Dr Tauro on the Rationale for Investigating ULK3 in Multiple Myeloma

Marilena Tauro, PhD, research scientist, postdoctoral fellow, Moffitt Cancer Center, discusses the investigation of ULK3 in patients with multiple myeloma.

Investigators from the Moffitt Cancer Center accessed a database containing patient information, including RNA sequencing results, from those with multiple myeloma to examine how individual autophagy signatures increase from the premalignant stage to later stages of the disease. Through this research, the investigators found that the presence of the ULK3 protein is associated with poorer overall survival in multiple myeloma, and that ULK3 expression levels could be utilized as a biomarker for patient responses to treatment.

Multiple myeloma is a plasma cell disease, and many patients diagnosed with this disease will relapse and become refractory to available treatment options, Tauro begins. Therefore, the overall purpose of this project was to determine why multiple myeloma cells become resistant to current treatment options, she says. Notably, theinvestigators also aimed to find a new treatment strategy for patients, Tauro adds.

The investigators evaluated autophagy, a newly discovered metabolic pathway that cancer cells use to become resistant to treatment, Tauro expands, adding that autophagy means self-eating. Therefore, some of the cancer cells try to kill themselves and digest their internal components to create ATP and amino acid for the surrounding cells to use, she emphasizes. This mechanism makes cancer cells resistant to the pro-apoptotic activity of standard chemotherapy, Tauro notes.

This project is innovative because the ULK3 protein has never been studied in this setting before, she continues. The investigators were able to target ULK3 in patient tissues to see that ULK3 levels increase as disease stage increases. Additionally, the investigators were able to create the novel small molecule autophagy inhibitors MA9060 and SG3014, which work synergistically with proteasome inhibitors (PIs) to inhibit the activity of ULK3 and sensitize the cancer cells to PI treatment, Tauro concludes.