Regulated intracellular proteolysis occurs through the ubiquitin-proteasome pathway, and proteasome inhibitors (PIs) have been validated as key therapeutic agents in multiple myeloma by studies from our group and others. Plasma cell capacity for protein turnover is reduced during their development, while they are at the same time faced with a high load of misfolded immunoglobulins, creating an imbalance and cellular stress which are further exacerbated by PIs, which may explain their unique sensitivity to this class of drugs. However, only a minority of patients in the relapsed/refractory setting achieve complete remissions with single agent therapy, while the vast majority eventually develop drug resistance. Our group has made the novel observation that chaperones responsible for new proteasome assembly, and their associated signaling pathways, are activated in the setting of PI resistance. Moreover, interruption of these pathways can both sensitize to PIs in the drug-nave setting, and overcome PI resistance in vitro and in vivo. These findings support our central hypothesis, which proposes that primary and secondary PI resistance is mediated by proteasome assembly chaperones which promote cellular expansion of proteasome capacity, and that these chaperones and their associated pathways are rational biomarkers of PI sensitivity, as well as potential targets for approaches to enhance the efficacy of PIs. To evaluate these possibilities, additional studies are proposed to further dissect the molecular pathways involved in proteasome assembly and PI resistance. In addition, genomic studies will be performed in association with prospective cooperative group trials of bortezomib and carfilzomib to validate the possibility that expression of one of our genes of interest, MUC20, and associated activation signatures of HGF/c-MET and p44/42 MAPK, may help to identify patients who are most likely to benefit from PI-based therapy. Finally, approaches to suppress the activity of these pathways, or possibly of enhancing MUC20 expression, will be evaluated for their ability to induce chemosensitization, and overcome chemoresistance in cell lines, primary samples, and physiologically relevant in vivo murine models.

Public Health Relevance

Successful completion of this research effort will expand basic knowledge about the pathways involved in cellular proteasome assembly, identify promising approaches to enhance the activity of proteasome inhibitors and overcome resistance to these agents which can be translated to the clinic to improve patient outcomes, and validate potential biomarkers of clinical sensitivity and resistance to proteasome inhibition.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA194264-02
Application #
9204811
Study Section
Basic Mechanisms of Cancer Therapeutics Study Section (BMCT)
Program Officer
Kondapaka, Sudhir B
Project Start
2016-02-01
Project End
2021-01-31
Budget Start
2017-02-01
Budget End
2018-01-31
Support Year
2
Fiscal Year
2017
Total Cost
$323,865
Indirect Cost
$110,755
Name
University of Texas MD Anderson Cancer Center
Department
Internal Medicine/Medicine
Type
Other Domestic Higher Education
DUNS #
800772139
City
Houston
State
TX
Country
United States
Zip Code
77030
Ni, Haiwen; Shirazi, Fazal; Baladandayuthapani, Veerabhadran et al. (2018) Targeting Myddosome Signaling in Waldenström's Macroglobulinemia with the Interleukin-1 Receptor-Associated Kinase 1/4 Inhibitor R191. Clin Cancer Res 24:6408-6420
Zhang, Xiaohui; Lee, Hans C; Shirazi, Fazal et al. (2018) Protein targeting chimeric molecules specific for bromodomain and extra-terminal motif family proteins are active against pre-clinical models of multiple myeloma. Leukemia 32:2224-2239
Purushothaman, Anurag; Bandari, Shyam K; Chandrashekar, Darshan S et al. (2017) Chondroitin sulfate proteoglycan serglycin influences protein cargo loading and functions of tumor-derived exosomes. Oncotarget 8:73723-73732
Baljevic, Muhamed; Zaman, Shadia; Baladandayuthapani, Veerabhadran et al. (2017) Phase II study of the c-MET inhibitor tivantinib (ARQ 197) in patients with relapsed or relapsed/refractory multiple myeloma. Ann Hematol 96:977-985
Wang, Hua; Baladandayuthapani, Veerabhadran; Wang, Zhiqiang et al. (2017) Truncated protein tyrosine phosphatase receptor type O suppresses AKT signaling through IQ motif containing GTPase activating protein 1 and confers sensitivity to bortezomib in multiple myeloma. Oncotarget 8:113858-113873
Manasanch, Elisabet E; Orlowski, Robert Z (2017) Proteasome inhibitors in cancer therapy. Nat Rev Clin Oncol 14:417-433
Lee, Hans C; Wang, Hua; Baladandayuthapani, Veerabhadran et al. (2017) RNA Polymerase I Inhibition with CX-5461 as a Novel Therapeutic Strategy to Target MYC in Multiple Myeloma. Br J Haematol 177:80-94
Zhang, Yu; Zhou, Liang; Leng, Yun et al. (2017) Positive transcription elongation factor b (P-TEFb) is a therapeutic target in human multiple myeloma. Oncotarget 8:59476-59491
Zhang, Xing-Ding; Baladandayuthapani, Veerabhadran; Lin, Heather et al. (2016) Tight Junction Protein 1 Modulates Proteasome Capacity and Proteasome Inhibitor Sensitivity in Multiple Myeloma via EGFR/JAK1/STAT3 Signaling. Cancer Cell 29:639-652
Shah, J J; Feng, L; Thomas, S K et al. (2016) Siltuximab (CNTO 328) with lenalidomide, bortezomib and dexamethasone in newly-diagnosed, previously untreated multiple myeloma: an open-label phase I trial. Blood Cancer J 6:e396

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