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.

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Marilena Tauro, PhD, discusses the investigation of ULK3 in patients with multiple myeloma.

Dr Tauro on the Rationale for Investigating ULK3 in Multiple Myeloma

Marilena Tauro, PhD, research scientist, postdoctoral fellow, Moffitt Cancer Center, discusses next steps planned for the development of novel autophagy inhibitory strategies to combat chemotherapy resistance in relapsed/refractory multiple myeloma.

Although the use of traditional chemotherapy in multiple myeloma has been proven to prolong patient survival, a substantial number of patients with this disease will become refractory to chemotherapy and experience relapse up to 5 years after diagnosis. Multiple myeloma is highly dependent on autophagy, in which the cell removes and destroys unnecessary or abnormal components to allow for regeneration in times of stress. Notably, the process of autophagy plays a major role in the development of proteasome inhibitor (PI) resistance.

Emerging studies identified ULK3 (EC50 90nM) as a key regulator of autophagy in multiple myeloma. To investigate ULK3 as a potential target for overcoming chemotherapy resistance, the novel inhibitors SG3014/MA9060 were developed and investigated in a preclinical study.

Results from this study showed that this drug class worked synergistically with PIs and can improve responses to current therapies in PI-resistant disease. Use of the Ex vivo Mathematical Myeloma Advisor (EMMA) platform demonstrated the efficacy of MA9060 in the treatment of CD138-positive, patient-derived myeloma cells. Moreover, this study showed that the addition of these novel inhibitors to standard-of-care (SOC) chemotherapies such as carfilzomib (Kyprolis) improved survival in relapsed and newly diagnosed disease, Tauro notes. These results reinforce the use of ULK3 as a viable target for the treatment of patients with refractory multiple myeloma.

Next steps for this research include an assessment of the cytotoxic profile of these regimens, as well as the development of more selective small molecular inhibitors for this population, Tauro states. Increasing selectivity will potentially decrease any added toxicity seen with the use of these agents, she explains. Furthermore, synergistic studies of SG3014/MA9060 plus SOC chemotherapy should be conducted to elucidate the optimal use of these treatments in a clinical trial setting, Tauro adds. The ability of these dual inhibitors to improve survival both in vivo and ex vivo supports the investigation of these molecules in the clinic.

Marilena Tauro, PhD, discusses next steps planned for the development of novel autophagy inhibitory strategies to combat chemotherapy resistance in relapsed/refractory multiple myeloma.
 

Dr Tauro on Next Steps for the Investigation of Novel Autophagy Inhibitors in R/R Multiple Myeloma

Marilena Tauro, PhD, research scientist, postdoctoral fellow, Moffitt Cancer Center, discusses the role for ULK3 in regulating autophagy in multiple myeloma.

At the Moffitt Cancer Center, investigators accessed a database containing patient information, including RNA sequencing, for those with multiple myeloma, Tauro begins. This allowed investigators to examine how an induvial autophagy signature increases from the premalignant stage to later stages of the disease. Particularly, the ULK3 protein can increase with the stage of the disease, and an increase in ULK3 is associated with poorer overall survival, Tauro adds. However, by detecting ULK3 in tissue microarrays, it could be used as a biomarker for patient stage and response to treatment, Tauro expands.

Preclinical research aimed to examine the ablation of ULK3, and it showed that multiple myeloma cells cannot survive without it, Tauro explains. Through further collaboration, investigators identified compounds that could inhibit these enzymes. Mouse models were also utilized to investigate different compounds and understand if selected combinations of therapies could benefit patients with increased ULK3, Tauro emphasizes. Mouse models demonstrated an increased overall survival and reduced tumor burden, Tauro continues.

Additionally, the Ex vivo Mathematical Myeloma Advisor (EMMA) platform allowed clinicians to test the combinations directly on patient samples. Cancer cells from patients were cultured with their microenvironment in order to understand how patients would respond to treatment without exposing them to unknown toxicity, Tauro notes. This approach could help screen patients to better understand which population could benefit from this treatment, Tauro concludes.

Marilena Tauro, PhD, discusses the role for ULK3 in regulating autophagy in multiple myeloma.


Marilena Tauro, PhD

Articles

Dr Tauro on the Rationale for Investigating ULK3 in Multiple Myeloma

Dr Tauro on Next Steps for the Investigation of Novel Autophagy Inhibitors in R/R Multiple Myeloma

Dr Tauro on the Role of ULK3 in Multiple Myeloma