Day 2 :
Keynote Forum
Myron Arlen
Hofstra University, USA
Keynote: Control in progression of a malignant lesion from onset to metastasis, utilizing an immunogenic oncofetal protein that characterizes and is capable of destroying the lesion merases
Biography:
He was trained as a cancer surgeon at Memorial Sloan-Kettering where he remained on staff for 20 years and was involved in the surgery of advanced cancer problems and the immunotherapeutic approaches to managing the patients.
Abstract:
It is well recognized that few instances of spontaneous regression of a malignant lesion have been reported. In general, once the genetic transformation has occurred with cells undergoing a field effect, progression of a malignant component will progress while the other sites are held in a dormant state. The host immune system seems to tolerate the without responding to presence of the malignant lesion as it continues to progress to that point that metastasis will eventually occur.
Speculation as to mechanisms suggest that while foreign invaders such as bacteria and viruses express a threshold level of immunogen that can be identified by the host immune system that the malignant growth, while containing immunogenic protein, express it at levels far below what is required for recognition by the hosts immunocytes. Antigen preparation for use in clinical trials was started in the 1970’s where with FDA supervision; pooled allogeneic tumor proteins were prepared. 20-30 operative specimens were used in preparing cell suspensions which were then sonicated to release surface membrane antigen. The suspension was passed over a Sephadex G-200 column to further separate those proteins in solution by M W. The cell suspension was then tested in patients by skin testing for DHR, three specific antigens were defined. mAbs were produced against them for purification and mass spec to develop a recombinant antigen. The antigens found for several malignancies examined were post translational modifications of oncofetal antigens present but in sub therapeutic levels of approximately 10-20 µgms. per entire lesion where in semi-purified form, 500 µgms were needed to elicit a clinical response. In colon cancer, the 3 antigens defined were post translational modifications of the oncofetal proteins A33, MUC5ac and CEAcam 5, 6. The mechanisms of activity of these antigens occurred via ADCC (antibody dependent cell cytotoxicity) and not a cell mediated CD8 response. Enhanced survival was defined in patients (colon cancer, pancreas cancer) with recurrent metastatic lesions having failed all known therapeutic agents who were then given the therapeutic mAbs. Expression of antigen is noted in premalignant cells adjacent to an existing tumor such as colon, lung, and pancreas, etc. Failure to totally remove these cells which can be identified only by immunohistochemistry of margins of resection results in recurrent tumor.
- Cancer Immunology| Renal Cell Cancers| Gynecologic Oncology | Cancer Stem Cells | Molecular Cancer | Immunotherapy | Cancer Therapy| Drug Delivery|Targeted Drug Delivery| Drug Transplantation Techniques
Location: Philadelphia
Session Introduction
Seung-Cheol Lee
University of Pennsylvania, USA
Title: Metabolic flux analysis of mantle lymphyoma cells upon bruton tyrosine kinase inhibition
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.
Lincoln A Edwards
Weill Cornell Medicine, USA
Title: Elucidating the mechanisms that underlie brain cancer stem cell regulation
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.
Nicole Simone
Thomas Jefferson University, USA
Title: Leveraging principles of aging to enhance cancer therapy
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.
Huihuang Yan
Mayo Clinic, USA
Title: Genome-wide identification of regulatory variation in t-cell prolymphocytic leukemia
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.
Rami I Aqeilan
The Hebrew University of Jerusalem, Israel
Title: MicroRNA's in oncogenesis: Size doesn’t matter
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.
Praveen Bommareddy
Rutgers Cancer Institute of New Jersey, USA
Title: Oncolytic HSV-1 viruses as novel therapies for melanoma treatment
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.
Oya Altinok
Drexel University College of Medicine, USA
Title: Mitochondria shuttle mechanisms in coupling of glycolysis and oxidative phosphorylation in colon cancer
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.