Biochemistry

The functions of a cell, such as growth, division, migration, and energy metabolism, are performed through a series of biochemical reactions mediated by macromolecules: proteins, carbohydrates and nucleic acids (DNA and RNA). Biochemistry as a discipline focuses on the characterization of the cell’s biochemical reactions, and the investigation of the structure, function, and interactions of the macromolecules. In particular, LICR investigators are examining how normal signal transduction, which occurs mainly through the sequential modification and interactions of macromolecules, is corrupted by carcinogenesis.

Programs

Patient Oriented Research

LICR scientists are using their knowledge of signal transduction, as well as protein structure and function, to develop inhibitors of the aberrant signaling that leads to cancer progression.

Epidermal Growth Factor Receptor Inhibitors

LICR is investigating several targeted therapies to treat the many cancers that result from the overexpression of, and thus increased signal transduction from, EGFR. One of these, the tyrosine kinase inhibitor (TKI) AG1478, is scheduled for early phase clinical trials in late 2004. Another treatment, the EGFR-specific monoclonal antibody 806, from the Antibody Targeting Program, is also scheduled for early phase clinical trials in 2004. LICR investigators are also involved in a large effort to design synthetic drugs based on their structural studies of EGFR.

Phosphoinositide 3-Kinase Inhibitors

LICR investigators have led a group of academic and non-academic collaborators to develop drugs that specifically inhibit signaling from one or more members of the PI3K family of signal transduction proteins. These drugs are currently being tested and optimized in the laboratory, and are expected to enter early phase clinical trials in 2005.

Vascular Endothelial Growth Factor Receptor Inhibitor

LICR investigators are developing molecules that inhibit signaling from VEGFR, to prevent Angiogenesis and Lymphangiogenesis, the growth of blood and lymphatic vessels, respectively. The blood and lymphatic vessels provide nutrients and oxygen to a tumor, thus allowing it to grow, and also provide a mechanism for the tumor cells to spread to other parts of the body, a process known as metastasis.

Platelet-derived Growth Factor Receptor Inhibitor

LICR investigators have discovered that inhibiting PDGFR lowers the high blood pressure in the small spaces around tumors, thus increasing the transport of chemotherapies to, and around, the tumor. The LICR team and their collaborators have also shown that PDGFR inhibitors improve the efficacy of several conventional chemotherapies in animal models, thus allowing the chemotherapy dose to be decreased. Clinical trials using PDGFR inhibitors with conventional chemotherapies are beginning, and will examine the possibility that the inhibitors will increase the efficacy of the drugs and decrease the side-effects associated with chemotherapy.