Over the next five years, Dr. Chioniso Patience Masamha will be studying the ways cancer cells multiply. The Butler University Assistant Professor of Pharmaceutical Sciences, who received a grant for $1,394,125 from the National Institutes of Health (NIH), hopes this project will lead to more effective strategies for detecting and treating the disease.
Cancer works by hijacking normal processes within the body, taking advantage of existing functions to cause the excessive multiplication of cells. Some of the same structures that allow our bodies to survive can be mutated in life-threatening ways. Normal, healthy genes that have the potential to become cancerous are called oncogenes.
Cyclin D1, the oncogene Dr. Masamha is focusing on for this research, normally plays an important role in driving cell progression and multiplication. In healthy cells, cyclin D1 only “turns on” when it is needed—such as when the body has been injured and needs to heal itself—then “turns off” when it is no longer needed.
When cancer hijacks this gene, it essentially removes the off switch. The cyclin D1 goes into overdrive, causing cells to continue dividing and growing uncontrollably. Abnormal cyclin D1 expression is common across several types of cancers, including pancreatic cancer, breast cancer, melanoma, and endometrial cancer, among others.
“When cyclin D1 is normally expressed in cells,” Dr. Masamha explains, “it is usually degraded within 30 minutes. However, in cancer cells, cyclin D1 can survive for up to eight hours without being degraded.”
We know this happens, but we don’t know how. So Dr. Masamha’s research studies the specific sequences of cyclin D1 expressed in cancer cells, as well as the proteins involved in processing cyclin D1, to try to understand the mechanisms that lead to the oncogene’s abnormal overexpression.
Dr. Masamha will look specifically at cyclin D1’s relationship to a type of lethal blood cancer called Mantle Cell Lymphoma (MCL). Why MCL? This type of cancer originates in the B-cell, a white blood cell that creates antibodies. In healthy B-cells, cyclin D1 is never actually active at all. But in cancerous B-cells, not only is the cyclin D1 active, it’s overactive—leading to the aggressive growth of cancer cells. This is associated with reduced survival in MCL patients.
Dr. Masamha believes the mechanisms that cause cancerous B-cells to activate their otherwise-dormant cyclin D1 could be the same mechanisms that put cyclin D1 into overdrive.
“If we figure out why cyclin D1 is expressed in this particular type of cancer,” she says, “then maybe we can try to target that mechanism that results in cyclin D1 overexpression in this and other types of cancers.”
In addition to determining how cyclin D1 becomes expressed in cancerous B-cells in the first place, Dr. Masamha aims to discover the consequences of the resulting cyclin D1-driven hyperproliferation—or multiplication—of tumor cells.
Healthy B-cells generate antibodies through a process of breaking apart chromosomes and putting them back together. In cancerous B-cells, increased cell division due to abnormal cyclin D1 expression makes it more likely that the broken chromosome pieces will end up reattaching to the wrong chromosomes.
The result is the formation of something called fusion genes, which are made up of DNA sequences that don’t belong together.
We know fusion genes happen frequently in MCL, but we don’t yet know exactly what they look like, or how to systematically detect them. Dr. Masamha’s project will use third-generation sequencing technology, allowing her to look at the full DNA sequences of individual genes and identify which types of fusion genes are present. Her findings could provide crucial information for both the diagnosis and treatment of cancers involving the abnormal expression of cyclin D1.
“If you can detect fusion genes early enough—so if you sequence someone’s DNA before they even get cancer and find fusion genes—you can know that those fusion genes might end up resulting in cancer,” she says, explaining that this could help identify preventative therapies. “Or, if the person already has cancer and you can detect what kind of fusion genes they have, you can identify which drugs would provide the best treatment.”
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