Sunday, May 5, 2024
5/5/2024
SUMMARY Multiple myeloma (MM) is an incurable and fatal disease. Reagents such as the proteasome inhibitor, bortezomib, have significantly extended overall survival but resistance can rapidly arise. To generate therapies that can provide durable responses, especially in the context of refractory disease, a deeper understanding of the genetics driving the disease and the evolution of therapy resistance is required. To this end, our team has performed RNASeq analysis of CD138+ MM cells derived from patients across the disease spectrum (n=815) and identified that Unc-51 Like Kinase-3 (ULK3) is highly expressed in newly diagnosed and refractory MM. Our emerging studies demonstrate a novel role for ULK3 in regulating autophagy in MM, a key program that sustains cell survival under times of stress and has been implicated as a major mechanism of proteasome inhibitor resistance. Of note, MM is known to be highly dependent on autophagy. Currently, specific ULK3 inhibitors are lacking. As a strategy to overcome resistance to single agents, our team has focused on the development of novel inhibitors such as SG3, that target multiple kinases including ULK3 (EC50 90nM) as well bromodomain protein 4 (BRD4)(3). BRD4 is a known driver of MYC and analysis of our patient RNASeq data again reveals increased BRD4 expression in refractory MM. The BRD4 inhibitor, JQ1, effectively impairs the tumorigenic potential of MM but resistance has also been noted with this reagent. Our agent SG3 inhibits BRD4 activity in the nM range (27 nM) similar to that of JQ1 (20 nM), and consistent with our ULK3 studies, SG3 treatment rapidly inhibits autophagy in MM cells. In vivo, we found SG3 significantly inhibits MM progression and induced bone disease. Excitingly, our team has already developed a 2nd generation SG3 derivative coined MA9 that is just as effective as SG3 in vitro and in vivo but has superior stability. We also show that MA9 can resensitize proteosome inhibitor resistant MM cells to bortezomib. The central hypothesis of this proposal is that ULK3 is a key regulator of autophagy in MM and represents a novel target for treatment of refractory disease and it will be tested with three Aims. Aim 1 will take a genetic approach and delete ULK3 to its role in regulating autophagy in MM as well in the progression of the disease in vivo using clinically relevant animal models. Aim 2 will interrogate the impact of our dual ULK3/BRD4 compound, MA9, in MM progression and overall survival in vivo compared to JQ1 and the autophagy inhibitor, chloroquine (CQ). Aim 3 will examine the efficacy of MA9 for the treatment of CD138+ MM isolated from naïve and refractory patients using a novel ex vivo high throughput platform developed at Moffitt. Here, we will also define the contribution of ULK3 in mediating proteasome inhibitor resistance using bortezomib resistant MM cell lines. Importantly, in each Aim, we will also determine the role of ULK3 in MM induced bone destruction - a clinically significant aspect of this disease. We expect our anticipated results will provide strong rationale for the translation of our novel dual ULK3/BRD4 inhibitors to the clinic.
HHS’ Tracking Accountability in Government Grants System (TAGGS) website provides access to detailed descriptions of grants, loans, aggregated direct payments and other types of financial assistance awarded by the HHS Operating Divisions (OPDIVs) and the Office of the Secretary Staff Divisions (STAFFDIVs).
