Dr. Jose Teodoro
Rosalind and Morris Goodman Cancer Research Centre
Department of Biochemistry
1. CIHR New Investigator Award, 2008-2013
2. FRSQ Chercheur-Boursier (Junior II), 2008-2010
Dr. Teodoro’s aim is to discover new mechanisms to inhibit blood vessel formation in tumors. His team approaches this problem in two ways:
1) Role of p53 in arresting tumor angiogenesis - Tumors must develop a network of blood vessels carrying oxygen and nutrients to their cells to enable their growth. This process, called angiogenesis, is absolutely necessary and is an ideal target point for new cancer therapeutics. Because angiogenesis generally occurs in adults only during specific instances such as wound healing, it is possible to inhibit angiogenesis as a cancer therapy without major side effects.
Our laboratory has shown that, in humans, natural tumor suppressor mechanisms work in part by inhibiting tumor angiogenesis; one of the most important of those is the p53 protein. As a tumor suppressor, p53 stimulates the production of natural anti-angiogenic factors. The gene that encodes p53 is mutated in more than half of all cancers and in diverse cancer types, resulting in increased angiogenesis and tumor growth. We have shown that the p53 tumor suppressor pathway can increase anti-angiogenic collagen production by activating a central enzyme in collagen synthesis called prolyl hydroxylase, whose increased expression can prevent tumor growth in our experimental mice almost entirely. The p53 protein can stimulate production of anti-angiogenic factors derived from collagen, such as Endostatin, Tumstatin and Arresten. Such factors have been shown by our lab and others to have potent anti-tumor activity. We have also shown that in human prostate cancers that have mutated p53, the amount of Arresten produced in much lower and may account for the particularly aggressive nature of these tumours.
2) Identification of new angiogenesis inhibitors - The Teodoro group is working to identify new angiogenesis inhibitors and the molecular pathways that increase their production. One approach is to analyze changes in secreted factors occurring when a cancer cell has a defective p53 pathway. One of our approaches in identifying new anti-angiogenic factors is a technique called two dimensional difference gel electrophoresis (2D-DiGE), a powerful way to visualize changes in the secreted proteins of cancer cells. Separation of proteins in this way allows factors of interest to be identified using mass spectroscopy, after which they can be directly tested directly in pre-clinical models of cancer in mice. These types of angiogenesis regulators are naturally secreted into the blood, resulting in their translation almost directly to clinical applications. It is our hope that the knowledge obtained from our work can eventually translate into novel therapies for human cancer.