Primary School Student

Think about when you are trying to find the right piece to fit into a puzzle that you are working on. You have to look at both the picture you’re trying to make and the shape you need to fit it in. Medicine works that same way inside of our bodies. When you have a fever, you take medicine in order to feel better. That medicine is like a puzzle piece, it must fit into a specific spot inside your body perfectly for it to work. Sometimes, when people get really sick, we don’t have any medicine that will help them. My research is on developing new medicines for people who are very sick. The hard part for me is that when we do a puzzle, we get to see the whole picture we are trying to make, but when we make medicine, we can’t always see where and how it is going to fit inside the body. When you can’t find the right puzzle piece you have to try a couple of different pieces in the same spot before you can find the right one. I have to try many different types of medicines to see what can actually treat an illness. Only when I make many different types of medicine can we begin to understand what works and help people who are really sick to feel better.

Secondary School Student

All proteins have specific jobs within the cell, and sometimes proteins will cause a specific effect. We focus on advillin, which is an actin-regulating protein. It has been observed that the protein advillin is implicated in glioblastoma multiform (GBM), which is a type of brain cancer. Increased advillin levels have recently been found in tumor cells while hardly any advillin is present in healthy tissue cells. The level of the protein advillin present in cells was also correlated with mortality rates, where more advillin led to higher mortality. Because of how important advillin is in the observance of GBM, it is a promising target for the treatment of GBM. My goal is to make a compound that can inhibit advillin, and in turn prevent the formation of GBM. The difficult part is that we do not know what advillin looks like, so we have to make a bunch of different drug analogues to see which changes allow the drug to inhibit the protein better. The drug that inhibits advillin the best can then be tested in mice, to then be eventually used in people to treat GBM.

College Student

Glioblastoma multiforme (GBM), a type of brain cancer, kills about 10,000 Americans each year. Once diagnosed, a majority of patients will die within a year. Currently treatment options for GBM include either one, or a combination of, surgical removal, chemotherapy, and radiotherapy. Previously, the gene AVIL was determined to be involved in the formation of GBM tumors. The gene AVIL codes for the protein advillin. The amount of the protein advillin in the body has a known correlation with patient survival. When there are high levels of this protein, there are high mortality rates. Further, this protein is hardly detected in healthy tissue, while it is heavily detected in tumor tissue. These discoveries make advillin an intriguing target for the treatment of GBM. Previously, many different drugs were synthesized with small changes made in the structure to determine what functional groups make the compound more, or less, potent. One of those analogues was very potent against a GBM cell line and chosen as our new chemical lead. To move this compound into clinical trials, we have begun development of an enantioselective synthesis of this lead compound, since we know that individual enantiomers interact differently in the body. In parallel, we have been developing enantiopure ether analogues. The ether analogues are viable because the methyl alcohol of the lead compound has little effect on the overall efficacy of the compound. These analogues can be synthesized in a simplified manner with enantiopure starting materials to allow for quick screening. This will accomplish two things; first, to reduce the metabolic of the benzyl group when someone takes our drug orally. Second, the chemical modification can be used to further probe the binding pocket of our target protein, advillin. This is done by placing different functional groups in different spots on the compounds and is necessary because the complete structure of advillin is not yet known. By understanding the impacts that these chemical modifications have on the ability to inhibit advillin, I will be able to develop new ideas on what the binding site looks like and what kinds of chemical structures might work best.

Graduate Student in Discipline

Glioblastoma multiforme (GBM), a type of brain cancer, kills about 10,000 Americans each year. Once diagnosed, a majority of patients will die within a year. Currently treatment options for GBM include either one, or a combination of, surgical resection, chemotherapy, and radiotherapy. Previous work by our collaborator, Dr. Hui Li (UVA Pathology), identified the gene AVIL as a novel oncogene for the formation of GBM tumors. AVIL codes for the protein advillin, and its expression levels have a known correlation with patient outcomes. When there is high advillin expression, there are high mortality rates. Further, advillin is hardly detected in healthy tissue, while it is heavily detected in tumor tissue. These discoveries make advillin an intriguing drug target for the treatment of GBM. Based on a screening hit and subsequent structure-activity relationship (SAR) study, the Hilinski lab has identified a new lead compound. To move this compound into clinical trials, we have begun development of an enantioselective synthesis of this lead compound. In parallel, we have been developing enantiopure ether analogues of the lead compound. These analogues seek to accomplish two things; first, to reduce metabolism of the phenyl ring. Second, to further probe the binding pocket of advillin, as a crystal structure has not yet been obtained. Upon completion of these goals, I plan to embark on further SAR studies of the lead compound to continue to elucidate the advillin binding site.

Expert

Glioblastoma multiforme (GBM) kills about 10,000 Americans each year. Once diagnosed, a majority of patients will die within a year. Currently treatment options for GBM include either one, or a combination of, surgical resection, chemotherapy, and radiotherapy. Previous work by our collaborator, Dr. Hui Li (UVA Pathology), identified the gene AVIL as a novel oncogene for the tumorigenesis of GBM. AVIL codes for the protein advillin, and its expression levels have a known correlation with patient outcomes. When there is high advillin expression, there are high mortality rates. Further, advillin is hardly detected in healthy tissue, while it is heavily detected in tumor tissue. These discoveries make advillin an intriguing drug target for the treatment of GBM. Based on a screening hit and subsequent structure activity relationship (SAR) study, the Hilinski lab has identified a new lead compound. To move this compound into clinical trials, we have begun development of an enantioselective synthesis of this lead compound, which contains a quaternary center. In parallel, we have been developing enantiopure ether analogues of the lead compound. These analogues seek to accomplish two things; first, to reduce metabolism of the phenyl ring making the drug more orally bioavailable. Second, to further probe the binding pocket of advillin as a crystal structure has not yet been obtained. Upon completion of these goals, I plan to embark on further SAR studies of the lead compound to continue to elucidate the advillin binding site.