Overall survival for patients with multiple myeloma (MM) has been substantially extended by treatment with the proteosome inhibitor bortezomib and the immunomodulatory agent lenalidomide. However, these patients invariably relapse with resistant disease, emphasizing the need for new therapeutic targets for the treatment of refractory MM. Research supported by this SPORE grant has demonstrated that mucin 1 (MUCI) is aberrantly expressed in MM cells. MUCI consists of two subunits: an extracellular N-terminal mucin subunit and a transmembrane C-terminal oncogenic subunit (MUC1-C). MUC1-C interacts with galecfin-3 at the cell surface and is targeted to the nucleus and mitochondria. Of importance, MUC1-C promotes the growth and survival of MM cells. Studies supported by this grant have also demonstrated that MUC1-C is a druggable target. In this context, treatment of MM cell lines and primary cells from patients with MUC1-C peptide inhibitors is associated with the induction of late apoptosis/necrosis. Inhibition of MUC1-C is also effective in treating MM tumor xenografts in immunocompromised mice with prolonged regressions. Our studies have further shown that treatment of MM cells with MUC1-C inhibitors is associated with increases in reactive oxygen species (ROS), and marked down regulation of NADPH and glutathione (GSH). Moreover, this induction of oxidative stress by MUC1-C inhibitors is responsible for MM cell death, indicating that targeting MUC1-C has a unique mechanism of action. Our hypothesis is therefore that MUC1-C is a novel target for treatment of MM that is resistant to available therapies.
The Specific Aims are: (1) To define the effects of inhibiting the MUC1-C intracellular domain in drug-resistant multiple myeloma cells;(2) To evaluate therapeutic approaches that target MUC1-C extracellular domains at the multiple myeloma cell surface;(3) To identify effective combination of MUC1-C inhibitors with other targeted agents for multiple myeloma treatment;and (4) To assess the pharmacodynamic effects of the MUC1-C inhibitor GO-203 in a Phase l/ll trial for patients with refractory multiple myeloma.
Treatment options are limited for patients with refractory multiple myeloma. The MUC1-C oncoprotein is aberrantly expressed in multiple myeloma cells and contributes to their growth and survival. Our proposed research focuses on the development of novel MUC1-C inhibitors for the effective treatment of patients with multiple myeloma resistant to available therapies.
|Ye, Shuai; Lawlor, Matthew A; Rivera-Reyes, Adrian et al. (2018) YAP1-Mediated Suppression of USP31 Enhances NF?B Activity to Promote Sarcomagenesis. Cancer Res 78:2705-2720|
|Hunter, Zachary R; Xu, Lian; Tsakmaklis, Nickolas et al. (2018) Insights into the genomic landscape of MYD88 wild-type Waldenström macroglobulinemia. Blood Adv 2:2937-2946|
|Szalat, R; Samur, M K; Fulciniti, M et al. (2018) Nucleotide excision repair is a potential therapeutic target in multiple myeloma. Leukemia 32:111-119|
|Bolli, Niccolò; Maura, Francesco; Minvielle, Stephane et al. (2018) Genomic patterns of progression in smoldering multiple myeloma. Nat Commun 9:3363|
|Gullà, A; Hideshima, T; Bianchi, G et al. (2018) Protein arginine methyltransferase 5 has prognostic relevance and is a druggable target in multiple myeloma. Leukemia 32:996-1002|
|Mazzotti, Céline; Buisson, Laure; Maheo, Sabrina et al. (2018) Myeloma MRD by deep sequencing from circulating tumor DNA does not correlate with results obtained in the bone marrow. Blood Adv 2:2811-2813|
|Samur, Mehmet Kemal; Minvielle, Stephane; Gulla, Annamaria et al. (2018) Long intergenic non-coding RNAs have an independent impact on survival in multiple myeloma. Leukemia 32:2626-2635|
|Xu, Yan; Deng, Shuhui; Mao, Xuehan et al. (2018) Tolerance, Kinetics, and Depth of Response for Subcutaneous Versus Intravenous Administration of Bortezomib Combination in Chinese Patients With Newly Diagnosed Multiple Myeloma. Clin Lymphoma Myeloma Leuk 18:422-430|
|Michallet, M; Chapuis-Cellier, C; Dejoie, T et al. (2018) Heavy+light chain monitoring correlates with clinical outcome in multiple myeloma patients. Leukemia 32:376-382|
|Ray, A; Das, D S; Song, Y et al. (2018) Combination of a novel HDAC6 inhibitor ACY-241 and anti-PD-L1 antibody enhances anti-tumor immunity and cytotoxicity in multiple myeloma. Leukemia 32:843-846|
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