The discovery of new therapeutic targets for treating multiple myeloma (MM) and elucidating their underlying molecular mechanisms are necessary for the progress in treatment of this disease. Despite significant recent progress in treating MM, such as the use of proteasome inhibitors, which have a > 70% response rate, the disease inevitably relapses and remains incurable. The oncogene c-Myc is a key driver in MM; it is activated in more than 60% of MM and in nearly 80% of proteasome inhibitor refractory MM. However, drugs that directly inhibit c- Myc do not yet exist, largely because c-Myc is a transcription factor and lacks a defined three- dimensional structure and pockets to which small molecules can bind. In addition to c-Myc, MM cells are strongly dependent on the ubiquitin-proteasome system for survival, as demonstrated by the proteasome inhibitors. In this proposal, we will test the hypothesis that targeting post-translational modifications by the small ubiquitin-like modifier (SUMO) can inhibit c-Myc-dependent pathways and also provide a means for overcoming proteasome inhibitor resistance. The proposed studies are based on our preliminary findings that SUMO modification regulates c-Myc protein levels and activity in MM cells. In addition, our preliminary findings suggest that the mechanisms of bortezomib (proteasome inhibitor) resistance not only could depend on SUMO modification, but also could render proteasome function more dependent on SUMO modification in resistant than in sensitive MM cells. We propose to elucidate the mechanism of how SUMOylation is involved in regulating c-Myc levels and function. In addition, we will elucidate the role of SUMOylation in the poorly understood mechanisms underlying proteasome inhibitor resistance. We will also validate initial in vitro findings in animal models. These studies will be enabled by SUMO E1 inhibitors that we have been developing over the last few years. The proposed studies will likely establish a novel therapeutic target and mechanism for the treatment of MM by offering targeted therapies and by providing therapeutic approaches to overcome resistance to proteasome inhibition. Inhibition of SUMOylation could also address a large population of other cancers that resist conventional therapies by developing drugs that are efficacious against c-Myc-driven cancers.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
7R01CA212119-04
Application #
10154320
Study Section
Molecular and Cellular Hematology Study Section (MCH)
Program Officer
Howcroft, Thomas K
Project Start
2017-07-01
Project End
2022-06-30
Budget Start
2020-07-01
Budget End
2021-06-30
Support Year
4
Fiscal Year
2020
Total Cost
Indirect Cost
Name
University of California, San Diego
Department
Surgery
Type
Schools of Medicine
DUNS #
804355790
City
La Jolla
State
CA
Country
United States
Zip Code
92093
Li, Yi-Jia; Du, Li; Wang, Jianghai et al. (2018) Allosteric Inhibition of Ubiquitin-like Modifications by a Class of Inhibitor of SUMO-Activating Enzyme. Cell Chem Biol :
Jiang, Xi; Hu, Chao; Ferchen, Kyle et al. (2018) Author Correction: Targeted inhibition of STAT/TET1 axis as a therapeutic strategy for acute myeloid leukemia. Nat Commun 9:670
Ambaye, Nigus; Chen, Chih-Hong; Khanna, Swati et al. (2018) Streptonigrin Inhibits SENP1 and Reduces the Protein Level of Hypoxia-Inducible Factor 1? (HIF1?) in Cells. Biochemistry 57:1807-1813
Yan, Wei; Wu, Xiwei; Zhou, Weiying et al. (2018) Cancer-cell-secreted exosomal miR-105 promotes tumour growth through the MYC-dependent metabolic reprogramming of stromal cells. Nat Cell Biol 20:597-609
Jiang, Xi; Hu, Chao; Ferchen, Kyle et al. (2017) Targeted inhibition of STAT/TET1 axis as a therapeutic strategy for acute myeloid leukemia. Nat Commun 8:2099
Lv, Zongyang; Yuan, Lingmin; Atkison, James H et al. (2017) Domain alternation and active site remodeling are conserved structural features of ubiquitin E1. J Biol Chem 292:12089-12099
Gong, Jun; Chen, Yuan; Yang, Lixin et al. (2017) MEK162 Enhances Antitumor Activity of 5-Fluorouracil and Trifluridine in KRAS-mutated Human Colorectal Cancer Cell Lines. Anticancer Res 37:2831-2838