Research led by Joan Garrett, Ph.D., research instructor in Hematology/Oncology, reveals a molecular mechanism that may explain why some forms of breast cancer become resistant to therapy.
This research by Garrett, who works in the laboratory of Carlos Arteaga, M.D., professor of Medicine and Cancer Biology and director of the Center for Cancer Targeted Therapies (CCTT), was selected for press coverage during the American Association for Cancer Research (AACR) Annual Meeting, held earlier this month in San Diego.
She was one of more than two dozen Vanderbilt-Ingram Cancer Center (VICC) investigators invited to introduce their latest research findings during the international conference, which attracted more than 18,000 researchers, patient advocates and other health care professionals.
Approximately 20 percent of breast cancers have elevated levels of the HER2 protein and clinical trials have found that using two drugs to block HER2-positive tumors is superior to single drug therapy. However, resistance to the dual blockage of HER2 eventually develops and the cancer progresses.
In the study, Garrett and colleagues treated mice whose tumors harbored a human HER2-positive breast cancer cell line with two anti-HER2 drugs. The tumors disappeared and treatment was stopped. In some mice, however, the tumors recurred and did not respond to further treatment. More than 90 percent of these tumors also failed to respond to a second combination of HER2-targeted therapies.
The investigators found one of the resistant tumors had extra copies of the genes FGF3, FGF4 and FGF19. These genes produce proteins that attach to fibroblast growth factor receptors (FGFRs), triggering cell growth. The group discovered that tumor cells with extra copies of the three genes showed signs of elevated FGFR activation which suggests that the amplification of FGFR signaling could be a trigger for treatment resistance.
The investigators are now testing whether drugs that block or inhibit FGFRs are effective in mice whose tumors have become resistant to a HER2 drug combination.
“If we observe tumor shrinkage or elimination in this setting and can show that FGFR signaling is amplified in HER2-positive breast tumors from patients treated with dual blockade of HER2, we will have a good rationale for considering clinical trials,” Garrett said.
Resistance to another form of breast cancer therapy was the topic of an oral presentation by Jennifer Giltnane, M.D., Ph.D., clinical instructor of Pathology, Microbiology and Immunology. Giltnane presented data about genomic alterations associated with resistance to anti-estrogen therapy.
Christian Young, Ph.D., postdoctoral fellow in Hematology/Oncology, presented data which found that the PI3K enzyme turns on epidermal growth factor receptor (EGFR) signaling in triple negative breast cancer.
Tanner Freeman, graduate student, discussed a VICC-led study on the loss of the Smad4 signaling protein and its effect on tumor development in the intestinal tract.
Wade Iams, M.D., second-year internal medicine resident, presented data on the use of the NRAS gene mutation as a predictor of response to immune-based therapies for patients with metastatic melanoma.
Robert Coffey Jr., M.D., Ingram Professor of Cancer Research, presented an overview, along with yet-to-be published data, on the role of KRAS gene mutations in colorectal cancer.
