University of Virginia Cancer Center researchers have identified a gene that is responsible for the spread of triple-negative breast cancer (TNBC) to other parts of the body, and which can render the cancer resistant to chemotherapy. Sanchita Bhatnagar, PhD, and her team have also developed a nanoparticle-delivered antibody that they hope could possibly address both TNBC metastasis, and resistance to treatment. They estimate that this strategy of blocking the TRIM37 gene could benefit approximately 80% of TNBC patients. “It is a kiss of death,” Bhatnagar said, “that selectively reduces the expression of TRIM37 in cancer cells and prevents the spread.” The researchers report on their findings in a paper in Cancer Research, which is titled, “Oncogenic TRIM37 Links Chemoresistance and Metastatic Fate in Triple-Negative Breast Cancer.”
Triple negative breast cancer (TNBC) is an aggressive form of breast cancer that is responsible for about 20% of all breast cancer cases, and accounts for 40,000 deaths in the U.S. annually, the authors noted. The majority of these deaths result from resistance to chemotherapy and subsequent aggressive metastases. “TNBC patients are disproportionately associated with the highest frequency of chemoresistance, relapse, and metastasis,” they wrote. However, while new and effective targeted therapies are urgently needed, developing such treatments is “ … fraught with multiple challenges attributed to limited understanding of genetic complexities, metastatic biology, and drivers of metastatic health.”
While there have been a number of oncogenes and tumor suppressors identified that are genetically or epigenetically altered in cancer and accumulate during tumorigenesis, its not known whether these drives of tumorigenesis are also responsible for metastatic transmission, the authors further pointed out. “Despite metastasis being the key reason for failure of cancer therapies, it remains poorly understood,” said Bhatnagar. “We do not clearly understand what drives the metastatic growth in patients. In general, several genes are altered during tumorigenesis. However, whether targeting the same genes will prevent metastatic transition remains to be addressed.”
Bhatnagar’s team was the first to identify TRIM37 as an oncogene. “We have originally described tripartite motif-containing protein 37 (TRIM37) as a breast cancer oncoprotein that can epigenetically silence tumor suppressors,” the investigators wrote in their newly released Cancer Research paper.
“Clinically, high-TRIM37 associate with poor overall survival.” However, they acknowledged, “while TRIM37 promotes tumorigenesis, its function in breast cancer metastasis and the therapeutic implications of TRIM37 targeting remain to be demonstrated.”
The latest work uncovered a molecular dependence of TNBC tumors on the TRIM37 network, which enables tumor cells to resist chemotherapy, and metastatic stress. The investigators described the use of genomic and genetic approaches in relevant TNBC cellular, preclinical murine models, and tumor biopsies, to uncover the involvement of TRIM37. “We show that TRIM37 alters chromatin modification to resist chemotherapy and enforces changes in gene expression to favour metastatic transition,” they explained. “TRIM37-directed histone H2A monoubiquitination enforce changes in DNA repair that rendered TP53-mutant TNBC cells resistant to chemotherapy … These results formed the underlying rationale for targeting TRIM37 as a therapeutic strategy for treating TNBC.”
Based on these findings, the Bhatnagar team, working with UVA’s Jogender Tushir-Singh, PhD, developed a new approach to stop the effects of TRIM37 and, hopefully, prevent or significantly delay the spread of triple-negative breast cancer. This could also lower the disease’s defenses against chemotherapy.
Bhatnagar and Tushir-Singh’s approach uses lipid liposome-based nanoparticle paired with specially engineered antibodies that bind to the cancerous cells, but not to healthy cells. “As soon as the antibody finds the triple negative breast cancer cell, it binds to the receptor and is taken up by the cell,” explained Tushir-Singh, PhD, at UVA’s Department of Biochemistry and Molecular Genetics. The approach could feasibly be used to deliver targeted treatments for many other cancers as well. “That would not only get the treatment where it needs to be but, hopefully, help prevent unwanted side effects. Besides preventing metastases, it adds selectivity,” Bhatnagar said.
Another problem in the field is, how to give a nanoparticle treatment to the patients? she continued. “Most of these nanoparticles are cleared by the liver, so they never have a chance to really do their job.” So for this study, the researchers bypassed the issue by delivering nanoparticles via the nasal route, increasing the rate of uptake in the lungs, which is one of the most common metastatic target sites in TNBC patients,” Bhatnagar added.
Although development of the new approach is in its early stages, tests with lab mice offered up encouraging indications. To verify that TRIM37 targeting might offer a potential treatment approach, Bhatnagar teamed up with husband Tushir-Singh, PhD, to test the technology in the lab. “And we find that our targeted nanoparticles significantly reduce metastatic lesions in the lungs of spontaneous metastatic murine [mouse] models—both immune compromised and immune sufficient,” she said. “This is an important proof-of-concept much needed for the bench-to-clinic transition of these important findings.”
Clinically, most women in the early stages of breast cancer are treated with surgery, followed by radiation, or chemotherapy. However, metastasis remains a challenging medical problem. Bhatnagar’s research offers a potential way to target a driver of metastasis that she hopes will prevent or slow metastatic progression and improve overall survival. The authors acknowledged that much more work needs to be done but, as Bhatnagar pointed out, “This is a delivery platform, not only for targeting our protein of interest but for many other chemotherapeutic drugs that can be packaged into the nanoparticles and selectively delivered.”
As the authors concluded, “… our results identify a new driver of metastatic progression in TNBC patients and provide a mechanistic link between the two clinically linked phenotypes: chemoresistance and metastasis. Our findings also raise the possibility of clinically targeting TRIM37 to diminish the resistance to therapy, reduce the dissemination of cancer cells, and infiltration of distant sites. We demonstrate that our therapeutic design selectively inhibits TRIM37 and attenuates metastatic progression of TNBC tumors in vivo … Our results also raise the possibility that molecularly targeted nanoparticles can deliver diverse payloads selectively to cancer cells.”
Early results from the lab are also forming a foundation for the lab’s current work exploring the role of TRIM37 in racial disparities in TNBC. Incidence of the disease is disproportionately higher in African-American women compared with other races, with a 5-year survival rate in African-American patients of only 14% compared with 36% in non-African-American women.