Research Project

Model-based Prediction of Redox-Modulated Responses to Cancer Treatments

Overview

Project Name

Model-based Prediction of Redox-Modulated Responses to Cancer Treatments

List of Collaborating Institutions

Georgia Institute of Technology
Indiana University
Wake Forest Health Sciences

Project Websites

http://kemp.gatech.edu/
http://www.wakehealth.edu/Research/Molecular-Medicine/Furdui-Lab/Furdui-Lab.htm
http://www.utsouthwestern.edu/labs/boothman/

Project Description

The goal of our U01 project is to advance precision medicine through consideration of cancer redox metabolism when predicting patient-specific responses to therapies. While the arsenal of approaches to selectively killing cancer cells is increasing, the majority of treatments rely on redox alterations of tumor cells and their microenvironment through chemotherapy, radiation, or some combination thereof. Compared to other cancers, the treatment options available for Head and Neck Squamous Cell Cancer (HNSCC) patients are particularly limited with only one targeted therapy currently approved by FDA for treatment; therefore, there is a need for new therapeutic strategies and methods to enable systematic/predictive selection of patients for treatment with targeted agents.

Specifically, we hypothesize that the response to a new class of redox-based chemotherapeutics can be predicted and enhanced by identifying specific metabolic network features contributing to the NAD(P)+/NAD(P)H redox balance and overall levels associated with the specific mechanism of action. We will be investigating the NAD(P)H-driven responses to the quinone-based chemotherapeutics, beta-lapachone (ß-Lap) and isobutyl-deoxynyboquinone (IB-DNQ) in laboratory models and clinical specimens of HNSCC. This project will require integration and expansion of our prior successful models of drug bioactivation networks and redox metabolic systems in a comprehensive systems-level approach to improve understanding and enhance prediction of phenotype-specific responses to chemotherapeutic strategies. Development and validation of predictive models of β-Lap or IB-DBQ lethality in HNSCC cell lines will rely upon novel genome-wide metabolomics approaches to identify key enzymatic contributors to NAD(P)H levels required for driving drug metabolism and DNA lesion repair. The predictive capabilities of our computational models will be enhanced by accounting for metabolic diversity across HNSCC tumors and RNAi manipulation of enzyme levels to extract predictive proteomic/metabolic signatures associated with quinone redox cycling. Finally, the model-based predictions of therapeutic outcomes will be tested with HNSCC clinical specimens via ex vivo assays and targeted metabolic profiling. We anticipate that our multi-disciplinary project – relying on a team of investigators in pharmacology, oncology, redox biology, mass spectrometry, and computational modeling – will identify metabolic regulatory features applicable to the treatment of other cancers by molecular or systemic chemotherapies .

Investigators

Principal Investigators

Melissa Kemp, Ph.D. (co-PI)

Melissa Kemp, Ph.D. (co-PI) is Associate Professor in the Wallace H. Coulter Department of Biomedical Engineering at Georgia Tech and Emory University. She is a Georgia Cancer Coalition Distinguished Scholar and 2009 NIH New Innovator, pioneering the use of computational modeling of metabolic networks to investigate the role of reversible cysteine modifications in regulating intracellular redox environments. Her research group develops experimental and analytical tools for quantifying subcellular dynamics of reactive oxygen species for applications in immunology, oncology, and regenerative medicine. Kemp also currently serves as the Associate Director of a NSF Science and Technology Center, Emergent Behavior of Integrated Cellular Systems, where she studies patterns that arise during stem cell differentiation by agent-based simulations of cellular communication.

Cristina Furdui, Ph.D.

Cristina Furdui, Ph.D. (co-PI) is Professor, Department of Internal Medicine, Section on Molecular Medicine, Wake Forest School of Medicine; Co-Director of the Center for Redox Biology and Medicine; Director of the Proteomics and Metabolomics Shared Resource. Dr. Furdui is an established investigator with research focused on the following areas of interest: 1) Development of Reagents and Methods for Tracking Redox Processes in Biological Systems, 2) Structure-Function Analysis of Redox Regulated Proteins, 3) Mitochondria-Cell Communication Networks in Pathophysiology (e.g., response to environmental stressors), and 4) Redox Control of Head and Neck Cancer Development, Response to Treatment and Quality of Life. Analytical tools and concepts developed in the context of these projects are further applied to a number of collaborative studies investigating redox effects in cancer and other diseases caused or associated with a redox imbalance such as aging, osteoarthritis, chronic kidney disease, inflammation, sepsis and others.

David Boothman, Ph.D.

David Boothman, Ph.D. (co-PI) is Professor of Pharmacology and Radiation Oncology. Dr. Boothman is a senior leader in the Simmons Comprehensive Cancer Center (SCCC), serving as Associate Director for Translational Research and co-Director of Experimental Therapeutics. Dr. Boothman works closely with all ET Program themes to promote preclinical and clinical translation. Dr. Boothman also co-leads (with Dr. Jinming Gao) a Cancer Nanomedicine Group within the SCCC. Dr. Boothman is elective representative for FASEB for the Society of Experimental Biology, and is currently president-elect for the Society for Experimental Medicine. His current research projects include: (a) Use of NQO1 bioactivatable drugs for therapy of human solid NQO1+ cancers alone and with ionizing radiation; (b) Use of NQO1 bioactivatable drugs to promote the tumor-selective use of DNA repair inhibitors, such as PARP inhibitors; and (c) Elucidating the roles of RNA termination factors for R-loop resolution, DSB repair defects, genetic instability and cancer vulnerabilities.

Baran D. Sumer, MD, FACS

Baran D. Sumer, MD, FACS (co-I) is an Associate Professor of Otolaryngology, Head and Neck Surgery at UT Southwestern Medical Center in Dallas Texas where he serves as the Chief of the Head and Neck Oncology Division in the Department of Otolaryngology. He obtained his MD degree from Case Western Reserve University School of Medicine in May 2001 and completed post-graduate residency training in otolaryngology at Washington University, Department of Otolaryngology in 2006. Following completion of residency, Dr. Sumer completed a one year Fellowship in Head and Neck Oncology, Transoral Laser Surgery, and Microvascular Reconstruction at Washington University. Dr. Sumer’s practice focuses on minimally invasive surgery for head and neck cancer including Transoral Robotic Surgery and reconstructive surgery. His primary research interest is in the development of nanoparticles and nanodevices for surgical applications. Recently in collaboration with Dr. Jinming Gao, Ph.D, Dr. Sumer established pH transistor nanoparticles (PTN) that in response to pH show binary off/on fluorescence behavior; these PTN have transformed tumor detection and also represent a new paradigm of digitizing an analog biologic signal with the exciting possibility other applications in tumor imaging, delivery of therapeutics and cellular targeting.

Noelle Williams, Ph.D.

Noelle Williams, Ph.D. (co-I) is a Research Professor in the Department of Biochemistry at UT Southwestern Medical Center where she directs the Preclinical Pharmacology Core facility. Her group is focused on the development of novel chemical leads as viable therapeutics in vivo. This includes exploring issues related to compound formulation, compound metabolic stability, in vivo pharmacokinetics and toxicology, as well as development of animal models suitable to the targeted signaling pathway. Her group makes extensive use of combination triple quadrupole/ion trap mass spectrometers for all their analytical work, and they are interested in using these mass spectrometry resources in unique ways beyond simple optimization of ADME properties. Examples of past applications include identifying novel prodrug anti-cancer therapeutics (Theodoropoulos, et al, Nat Chem Biol, 2016, 12:218), showing stoichiometry in drug-protein interactions (Han, et al, Science 2017, 356: eaal3755), and following endogenous metabolites (Sun, et al Circulation, 2016, 133:2038).

Merecedes Porosnicu, M.D.

Merecedes Porosnicu, M.D. (co-I) is Associate Professor, Department of Internal Medicine, Section on Hematology and Oncology, Wake Forest School of Medicine and Leader of the Comprehensive Cancer Center Head and Neck Cancer Disease Oriented Team. Patients with Head and Neck Cancer are notoriously difficult to treat. Dr. Porosnicu is a physician scientist focusing on advancement of new therapeutic options for Head and Neck Cancer patients through precision medicine, targeted drug therapy and oncolytic viruses-based immunotherapy. She designed and secured funding for five investigator-initiated therapeutic clinical trials and conducted at Wake Forest more than twenty other multi-institutional large clinical trials to evaluate new biologic agents, targeted drug therapies and immunotherapies for these patients. Another important target of Dr. Porosnicu’s translational and clinical research activity focuses on finding predictors of response to therapy in order to identify the best treatment for each patient with head and neck cancer.

Allen W. Tsang, Ph.D.

Allen W. Tsang, Ph.D. (co-I) is Associate Professor, Department of Internal Medicine, Section on Molecular Medicine, Wake Forest School of Medicine. Dr. Tsang’s research interests are in the area of cancer etiology studying the role of infectious pathogens in cancer development and regulation by redox-altering natural compounds. A seminal finding of his research over the past years has been the discovery of host cell Epidermal Growth Factor Receptor (EGFR) upregulation and activation by infection with the sexually transmitted intracellular pathogen, Chlamydia trachomatis. Upregulation of EGFR is a hallmark of Head and Neck Cancer amongst others. Building on this finding, current projects in Tsang’s laboratory include: 1) Exploring the Pro- and Antioxidant Properties of Spilanthol and Sulforaphane in Treatment of Chlamydial Infections and Cancer Prevention, 2) Applying Systems Biology Approaches to Evaluate the Infectious Etiology of Breast Cancer, and 3) Discovery of New Redox Altering Natural Compounds with Anti-Cancer Properties.