Brain Tumors
Pediatric Low-Grade Astrocytoma (LGA) Program
Flagship Project
Conventional cancer therapies such as radiation and cytotoxic drugs kill all dividing cells — they are not targeted to tumor cells. Collateral damage to normal cells puts severe limitations on the amount of untargeted therapeutics that can be administered to growing children. The goal of modern cancer medicine is to develop targeted therapeutics (so-called "smart drugs") that attack mutated proteins found only in tumor cells. Unfortunately the major pharmaceutical houses that develop these smart drugs are focusing on the more common adult cancers such as breast, lung, colon and prostate. The goal of the flagship project for the LGA Program is to identify a drug-susceptible target for low-grade astrocytoma within a five-year period of time. Towards this end, we propose a two-pronged attack: the use of SNP Arrays and Shape-based Gene Sequencing.
A technology called "SNP arrays" allows investigators to screen all of the genes in a sample of tumor DNA in an unbiased way to identify genes that are mutated in the cancer. The advantages of SNP arrays are: 1) the technology is proven, and 2) it takes an unbiased look at all of the ~25,000 genes in the genome. The disadvantages of SNP technology are: 1) many of the genes that are discovered by SNP are of no practical value in tumor medicine as the proteins they encode are currently "undruggable" and 2) the work will be very slow and tedious because the investigators must use very pure samples of tumor cells that have been obtained by highly trained pathologists through a method called "laser-capture dissection."
A new technology called "Shape-based DNA sequencing" has shown great promise in controlled, developmental studies. The advantages of Shape-based DNA sequencing are: 1) the method can be targeted to screen for mutated genes that encode druggable proteins such as protein kinases, and 2) the work can go very quickly because the technique does not require pure, laser-captured tumor samples. The exciting next step, which will be explored within the LGA Program, is to test Shape-based DNA sequencing in a meaningful clinical context.
Figure 1. A two-pronged attack on druggable targets for low-grade astrocytoma.
The underlying rationale for the two arms of this attack can be explained in lay terms: The human genome encodes the roughly 25,000 different proteins, and SNP Arrays technology allows us to screen all of them for mutations. Many, but not all, of these proteins are viable candidates for development of targeted therapeutic drugs. About 500 genes encode protein kinases — a type of protein that is particularly attractive from the perspective of drug development. Targeting screens through shape-based gene sequencing can identify these types of proteins.
It should be noted in Figure 1 above that the subset of expressed genes varies from one tissue to the next. The expression profiling work that has already been initiated by Dr. Kieran will set the stage for this flagship project by helping to identify that subset of genes that are expressed in LGA cells.
