International Conference on Cancer Biology and Drug Delivery September 18-19, 2017 Philadelphia, Pennsylvania, USA

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.

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 4^th 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.

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.

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.

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.

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.

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 C_max (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.

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.

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 2^nd 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.

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.

Biography:

Seung-Cheol Lee has completed his PhD from Korea Advanced Institute of Science and Technology in 2001, and has completed his Post-doc at the Korea Basic Science Institute and the University of Pennsylvania. He is a Research Assistant Professor of Radiology at the University of Pennsylvanis since 2011. His research focus is on imaging cancer metabolism in the cellular level, animal models and human patients using NMR and mass spectrometry.

Abstract:

Ibrutinib, a Bruton tyrosine kinase inhibitor, is being popularly used for treatment of relapsed/refractory mantle cell lymphoma (MCL) as well as chronic lymphocytic leykemia/small lymphocytic lymphoma (CLL/SLL). We are working on metabolic pathway analysis of MCL cells upon ibrutinib treatment using novel 13C NMR and mass spectrometry techniques and flux analysis methods. Ibrutinib sensitive MCL-RL cells and ibrutinib less sensitive Jeko-1 cells were studied. Cells were incubated in the medium containing 1, 6-13C glucose, 1, 2-13C glucose or U-13C glutamine for 8 hours to reach steady state of labeling enrichment of intracellular metabolites, and 13C labeling information was obtained using NMR or liquid chromatography mass spectrometry (LC-MS) techniques. Bonded cumomer and fragmented cumomer analysis methods were employed for analysis of NMR and LC-MS data. Significant changes were observed in the fluxes of glycolysis, glutaminolysis, reductive carboxylation and fatty acid syntheis in MCL-RL cells after ibrutnib treatment while less or no changes in JeKo-1 cells. Glycolytic flux changed to 1/4 in MCL-RL cells while to 1/2 in in JeKo-1 cells. Glutaminolysis changed by 90% in MCL-RL cells while no change in JeKo-1 cells. When a glutaminase inhibitor, CB-839, was added to medium, JeKo-1 cells exhibited remarkable response in cell growth while MCL-RL cells did not. This study demonstrates that metabolic flux analysis provides an important clue of what pathway is being affected and what pathway is not to specific kiniase inhibitors and which metabolic pathway should be further targeted with additional drugss.

Biography:

Lincoln Edwards completed his PhD at the University of British Columbia, (Canada) and his postdoctoral studies from the National Institutes of Health, National Cancer Institute in the department of Neuro-Oncology. Lincoln then went to the Department of Neurosurgery at Cedars-Sinai Medical Center serving as a research scientist before moving to New York where he is currently an Instructor of Neuroscience, Neuro-Oncology at Cornell University, Weill Cornell Medical College. Lincoln has been serving as a review board member for the journal Frontiers of Oncology and has published in such journals as JNCI, Cancer Cell, Scientific Reports and Molecular Cancer Therapeutics. His work has led to the initiation of clinical trials for the treatment of brain cancer.

Abstract:

Cancer stem cells are a small subset of cells that drive the propagation and the initiation of certain cancers. In glioblastoma multiforme (GBM), the most common and aggressive primary brain tumor, glioma stem cells (GSCs) can affect patient survival by imparting the virulence of unabated tumor growth through cancer stem cell self-renewal and the inhibition of GSC differentiation. The molecular mechanisms underpinning these properties of GSCs are poorly understood. Here we show that ZEB1 (Zinc Finger E-Box-Binding Homeobox 1) regulates stem cell self-renewal and differentiation (stemness) and its deletion negatively impacts patient survival. DNA pull down experiments confirmed novel E-box-ZEB1 binding sites within the promoter region of the stemness promoting factor LIF, allowing ZEB1 to repress LIF activation. We have identified that a majority of GBM patients (n>500) bear ZEB1 deletion with frequent loss of heterozygosity, leading to LIF and subsequent stem cell activation. Mimicking ZEB1 loss with ZEB1 knockdown in GSCs resulted in the induction of LIF commensurate with GSC self-renewal and inhibition of differentiation. Exposure of GSCs to IFN-γ, which causes ZEB1 induction, aborted these GSC characteristics. These findings run counter to the present literature, which would suggest that ZEB1 expression increases tumorigenicity. Surprisingly, our findings illustrate that the loss of the ZEB1 gene is common in glioblastomas and that ZEB1 loss is associated with propagation of the glioma stem cell population. This implies a biologically selective role for ZEB1 that when mutated or deleted favors propagation particularly of the cancer stem cell component. These findings link ZEB1 loss to stemness with actionable implications for prognostication and treatment.

Biography:

Dr. Nicole Simone is the Margaret Q. Landenberger Associate Professor of Radiation Oncology, Co-Leader of the Breast Cancer Research Program at the Sidney Kimmel Cancer Center at Thomas Jefferson University. She received her MD from Rutgers – New Jersey Medical School and did her radiation oncology training at the National Cancer Institute. As a Physician-Scientist she studies how caloric restriction augments chemotherapy and radiation. She translates laboratory findings to patients with 3 open clinical trials using diet for breast, prostae, and endometrial cancer. She has authored over 40 research publications, sits on national grant review committees, and breast cancer clinical trial committees.

Abstract:

The aging population in the United States will double from 2020 to 2060. Diseases of aging such as heart disease and cancer will therefore increase and the healthcare infrastructure must respond with therapies that are less toxic and tolerable for this population. Caloric restriction (CR) as an intervention has consistently been shown to extend life and reduce age-related chronic diseases, such as cardiovascular disease and cancer, in animal models. CR does this by reducing oxidative stress and improving insulin sensitivity. Furthermore, breast cancer incidence in humans has been shown to be strongly correlated to dietary intake in retrospective studies. These observations have led the Simone laboratory to harness the principles of CR to use in combination with standard cancer treatment. In multiple preclinical models, we have shown that CR enhances the efficacy of radiation and chemotherapy. At the molecular level, it does so my decreasing oxidative stress and improving insulin sensitivity. We have now translated these findings into multiple clinical trials. Our pre-clinical and clinical findings, demonstrate the utility of harnessing the anti-aging properties of caloric restriction to enhance cytotoxic therapy for cancer.

Biography:

Huihuang Yan is an Assistant Professor in the Division of Biomedical Statistics and Informatics, Department of Health Sciences Research at Mayo Clinic. He has received his PhD from the Chinese Academy of Agricultural Sciences in Genetics. As part of the Mayo Clinic Center for Individualized Medicine, his research primarily focuses on cancer genomics and epigenetics and the development of algorithms for analyzing next-generation sequencing data from patients. He has published 50 peer-reviewed articles.

Abstract:

T-cell prolymphocytic leukemia (T-PLL) is a rare disease with a median survival of <1 year. T-PLL demonstrates poor response to conventional chemotherapy and inevitable relapse after immunotherapy due to resistance. Cytogenetic analysis, whole-exome and whole-genome sequencing have identified primary structural alterations in T-PLL, including inversions, translocations, and copy number variation. Recurrent somatic mutations were identified in genes encoding chromatin regulators and those in the JAK-STAT signaling pathway. Epigenetic mechanism defines cell type-specific transcriptional program, whose misregulation is implicated in disease susceptibility and progression. However, a lack of genome-wide epigenetic data has limited the mechanistic study of T-PLL carcinogenesis. Here, we used micrococcal nuclease digestion of linker DNA and sequencing of nucleosome-free DNA fragments (MNase-seq) to profile the open chromatin regions, i.e., gene regulatory regions such as promoters, enhancers and insulators, in T-PLL patients and age-matched healthy individuals. Samples were collected with written consent and approval from the institutional review board at Mayo Clinic. Clustering of normalized read density revealed distinct differences in chromatin accessibility, with both gains and losses of open chromatin regions in T-PLL relative to the normal controls. We also identified alterations of enhancers in T-PLL using histone H3 lysine 4 monomethylation (H3K4me1) and lysine 27 acetylation (H3K27ac) ChIP-seq. Our analysis provided insights into the epigenetic mechanisms that drive oncogenic activation in T-PLL.

Biography:

Dr. Rami Aqeilan has completed his PhD at the age of 27 years from Hebrew University of Jeruslam and postdoctoral studies from Thomas Jefferson University – Kimmel Cancer Cenetr. He is the Chariman of Cell Biolohy, Immunology and Cancer Reserach divison at Hebrew University-Hadassah Medical School. He has published more than 100 papers in reputed journals and has been serving as an editorial board member of Cell Death & Disease, Cell Death and Discovery and Journal of Cellular Biochemistry.           

Abstract:

Protein-coding genes comprise only 3% of the human genome, while the fast majority of the genome is comprised of non-coding genes; RNAs but do not code for proteins. MicroRNAs (miRNAs) are short non-coding RNAs that play critical roles in numerous cellular processes through post-transcriptional regulating functions. During the last decade, we and others have reported that unique miRNA signatures associate with the pathogenesis and progression of several types of cancer. MiRNAs can act as tumor suppressors or behave as oncogenes depending on cellular context. In the last few years, our attempts were focused to design potent miRNAs as anticancer drugs and drug targets. Typically, one strand of a miRNA duplex is bound by argonaute proteins, loaded on microRNA-induced silencing complex (miRISC), and guides the miRISC to target mRNAs. This strand is called “lead” or “guide” strand. The other strand is usually mostly degraded and presented in the cell at much lower level. This strand is called “passenger” or “star” strand and designated as miR*. We recently found that the passenger strand of miRNAs (miR*) can have potent biological effects. We demonstrated that, for example, miR-16-1* and miR-16-2* inhibits primary tumor growth, metastasis, and chemoresistance and invasiveness of human cancer cells. Noteworthy, star miRNAs have different, although strongly overlapping functions with leading strand miRNAs. Importantly, systemic delivery of miR* in vivo have promising anti-tumor effects which prompt us to expand use of miR* in clinical trials for the treatment of relevant cancer types. Our findings indicate that deregulation of miRNA expression is a driving force in oncogenesis that can be utilized to target tumor cells.

Biography:

Oncolytic viruses are native or modified viruses that directly kill tumor cells, but spare normal tissue, and promote host anti-tumor immunity. An oncolytic herpes simplex virus (oHSV) type 1 encoding human granulocyte-macrophage colony-stimulating factor (GM-CSF), demonstrated significant clinical benefit in a randomized phase III clinical trial for patients with advanced melanoma leading to regulatory approval in 2015. In this review, we will describe the general characterization of herpes simplex viruses; and discuss methods for vector modification that can help limit viral pathogenicity and immunogenicity while promoting anti-tumor immunogenicity. We will also provide insight into general strategies for using oHSV agents in tumor immunotherapy regimens for the treatment of cancer and briefly review some of the current pre-clinical and clinical data emerging to support an important role for such agents in the treatment of cancer.

Abstract:

Oncolytic viruses are native or modified viruses that directly kill tumor cells, but spare normal tissue, and promote host anti-tumor immunity. An oncolytic herpes simplex virus (oHSV) type 1 encoding human granulocyte-macrophage colony-stimulating factor (GM-CSF), demonstrated significant clinical benefit in a randomized phase III clinical trial for patients with advanced melanoma leading to regulatory approval in 2015. In this review, we will describe the general characterization of herpes simplex viruses; and discuss methods for vector modification that can help limit viral pathogenicity and immunogenicity while promoting anti-tumor immunogenicity. We will also provide insight into general strategies for using oHSV agents in tumor immunotherapy regimens for the treatment of cancer and briefly review some of the current pre-clinical and clinical data emerging to support an important role for such agents in the treatment of cancer.

Biography:

Dr. Kelly Conlon is currently working in Midatech Pharma, UK. Midatech is an international specialty pharmaceutical company focused on developing and commercialising products in oncology and other therapeutic areas. Midatech’s core technology platform is based on a patented form of gold nanoparticles (GNPs), which has been developed to improve key parameters when bound to existing and new drugs. GNPs aim to target individual cell types with specific targeting agents and deliver a therapeutic payload into the tumour cell, and reduce the current side-effect profile associated with chemotherapy.

Abstract:

Cytotoxic chemotherapy is the standard of care for many types of cancer despite frequently observed severe side effects. The primary goal of a new cancer treatment is to enhance therapeutic efficacy and minimise harmful side effects. Gold nanoparticles (GNP’s) are promising candidates for drug delivery systems for cancer therapeutics due to both the intrinsic non-toxic properties of the gold nanocore and the ability to tailor the functionality of the surface.  The highly potent microtubule inhibitor maytansine, is a potent anti-cancer agent, however clinical development was halted due to toxicity.  DM1 is a derivative of maytansine.  Here we describe how tumour targeting of DM1 using ultra small GNP’s (MTC-100038) results in improved efficacy and tolerability compared to DM1 alone in pre-clinical HCC cancer models. In subcutaneous and orthotopic xenograft mouse models (BALB/c nude, NOD/SCID) using human hepatoma cell lines (BEL7404, Hep3B), MTC-100038 increased both the tolerability of DM1 and demonstrated potent anti-tumour activity compared to controls. When comparing reduction in tumour growth, the highest tolerated dose of DM1 alone (150 μg/kg) was not significantly different to vehicle control. Peak reduction in tumour growth with MTC-100038 (337.5 μg/kg) was greater than six-fold (mean reduction more than three-fold) compared to the highest tolerated dose of the current standard of care (SOC) sorafenib (60 mg/kg) in the same studies.  In summary, MTC-100038 delivered significant efficacy in mouse models of HCC when compared to the maximum tolerated doses of both DM1 alone, and the current HCC SOC, sorafenib.  MTC-100038 will now enter IND enabling studies.

Biography:

Oya Altinok is a graduate student at Drexel University College of Medicine and Drexel School of Biomedical Engineering, Science and Health Systems. She is currently working on a Master Thesis in the field of colon cancer metabolism.

Abstract:

The requirement for metabolic efficiency forces cancer cells to generate sufficient energy equivalents to support their high proliferative activity. One cycle of glycolysis supplies cells with two molecules of ATP only, while oxidative phosphorylation provides around 36 molecules of ATP. Therefore, many cancer types, including colon cancer, reprogram their metabolism to accelerate mitochondria processes to fulfill the elevated energy demands of cancer cells. However, the long known signature of cancer is elevated glycolysis. We hypothesized that glycolysis and oxidative phosphorylation are functionally coupled processes. In this work we studied the malate-aspartate and lactate shuttle mechanisms of colon cancer mitochondria. The two shuttles cooperate with each other in regulating the NAD⁺/NADH pool to enable aerobic oxidation of glucose by mitochondria.