Triple negative breast cancer is an aggressive subtype of breast cancer with worse survival outcomes than most. Although effective drugs and therapies have been developed for most breast cancer subtypes, triple negative breast cancer lacks the key receptors that these drugs interact with – in other words, it's negative for the three receptors for which therapies exist.
Chemotherapy, then, remains the primary treatment for triple negative breast cancer.
Initially, these patients really show good response to chemotherapy, but then they develop resistance in a very short time. And then almost nothing works afterwards, basically."
Ozgur Sahin, Ph.D., MUSC Hollings Cancer Center researcher, the SmartState Endowed Chair in Lipidomics and Drug Discovery in the Department of Biochemistry and Molecular Biology
Sahin is hoping to change that. In 2020, while at the University of South Carolina (USC), he published a paper, which has been highly cited since then, showing that targeting lysyl oxidase, or LOX, overcomes chemotherapy resistance. Now, the National Cancer Institute has awarded Sahin's startup, LoxiGen, Inc., a three-year Fast-track Small Business Technology Transfer (STTR) grant to develop his findings. The goal is a drug eligible for Investigational New Drug status from the U.S. Food and Drug Administration.
"Most of the time, people target the tumor itself, but in this case, we are targeting both the tumor and the tumor stroma – what we call the tumor microenvironment," Sahin said. The stroma is the mix of connective tissue, blood vessels and inflammatory cells that surrounds the cancerous tumor, providing a protective barricade as well as the signals to help the tumor to grow.
"Our expectation is if you block this protein called LOX, or lysyl oxidase, then you can open up the stroma, which is very stiff in this patient group. Then you can make chemotherapy penetrate better and be more efficacious.
"In addition to that, LOX also has some tumor-centric effects. It can also activate some biological processes in the tumor itself, and by inhibiting LOX, we are hitting both the tumor and stroma at the same time."
And although Sahin won't be studying metastasis in this grant, other researchers have shown that LOX has a role in cancer metastasis. Therefore, he said, it's possible that the inhibitor under development will affect metastasis as well as the tumor and the tumor microenvironment.
Developing the inhibitor will involve a collaboration among LoxiGen; Hollings investigators Craig Lockhart, M.D.; Nancy Klauber DeMore, M.D.; Elizabeth Hill, Ph.D.; USC researcher Campbell McInnes, Ph.D.; and Sahin.
The initial work of screening more than 5,000 compounds for those that inhibit LOX has come up with numerous possibilities. But just because a compound works in a cell culture in the lab doesn't mean it will work safely and efficiently in a human body. The painstaking work of drug development includes figuring out the pharmacokinetics – or the effects that the body has on the drug – and the pharmacodynamics, or what the drug is doing at the cellular level in the body.
The most important thing is to ensure that a compound isn't toxic, Sahin said. After that, researchers look for "drug-like properties," meaning the compound is metabolically stable, soluble and permeable.
"Our phase one milestone is to synthesize around 30 novel compounds and test them in in vitro assays with respect to efficacy, toxicity and selectivity," Sahin explained. And when we meet that milestone, then in phase two, those molecules will move to in vivo animal studies."
Drug development is a long process, typically eight to 12 years, he said. The STTR Fast-Track grant provides a way to speed up this process somewhat while still maintaining safety standards.
"We are very pleased to have the chance to translate our bench work to patients with this NIH support by developing better drug-like LOX inhibitors so that we can initiate clinical trials and eventually have an impact on patients in the clinic in the future."