Dr. Lewis Cantley: My name is Lewis Cantley. And I am the chief of the division of signal transduction a Beth Israel Deaconess Medical Center. And, the work that my lab focuses on is understanding, essentially, the wiring of a cell. The more we know about the wiring diagram of the cell, the more likely we are to come up with drugs that have the maximum benefit with the minimum side effects to patients with tuberous sclerosis.
Signal transduction is literally how a cell makes decisions. It's the logical network that allows a cell to decide what to do. And a cell can decide to grow, it can decide to make a copy of itself to divide, to make two cells from one. Or cells can decide to die because they are in the wrong environment. These are all logical networks that are similar to logical networks in your computer. In a cell, the, the mechanism of logic goes through protein signaling pathways, so one protein bumps into another protein and it tells it to do something and spread the word, and it then bounces into other proteins and tells them what to do.
By studying this protein signaling network we can better understand how the mutations that occur in tuberous sclerosis complex cause tumors to grow.
Lets look at a single cell in your body. There are many, many proteins within the cell but we're going to focus on a handful that are important to cell growth. These proteins are AKT, tuberin, hamartin, Rheb and TOR.
Tuberin and hamartin are the two proteins encoded by the tuberous sclerosis genes. These two proteins associate with each other in the cell and their function is to act as a brake on cell growth. They prevent the cell from growing and dividing.
Now if the body actually wants a cell to grow and divide here's what happens. A growth factor bumps into the outer surface of the cell causing a series of events to occur. Ultimately the protein AKT is activated. AKT bumps into tuberin and hamartin and takes out their function temporarily. So now the brake is turned off, the signal passes through and the protein Rheb is turned on which bumps into the protein TOR. TOR sends signals to the nucleus of the cell and to the protein synthesis machinery to tell the cell to take up more nutrients, to make more proteins and to grow and divide.
What happens in tuberous sclerosis then is, that these proteins, tuberin and hamartin are malfunctional. They either don't exist at all, or they exist in a way that they are not good braking systems. As a consequence, the Rheb protein is continually turned on. TOR is continually turned on. And the cell thinks that there's a growth factor outside telling it to grow continuously. And so, it does grow continuously. This uncontrolled cell growth and division leads to a tumor.
Now, this sort of alphabet soup list of names can sound very confusing. So let's focus for a moment on the TOR protein. TOR stands for Target of Rapamycin and as the name implies, this is a target for the drug Rapamycin, which is known to inhibit or block cell growth. So by taking Rapamycin, or a Rapamycin like drug, a person can effectively replace the function of tuberin and hamartin and stop cells from growing out of control.
And with more research we may find a more effective and a more focused way, to treat tuberous sclerosis such as other drug targets downstream of TOR. In addition, it's possible that Rheb may be doing other things that are contributing to this disease. And therefore, looking for downstream responses of Rheb, where we might also intervene with drugs, could provide new approaches, more focused for this disease, with fewer side effects.
If we can figure out other targets besides TOR itself, that may be downstream of TOR that we can also intervene with drugs, a combined therapy of Rapamycin plus another target downstream, there may be something in glycolysis, could give us a more unique focus on the subset of cells that have tuberous sclerosis.
We're very excited because this research is beginning to tell us a lot about what controls cell growth. It is not only going to be beneficial for treating patients with tuberous sclerosis, but also for cancers. Many cancers have defects in the same pathway. And these same drugs, we think will have a broad benefit for cancer as well.
© 2006 The General Hospital Corporation.