*NEW PROJECT*: Developing a specific mTORC1 inhibitor

Grant holder: Dr Kacper Rogala
Whitehead Institute

Project status: New project

TSC complex is a collective of proteins found in human cells that act as a hand break for another protein called mTOR. This is a very important role for TSC because mTOR is a driver of cellular growth, and therefore if not properly regulated, it can lead to many disease states, including cancer, diabetes and neurodegeneration.

Genetic mutations found in TSC patients do exactly that – they cripple the TSC proteins, making them no longer able to block mTOR, and thus leaving it completely out of control. In order to keep such hyperactivated mTOR in check, researchers have been using a natural product, rapamycin, to block mTOR activity directly. This is equivalent to storming a fortress via the front gate, and although effective to some degree, it comes at a great cost. TSC patients who take rapamycin over long periods of time develop a range of unwanted side effects that in some cases make them drop the treatment altogether. They experience those side effects because rapamycin, instead of only blocking the hyperactive mTOR in cells, also blocks populations of mTOR molecules that do other useful functions in our bodies, such as stabilising levels of sugar in the blood.

The main idea of this project is to develop drugs that only act on the hyperactive mTOR in TSC patients. To do so, we plan to take a novel approach, and instead of targeting the front gate, we go for the back door. Such back door in the context of mTOR is its ability to anchor on recycling factories of cells, called lysosomes. The surface of those lysosomes is the standard location where mTOR performs its duties within the cell, and where in the absence of the TSC protein it becomes hyperactivated. Our goal is to limit the number of mTOR molecules that can anchor at the surface of lysosomes by developing drugs that interfere with the anchoring process. Such drugs will conceptually serve as a substitute for the defective hand break normally provided by the TSC protein, and unlike rapamycin, they will only affect lysosomal mTOR, and not any other mTOR that does other useful things in the cell.
Because proteins are small objects of one millionth of a millimetre, we need to use specialised microscopes to take images of mTOR anchored at lysosomes. These images will help us better understand how the anchoring process works, and how we can modulate it with drugs.

The ultimate long-term goal of this project is to make a drug that alleviates all symptoms of TSC, and which TSC patients can take daily, like Aspirin, without having to worry about risks of developing diabetes. Making new medicines is a long process due to many requirements a drug candidate needs to fulfil in order to be approved by a regulatory agency. What we want to achieve from this project is a selection of tangible alternative drug leads that we can study in a test tube and show that they are effective in stopping mTOR from docking at lysosomes and rescuing the function of mutant TSC proteins in cultured cells.

Such a proof-of-principle will reduce the risks associated with advancing our science into treatments for TSC. The process of drug development can take several years, but it has a major advantage over short-term, quick solutions, and this advantage lies in its novelty. We will explore a completely different mode of drug action than that of rapamycin or any other potential drugs that are currently in clinical trials. By diversifying, we have a better chance of succeeding.

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