FUNDED INVESTIGATORS
 |
|
| Frank Rauscher, III, Ph.D. |
Arthur Zelent, Ph.D. |
| Wistar Institute |
Institute of Cancer Research |
Targeting the Snail Machinery that Controls the EMT Differentiation Program during Metastasis
The research Drs. Rauscher and Zelent are pursuing is designed to define the molecular mechanisms in cancer cells that silence genes and therefore cause cancer. We already know that reactivating these genes can be a very powerful and non-toxic therapy for these cancers. This paradigm has been pioneered by investigators of the SWCRF, and directly led to the recognition and use of Retinoic Acid as a curative drug for leukemia.
The problem now is that we need more targets for reversing gene silencing. By defining new targets for relief of gene silencing in cancers and then using these targets to develop new drugs, this research could have a major impact on cancer treatment. The mission and aims of the SWCRF Institute without Walls are completely aligned with my career aims and goals. For the
past 20 years, Dr. Rauscher has been highly interested in targeting genes in cancers to achieve highly selective, non-toxic, chemo-and differentiation-therapies.
A major impediment to achieving selective therapy is defining which genes are on or off in a particular tissue or tumor. The basis for this dichotomy in gene regulation is the following: Each of us is born with around 60,000 genes. However, only a fraction of those genes are turned on at any time in any particular tissue. These subsets of genes are turned on in particular tissues
and function to make an eye an eye, a liver a liver, and a kidney a kidney (for instance). Thus, though each cell in the body has the exact same sixty thousand genes, a highly evolved process is present to only allow certain genes to be on and the vast majority of genes to be off (or silenced) in other tissues. Dr. Rauscher's laboratory is interested in the mechanisms whereby the human body can silence the vast majority of genes (in normal tissues and in tumors).
The best analogy that one could use to describe this biochemical phenomenon is the analogy between a computer's hard drive and its software. The hard drive is analogous to the 60,000 genes that we inherit from our mothers and fathers. However, each individual tissue and tumor type has a separate software package, which allows it to turn on or off a select set of genes, allowing a kidney or brain to function or a tumor to form. This software acts largely at the level of gene regulation and the packaging of our genes into chromatin structures at the molecular level. One can imagine that the computer's hard drive is relatively immutable. However, the software in a particular tissue can be easily subverted with dire consequences. This is often what we see in the development and progression of cancer; that is, genes that are aberrantly expressed compared to the normal tissue.
In order to understand this process and target it with drugs, they must identify the critical mechanisms the cell uses to maintain gene silencing and therefore define the cellular software that does that. With the support of the SWCRF "Institute without Walls", they have been able to discover and characterize a new pathway that is controlled by protein-protein interactions that regulate the EMT differentiation event during tumor spread and metastasis. This approach has great therapeutic potential in solid tumors.
*Arthur Zelent is also collaborating with Ming-Ming Zhou on a collaborative research project. Click here to read more.
