Protein Targets

Understanding the genes that contribute to cancer resisting treatment is important for developing drugs to block that resistance. In the initial experiment involving the whole-genome assay a number of genes were identified by removing them from the cells using RNA Interference. In order to mimic the effect of removing certain genes from the genome, which is much harder to do in human patients, we need to design drugs that interfere with the products of genes, the proteins. Why is it necessary to focus on proteins? Learn about the role of proteins in the cell here or Learn about the interaction of genes and proteins here.

Picking a Target

When investigating the genes that were identified as helping cancer resist chemotherapy in the whole-genome assay researchers classified the genes based on what proteins they produced. Because the process of creating proteins from the genome is well understood (see genes and proteins ) knowing the gene in a cell allows you to determine the identity of the protein that it produces. Every gene is important mostly for the protein that it produces, and the gene sequence codes directly for protein, that is sometimes modified by other proteins, and is responsible for the gene's effect in the cell. The gene that the researchers chose to focus on was called ACRBP . It was chosen because it is expressed commonly in breast, lung, and ovarian cancers (and in the testes) and the gene assay revealed that removing the protein from a cell increased its sensitivity to the chemotherapy drug paclitaxel 10,000 fold. Other genes that could have been targeted were potentially too damaging to normal cells, because they control extremely necessary cell processes, or not specific enough to cancer because they are expressed by every cell in the body.

Hitting the Cell where it Works

After selecting a protein to focus research on, the researchers needed to determine if it did cause resistance to the chemotherapy drug paclitaxel in a cell culture, and that it was actually being produced in resistant cancer cells. By breaking the cells apart and measuring the amounts of ACRBP in cancer cells vs normal cells, as well as how ACRBP related to the ability of the cells to resist paclitaxel it was determined that that protein is indeed responsible for helping cells resist the chemotherapy drug. By determining that this protein was responsible for increasing resistance the researchers knew that they needed to determine what other proteins it interacted with to create this resistance. By being able to disrupt the interaction of the proteins, ACRBP would not be able to stabilize the cell and allow it to resist chemotherapy.

Any set of interactions that produces a protein in a cell is the result of a series of genes and proteins interacting. It is important to understand the complete interaction between all the genes and proteins that go into producing a particular effect in order to understand how to develop drugs to treat it. Ongoing research in the Whitehurst lab is focused on compeltely understanding the full series of steps that allows cancer to resist chemotherapy by using ACRBP. Once the pathway is understood any number of drugs can be developed to throw a wrench in the works of the carefully balanced pathway. A few examples of how drugs can disrupt the production of a protein are shown.

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