The underlying theme in the Modiano lab is to understand mechanisms of neoplastic transformation and tumor progression. Ongoing projects include:
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.
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.
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.