Metastatic Breast Cancer Metastatic Breast Cancer Metastatic Vulnerabilities May Be New Targets: Newsroom
DALLAS – January 12, 2022 – Metastatic differences in metabolism could explain why some metastatic breast cancer cells rapidly generate tumors after migrating from primary tumors to the brain, while others linger for months or years before forming these secondary tumors, report scientists from UT Southwestern in a new study. The conclusions, published in Cell metabolism, highlight metabolic vulnerabilities in malignant cells that could eventually lead to new cancer therapies.
Srinivas Malladi, Ph.D.
“Brain metastases are a major problem for breast cancer patients, and most of the treatments we have are not that effective. We have identified unique characteristics of metastatic breast cancer cells that could serve as new targets, ”said Srinivas Malladi, Ph.D., assistant professor of pathology and member of the Harold C. Simmons Comprehensive Cancer Center, who co-led the study with Pravat Kumar Parida, Ph.D., postdoctoral fellow at the Malladi laboratory.
The brain is a common site for breast cancer metastasis, especially for patients with a subtype of this disease known as HER2 +. About half of patients with HER2 + breast cancer develop secondary tumors at some point after their primary tumor is diagnosed, explained Dr Malladi, a phenomenon known as metachronous brain metastasis (M-BM). . Synchronous brain metastases (S-BM), when secondary brain tumors are diagnosed at the same time as the primary breast tumor, are rarer – but patients with S-BM have a much worse prognosis, with a median overall survival only six months after diagnosis. Patients with HER2 + breast cancer with latent brain metastatic cells (Lat) are asymptomatic and likely to develop BM-BM over varying durations.
Pravat Kumar Parida, Ph.D.
Using an animal model developed in Malladi’s lab, Drs. Malladi, Parida and their colleagues found significant differences in the metabolism of these different types of brain metastatic cells. For example, while S-BM cells used glucose as their primary fuel source, M-BM and Lat cells used a related sugar called glutamine. In addition, Lat cells secreted less lactate, a form of lactic acid, than M-BM and S-BM cells. Lactate helps M-BM and S-BM cells escape innate immune surveillance and therefore may promote tumor survival.
Additionally, researchers found higher amounts of a protein known as xCT, which mediates oxidative stress, in M-BM and Lat cells compared to S-BM. Stemming the activity of this protein using genetic techniques and chemical inhibitors significantly reduced the metastatic activity of M-BM and Lat cells and made them more vulnerable to drugs targeting HER2 + cells.
Dr Malladi noted that the differences identified in the study suggest potential targets for attacking brain metastases in breast cancers and potentially other types of malignancies. Because an xCT inhibitor is already being tested in clinical trials for multiple myeloma, he added, its use could represent a particularly promising strategy for attacking metabolic vulnerabilities in brain metastases.
Bioluminescent images of mice with overt and latent brain metastases
The Simmons Cancer Center, the only National Cancer Institute-designated comprehensive cancer center in North Texas, is ranked among the nation’s top 25 cancer centers by American News and World Report. UT Southwestern, home to the Peter O’Donnell Jr. Brain Institute, is also ranked among the top 20 hospitals for neurology and neurological surgery by US News.
Other UTSW scientists who contributed to this study include Mauricio Marquez-Palencia, Vidhya Nair, Akash K. Kaushik, Kangsan Kim, Jessica Sudderth, Eduardo Quesada-Diaz, Ambar Cajigas, Vamsidhara Vemireddy, Paula I. Gonzalez- Ericsson, Melinda E. Sanders, Bret C. Mobley, Kenneth Huffman, Sunati Sahoo, Prasanna Alluri, Cheryl Lewis, Yan Peng, Robert M. Bachoo, Carlos L. Arteaga, Ariella B. Hanker, and Ralph J. DeBerardinis. Disclosures are available in the document.
The research was funded by grants from the Cancer Prevention and Research Institute of Texas (RP210041 and RR170003), the National Science Foundation (2019281049), the National Cancer Institute (R35CA22044901), the American Cancer Society (RSG-20- 47-01- CSM) and METAvivor (GAA202106-0027).
Dr Arteaga, director of the Simmons Cancer Center, holds the Lisa K. Simmons Distinguished Chair in Global Oncology. Dr. Bachoo, Associate Professor of Neurology, holds the Miller Family Chair in Neuro-Oncology. Dr DeBerardinis, Head of the Division of Pediatric Genetics and Metabolism, is the Joel B. Steinberg, MD Distinguished Chair in Pediatrics, and is a Sowell Family Scholar in Medical Research at UTSW.
About UT Southwestern Medical Center
UT Southwestern, one of the nation’s leading academic medical centers, integrates pioneering biomedical research with exceptional clinical care and education. The institution’s faculty has been awarded six Nobel Prizes and includes 25 members of the National Academy of Sciences, 16 members of the National Academy of Medicine and 14 researchers of the Howard Hughes Medical Institute. The full-time faculty of more than 2,800 is responsible for revolutionary medical advancements and is committed to rapidly translating science-driven research into new clinical treatments. Doctors at UT Southwestern provide care in approximately 80 specialties to more than 117,000 inpatients, more than 360,000 emergency room cases and supervise nearly 3 million outpatient visits per year.