Cancer

Dr. David Margolis MD, PhD, is a board certified orthopaedic surgeon with sub-specialty certification in hand surgery. In addition to treating patients, he oversees the Biomaterials and Tissue Engineering Laboratories within the Department of Orthopaedic Surgery. He collaborates with colleagues across campus in the departments of biomedical engineering, systems engineering, pharmacology and chemistry. His research specifically focuses on bone and cartilage tissue regeneration and development of implantable sensors that continuously monitor fracture healing and bone health. His research interests also include carpal tunnel syndrome, osteoporosis and bone cancer pain.

My major interests include epigenetic regulation of angiogenesis and vascular development. Angiogenesis plays a critical role in both physiological and pathological conditions. I am investigating various mechanisms involved in angiogenesis with development and aging of organisms and its role in organ development as well as cancers.

My other area of investigation is involving adipose-derived stem cells and their usefulness in treating osteoarthritis, diabetes, stroke, traumatic brain injury, myocardial infarction, and spinal cord injuries following road traffic accidents.

 

Papillomaviruses (PVs) are a diverse family of dsDNA viruses infecting most, if not all, amniotes. Papillomaviruses infect cutaneous or mucosal epithelia. While most infections are self-limiting, persistent infection with specific human papillomaviruses has been shown to be the causative agent for cervical cancer. All established oncogenic HPV types belong to a single viral genus (the Alphapapillomaviridae). Of note, phylogenetically, these oncogenic HPV types cluster into a so-called high-risk (HR) clade, indicating an evolutionary relationship between these viruses. Importantly, not all HPV types within this HR clade are associated with cancer. I am intrigued by the observation that only a limited subset of human papillomaviruses is oncogenic. Throughout my studies I have used a combination of biochemical assays and computational analyses to understand why evolutionarily related viruses differ in their ability to cause cancer in humans. It is improbable that the ability to cause cancer provides papillomaviruses with an evolutionary advantage. It is likely that many of the viral functions linked to oncogenesis were evolutionarily beneficial as papillomavirus adapted to novel environmental niches on the host (e.g. external genitalia vs. cervix). Papillomaviruses have evolved to usurp the cellular machinery to complete their life-cycle. The papillomaviral lifecycle perturbs the normal differentiation cycle of the infected cell, forcing cells to divide far beyond their normal lifespan. It is feasible that the continued insult provided by replicating viruses eventually results in malignant transformation of the infected cell. However, while persistent infection is key to viral oncogenesis, many long-term persisting viruses do not cause cancer. By carefully interrogating the differences between these viruses, I believe it will be possible to elucidate which viral phenotypes are associated with oncogenic progression. The pathways targeted by these viruses may represent powerful targets for therapeutic intervention

We study control of cell fate and self-organization in intestinal renewal and drug response in cancer. Utilizing the fascinating characteristics of intestinal stem cells combined with chemical biology and computational image analysis approaches, we are addressing fundamental questions of multicellular systems: How do cells identify, measure, and respond to each other and to their environment? What are the signals that control the renewal and regeneration of tissues? How do these signals become defective in colorectal cancer? Our long-term goal is to uncover an underlying circuit theory behind these behaviors – a set of predictive principles that tell us how complex functionality arises from simpler biological components. We have a particular interest in kinase networks that regulate healthy tissue homeostasis and become damaged in cancer. Through our quantitative high-throughput imaging and drug discovery efforts, we are finding new ways to understand and repair these networks. Keywords: Stem cells, Cancer, Regeneration, Drug discovery

Dr. Cynthia Thomson, PhD, RD, is a Professor and Director of the Canyon Ranch Center for Prevention and Health Promotion in the Mel and Enid Zuckerman College of Public Health at the University of Arizona. Dr. Thomson holds joint appointments in the College of Agriculture and Life Sciences and the College of Medicine. Her research emphasis includes dietary intervention in breast and ovarian cancer survivors, as well as behavioral interventions for weight control and metabolic regulation. Dr. Thomson received her Ph.D. from the Interdisciplinary Program in Nutritional Sciences, University of Arizona and completed NCI-sponsored post-doctoral training at the University of Arizona Cancer Center with a focus on diet and cancer prevention.

My laboratory investigates the normal biology of the Epidermal Growth Factor Receptor (EGFR, and its family members, HER2 and ErbB3), as well as their role in transformation and metastasis. These oncogenes are a family of transmembrane tyrosine kinases that drive a wide-variety of cancers including HER2 positive and triple negative breast cancer, squamous cell lung cancer and glioblastoma. Our work focuses on kinase-independent activities of these receptors (such as modulation of calcium signaling and functions as transcriptional co-factors) and how the receptors are mis-regulated during cancer progression (by a loss of lysosomal degradation). These studies include investigations into receptor trafficking, nuclear translocation and protein-protein interactions that are unique to cancer survival and metastasis. We are currently focused on understanding how EGFR enters the retrotranslocation pathway that allows for it to traffic to the nucleus and directly affect gene transcription, as well as understanding how these events drive migration and survival. Based on these studies, we have developed peptide-based therapeutics for cancer that block protein-protein interactions that promote EGFR retrotranslocation. We are developing these peptide-based therapeutics for clinical applications through peptide stability studies including hydrocarbon stapling and mutational analyses. To promote the clinical translation of these discoveries, the biotech start-up company Arizona Cancer Therapeutics was founded in my lab at the Arizona Cancer Center. We are currently performing toxicity testing of our compounds with the goal of applying for approval from the FDA for clinical trials. These studies have been accomplished through the hard work and dedication of the over 50 undergraduate students, 2 MS and 11 PhD students who have studied in my lab since 2002.

Dr. Monika Schmelz is a Assistant Professor of Pathology and Member of the University of Arizona Lymphoma Consortium. Dr. Schmelz pursuing research on mechanisms for immune escape in aggressive lymphoma with poor survival rates. Dr. Schmelz received a 2 year award (2013-2015) from The Hope Foundation to study how tumor cells escape immunosurveillance, which is a hallmark of cancer, in aggressive diffuse large B-cell lymphoma (DLBCL) with poor patient outcome, and how immunosurveillance can be manipulated for therapeutic purposes. ( see also link: http://pathology.arizona.edu/news/dr-monika-schmelz-recipient-2013-swog-development-award). Dr. Schmelz also is pursuing biorepository science. She received a multi-million dollar award for hosting the Biorepository for a NCI funded clinical trial. ANCHOR is a multi-site phase III clinical trial entitled “Topical or Ablative Treatment in Preventing Anal Cancer in Patients with HIV and Anal High-Grade Squamous Intraepithelial Lesions”. 17,385 participants will be screened to identify and to enroll 5,058 eligible participants. An estimated 314,535 biospecimens over the duration of the clinical trial (8 years) will be collected and sent to Dr. Schmelz's lab. The biorepository is an extremely important factor for the outcome of this clinical trial, since correlative translational studies on biomarkers for early detection of anal cancer development in these specimens are planned by the NCI. Keywords: Cancer, Diffuse Large B-Cell Lymphoma (DLBCL), Therapeutic Biomarkers

Donato Romagnolo, MSc, PhD, has served as a member of study sections for the National Institutes of Health, the U.S. Department of Defense, the Susan G. Komen Breast Cancer Foundation, and as a scientific reviewer for nutritional, cancer, and pharmacology and toxicology scientific journals. Dr. Romagnolo is a member of the Training Grant in Cancer Biology at the University of Arizona. Dr. Romagnolo's research focuses on: 1) mechanisms of epigenetic silencing of tumor suppressor genes by environmental and dietary xenobiotics, and 2) role of dietary bioactive food components in the etiology and prevention of cancer and inflammation. For the last 14 years, Dr. Romagnolo's research has been funded by grants from the National Institutes of Health, the U.S. Army Department of Defense, the Susan G. Komen for the Cure and the Arizona Biomedical Research Commission.Some of his research reveals humans are exposed to a complex mixture of ligands of the aromatic hydrocarbon receptor (AhR). Prototypical AhR agonists include the polycyclic aromatic hydrocarbon (PAH) benzo[a]pyrene (B[a]P), and the dioxin-like compound 2,3,7,8 tetrachlorodibenzene(p)dioxin (TCDD). Increased incidence of breast cancer is documented in human populations of industrialized areas where high levels of dioxins are found in the air, soil, drinking water, and cow milk. Unlike PAH, TCDD is not metabolized and it promotes tumor development. Population studies reported the presence of TCDD in breast milk, suggesting this agent may accumulate in breast tissue and be a potential risk factor in mammary neoplasia. The in-utero activation of the AhR with TCDD increased the susceptibility to mammary carcinogens in rat female offspring. The activation of the AhR pathway may increase the susceptibility to breast cancer through epigenetic silencing of tumor suppressor genes, including p16 and p53, while inducing transcription of the proinflammatory COX-2 gene.

Research Interests Our objective is to define how integrin interactions within the tumor microenvironment impact prostate cancer development, hormonal resistance, and metastasis. Our approach is to understand the normal biology of the prostate gland and its microenvironment, as well as the bone environment, to inform on the mechanisms by which tumor cells remodel and use that environment to develop, acquire hormonal resistance, and metastasize. Our research is focused in three primary areas: 1) developing in vitro and in vivo models that recapitulate human disease based on clinical pathology, 2) identifying signal transduction pathway components that could serve as both clinical markers and therapeutic targets, and 3) defining the genetic/epigenetic programming involved in prostate cancer development.

Katrina Miranda, PhD, claims nitric oxide (NO), which is synthesized in the body via enzymatic oxidation of L-arginine, is critical to numerous physiological functions, but also can contribute to the severity of diseases such as cancer or pathophysiological conditions such as stroke. This diversity in the responses to NO biosynthesis is a reflection of the diverse chemistry of NO. For instance, NO can alter the function of enzymes by binding to metal centers. This type of interaction could result in outcomes as disparate as control of blood pressure or death of an invading bacterium. NO can also be readily converted to higher nitrogen oxides such as N2O3 or ONOOH, which have very different chemical and biological properties. The ultimate result will depend upon numerous factors, particularly the location and concentration of NO produced. Therefore, site-specific modulation of NO concentration offers intriguing therapeutic possibilities for an ever expanding list of diseases, including cancer, heart failure and stroke. As a whole, Dr. Miranda is interested in elucidating the fundamental molecular redox chemistry of NO and in developing compounds to deliver or scavenge NO and other nitrogen oxides. These projects are designed to answer questions of potential medical importance through a multi-disciplinary approach, including analytical, synthetic, inorganic and biochemical techniques.The project categories include five major disciplines. First, she will work on the development and utilization of analytical techniques for detection and measurement of NO and other nitrogen oxides as well as the resultant chemistry of these species. Second, she will synthesize potential donors or scavengers of NO and other nitrogen oxides. Third, it’s necessary to describe chemical characterization of these compounds (spectroscopic features, kinetics, mechanisms and profiles of nitrogen oxide release, etc.). Fourth, Dr. Miranda will try to describe the biological characterization of these compounds (assay of effects on biological compounds, mechanisms and pathways, in vitro determination of potential for therapeutic utility, etc.). Fifth, she will identify of potential targets, such as enzymes, for treatment of disease through exposure to nitrogen oxide donors. Keywords: cancer treatment, pain treatment