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 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.