Two recent research papers by University of Colorado Cancer Center member Traci Lyons, PhD, reveal that semaphorin 7A, a neuroimmune, inflammatory, and pro-fibrotic protein, is a promising target for breast cancer treatment.

Both papers, published in the journal Cell Reports, were funded by pilot grants from the CU Cancer Center.

Driver of immunosuppression

The first paper, published in May and first-authored by Alan Elder, PhD during his graduate studies, explores how semaphorin 7A works with the immune-regulating protein PD-L1 to drive immunosuppression in breast cancer during mammary involution — the post-lactation period where the mammary gland returns to its pre-pregnancy state — and its potential as a target in postpartum breast cancers, as well as all breast cancers that express this member of the semaphorin family.

“We showed in that paper that semaphorin 7A results in increased PD-L1 in the tumor, and since there are existing immunotherapies that target PD-L1, we thought maybe there is a specific subset of breast cancers that could be treated with an anti-PD-L1 therapy,” says Lyons, who has been studying semaphorin 7A for the past decade. “That initially showed promise, but we found that though immunotherapy works well initially, resistance emerges rapidly.”

Related: Turning Off the Breast Cancer Switch: Federal Grant Powers Study of Therapy Resistance

Lyons and the other researchers in her lab discovered one reason for that resistance: the cancer cells that became resistant to the immunotherapy had high levels of semaphorin 7A. Lyons, who has helped to develop a monoclonal antibody to target semaphorin 7A, says that drug worked better than the anti-PD-L1 therapy to treat those cancers.

“Immunotherapy works by reactivating the immune system to kill the tumor,” she says. “One of the mechanisms we revealed in that paper is that not only will semaphorin 7A promote survival of the tumor cells, but it also helps them hide from the immune system. One therapeutic strategy could be that if the anti-PD-L1 drug doesn't work in a patient, you could treat them with our antibody.”

Related: What is Immunotherapy?

Semaphorin 7A and childbirth

The second paper published by Lyons’ lab, this one in August and first-authored by Kelsey Kines, PhD,  explains how semaphorin 7A is partially responsible for what is known as the dual effect of pregnancy on breast cancer risk — that childbirth lowers the lifetime risk for breast cancer, but childbirth temporarily increases breast cancer risk for several years immediately following birth.

“One of the reasons we think that postpartum breast cancer — breast cancer diagnosed five to 10 years after a woman gives birth — is becoming much more prevalent is because more women over 30 than under 30 are having children these days,” Lyons says. “We also know that as women get older, if they've had a child, they can experience a protection from getting breast cancer. However, every pregnancy results in a transient increase in developing breast cancer, which is higher and longer the older you are when you have your first child.”

Examining tumor samples from the Young Women’s Breast Cancer Translational Program tissue cohort and the CU Cancer Center biobank, Lyons and her co-researchers found that the breast tumors of women over the age of 30, and women who had children over the age of 30, contained higher amounts of semaphorin 7A than the tumors of their counterparts under 30, leading to increased tumor growth and metastasis to other sites in the body. 

“We looked at the changes semaphorin 7A induces in the breast tissue,” Lyons says. “We found that semaphorin 7A is expressed in the murine mammary epithelium during postpartum mammary gland involution. We hypothesize that the aging mammary gland promotes semaphorin 7A expression, which allows tumor cells to proliferate and metastasize.”

Again, using the monoclonal antibody targeting semaphorin 7A, the researchers showed that targeting the protein could not only prevent metastases, but also causes current metastases to stop growing and, in some cases, shrink.

Promising target

Both studies, Lyons says, allowed her and her team to test their novel monoclonal antibody that targets semaphorin 7A. Lyons and her fellow CU Cancer Center breast cancer researcher Virginia Borges, MD, founded a biotech startup company, Pearl Scientific, to produce the antibody, which they hope to eventually test in a clinical trial for breast cancer patients who have failed other therapies.

“That has been a long journey, but we're getting closer every day,” Lyons says. “Through funding from several sources on campus, including the Chancellor's Development Initiative and the Gate Institute, as well as external funding from the NCI and American Cancer Society BrightEdge Entrepreneurial Program, we are progressing the drug toward clinical trials.”

It’s too early to know for sure, but Lyons and Borges both are optimistic that semaphorin 7A could become the next big target in breast cancer, similar to the HER2 protein targeted by the current cancer drug trastuzumab (Herceptin). 

“Semaphorin 7a looks to have the potential to be the next defining marker for a breakthrough in breast cancer treatment, “ Borges says. “We know from past discoveries in breast cancer, such as the identification of HER2 in the late 1980s, that finding a target that is driving cancers to behave aggressively can lead to greater gains in treatment benefit for our patients.”   

Adds Lyons: “The end goal here, in my mind, is that every breast cancer patient would be tested for semaphorin 7A like they are tested for HER2, and then their therapy would be based on their semaphorin 7A expression."