Cellular Soldiers: Harnessing the Power of Proteins

Proteomics is one of the latest buzzwords in medical research and the next step after the human genome project. But what does it mean and how do scientists use it? And what does it have to do with curing cancer?

Just as genomics is the study of all of the genes in an organism, proteomics is the study of all of the proteins. “Proteins are the soldiers participating in all actions at the cellular level,” explains Amrita Cheema, PhD, operations manager of the Proteomics Shared Resource at Lombardi Comprehensive Cancer Center. “A disease condition occurs because of proteins. It is in the proteins where some metabolic change occurs.”

Some proteins are enzymes that help chemical reactions in our cells produce energy, others may act as signals and can be transported to the surface of a cell – or they may even be the transporters for other proteins. Genes, on the other hand, make up the DNA, which always stays in the nucleus of a cell.

When scientists talk about a gene being activated or “turned on,” that usually means that the gene has been activated to produce a protein, which then performs the action. But these proteins do not work in a vacuum. Most often they work with other proteins, sometimes one-on-one, but in some cases they bind together to form large structures that collectively carry out a task.

All these interactions between proteins depend on having very precise properties, including shape and electrical charge. Think of a lock and key; the lock is perfectly shaped to only be opened by a key with the right grooves on it. Just like turning a key in a lock makes a door open, it is when proteins bind together that they often perform their work.

Proteomics allows scientists to study what other proteins bind to the one that they are studying. This is very important for developing new drugs because keeping two proteins apart may reduce the symptoms of a disease or even eliminate the disease altogether.

Developing a Cure

Joanna Kitlinska, PhD, conducts research on neuroblastoma, a cancer that affects infants and children. She is studying Neuropeptide Y (NPY), a protein that stimulates tumor growth. Kitlinska believes that if she can block the activity of NPY, she may have found a way to halt the growth of neuroblastoma tumors.

To do this, Kitlinska must first discover what other proteins NPY interacts with. By knowing the binding partners, she will be able to understand what kind of blocker is needed to keep NPY from stimulating tumor growth. In molecular biology, the small blocker is a potential drug that can stop the disease function of NPY.

This is where proteomics can help. The proteomics core at Lombardi provides Kitlinska with the tools needed to identify the binding partners of NPY. Using mass spectroscopy and other recent advances in proteomics, she is able to analyze the binding partners quickly. Already, she has identified a protein on the surface of the cell that interacts with NPY to transmit the growth signal. Kitlinska is currently working to develop a drug to block that interaction – something that will work to stop the key from fitting into the lock.

Detecting the Disease Early

Proteomics has also impacted the field of early detection. Radoslav Goldman, PhD, studies biomarkers released by a tumor found on the blood or urine. “We can find these molecules before we look for the cancer itself, which translates to an efficient screening process. The problem is that there are so many molecules in the bloodstream that it’s hard to sort them out,” he explains.

Men can be screened for elevated levels of prostate specific antigen (PSA), a biomarker found in the bloodstream, helping physicians catch cancer early. Goldman is searching for similar biomarkers for liver cancer and head and neck cancers.

Rather than trying to identify a single protein that indicates disease, Dr. Goldman looks for a combination of proteins seen in blood samples from patients with the cancer. The new technologies developed for proteomics – such as protein arrays – allow him to screen many proteins found in the bloodstream with high sensitivity. This means he can gain a more accurate indication of whether a person has cancer since it relies on multiple markers.

Speeding Toward the Cure

Goldman is very excited about the new research that proteomics has made possible. Using the classic approach, researchers had to know what they were looking for when they began an experiment. Now, Goldman can search for proteins in blood associated with cancer, instead of working to identify a single protein that is known to be altered in cancer tissue.

The beauty of proteomics is that you can profile the protein differences between someone with cancer and someone without; someone who has been treated for their cancer and someone who has not; metastatic cancer and non-metastatic cancer. Understanding these differences allows scientists to develop not only screening tests, but diagnostic tests, personalized treatment regimens, and new drugs that target previously unknown disease pathways.

Lombardi Associate Professor Todd Waldman, MD, PhD, uses proteomics to study the role of the PTEN gene in glioblastoma, one of the most aggressive brain cancers. The PTEN gene is mutated in more than half of patients with glioblastoma, so Dr. Waldman hopes to discover a way to target the mutated PTEN protein through its interactions with other proteins.

“Fifteen to twenty years ago, there were a lot of ‘firsts’; the first oncogene, the first tumor suppressor. Now, there are not as many firsts, but we’re working to fill in the important details. Proteomics allows us to do this much faster than we ever could before.”

By Allison Whitney, excerpted from the 2007 Lombardi Annual Report: Overcoming the Odds