Eyes on the Prize: Developing Better Treatments for Uveal Melanoma

27
Mar

Figure 1.PLX51107 clinical trial (patient #3)
1. Treatment history of patient #3 in the PLX51107 trial. Biopsies were collected from metastases prior to treatment with PLX51107 and shortly after the patient was removed from the trial.
2. MRI scans of the patient’s abdomen pre‐ and post‐PLX51107 treatment. Increase in size and number of hepatic lesions (red arrows) were observed post‐treatment.
Source: DOI:10.15252/emmm.201809081

Uveal melanoma arises in the eye, in contrast to the more widely known skin melanoma, and it often spreads to the liver, where it becomes highly resistant to treatment. Researchers from the Sidney Kimmel Cancer Center – Jefferson Health (SKCC) in Philadelphia and Columbia University in New York have teamed up to investigate the efficacy of a particular class of inhibitor drugs in uveal melanoma patients.

The research team, which includes SKCC investigators Andrew Aplin, PhD; Vivian Chua, PhD; Marlana Orloff, MD; and Takami Sato, MD, PhD, recently published the results of their work in the journal EMBO Molecular Medicine.  Chua and Aplin are co-corresponding authors of the new study.

The group examined the activity of inhibitors that target transcription factors known as bromodomain and extraterminal (BET) proteins. Previously, in a multi-site clinical trial testing a novel BET inhibitor named PLX51107, liver metastases of uveal melanoma patients were observed to progress rapidly following BET inhibitor treatment, raising the question of how the cancer cells are able to become resistant to the drug so quickly. In this new study, the researchers identified a mechanism involving a growth factor that is released by non-tumorous cells near the tumor, which reaches the uveal melanoma and allows melanoma cells to evade growth inhibition by BET inhibitors.

BET inhibitors were found to induce expression of fibroblast growth factor 2 (FGF2) in stromal cells surrounding the tumor, an effect that was observed in uveal melanoma cell lines as well as patient samples. In addition, the FGF receptor (FGFR) that binds to and is activated by FGF2 was also upregulated by the BET inhibitors in the tumor cells. Taken together, these findings reveal that in uveal melanoma cells treated with BET inhibitors, increased expression of FGFR as well as its stimulatory ligand secreted from nearby cells causes the tumor cells to boost their growth ability enough to rapidly become resistant to the growth-suppressing effects of the inhibitor.

“Our study highlights the importance of inhibitor-induced upregulation of certain growth factors and their receptors in promoting the growth of uveal melanoma cells and allowing them to overcome the effects of therapeutic inhibitors,” said Aplin, Associate Director of Basic Research at SKCC and the Kalbach-Newtown Professor in Cancer Research.

The study also has major implications for the design of new clinical trials to improve treatment of uveal melanoma. The team found that combining two different inhibitors, PLX51107 to target BET proteins and a second drug known as AZD4547 to target FGFR, resulted in a more durable growth suppression of uveal melanoma cells transplanted into mice.

“These results suggest that co-targeting the FGFR signaling pathway along with the BET proteins might offer an effective new approach to treating uveal melanoma patients, an idea that we hope to explore further in the lab and develop into future clinical trials,” Aplin explained.

Overall, the study highlights the strong collaborations between basic scientists and medical oncologists in an area that is a major clinical strength at the Wills Eye Institute and Thomas Jefferson University.

“The SKCC uveal melanoma group is truly exceptional and has been fast-tracking discoveries to the clinic through working as a multidisciplinary team. We are enthusiastic about the translational promise of these findings for developing new ways to treat uveal melanoma,” said Karen E. Knudsen, PhD, EVP of Oncology Services and Enterprise Director of the Sidney Kimmel Cancer Center – Jefferson Health.