Lyons, an associate professor in the University of Colorado School of Medicine, first came to the school in 1999 as a professional research assistant in the Department of Microbiology. She completed her doctoral studies with Steve Anderson, PhD, in the Department of Pathology in 2006, and continued as a postdoc fellow in the lab of CU Cancer Center member Virginia Borges, MD, a professor in medical oncology and leader of the Young Women’s Breast Cancer Translational Program. It was there that Lyons began her research on semaphorin 7a, a molecule that appears to drive metastasis of breast cancers. Her lab’s recent publication suggests this may be particularly important in estrogen receptor (ER) positive breast cancer. Cancer cells in ER-positive breast cancer have receptors that allow them to use the hormone estrogen to grow.
“Women with metastatic ER-positive breast cancer often face their cancers developing resistance to antiestrogen drugs such as Tamoxifen or Fulvestrant. We think that the expression of this semaphorin molecule is one reason this resistance occurs.” Lyons says.
Looking for a new standard of care
So Lyons set out on a search for existing drugs that would have an effect on semaphorin 7a and stop cancer cell growth. For her efforts, the nonprofit organization METAvivor— which funds research specifically on stage 4 metastatic breast cancer — presented her with its Translational Research Award earlier this year. The grant award includes funds for Lyons to continue her collaborative research with Borges.
Lyons has identified two promising drugs for this lab research so far: immunotherapy, and a drug called venetoclax (Venclexta). These drugs are currently under study for ER-positive breast cancer, and this project hopes to better define who could derive the best benefit from them. Through the efforts of two other CU Cancer Center researchers — Dan Pollyea, MD, MS, and Craig Jordan, PhD — venetoclax recently secured FDA approval for the treatment of acute myeloid leukemia (AML).
“I’m part of the Department of Medicine Outstanding Early Career Scholar program with Dan, and when he presented his work on venetoclax, there was some evidence that the molecule it targets might be involved in our pathway as well,” Lyon says. “We obtained advice on venetoclax studies from Dr. Jordan’s lab, and when tested in the lab, the tumors that were resistant to ER-positive drugs were sensitive to venetoclax.”
Impact on postpartum patients
Lyons’ research is of special importance to women who have recently given birth, as postpartum women not only have a higher risk of developing breast cancer, but their tumors appear to be more likely to contain higher levels of semaphorin 7a and more likely to recur if semaphorin 7a is high.
“It has been long recognized that if you have a child at some point in your life, your lifetime risk of breast cancer goes down, but all women who have children have a transient increased risk for developing breast cancer,” Lyons says. “That ranges from an almost 10-year risk if you have your first child in your early 20s to a 20-year risk if you have your first child in your late 20s. If you’re older than 30 when you have your first child, however, you may never get that protective effect. In fact, these women may be at increased risk for developing breast cancer until their 80s.”
A major reason for the increased risk is the changes the breast undergoes after a woman has a child, Lyons says.
“When a mammary gland starts making milk, it looks very different than when it’s not making milk,” she says. “When a woman weans, it’s like a large wound-healing event. All of the cells die that arose in the tissue to make the milk, and it creates inflammation in the breast. Semaphorin 7a is part of that inflammatory program.”
Role of biology
Lyons hopes her research will confirm the importance of semaphorin 7a in ER-positive metastatic breast cancer and support the work going into a future clinical trial for women with these types of tumors. A main focus of the project is to confirm if venetoclax or immunotherapy, in addition to current standard treatments, can hit the semaphorin 7a target and prevent cancer growth and metastasis.
“Ultimately, we hope to be able to identify specific treatments for breast cancer patients and postpartum patients, based on the biology of their tumor,” she says. “A breast cancer patient with ER-positive metastatic breast cancer would not routinely get immunotherapy or venetoclax right now, but if we can nail this down in the lab, then perhaps we can have a clinical trial aimed specifically at semaphorin 7a-expressing tumors with venetoclax or immunotherapy and prove that semaphorin 7a is an important target for treatment and a hope for improving the survivability of women with breast cancer.”