A newly available drug may improve the effectiveness of immunotherapy in hard-to-treat cancers of the upper urinary tract, suggests a study published by Weill Cornell Medicine and NewYork-Presbyterian investigators.
For the study, published July 5 in Nature Communications, the research team set out to learn more about the biological characteristics of upper tract urothelial carcinoma (UTUC) to help develop more targeted therapies. Among other hallmarks, they discovered that UTUC tumors have a lower number of the cancer-killing immune cells called T cells.
“We discovered the defining biological characteristics of UTUC tumors which set them apart from urothelial cancer of the bladder,” said senior author Dr. Bishoy Faltas, the Gellert Family-John P. Leonard, M.D. Research Scholar, an assistant professor of medicine and of cell and developmental biology, and a member of the Sandra and Edward Meyer Cancer Center at Weill Cornell Medicine, and an oncologist who specializes in urothelial cancers at NewYork-Presbyterian/Weill Cornell Medical Center.
Only about 10 percent of cancers affecting the lining of the urinary tract arise in the upper segment that collects and carries urine from the kidneys to the bladder. These UTUCs tend to be more aggressive than bladder cancers and are usually not be detected until they have become advanced.
To understand the key biological features of UTUC, Dr. Faltas and his collaborators sequenced all the genes and their RNA messages in UTUC tumors collected from patients at Weill Cornell Medicine, Baylor College of Medicine and MD Anderson Cancer Center. Then, they compared their data to the molecular profiles of urothelial carcinoma of the bladder from the Cancer Genome Atlas.
The genetic information they analyzed, helped Dr. Faltas and the team —which includes Drs. Olivier Elemento, Brian Robinson and Panagiotis Valchostergios from Weill Cornell Medicine and NewYork-Presbyterian—understand why there is a shortage of T cells in these tumors. They found that a gene called FGFR3 is hyperactive in these cancers, particularly in tumors with very low T-cell signatures. They discovered that inhibition of FGFR3 upregulates genes in the interferon-gamma pathway, suggesting a link between FGFR3 and the immune system.
When the investigators treated urothelial cancer cells that displayed hyperactive FGFR3 signaling with a new FGFR3-inhibiting drug called erdafitinib in the laboratory, it increased the activity of the BST2 gene, a hallmark of immune system activation. “By inhibiting FGFR3, we are able to upregulate genes that are associated with activation of the antitumor immune response,” Dr. Faltas said. “In the future, we could potentially use this strategy to reverse the T cell depletion in these tumors.”
Dr. Faltas, who is also director of bladder cancer research at the Caryl and Israel Englander Institute for Precision Medicine said the findings suggest that combining FGFR3 inhibitors like erdafitinib with PD-1/PD-L1 inhibitors, a form of cancer immunotherapy that stops tumor cells from evading T cells, is a promising strategy for treating UTUC cancers.
“Our paper provides the biological rationale for the combination and shows how the FGFR3 signaling and the immune response are linked," he said.
The U.S. Food and Drug Administration approved erdafitinib for treating metastatic cancers in the lining of the urinary tract in April 2019, which means the drug can now be used in patients, Dr. Faltas explained. He and his colleagues at Weill Cornell Medicine and NewYork-Presbyterian are already participating in a multicenter trial testing an erdafitinib-immunotherapy combination for treating urothelial cancer patients.
“We are hoping that in the future,” Dr. Faltas said, “as we gain a deeper understanding of the drivers of UTUC's unique biology, that we will be able to develop specifically targeted treatment strategies for this cancer.”