estradiol-stimulation studies validated DP103 to be an estrogen-inducible gene. Interestingly, DP103 was also indentified as a potential modulator of ERα transcriptional activity. Silencing DP103 inhibited estradiol-induced ERα DNA-binding activity, expression of ERα target genes, cell growth and colony forming ability. These findings summarise a novel role of DP103 in acquired drug resistance; presenting a potential surrogate biomarker for predicting drug response in breast cancer. In addition, we have also uncovered a positive feed-forward loop between DP103 and ERα that could regulate the activity of the latter in ERα positive breast cancer.
Pandurangan Ramaraj
A.T. Still University, USA
Title: Differential Effects of Dehydroepiandrosterone (DHEA) between Mouse and Human Melanoma Cell Lines
Time : 10:40-11:10
Biography:
He is currently working in Department of Biochemistry, Kirksville College of Osteopathic Medicine at A.T. Still University, USA
Abstract:
Androgens such as dehydroepiandrosterone (DHEA), androstenedione (AD) and testosterone (T) are essential for healthy skin. They play important roles in growth and differentiation of sebocytes, hair growth and wound healing in the skin. Decrease in DHEA level with age was attributed to cancer and other problems of aging. So, the effect of DHEA on melanoma, a fatal form of skin cancer was checked. DHEA’s purported beneficial effects (such as anti-cancer action) were observed in mouse and other rodents, but not in humans. Our previous study on DHEA biological functions using a variety of cell lines showed that the differences existed not only at the systemic level, but also at the cellular level. Hence, we decided to compare the in-vitro effects of DHEA between mouse (B16F10) and human (BLM) melanoma cell lines. Results indicated that DHEA actions were mediated through androgen receptor (AR) in both cell lines. DHEA showed significant growth inhibition and induced autophagy in mouse cell line, whereas it showed a muffled inhibition and induced apoptosis in human cell line. Moreover, co-incubation of DHEA with progesterone showed an additive effect in decreasing the cell growth in mouse cell line, but not in human cell line. These differential in-vitro effects between mouse and human melanoma cell lines were in line with previously published in-vivo and in-vitro effects of DHEA.
Conclusion: These differential in-vitro effects of DHEA suggested a possible difference in intracellular processing of DHEA between mouse and human melanoma cell lines and this mechanism was able to explain the systemic differences observed between mouse and human in-vivo experiments.
Amandine Grimm
University of Basel
Switzerland
Title: Sex hormones, Alzheimer’s disease and mitochondria
Time : 12:35-13:05
Biography:
Dr Amandine GRIMM has performed a joint PhD between the University of Strasbourg, France, specialty Neuroscience, and the University of Basel, Switzerland, specialty Pharmaceutical Sciences. She has obtained her PhD degree in January 2015 and is now a postdoctoral fellow in the Neurobiology Lab for Brain Aging and Mental Health (Psychiatric University Clinic of Basel (Switzerland)). In the course of her Joint-PhD and postdoctoral researches, Dr. Grimm has published nine papers, including six original articles, reviews and book chapters signed as first author.
Abstract:
Metabolic impairments are common hallmarks of Alzheimer’s disease (AD), and amyloid-β (Aβ) peptide and hyperphosphorylated tau protein – the two foremost histopathological signs of AD - have been implicated in mitochondrial dysfunction.
Epidemiological studies showed that women represent two thirds of AD patients and exhibit a greater vulnerability to the disease compared to men but little is known about the influence of sex steroid hormones on AD-related mitochondrial dysfunction.
Thus, we aimed to investigate whether sex hormones could attenuate the toxic effects of Aβ and abnormal tau on bioenergetic parameters, such as ATP production, mitochondrial membrane potential (MMP), mitochondrial respiration and glycolysis, in cellular models of AD (SH-SY5Y neuroblastoma cells overexpressing either the human amyloid precursor protein (APP) or mutant tau (P301L)).
After a treatment of 24 h, the majority of these steroids were effective in enhancing bioenergetic outcomes in cells overexpressing APP and mutant tau, attenuating the mitochondrial dysfunction that is present in these cell lines when compared to the respective control cells. Interestingly, testosterone (the main male sex hormone) was more efficient in alleviating Aβ-induced mitochondrial deficits, while progesterone and estrogen (the female sex hormones) were the most effective steroids in our model of AD-related tauopathy.
Thus, our results provide new insights in re-defining the biological model of how steroids control neuronal and bioenergetic functions, and may open new avenues for the development of gender-based therapeutic approaches in AD.
This work was supported by grant from the Swiss National foundation (SNF 31003A_149728) and Synapsis Foundation.
Rene Wenzl
Medical University of Vienna
Austria
Title: Hormonal treatment in patients with Endometriosis
Biography:
René Wenzl has completed his residency in obstetrics and gynecology from Medical School of Vienna in 1995 and master degree of Science from Donau-Universität-Krems in 2005. He has been senior physician at the Department of OB/GYN in 2004 and was announced as Head of the Centre for Endometriosis at the Medical University of Vienna in 2010. His scientific dedication applies to the research of pathogenesis and effective treatment of endometriosis and its concomitant diseases. He is fellow member for various societies such as The Johns Hopkins Medical and Surgical Association, European Society for Gynecological Endoscopy and New York Academy of Science. He has published more than 70 papers in reputed journals and serving as an editorial board member of repute.
Abstract:
Endometriosis is a painful, chronic disease occurring when endometrium is located outside the uterus, affecting at least 6 million women worldwide. Symptoms like dysmenorrhea, dyspareunia, dysuria, fatigue or other gastrointestinal indications such as diarrhea, constipation, nausea are responsible for severe aggravation of women’s life. Endometriosis compromises the quality of life of countless women worldwide and is a leading cause of disability. Clinical symptoms of endometriosis can be very heterogeneous leading to a long interval between onset of symptoms (commonly 7 years) and surgical diagnosis. Treatment for endometriosis is usually with medications or surgery. Supplemental hormones are sometimes effective in reducing or eliminating the pain of endometriosis. That's because the rise and fall of hormones during the menstrual cycle causes endometrial implants to thicken, break down and bleed. Hormone medication may slow the growth and prevent new implants of endometrial tissue such as Hormonal contraceptives, Gonadotropin-releasing hormone (Gn-RH) agonists and antagonists, Progesterone and progestin or Danazol. The lecture should provide an overview of current treatment options apart from surgical interventions such laparoscopy and hysterectomy.
- Steroids in Sports
- Anabolic Steroids and Supplements