Every day, women arrive at MUSC Hollings Cancer Center for mammograms, genetic counseling and treatment for breast cancer. Even as they come and go on the first three floors of the peninsular Charleston building, members of the Sahin Lab on the seventh floor are homing in on potential treatments for breast cancer, especially drug resistant and metastatic breast cancer.
This integration of clinical care and research is part of what drew Ozgur Sahin, Ph.D., to Hollings. He brought his lab to MUSC in May as a professor and the SmartState Endowed Chair in Lipidomics and Drug Discovery in the Department of Biochemistry and Molecular Biology. Although he's been here only a few months, he's already worked with some Hollings researchers through his former position as an associate professor at the University of South Carolina, and since arriving at MUSC, he's started collaborations with some of his hallmates in Hollings.
Sahin said he's spent most of his career at cancer centers, so he appreciated that Hollings is an NCI-designated cancer center. Plus, the Charleston location didn't hurt.
"I spent almost 10 years in Germany, in Europe. I like the European style of the town, so this old historic town really gives me a good feeling," he said.
Sahin has three major points of focus in his research. First is to understand the mechanism of cancer therapeutics; second is to understand the mechanism of drug resistance; and the third is a focus on metastasis.
"Basically, we are focusing on the processes that make breast cancer – or other cancers – quite aggressive and deadly," he said.
Sahin said his research starts and ends with patients, beginning with patient samples that they use to create models of the disease.
"Then we use genomics and proteomics approaches," he said. "We combine them, and we come up with novel drug candidates. Then we go back to patient data and samples. We test if they are clinically relevant; then we collaborate with people from medical oncology, pathology as well as medicinal chemistry. And then we develop novel compounds, and we go back to patients. So, we complete the circle."
New molecules to target breast cancer
That process has yielded a couple of potential new drug candidates as well as ideas for repurposing existing drugs. As part of the drug development process, Sahin has established two startup companies, OncoCube Therapeutics and LoxiGen Inc., to shepherd these drug candidates through the process.
He hopes that one candidate, a TACC3 inhibitor, will be ready for clinical trials next year. An overabundance of TACC3 shows up in a lot of cancers, including breast cancer, and that "upregulation" of TACC3 goes hand in hand with worse survival outcomes for patients with breast, lung and gastric cancers. Upregulation means that a cell has is increasing the amount of a cellular component.
The TACC3 inhibitor would target a process called centrosome clustering. Centrosomes are involved in cell division, but cancer cells often have too many centrosomes, referred to as centrosome amplification. The presence of too many centrosomes usually leads to cell death, but cancer cells get around this by clustering the centrosomes together – they fake out the process, like two people squeezing through a subway turnstile together.
Sahin said that TACC3 is overexpressed in tumors with centrosome amplification, and that centrosome amplification tends to be associated with aggressive cancer. Because centrosome amplification is found in many types of cancer, a TACC3 inhibitor could potentially be useful for many cancer patients beyond breast cancer patients.
In another line of inquiry, the lab is developing lysyl oxidase (LOX) inhibitors. The Sahin Lab has recently shown that the protein LOX is a major factor in chemotherapy resistance in triple negative breast cancer, one of the most aggressive and least treatable forms of breast cancer.
Although there are some LOX-family inhibitors, there are no inhibitors on the market that are specific to LOX, Sahin said.
"If it works, it will be the first-in-class LOX-specific inhibitor," he said. "We are excited about that."
In a third project, the lab is nearing the end of some preclinical trials using drugs that are already in use in some neurological diseases. Drug repurposing, or finding new and effective uses for drugs that are already approved and safe for use, is an increasingly common strategy as researchers work to get more potential treatments through the time-consuming drug development pipeline.
Sahin said that the process of discovery keeps him motivated.
"I want tomorrow to be different than today, and after tomorrow, it'll be different, too," he said. "So that keeps me moving. I like research. Cancer is a major problem that affects everybody, so I want to do my best, not only in solving mechanisms and identifying new players but also in developing therapeutics to really touch the lives of patients. So that's the motivation."
