Dr Hillman on Identifying New Therapy Candidates in Adult-Type Granulosa Cell Tumor

"Other models that we've developed include the first genetically inducible mouse model of this disease that relies on an engineered FOXL2 allele, and we think that that is going to really move us forward, as far as having a high-fidelity animal model for the first time, [which] will let us do kinds of investigations that weren't really possible before."

R. Tyler Hillman, MD, PhD, assistant professor, Department of Gynecologic Oncology and Reproductive Medicine, Division of Surgery, assistant professor, Department of Genomic Medicine, Division of Cancer Medicine, The University of Texas MD Anderson Cancer Center, discusses ways of identifying new drug therapy candidates in patients with adult-type granulosa cell tumor (AGCT) of the ovary.

One of the focuses of Hillman’s lab is to develop new candidates for drug development that can be tested in phase 1/2 clinical trials or provide proof of principle that certain drugs can be repurposed from their use in other diseases. The other focus is on developing a mechanistic understanding of how FOXL2 mutations may cause AGCT tumors, with the hope of uncovering a previously unthought-of pathway toward drug development. As such, Hillman and his collaborators have focused on model development, which has led to the university’s first organoid derivation program for patients with AGCT undergoing surgery. The samples that are collected are used for drug tests and other experimentation, including high-throughput screening. This process led to the discovery that glucocorticoids can stimulate the growth of AGCT cells, but only in the presence of mutations in FOXL2, indicating a true pharmacogenetic effect, Hillman says.

These findings, which were published in Gynecologic Oncology Reports in 2023, provided evidence that glucocorticoids as a class stimulated the growth of KGN-FOXL2WT/C402G cells with nanomolar EC50, whereas they lacked this activity in KGN-FOXL2–/– cells. Now, Hillman and his team are investigating ways of modulating glucocorticoid receptor signaling, either through single-agent or combination therapy, which Hillman theorizes will be a chemotherapeutic regimen of some sort. Additional models that have been fully developed include the first genetically inducible mouse model of AGCT, Hillman says. The model relies on an engineered FOXL2 allele and is believed to hold the potential to push the field of drug discovery forward.