A team of Indiana University School of Medicine researchers has developed a novel antibody-drug conjugate for treating triple negative breast cancer.
The study, led by senior author Xiongbin Lu, Vera Bradley Foundation Professor of Breast Cancer Innovation at the IU School of Medicine, has been published in the prestigious interdisciplinary medical journal, Science Translational Medicine.
Triple negative breast cancer accounts for about 15 percent of all breast cancer cases. When a patient tests negative for estrogen receptors and progesterone receptors and has low levels of a protein called HER2, the patient is considered to have “triple negative” breast cancer. Patients with triple negative breast cancer typically have the poorest prognosis because there are not very many treatment options.
All breast cancers are often missing a chromosome fragment known as 17p, which contains genes that can help the body suppress cancerous tumors.
Lu and his team combined trastuzumab — a targeted cancer drug for HER2-positive breast cancer patients — with alpha-amanitin, a small-molecule inhibitor that is originally isolated from a toxic mushroom, to create a novel drug called T-Ama.
Although historically, trastuzumab has not been effective at targeting tumors for triple negative breast cancer patients by itself, Lu and his team found that T-Ama was effective at killing breast cancer cells with low HER2 levels in animal models during their study. They also determined that the loss of chromosome 17p makes the tumor cells more likely to respond to alpha-amanitin.
“Our big question was whether we could find a new drug that can efficiently kill cancer cells and also enhance the immune response of tumors to cancer immunotherapy,” said Lu, who is also a researcher at the IU Melvin and Bren Simon Comprehensive Cancer Center. “Our work aims to fulfill both of those.”
While the chromosome 17p loss can promote breast tumor growth, Lu said it also opens up opportunities to develop precision immunotherapy targeted to that area. Lu said the safety and efficacy of T-Ama has already been validated, so the team’s next step will be a clinical study for humans. Lu and one of his postdoctoral fellows have already been awarded the U.S. patent for T-Ama.
“The drug will be able to be used alone or in combination with current immune checkpoint inhibitors,” Lu said. “I think it will be a game-changer for the field of triple negative breast cancer therapy.”
Lu said developing T-Ama has been a team effort, as researchers at the Vera Bradley Foundation Center for Breast Cancer Research — such as Xinna Zhang, Dr. Bryan Schneider, Milan Radovich and Dr. Kathy Miller — have collaborated with Heidelberg Pharma, a German pharmaceutical company. Zhang, Schneider, Radovich and Miller are also physician-scientists at the IU School of Medicine and the IU Simon Comprehensive Cancer Center. Two of Lu’s lab members, Yujing Li and Yifan Sun, are co-first authors of the study. Li did a large amount of the benchwork for this study, while Sun contributed on the bioinformatic side.
Lu is co-leading a cancer immunotherapy program for triple negative breast cancer as part of the IU Precision Health Initiative. Zhang is also involved in the initiative for developing novel breast cancer immunotherapy. The Precision Health Initiative, the first recipient of funding from IU’s Grand Challenges Program, is enhancing the prevention, treatment and health outcomes of human diseases through a more precise analysis of genetic, developmental, behavioral and environmental factors that shape an individual’s health.
This study was supported by the IU Grand Challenge Precision Health Initiative, the IU Strategic Research Initiative fund, the Vera Bradley Foundation for Breast Cancer and the National Cancer Institute.
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