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, PhD, Vera Bradley Foundation Professor of Breast Cancer Innovation at 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, 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 your body suppress cancerous tumors.
Lu and his team combined trastuzumab—a targeted cancer drug for HER2-positive breast cancer patients—with α-amanitin, a small-molecule inhibitor which is originally isolated from a toxic mushroom, to create a novel drug called T-Ama. Even though 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 α-amanitin.
“Our big question was whether we could find a new drug which 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 Indiana University 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 their 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,” said Lu. “I think it will be a gamechanger for the field of triple negative breast cancer therapy.”
INDIANAPOLIS—Researchers at the Indiana University Melvin and Bren Simon Comprehensive Cancer Center have identified how breast cancer cells hide from immune cells to stay alive. The discovery could lead to better immunotherapy treatment for patients.
Xinna Zhang, PhD, and colleagues found that when breast cancer cells have an increased level of a protein called MAL2 on the cell surface, the cancer cells can evade immune attacks and continue to grow. The findings are published this month in The Journal of Clinical Investigation and featured on the journal’s cover.
“Like other cancer cells, breast cancer cells present tumor-specific antigens on the cell membrane, which immune cells recognize so they can kill the tumor cells,” Zhang said. “But our study found that MAL2 can reduce the level of these antigens, so these tumor cells are protected and can no longer be recognized as a threat by these immune cells.”
Considered the future of cancer treatment, immunotherapy harnesses the body’s immune system to target and destroy cancer cells. Understanding how cancer cells avoid immune attacks could offer new ways to improve immunotherapy for patients, explained Xiongbin Lu, PhD, Vera Bradley Foundation Professor of Breast Cancer Innovation and cancer center researcher.
“Current cancer immunotherapy has wonderful results in some patients, but more than 70% of breast cancer patients do not respond to cancer immunotherapy,” Lu said. “One of the biggest reasons is that tumors develop a mechanism to evade the immune attacks.”
The collaborative research team set out to answer key questions: How do breast cancer cells develop this immune evasion mechanism, and could targeting that action lead to improved immunotherapies?
Zhang and Lu, members of the Vera Bradley Foundation Center for Breast Cancer Research, turned to biomedical data researcher Chi Zhang, PhD, assistant professor of medical and molecular genetics at IU School of Medicine. Chi Zhang developed a computational method to analyze data sets from more than 1,000 breast cancer patients through The Cancer Genome Atlas. That analysis led researchers to MAL2; it showed that higher levels of MAL2 in breast cancer, and especially in triple-negative breast cancer (TNBC), was linked to poorer patient survival.
“Dr. Chi Zhang used his advanced computational tool to build a bridge that connects cancer genetics and cancer genomics with a clinical outcome,” Lu said. “We can analyze molecular features from thousands of breast tumor samples to identify potential targets for cancer immunotherapy. From that data, MAL2 was the top-ranked gene that we wanted to study.”
Xinna Zhang took that data to her lab to determine MAL2’s purpose in the cells, how it affects breast cancer cell growth and how it interacts with immune cells. Using breast cancer tissue samples from IU patients, cell models and animal models, she found that breast cancer cells express more MAL2 than normal cells. She also discovered that high levels of MAL2 significantly enhanced tumor growth, while inhibiting the protein can almost completely stop tumor growth.
In Lu’s lab, he used a three-dimensional, patient-derived model called an organoid to better understand how reducing MAL2 could improve patient outcomes.
“Tumor cells can evade immune attacks; with less MAL2, the cancer cells can be recognized and killed by the immune system,” Lu said. “MAL2 is a novel target. By identifying its function in cancer cells and cancer immunology, we now know its potential as a cancer immunology target.”
Researchers now are exploring ways these findings could be used to develop and improve breast cancer therapies.
Lu is co-leading a cancer immunotherapy program for triple negative breast cancer as part of the Indiana University Precision Health Initiative. Both Xinna Zhang and Chi Zhang are also involved in the initiative for developing novel breast cancer immunotherapy. The Precision Health Initiative, the first recipient of funding from the Indiana University 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.
Additional authors are Bryan P. Schneider, MD, Yunlong Liu, PhD, and Sha Cao, PhD, of IU Simon Comprehensive Cancer Center; Yuanzhang Fang, PhD, Lifei Wang, Changlin Wan, Yifan Sun, Kevin Van der Jeught, PhD, Zhuolong Zhou, PhD, Tianhan Dong, Ka Man So, Tao Yu, PhD, Yujing Li, PhD, Haniyeh Eyvani, Austyn B. Colter, Edward Dong, George E. Sandusky, PhD, of IU School of Medicine; and Jin Wang, PhD, of Baylor College of Medicine.
This study was supported by the Vera Bradley Foundation for Breast Cancer Research, the American Cancer Society Institutional Research Grant, and the National Institutes of Health (R01CA203737 and R01CA206366).
Contact: Candace Gwaltney, firstname.lastname@example.org
About IU School of Medicine
IU School of Medicine is the largest medical school in the U.S. and is annually ranked among the top medical schools in the nation by U.S. News & World Report. The school offers high-quality medical education, access to leading medical research and rich campus life in nine Indiana cities, including rural and urban locations consistently recognized for livability.
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