Day 1 :
Keynote Forum
Diana Anderson
University of Bradford, UK
Keynote: An empirical assay for assessing genomic sensitivity and for improving cancer diagnostics
Time : 10:00-10:30
Biography:
Diana Anderson holds the Established Chair in Biomedical Sciences at the University of Bradford. She has obtained her first degree in the University of Wales and second degree in the Faculty of Medicine, University of Manchester. She has 450+ peer-reviewed papers, 9 books, has successfully supervised 29 PhDs, and been a Member of Editorial Boards of 10 international journals. She has been or is Editor in Chief of a book series on Toxicology for J Wiley and Sons and the Royal Society of Chemistry respectively. She gives key note addresses at various international meetings. She is a consultant for many international organizations, such as the WHO, NATO, TWAS, UNIDO and the OECD. Her h index = 54.
Abstract:
Detection tests have been developed for many cancers, but there is no single test to identify cancer in general. We have developed such an assay. In this modified patented Comet assay, we investigated peripheral lymphocytes of 208 individuals: 20 melanomas, 34 colon cancers, 4 lung cancer patients, 18 suspect melanomas, 28 polyposis, 10 COPD patients and 94 healthy volunteers. The natural logarithm of the olive tail moment was plotted for exposure to UVA through different agar depths for each of the above groups and analyzed using a repeated measures regression model. Response patterns for cancer patients formed a plateau after treating with UVA where intensity varied with different agar depths. In comparison, response patterns for healthy individuals returned towards control values and for pre/suspected cancers, were intermediate with less of a plateau. All cancers tested exhibited comparable responses. Analyses of receiver operating characteristic curves, of mean log olive tail moments, for all cancers plus pre/suspected-cancer versus controls gave a value for the area under the curve of 0.87; for cancer versus pre/suspected-cancer plus controls the value was 0.89; and for cancer alone versus controls alone (excluding pre/suspected-cancer), the value was 0.93. By varying the threshold for test positivity, its sensitivity or specificity can approach 100% whilst maintaining acceptable complementary measures. Evidence presented indicates that this modified assay shows promise as both a stand-alone test and as a possible adjunct to other investigative procedures, as part of detection programs for a range of cancers.
Recent Publications:
- Diana Anderson et al, (2014) Sensitivity and specificity of the empirical lymphocyte genome sensitivity (LGS) assay: implications for improving cancer diagnostics. The FASEB Journal article. 28 (10): 4563-4570.
Keynote Forum
Michael Retsky
Harvard TH Chan School of Public Health, USA
Keynote: Perioperative use of NSAID might prevent early relapses in breast and other cancers: an upstream approach
Time : 10:30-11:00
Biography:
Michael Retsky is working as Staff at Harvard TH Chan School of Public Health and Faculty at University College London. He was on Judah Folkman’s Staff at Harvard Medical School for 12 years. He is the Editor of a Nature/Springer Book on the Breast Cancer Project to be published in 2017. He was the first person to use what is now called Metronomic Adjuvant Chemotherapy and is a Founder and on the Board of Directors of the Colon Cancer Alliance. He has published more than 60 papers in Physics and Cancer.
Abstract:
A bimodal pattern of hazard due to relapse among early stage breast cancer patients has been identified in multiple databases from US, Europe and Asia. We are studying these data to determine if this can lead to new ideas on how to prevent relapse in breast cancer. Using computer simulation and access to a very high quality database from Milan for patients treated with mastectomy only, we proposed that relapses within three years of surgery are stimulated somehow by the surgical procedure. Most relapses in breast cancer fall in this early category. Retrospective data from a Brussels Anesthesiology Group suggests a plausible mechanism. Use of ketorolac, a common NSAID analgesic, used in surgery was associated with far superior disease-free survival in the first five years after surgery. The expected prominent early relapse events in months 9-18 are reduced five-fold. Transient systemic inflammation, accompanying surgery (identified by IL-6 in serum) could facilitate angiogenesis of dormant micrometastases, proliferation of dormant single cells, and seeding of circulating cancer stem cells (perhaps in part released from bone marrow) resulting in early relapse and could have been effectively blocked by the perioperative anti-inflammatory agent. If this observation holds up to further scrutiny, it could mean that the simple use of this safe, inexpensive and effective anti-inflammatory agent at surgery might eliminate early relapses. We suggest this would be most effective for triple negative breast cancer and be especially valuable in low and middle income countries. Similar bimodal patterns have been identified in other cancers suggesting a general effect.
Biography:
Jianhua Luo has been studying Molecular Pathology related to human malignancies from the last 25 years. Currently, he is a Professor of Pathology and Director of High Throughput Genome Center at University of Pittsburgh. In the last 17 years, he has been largely focusing on the genetic and molecular mechanism of human prostate and hepatocellular carcinomas. In this period, his group has identified and characterized several genes that are related to prostate cancer and hepatocellular carcinoma, including SAPC, myopodin, CSR1, GPx3, ITGA7, MCM7, MT1h and GPC3. He has characterized several signaling pathways that play critical role in prostate cancer development. He is one of the pioneers in utilizing high throughput gene expression and genome analyses to analyze field effects in prostate cancer and liver cancer. He is also the first in using methylation array and whole genome methylation sequencing to analyze prostate cancer. His group found that patterns of copy number variants of certain specific genome loci are predictive of prostate cancer clinical outcomes, regardless tissue origin. Recently, his group discovered several novel fusion transcripts and their association with aggressive prostate cancer. One of the fusion genes called MAN2A1-FER, was found present in 6 different types of human cancers. He later defined a critical MAN2A1-FER/EGFR signaling pathway that is essential for MAN2A1-FER mediated transformation activity. In addition, his group developed a genome intervention approach to treat human cancers that are positive for fusion gene.
Abstract:
Mutations and chromosome rearrangement are some of the key features of human malignancies. Recently, we discovered a panel of cancer-specific fusion genes that play key roles in human cancer development. One of these fusion genes called MAN2A1-FER generated a constitutively activated tyrosine protein kinase. The fusion translocates FER kinase from the cytoplasm to Golgi apparatus. The fusion protein ectopically phosphorylates the N-terminal domain of EGFR, and activates the EGFR signaling pathway in the absence of a ligand. MAN2A1-FER has been found in a variety of human malignancies. It transforms immortalized cell lines into highly aggressive cancer cells. Expression of MAN2A1-FER produces spontaneous liver cancer in animals. Cancer cells positive for MAN2A1-FER are highly sensitive to several tyrosine kinase inhibitors, and can be targeted by genome therapy intervention. Thus, targeting at MAN2A1-FER or other oncogenic fusion genes may hold promise to treat human cancer effectively.
Biography:
Andrei L Gartel is working as 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 88 peer-review publications that include more than 25 reviews. He has more than 11,000 citations and his h-index is 38. His scientific interests include cancer, regulation of oncogenic transcription factors FOXM1, protein-protein interactions; cell cycle and regulation of CDK inhibitor p21. 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. Chaperone HSP70 is induced after treatment with proteasome inhibitors 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. Honokiol is a natural product that inhibits FOXM1-mediated transcription and FOXM1 protein expression. We found that honokiol’s inhibitory effect on FOXM1 is a result of direct binding of honokiol to FOXM1. This binding is specific to honokiol, a dimerized allylphenol, and was not observed in compounds that either were monomeric allylphenols or un-substituted dihydroxy phenols. We have previously shown that FOXM1 interacts with nucleophosmin (NPM) in cancer cells and NPM determines cellular localization of FOXM1. Mutations in NPM1 result in cytoplasmic re-localization of NPM (NPM1mut) and favorable outcome for the AML patients. We found the evidence that improved outcomes in the subset of NPM1mut AML may be partially explained by the cytoplasmic re-localization and consequent functional inactivation of FOXM1. We also showed an important role of FOXM1 in chemo-resistance in AML with nuclear, but not cytoplasmic FOXM1. These data imply that suppressing of FOXM1 in AML could increase sensitivity to standard chemotherapy, while overexpression of FOXM1 would increase chemo-resistance of AML cells.
- Cancer and Cell Biology | Organ Specific Cancer | Oncogenomics | Cancer Imaging | Cancer Biomarkers | Cancer Pharmacology | Hematology-Oncology| Epithelial Cancers| Cancer Treatments and Vaccines| Cancer Screening| Cancer Epidemiology| Global Market for Cancer Treatments
Location: Philadelphia
Session Introduction
Mark Hurwitz
Thomas Jefferson University, USA
Title: Thermally targeted drug delivery
Biography:
Mark Hurwitz, M.D. is Professor, Vice-Chair of Quality, Safety and Peformance Excellence and Director of Thermal Oncology at Thomas Jefferson University in Philadelphia, PA. Dr. Hurwitz is a past-president of the Society for Thermal Medicine. He serves as an associate editor for the International Jounral of Hyperthermia and is a widely recognized expert in both genitourinary and thermal oncology. He has published extensively on these topics and is a sought after speaker both nationally and internationally. He has successfully led multi-national clinical trials including on behalf of industry, the Cancer and Leukemia Group B, Radiation Therapy Oncology Group, and NRG Oncology.
Abstract:
Thermal Oncology includes use of both sensitizing and ablative temperature change. Mild to moderate hyperthermia involves elevation of temperature between 39-45°C. These modest temperature changes have been shown in multiple randomized trials to increase the effectiveness of radiation therapy and chemotherapy in treatment of cancer. Thermal ablation involves use of more extreme temperatures to achieve direct tumor cell destruction. Ablation also includes a heated but not ablated rim of tissue to which the principles of hyperthermic sensitization apply. Pre-clinical and clinical studies demonstrating current and emerging roles for heat in combination with radiation, chemotherapy and immunotherapy will be presented. In regard to systemic oncologic therapy, a rapidly expanding area of research is use of targeted drug delivery. Targeted drug delivery has the advantage of greatly concentrating oncologic drug release directly into or adjacent to tumor while minimizing systemic toxicity. Heat can be used in combination with thermally sensitive drug carriers including liposomes, magnetic nanoparticles and microbubbles to achieve targeted drug delivery. Results of both pre-clinical and clinical studies of thermally targeted drug delivery utilizing a range of drug carriers will be presented and future directions discussed.
Lyuba Varticovski
National Cancer Institute, USA
Title: Genome-wide enhancer signature predicts metastatic potential of bladder cancer
Biography:
Lyuba Varticovski has completed her Undergraduate training and started her Medical Schooling. She has finished Internal Medicine training in Albany MC, Albany, NY. Her Hematology and Oncology fellowship was at the New England Medical Center in Boston, MA, where she has continued as an Academic and Clinical Faculty Member for 20 years. She has joined NCI Center for Cancer Research in 2003. She is currently an Associate Staff in the Laboratory of Receptor Biology and Gene Expression, NCI, NIH. She is Board-certified in Internal Medicine and Hematology/Oncology and has published over 100 peer-reviewed manuscripts, 14 book chapters and has several patents.
Abstract:
Bladder cancer is the 4th most common cancer in men in the US and metastatic disease carries poor prognosis. To date, only few driving mutations have been identified in this tumor type, but altered gene expression involving an estimate of >2,300 coding sequences involving many chromatin modifiers. These data indicate that chromatin organization plays an important role in bladder cancer development and progression. We compared whole exome sequencing and mRNA expression with analysis of DNase I hypersensitivity combined with deep sequencing (DHS-seq) on multiple cell lines developed by in vivo selection. Bioinformatics of DHS-seq was performed using algorithms developed at LRBGE. Analysis of microarray expression was performed using Ingenuity Pathways (IPA). Only few additional mutations and gene expression marked the progression to metastatic phenotype and these did not correspond to specific pathways. In contrast, enhancers analysis assigning to nearest neighbor gene identified genes involved in cell-to-cell interaction, with a decrease in genes involved in cell adhesion and increase in genes associated with EMT. Gene expression profile correlated with nearby chromatin remodeling of regulatory regions. Genome-wide analysis of DHS showed large-scale changes in chromatin landscape during tumorigenesis indicating massive reprogramming of regulatory networks. Thus, combination of global unbiased chromatin landscape, exome sequencing, and microarray profiling opens a new valuable view of enhancers signature for establishing biomarkers, analysis of tumor progression and understanding the biology of bladder cancer.
Kavindra Nath
University of Pennsylvania, USA
Title: Selective Acidification and De-energization of Cancers with Lonidamine for Sensitization to Chemo and Radiation Therapy
Biography:
Kavindra Nath is a Research Assistant Professor at the University of Pennsylvania, Perelman School of Medicine. He did Ph.D. in Magnetic Resonance Imaging and Spectroscopy (MRI/MRS) from premier medical institution in India. In Ph.D. he studied the role of MRI and MRS techniques in the differential diagnosis of cystic intracranial mass lesions in patients. His current research at University of Pennsylvania is utilizing multi-nuclear (1H, 31P, 13C) MRS and other techniques in vitro and in vivo in order to delineate the mode of action of various monocarboxylate transports, mitochondrial pyruvate carrier and electron transport chain inhibitors, which distinguishes normal cells from malignant cells and potentiates the activities of various chemotherapeutic drugs, radiation therapy and hyperthermia in a variety of human cancers. He has published more than 30 papers in reputed journals and has been serving as an editorial board member of many reputed journals.
Abstract:
As a consequence of high levels of aerobic glycolysis, tumors exhibit an acidic extracellular pH (pHe) and a neutral to alkaline intracellular pH (pHi) leading to an acid-outside/neutral to mildly alkaline inside plasmalemmal pH gradient. This gradient also impacts tumor response to certain chemotherapeutic agents and to radiation therapy, hyperthermia, and photodynamic therapy. Manipulation of pHe and/or pHi of tumors have considerable impact on tumor growth and metastasis as well as response to therapy. Extracellular tumor acidification has been modified by administering sodium bicarbonate in order to increase the pHe and thereby reduce tumor invasiveness and facilitate uptake of weakly basic chemotherapeutic drugs. In contrast, our aim was to decrease the pHi in order to increase the intracellular activity of N-mustards and doxorubicin against varoius cancer xenografts. We accomplished this by administering lonidamine (LND, 100 mg/kg, intraperitoneal), an inhibitor of the monocarboxylate transporter (MCT), mitochondrial pyruvate carrier and complex II of electron transport chain that blocks cellular export of lactic acid and also inhibits transport of pyruvate into mitochondria, thereby inhibiting tumor energy production. LND sensitizes tumors to radiation therapy by increased tumor oxygenation and decreased ATP levels and decreased levels of glutathione. Other MCT inhibitors such as AZD3965, manufactured by AstraZeneca, alone or in combination with complex I inhibitors (metformin, phenformin) may exhibit similar properties to LND in modifying tumor pHi and bioenergetics. These agents may, therefore, play an important role in modifying the tumor microenvironment to make more susceptible to certain classes of chemotherapeutic agents and to radiation therapy.
Zulfiya Orynbayeva
Drexel University College of Medicine, USA
Title: Prostate and Colon Cancer metabolisms. What they thought us about processes behind the Warburg effect?
Biography:
Zulfiya Orynbayeva earned her PhD in Biophysics/Bioenergetics from Tashkent University in Uzbekistan. She completed postdoctoral training at Ben-Gurion University of the Negev in Israel and Martin-Luther University Halle-Wittenberg in Germany. She leads the Mitochondria Pathophysiology Laboratory at the Department of Surgery, Drexel University College of Medicine. She published more than 28 articles in high impact journals.
Abstract:
Cancer is a metabolic disease. Dysregulation of energy generating processes is essential in cancer development and progression. Elevated glycolysis under the condition of malfunctioning mitochondria is known as the Warburg Effect, which was proposed in 1924. 93 years later what lies behind the increased consumption of glucose by malignant cells is poorly understood. In addition, as research is progressing, it has become evident that cancer mitochondria performance is not weak, but rather oxidative phosphorylation is more intense in cancer than in healthy cells. Our group has demonstrated that prostate and colon cancers acquire highly oxidative mitochondria. The higher membrane potential, increased calcium retention capacity, higher activities of respiratory enzymes are among mitochondria features that enable cancer cells to escape apoptosis. We study mitochondria changes induced by cancer to understand whether glycolysis and oxidative phosphorylation are functionally disconnected or support each other. We hypothesize that these two major energy generating pathways have a special cooperative relationship in supporting highly proliferative cancer cells. The mitochondria malate-aspartate and lactate shuttles are the focus of our research as a bridging mechanism between cytosolic glycolysis and mitochondria oxidative phosphorylation.
Virendra N Pandey
New Jersey Medical School, USA
Title: Molecular mechanism of tumorigenesis induced by fuse binding protein 1: A potential target for anticancer drug development
Biography:
Dr. Virendra Pandey received his Ph.D. in 1985 from the University of Mumbai at Bhabha Atomic Research Center (BARC), India. He served as Professor (Scientist-F) at BARC until 1994 and received the most prestigious Shanti Swaroop Bhatnagar Award in 1991 for his research contribution in Life Sciences. He has published more than 90 research articles in reputed peer reviewed journals and has received continuous research funding from the National Institute of Health for the past 20 years. Currently, he is tenured senior faculty and a member of the Rutgers University Senate.
Abstract:
Persistent Hepatitis C virus (HCV) infection leads to chronic hepatitis C (CHC), which often progresses to liver cirrhosis (LC) and hepatocellular carcinoma (HCC). We recently identified an oncogenic cellular factor, FUSE binding protein 1 (FuBP1), which antagonizes the function of tumor suppressor p53 and promotes persistent HCV replication and associated pathogenesis. We found that the direct target of FuBP1 in cancer cells is the tumor suppressor p53, the function of which is actively suppressed by FuBP1. Knockdown of FuBP1 in cancer cells significantly activates p53, increases their sensitivity to apoptotic stimuli, and drastically reduces cell proliferation and migration. We found that FuBP1 physically interacts with the wild-type p53 as well as all the p53 isoforms found in cancers. FuBP1 interaction with p53 strongly inhibits the target DNA binding function of p53. Mapping of the FuBP1-interaction site on p53 molecule indicated DNA binding domain of p53 as the site of FuBP1 interaction. Since FuBP1 expression is undetectable in normal differentiated cells, its overexpression in most cancers including HCC suggests that it is a potential target for drug development.
Alena Kreychman
Baystate Medical Center, USA
Title: Xofigo, radioactive ra 223 treatment of castrate resistant prostate bony metastasis
Biography:
Alena Kreychman is a radiologist at Baystate Medical Center and Radiology and Imaging, Inc. She is an Assistant Professor of Radiology at UMMS-Baystate, an Adjunct Assistant Professor of Radiology at Tufts University Medical School, and serves as visiting faculty at Harvard Medical School.
She is an active member of the Baystate Organization Women Advancing and Achieving in Medicine (WAAM), and serves as Administrative Officer for the organization.
Abstract:
Xofigo is an alpha-particle emitting radio isotope radium-223 dichloride. The drug mimics calcium and forms complexes with the bone mineral at sites of bone metastatses. It then emits alpha particles, causing the destruction of DNA in nearby cells, resulting in cancer cell death in the bone. Xofigo is the only therapeutic radiopharmaceutical in treatment of bony metastasis. When it comes to unsealed sources of radiation, this is the first one that has shown significant survival benefits. That is a historical event in the radiotherapies. There are also secondary benefits, including delaying time to first skeletal-related event. It is also the first alpha emitter that has been FDA approved. The critical feature of an alpha emitter is that it is a much more powerful particle, which travels a shorter distance while hitting the cancer cells harder and avoding the healthy cells, so the complication rates are decreased. Because of those reasons, Xofigo is really making a huge impact in the history of oncologic interventions.
Vaishnavi Sambandam
The University of Texas MD Anderson Cancer Center, USA
Title: Metabolic dysregulation drives sensitivity after pi3k/mtor inhibition in HNCCC
Biography:
Dr. Vaishnavi Sambandam is a Postdoctoral Fellow in The University of Texas MD Anderson Cancer Center and she is associate with Dr. Faye Johnson Laboratory.
Abstract:
Genomic alterations in the PI3K/mTOR pathway occur in 54% of HNSCC patients. However, clinical trials of PI3K/mTOR pathway inhibitors had limited success even in those tumors with pathway alterations, including PIK3CA mutations. To identify mechanisms driving sensitivity in HNSCC, we tested the efficacy of 7 PI3K/mTOR pathway inhibitors in 59 HNSCC cell lines and classified the cell lines as sensitive and resistant to drugs based on Cmax (peak plasma concentration). After PI3K/mTOR inhibition, the sensitive lines showed significantly reduced clonogenic growth in vitro (0.4/ 0.9-fold in HN31/PCI15B; P<0.05) and significant tumor growth inhibition in vivo using Orthotopic oral xenograft mouse models (1.7 and 2-fold in UMSCC22A and HN31; P<0.01). As no canonical pathways account for the underlying mechanism of sensitivity, we measured the level of 301 proteins by reverse phase protein array (RPPA) in 3 sensitive and 3 resistant lines after GSK2126458 treatment. The protein levels of glutaminase and glutamate dehydrogenase were differentially regulated in sensitive lines. Thus, we hypothesized that PI3K/mTOR inhibition in responding cell lines induced reactive oxygen species (ROS)-mediated apoptosis via metabolic alterations. Consistent with this hypothesis, sensitive lines exhibited increased ROS production after GSK2126458 treatment. It also increased the levels of phosphogluconate dehydrogenase (PGD) and decreased levels of glutamate. Metabolic pathway inhibitors targeting glutaminolysis, in combination with GSK2126458 decreased cell viability in resistant cell lines. In addition, we identified that sensitive HNSCC cells that underwent apoptosis after PI3K/mTOR pathway inhibition harbored NOTCH1 mutation. The underlying mechanism may involve the effect of NOTCH pathway on tumor metabolism and ROS production. This work is significant because inactivating NOTCH1 mutations, which occur in 18% of HNSCC patients and SCCs of the lung, esophagus, and other sites, may serve as a biomarker for response. Our future work may uncover previously unknown crosstalk between the PI3K/mTOR and NOTCH pathways in SCCs.
Muhammad Bhatti
University of Texas Rio Grande Valley, USA
Title: Radio frequency electromagnetic waves induce cancer cell death
Biography:
Professor Muhammad Bhatti recieved Ph. D. From the University of Notre Dame, IN, USA. He completyed postdoctoral studies from the University of Vanderbilt. He has been serving as a professor at the University of Texas Rio Grande Valley in the department of Physics. He has published more than 50 papers in reputed journals and has been serving as an editorial board member of repute and serving as manuscript reviewer for several prestigious journals.
Abstract:
The primary objective of this research endeavor is to study and to understand the natural physics phenomenon of electromagnetic resonance in one end closed cavity for the eventual purpose of cancer treatment. Radio Frequency waves are discharged into a coaxial cavity filled with a small amount (1.6 mL) of breast cancer cells (BT549) and the reflection as well as the power input is measured to determine the absorption power into the vitro cancer cell experiment. When the reflection of the RF waves from the loaded sample of cancer cells is at its lowest power, the RF Frequency is noted and seen to be approximately close to the resonant frequency of that cavity. This cavity can potentially be used as a control method of testing RF frequencies on various types of cancer cells, such as the available BT549 cancer cell line from Biology department. The determined frequency for 1.6 mL of sample article is found to be in the range of radio frequency, but there is much room for improvement depending on the coaxial cavity design such as length and the radii of the coaxial tubes which is currently under investigations. Some preliminary results are obtained which show that the electromagnetic waves induce cancer cell death which is known as apoptosis. At the Cancer-2017 conference, results of the experiment for the teatment of cancer cells will be presented.
Sajid Iqbal
Emirates College of Technology, UAE
Title: A srudy on breast cancer risk factors in pakistani population
Biography:
Sajid Iqbal has completed his Pre-doctoral program in Biomedical Sciences from Department of Human Genetics, KU Leuven University, Belgium. Currently, he is working as Institution Research Manager with Emirates College of Technology, Abu Dhabi, UAE. Few of his publications are in international journals.
Abstract:
Breast cancer (BC) is the second most widespread and the highest conjoint cancer among world female population. This cross-sectional case control study aims not only BC profiling but also to determine the associated risk factors, and quantification of the BC risk in Pakistani women. 210 females were studied, including 105 confirmed BC patients and equal number of controls (healthy women). Demographic characteristics along with potential risk factors information were collected via well-structured questionnaire. Logistic regression, Pearson’s Chi square/ Fisher’s exact tests were applied. Among cases, the most frequent age at diagnosis was 31–50 years and 2nd stage observed as most frequent stage. The utmost common histology was unilateral IDC. Female with a positive family history were at higher risk for developing BC (OR = 1.23, 95% CI = 0.6 – 2.3). An early age at menarche, menopausal status and age at last pregnancy found as a strong risk factor for developing BC (P value <0.05) In multivariate models, Environmental area and exposure to X-Ray radiations were found significantly associated with BC risk (p = 0.012, 0.03). This study provides important background information for designing detailed studies that aim to improve our understanding of the epidemiology of breast cancer in the Pakistani population, including the gene interactions and environmental effect.
Biography:
Rajagopal Chattopadhyaya is currently working at Bose Institute, India.
Abstract:
The influence of substoichiometric amounts of seven plant extracts in the Fenton reaction-mediated damage to deoxynucleosides, deoxynucleoside monophosphates, deoxynucleoside triphosphates and supercoiled plasmid DNA were studied to rationalize anticancer properties reported in the extracts Acacia catechu, Emblica officinalis, Spondias dulcis, Terminalia belerica and Terminalia chebula. Extracts from these five plants, as well as gallic acid, epicatechin, chebulagic acid and chebulinic acid enhance the extent of damage in Fenton reactions with all monomeric substrates but protect supercoiled plasmid DNA, compared to standard Fenton reactions. However, Dolichos biflorus and Hemidesmus indicus extracts generally do not show this enhancement for the monomeric substrates though they protect plasmid DNA. Compared to standard Fenton reactions for deoxynucleosides with ethanol, the presence of these five plant extracts render ethanol scavenging less effective as the radical is generated near the target. Since substoichiometric amounts of these extracts and the four compounds produce this effect, a catalytic mechanism involving the presence of a ternary complex of the nucleoside/nucleotide substrate, a plant compound and the hydroxyl radical was proposed. Such a mechanism cannot operate for plasmid DNA as the planar rings in the extract compounds cannot stack with the duplex DNA bases. These plant extracts, by enhancing Fenton reaction-mediated damage to deoxynucleoside triphosphates, slow down DNA replication in rapidly dividing cancer cells. In another set of experiments, extracts of Acacia catechu, Emblica officinalis, Terminalia belerica, Terminalia chebula, Spondias dulcis, completely inhibit human topoisomerase I at 40 μg/ml concentration while Hemidesmus indicus and Dolichos biflorus extracts inhibit partially at the same concentration when included in standard assays. Extracts of the same five plants which inhibit human topoisomerase I strongly are known to possess anticancer activity, while the other two are antioxidant only. Extracts of Acacia catechu, Terminalia chebula and Spondias dulcis show 20 to 80% inhibition of human topoisomerase I at even 9 μg/ml concentration. All seven plant extracts partially inhibit human topoisomerase II at 120 μg/ml concentration in the decatenation assay. Chebulagic and chebulinic acid purified from Terminalia chebula extract inhibited human topoisomerase I at around 2 μM and 3 μM respectively. The nuclear fragmentation leading to apoptosis observed earlier in cancerous cell lines in the presence of such plant extracts may thus be explained by the inhibition of topoisomerases in addition to modulation of Fenton reaction-mediated damage to DNA constituents.
Lixian Zhong
Texas A&M University, USA
Title: Cost-effectiveness of Niraparib, Olaparib and Rucaparib in treatment of platinum sensitive, recurrent ovarian Cancer
Biography:
Dr. Lixian Zhong is a health economist who has conducted research on the costs and outcomes associated with pharmaceutical products in both academic institutes and pharmaceutical industry settings. She received her Ph.D from Duke University. Her research has been cited over 600 times. Her research interest lies at the intersection of science, medicine and economics to assess clinical, economic and humanistic values of pharmaceutical interventions. She has conducted research using clinical trial data, real world data and economic modeling to study cost-effectiveness of new interventions for cancer and multiple sclerosis. She is currently an assistant professor in College of Pharmacy at Texas A&M University.
Abstract:
Objective: To evaluate the cost-effectiveness of new ovarian cancer PARP inhibitor targeted therapy olaparib, rucaparib and nirparib as maintenance therapy for platinum sensitive, recurrent gBRCA ovarian cancer. Methods: We constructed an economic model to compare the costs and effectiveness associated with each of these treatment options based on clinical trial results from a healthcare sector perspective. Costs were measured in 2017 USD and included not only drug costs but also costs of disease monitoring and management of adverse events throughout the treatment course until disease progression. Effectiveness was measured in quality-adjusted progression-free survival years (QA-PFS) which was computed by adjusting progression free survival years (PFS) by the reported quality of life in these patients. We evaluated the incremental cost-effectiveness ratio (ICER) as measured by dividing the incremental costs by the incremental effectiveness. Results: At base case, niraparib the most effective treatment option with the highest QA-PFS followed by olaprib and rucaparib. Niraparib was also associated with the highest costs followed by olaprib and rucaparib. The ICERs for niraparib compared to placebo is $260k and $155k compared to olaparib. Sensitivity analysis suggested that BRCA status impact ICERs significantly. Conclusions: PARP inhibitors significantly extends PFS in recurrent ovarian cancer patients who are sensitive to platinum based chemotherapy but are also associated with high drug costs of over 10k a month. Given a willingness to pay (WTP) between 100-150 QA-PFS, niraparib could be a cost-effective option compared to olaparib when treating patients population with at least 21% carrying BRCA mutations.