Hollings researchers find new angles to boost breast cancer care

Nancy Klauber-DeMore is understandably delighted when her breast cancer patients do well. She sees patients several days a week as a surgical oncologist at MUSC Hollings Cancer Center in Charleston, South Carolina. When some, however, develop metastatic disease, there is sometimes nothing the team can do to prevent the worst. “It’s devastating,” she says.

These situations drive Klauber-DeMore’s research at Medical University of South Carolina (MUSC) Hollings Cancer Center. “I have to find treatments that are going to change things,” she says. “That’s a strong motivating force.”

As South Carolina’s only National Cancer Institute-designated cancer centre, Hollings brings to bear the state’s largest academic-based cancer research programme against the cancer burden in South Carolina and across the United States.

In breast cancer, specialist researchers are developing innovative treatments, as well as generating insights about the disease’s development, and why stark disparities in outcomes exist between South Carolina’s diverse communities. The fruits of these labours have been exciting, and at times unexpected.

Angiogenesis inhibition in breast cancer, and beyond

Klauber-DeMore’s research interests began in a cancer research fellowship at Harvard Medical School, under the mentorship of Judah Folkman, where she studied angiogenesis – the formation of new blood vessels. When she joined the faculty, bevacizumab (marketed as Avastin) was in clinical studies to determine whether blocking vascular endothelial growth factor (VEGF), a protein that stimulates new blood vessel formation, would help cancer patients. The drug received FDA approval but did not improve overall survival rates in breast cancer. Klauber-DeMore wanted to know why, hypothesizing that breast cancers must be making other angiogenesis factors that continued stimulating tumour growth even when VEGF was blocked.

This was the origin of Klauber-DeMore’s research using human tumour tissues acquired from breast cancer operations on an IRB-approved protocol. She developed a technique to micro-dissect blood vessels and extract RNA to look at differences between gene expression in tumour vessels and normal vessels from patients undergoing breast reduction. The process allowed her to look for genes, not previously described in angiogenesis, that encoded proteins secreted or on the membrane, making tumours more likely to develop. This led to research into a novel angiogenesis factor, secreted-frizzled-related protein 2 (SFRP2), which “was surprising because SFRP2 had never been known to stimulate tumour angiogenesis”, Klauber-DeMore says. She found it also had a direct effect on tumour survival and immunology.

Klauber-DeMore’s lab developed a monoclonal antibody to SFRP2 (IVT-8086), finding it was effective at inhibiting triple negative breast cancer (TNBC) in mice. She co-founded Innova Therapeutics to manufacture the antibody and take it into clinical studies.

While Klauber-DeMore is a breast cancer scientist, her research had another use. Her daughter’s best friend developed paediatric osteosarcoma, ultimately dying after exhausting the available therapies. Klauber-DeMore was heartbroken that for 20 years there had been no new therapies developed for metastatic osteosarcoma, and wondered whether IVT-8086 might change that. Around that time, Jason Yustein’s lab at Baylor College of Medicine published a seminal paper showing the importance of SFRP2 in metastatic osteosarcoma.

“It became a passion to see if IVT-8086 would work in osteosarcoma,” she said. The lab examined the role of SFRP2 on the tumour immune system, and found that SFRP2 regulates PD-1 and CD38 expression in T cells. In addition to looking at SFRP2 for breast cancer, she began collaborating with Yustein, finding that IVT-8086 not only worked as a single agent in metastatic osteosarcoma, but was synergistic with immunotherapy. The FDA granted rare pediatric and orphan disease designations for IVT-8086. Once funding is secured, Innova Therapeutics plans to implement clinical trials for adult tumours, including breast cancer, as well as for paediatric osteosarcoma. “Developing new therapeutic options for incurable cancers is critical,” Klauber-DeMore says.

A fresh look at racial disparities in TNBC

Elsewhere at Hollings, Peggi Angel’s work focuses on collagen’s role in breast cancer disparities. “Black women have a 36% higher breast cancer mortality rate than other races, despite having a similar incidence as white women,” says Angel, associate professor in cell and molecular pharmacology and experimental therapeutics at MUSC. Black women are diagnosed with later stages and higher grades of breast cancer. This is especially true for TNBC, she adds.

“My hypothesis is that collagen changes are involved,” Angel says. “These changes are creating a way for the metastasis and higher grades to happen quickly.” Research has shown that cancer fibroblasts can take over collagen production at tumour borders to accelerate the spread to nearby tissue, and this process may start earlier in African American women.

Angel invented a proteomic method to identify the spatial distribution of collagen protein. Her approach uses an unconventional enzyme, collagenase-3, to look at the protein structure of fibrillar collagen within the triple helical region. When cells move through this three-dimensional environment, she says, the triple helical domain exposes bits of information that the cells read like a code, changing what they secrete. She anticipated that from a proteomic level they would start understanding the changes.

Angel hypothesizes that the collagen protein affects whether it can recruit different types of cells to the tumour microenvironment. Her approach allows scientists to define collagen protein structure spatially, so they can see where the collagen structure is post-translationally modified, but also its location – for instance if it’s at the tumour margin.

Her team is trying to identify differences between Black and white subjects that might lead to more aggressive breast cancers in Black women. “Collagen organization changes systematically with breast cancer progression and is predictive of outcomes,” she says.

Angel is researching diaspora populations in South Carolina such as Sea Islanders, who have origins on the West African coast. This population has unique genetic features that have remained in this tight-knit community, which may predispose the women to breast cancer.

Angel hopes to discover the molecular signatures that form tumour-permissive breast density and to develop therapeutic approaches that can reverse this change. The molecular signatures could also be used to develop more specific breast cancer diagnoses and identify subtypes.

Angel’s work has benefited from collaboration with Marvella Ford, associate director of population sciences and cancer disparities at Hollings, who brings specialist insights to the project. “Marvella has done a huge amount of work reaching out to the Sea Islander population to understand why they have higher cancer risks,” says Angel.

With researchers across more than 20 academic departments and six medical colleges, there’s no shortage of opportunities for collaboration at Hollings. The institution’s research targets reducing the cancer burden and tackling disparities across South Carolina. Specialists work together, pursuing shared objectives to answer complex questions. “Modern research”, concludes Angel, “is a collective effort.”