During the previous funding period, we utilized our in vitro and in vivo models of the multiple myeloma (MM) cell in the bone marrow (BM) milieu to demonstrate the molecular mechanisms whereby proteasome inhibitors target tumor cells, host tumor interactions, and the BM microenvironment to overcome conventional drug resistance. We then rapidly translated these laboratory findings to the clinic leading to the FDA approval of Bortezomib for relapsed refractory MM in 2003 and relapsed MM in 2005. Importantly, our correlative science studies of patient samples have identified genomic profiles of patients most likely to respond. Although Bortezomib represents a major advance, not all patients respond, those that respond relapse, and no patients are cured. This proposal will therefore focus on using oncogenomics to define mechanisms of Bortezomib resistance. We will then validate novel targeted therapies to overcome Bortezomib resistance for evaluation in derived clinical trials.. To achieve these goals, we will pursue the following Specific Aims: to define the molecular determinants of proteasome inhibitor resistance using high throughput RNAi screens interrogating the effects of silencing the "druggable genome" in a proteasome inhibitor resistant MM cell line (Specific Aim 1);to define strategies to overcome proteasome inhibitor resistance using in vitro preclinical models (Specific Aim 2);and to conduct preclinical in vivo studies and clinical trials to enhance sensitivity or overcome resistance to proteasome inhibitors (Specific Aim 3). This new paradigm to overcome proteasome inhibitor resistance in MM has great promise not only to change the natural history of MM, but also to serve as a model for targeted therapeutics directed to improve outcome of patients with other hematologic malignancies as well as solid tumors.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Specialized Center (P50)
Project #
5P50CA100707-10
Application #
8382438
Study Section
Special Emphasis Panel (ZCA1-GRB-I)
Project Start
Project End
2013-08-31
Budget Start
2012-09-01
Budget End
2013-08-31
Support Year
10
Fiscal Year
2012
Total Cost
$285,079
Indirect Cost
$78,938
Name
Dana-Farber Cancer Institute
Department
Type
DUNS #
076580745
City
Boston
State
MA
Country
United States
Zip Code
02215
Das, D Sharma; Ray, A; Das, A et al. (2016) A novel hypoxia-selective epigenetic agent RRx-001 triggers apoptosis and overcomes drug resistance in multiple myeloma cells. Leukemia 30:2187-2197
Tagde, Ashujit; Rajabi, Hasan; Stroopinsky, Dina et al. (2016) MUC1-C induces DNA methyltransferase 1 and represses tumor suppressor genes in acute myeloid leukemia. Oncotarget 7:38974-38987
Lin, Jianhong; Zhang, Weihong; Zhao, Jian-Jun et al. (2016) A clinically relevant in vivo zebrafish model of human multiple myeloma to study preclinical therapeutic efficacy. Blood 128:249-52
Hunter, Zachary R; Xu, Lian; Yang, Guang et al. (2016) Transcriptome sequencing reveals a profile that corresponds to genomic variants in Waldenström macroglobulinemia. Blood 128:827-38
Ray, Arghya; Ravillah, Durgadevi; Das, Deepika S et al. (2016) A novel alkylating agent Melflufen induces irreversible DNA damage and cytotoxicity in multiple myeloma cells. Br J Haematol 174:397-409
Mullikin, Trey C; Rajkumar, S Vincent; Dispenzieri, Angela et al. (2016) Clinical characteristics and outcomes in biclonal gammopathies. Am J Hematol 91:473-5
An, Gang; Acharya, Chirag; Feng, Xiaoyan et al. (2016) Osteoclasts promote immune suppressive microenvironment in multiple myeloma: therapeutic implication. Blood 128:1590-603
Tagde, Ashujit; Rajabi, Hasan; Bouillez, Audrey et al. (2016) MUC1-C drives MYC in multiple myeloma. Blood 127:2587-97
Jiang, H; Acharya, C; An, G et al. (2016) SAR650984 directly induces multiple myeloma cell death via lysosomal-associated and apoptotic pathways, which is further enhanced by pomalidomide. Leukemia 30:399-408
Gullà, Annamaria; Di Martino, Maria Teresa; Gallo Cantafio, Maria Eugenia et al. (2016) A 13 mer LNA-i-miR-221 Inhibitor Restores Drug Sensitivity in Melphalan-Refractory Multiple Myeloma Cells. Clin Cancer Res 22:1222-33

Showing the most recent 10 out of 351 publications