Joseph C. Loftus, Ph.D., studies the role of integrin-mediated adhesion and signaling in the regulation of cell migration and cell growth. The long-term goal of Dr. Loftus' research team is to develop effective therapies for the treatment of glioblastoma, which is the most common form of primary brain tumor.
Dr. Loftus' team makes extensive use of molecular biological techniques, biochemistry and cell culture — coupled with validation in animal models — to identify gene candidates and define signaling pathways that regulate the invasion of malignant cells. Cellular invasion confers high resistance to current therapeutic approaches to glioblastoma treatment and virtually assures tumor recurrence.
Dr. Loftus' research has been funded by the National Institutes of Health, National Cancer Institute and Mayo Clinic.
- What is the relationship between proliferation and cell migration in glioma? Dr. Loftus is working to better understand the oncology of invasive glioma, which is firmly rooted in the inverse relationship between invasion and proliferation.
Increased commitment to invasion is accompanied by decreased proliferative activity and increased resistance to chemotherapeutics and radiation. Decreased invasion is accompanied by increased proliferation and tumor growth, which will seed further invasion.
Dr. Loftus' team has identified the focal adhesion kinases FAK and Pyk2 as critical mediators of the phenotype of malignant glioma cells. They have determined that the dynamic balance between FAK and Pyk2 activity and their differential activation are determining factors in the development of proliferative or invasive phenotypes.
Dr. Loftus is investigating the molecular basis of their specific activation and identifying downstream effectors of these kinases as new targets to exploit to improve outcome.
- Can small molecule inhibitors be developed to target protein interactions that regulate cell invasion? Dr. Loftus' team is examining the potential of developing small molecule inhibitors designed to bind to specific functional domains within the kinase Pyk2 to block protein-protein interactions that regulate kinase activity.
Current approaches to inhibit cellular kinase activity depend on targeting the active site. These approaches lack specificity and have significant side effects. Dr. Loftus' identification of a regulatory domain in Pyk2 provides a novel approach for the development of highly specific inhibitors that can be optimized for delivery to the brain.
- What is the role of stem cells in glioma resistance and recurrence? It is well appreciated that recurrence of glioma following initial treatment is nearly universal. It has been proposed that recurrence is due to a small population of highly resistant brain tumor cells that repopulate secondary tumor growth and disease progression.
Dr. Loftus is interested in identifying critical genes that confer resistance to this population of cells as a means to improve efficacy of cytotoxic agents.
Significance to patient care
Dr. Loftus' research into the molecular basis of malignant cell invasion will help the efficacy of current therapeutic regimens and improve quality of life for patients with glioblastoma, while also providing insights into improved clinical management across a broad range of invasive cancers.
- Co-Leader, Neuro-Oncology Program, Mayo Clinic Cancer Center, 2008-present