Research Programs: Genetic Mechanisms of Cancer, Immunology
Director, Animal Cancer Care and Research Program, College of Veterinary Medicine
Perlman Professor of Oncology and Comparative Medicine, Veterinary Clinical Sciences
612-625-7436 — office
Preferred method of contact: e-mail
Dr. Modiano completed his veterinary training and Ph.D. 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, Colo., (1991-1993), and a post-doctoral fellowship at the National Jewish Medical and Research Center in Denver. He was assistant professor of veterinary pathobiology at Texas A & M University between 1995 and 1999. From 1999 to 2007, he returned to Denver, where he held scientist and senior scientist appointments at the AMC Cancer Research Center and was associate professor of immunology and a 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.
Dr. Modiano is a partner at Veterinary Research Associates, LLP, a company focused on development and implementation of diagnostics for veterinary medicine, and he is 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. He is the director of the Animal Cancer Care and Research Program.
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 area 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 Detection 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.
Tamburini BA, Trapp S, Phang TL, Schappa JT, Hunter L, Modiano JF (2009). Gene expression profiles of sporadic canine hemangiosarcoma are uniquely associated with breed. Available online May 19 on PLoSONE Web site.
Thomas R, Wang HJ, Tsai P-C, Langford C, Fosmire SP, Jubala CM, Getzy DM, Cutter GR, Modiano JF, Breen M (2009). Influence of genetic background on tumor karyotypes: evidence for breed-associated cytogenetic aberrations in canine appendicular osteosarcoma. Chromosome Res, 2009 Apr 1. (Epub ahead of print)
Willoughby Sr JA, Sundar SN, Cheung M, Tin AS, Modiano J, Firestone GL (2009). Artemisinin blocks prostate cancer growth and cell cycle progression by disrupting Sp1 interactions with the cyclin-dependent kinase-4 promoter and inhibiting CDK4 gene expression J Biol Chem, 284(4), 2203-2213
Modiano JF, Johnson LDS, Bellgrau D (2008) Negative regulators in homeostasis of naïve peripheral T cells. Immunol Res, 41(2), 137-153
Jubala C, Lamerato-Kozicki AR, Borakove M, Lang J, Gardner LA, Coffey D, Helm KA, Schaack J, Baier M, Cutter GR, Bellgrau D, Modiano JF (2009) MHC-dependent desensitization of intrinsic anti-self reactivity. Cancer Immunol Immunother, 58(2), 171-185
Breen M and Modiano JF. Evolutionarily conserved cytogenetic changes in hematologic malignancies of dogs and humans — Man and his best friend share more than companionship. Chromosome Res. 2008;16:145-154.
Lin P-Y, Fosmire SP, Park S-H, Park J-Y, Baksh S, Modiano JF, Weiss RH. Attenuation of PTEN increases p21 stability in kidney cancer cells: potential mechanism of chemotherapy resistance. Mol Cancer 2007;6:6.
Modiano JF, Breen M, Valli VEO, Wojcieszyn JW, Cutter GR. Predictive value of p16 or Rb inactivation in a model of naturally occurring canine non-Hodgkin lymphoma. Leukemia 2007;21:184-187.
Khanna C, Lindblad-Toh K, Vail D, London C, Bergman P, Barber L, Breen M, Kitchell B, McNeil E, Modiano JF, Niemi S, Comstock K, Ostrtander E, Westmoreland S, Withrow S. Dogs, cancer, translation and genomics: a novel comparative opportunity. Nat Biotech. 2006;24:1065-1066.
Lamerato-Kozicki AR, Helm K, Jubala CM, Cutter GC, Modiano JF. Canine hemangiosarcoma originates from hematopoietic precursors with potential for endothelial differentiation. Exp Hematol. 2006;34:870-878.
Modiano JF, Breen M, Burnett RC, Parker HG, Inusah S, Thomas R, Avery PR, Lindblad-Toh K, Ostrander EA, Cutter G, Avery AC. Distinct prevalence of B and T cell lymphoproliferative diseases among dog breeds is an indicator of heritable risk traits. Cancer Res. 2005;65:5654-5661.
Frazer-Abel AA, Baksh S, Fosmire SP, Willis D, Pierce AM, Meylemans H, Linthicum DS, Burakoff SJ, Coons T, Bellgrau D, Modiano JF. Nicotine activates NFATc2 and prevents cell cycle entry in T cells. J Pharmacol Exp Ther, 2004;311:758-769.
Bianco SR, Sun J, Fosmire SP, Hance K, Padilla M, Ritt MG, Getzy D, Duke RC, Withrow S, Lana S, Matthiesen DT, Dow S, Bellgrau D, Cutter G, Helfand SC, Modiano JF. Enhancing anti-melanoma immune responses through apoptosis. Cancer Gene Ther. 2003;10:726-736.
Baksh S, Widlund H, Frazer-Abel AA, Du J, Fosmire S, Fisher DE, DeCaprio JA, Modiano JF, Burakoff SJ. NFATc2-mediated repression of cyclin-dependent kinase 4 expression. Mol Cell 2002;10:1071-1081.
Modiano JF, Mayor J, Ball C, Fuentes MS, Linthicum DS. Cdk4 expression and activity are required for cytokine responsiveness in T cells. J Immunol 2000;165:6693-6702.