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Department of Veterinary Clinical Sciences
University of Pennsylvania, 1991, V.M.D., Ph.D.
Office phone: 612-625-7436
Lab phone: 612-626-6890
Dr. Modiano completed his veterinary training and PhD in Immunology at the University of Pennsylvania in Philadelphia (1984-1991), followed by a residency in Veterinary Clinical Pathology at Colorado State University in Fort Collins, CO (1991-1993), and a post-doctoral fellowship at the National Jewish Medical and Research Center in Denver, CO. He was Assistant Professor of Veterinary Pathobiology at Texas A&M University between 1995 and 1999, returned to Denver from 1999 to 2007, where he held Scientist and Senior Scientist appointments at the AMC Cancer Research Center and was Associate Professor of Immunology and Full Member of the Cancer Center at the School of Medicine of the University of Colorado, Denver. Between 2001 and 2003, Dr. Modiano served as Director of Cancer Immunology and Immunotherapy for the Donald Monk Cancer Research Foundation; he also is a partner at Veterinary Research Associates, LLP, a company focused on development and implementation of diagnostics for veterinary medicine and a founder/scientist at ApopLogic Pharmaceuticals, Inc., a biotechnology company focused on development of cancer therapeutics. In July of 2007, Dr. Modiano joined the College of Veterinary Medicine and the Masonic Cancer Center, University of Minnesota, where he continues his research program as Professor of Comparative Oncology holding the Al and June Perlman Endowed Chair.
The underlying theme in Dr. Modiano's lab is to understand
mechanisms of neoplastic transformation and tumor progression.
Ongoing projects include:
a) Cancer Biology and Pathogenesis. We operate from the premise that in order to treat a disease, we must first understand it. Our efforts are focused on two major areas of emphasis. The first seeks to identify heritable factors that contribute to risk, origin and progression of cancer using naturally occurring diseases of dogs as a model that provides both genetically “homogeneous” and highly outbred populations. Our efforts have shown breed-specific patterns of prevalence for various types of cancer in dogs, but perhaps more importantly, the tumors also show breed-specific genetic abnormalities and gene expression signatures that reflect the existence of unique risk factors that modulate tumor behavior.
Another are of emphasis in the lab is to define and characterize so called “cancer stem cells” or “tumor-initiating cells”. These cells are theorized to comprise a small subpopulation in any (or in many) tumors that are responsible for originating and maintaining the tumor, as well as for therapy failures because they are intrinsically resistant to conventional treatments. While the cancer stem cell theory continues to be a subject of debate, the preponderance of evidence suggests it applies to a diverse group of solid and hematopoietic cancers. This in turn establishes the possibility to target these cells as a means to provide curative therapies for these cancers. Our lab has provided the first lines of evidence to support the possible existence of cancer stem cells in canine hemangiosarcoma and non-Hodgkin lymphoma. Our current efforts are geared to understanding the origin of these cells (do they arise from a true “stem cell” or from a “de-differentiated” somatic cell), their potential plasticity to make multiple types of cells or tissues, and their intrinsic resistance to chemotherapy and radiation.
Finally, we have spent considerable effort identifying new targets and developing innovative diagnostic and treatment approaches. Long-standing collaborations have helped us to identify cellular receptors, cell cycle regulatory molecules, and metabolic enzymes that are vital for cancer progression and survival. Various projects seek to leverage this understanding to launch new diagnostic tools that will aid in early detection, as well as new therapies that will improve quality of life and outcome for humans and companion animals with cancer.
b) Novel Approaches for Cancer Immunotherapy. Cancer is the leading cause of death in adults younger than 85 years old in the United States and the second leading cause of death in children and the elderly. Cancers use a variety of strategies to evade the immune system, and generally the cause of death from cancer is distant spread of the tumor and eventual organ failure. Surgery, radiation, and chemotherapy are the mainstays of cancer therapy, but immunotherapy is slowly gaining acceptance as an important adjuvant that may improve outcomes by selectively targeting and eliminating tumor cells while sparing normal tissues. Passive immunotherapy (administration of an antibody) has become part of the standard of care for non-Hodgkin lymphoma in people (Rituximab), as well as for some forms of breast cancer, colon cancer, kidney cancer, and melanoma. In companion animals, a cancer vaccine recently received conditional approval from FDA, and numerous clinical trials are underway testing a number of different approaches that employ both passive and active (induction of immune response by the patient’s own immune system) immunotherapy approaches. Our group is part of collaborative efforts to develop effective therapies using gene-based approaches (Fasaret, through ApopLogic) as well as adoptive cell-based immunotherapy (NK cells and T cells) for various cancers.
c) Lymphocyte Growth Regulation. Lymphocytes
are cells of the vertebrate immune system responsible for
adaptive immunity. T cells, which orchestrate immune responses,
include a wide repertoire of cells that bear highly specific
antigen receptors. In mammals, these receptors arise from
recombination of segments in four regions of the genome (T
cell receptor alpha, beta, gamma, delta), mostly in the thymus.
Mature T cells circulate throughout the body, interacting
with professional antigen presenting cells and with other
somatic cells to combat infections and to help eliminate cells
that have acquired disease potential through age, mutation,
or metabolic abnormalities. There are fine lines that define
the balance between too little immunity (immunodeficiency),
which can be deadly, and too much immunity (autoimmune disease),
which can similarly cause severe morbidity and even death.
Intrinsic and extrinsic mechanisms regulate T cell responses. Our group (along with various collaborators) was among the first to show that T cell proliferation is actively enforced, and our work continues to study mechanisms that control lymphocyte activation. Our goals are to establish a framework to manage clinically relevant immunopathology, such as excessive immunity associated with diseases such as diabetes, or insufficient immunity such as the subtle defects seen in habitual users of tobacco products or the more severe defects seen when the immune system fails to control tumors.
These different aspects are funded by the NIH and by various non-profit foundations. They include ongoing collaborations with scientists within and outside the United States.
Updated: June 8, 2009