Multiple myeloma is a clinically and genetically heterogeneous disease. One half of patients have hyperdiploidy and the other half have one of five recurrent immunoglobulin gene translocations. In both cases these are felt to represent primary genetic events, with the consequence of dysregulation of the expression of a cyclin D gene. Subsequent tumor progression occurs with activating mutations of RAS, secondary translocations of MYC, and inactivating mutations of p53. Recently we have identified a promiscuous array of mutations that activate primarily the non-canonical NFkB pathway. The most common is inactivation of TRAF3 in -13% of MM patients that appears to identify patients with a low response to glucocorticoids, and a high response to proteasbme inhibitors. The tumor acquisition of so many mutations focused on this single pathway highlights its critical importance to the MM cell. We hypothesize that in the majority of patients the pathway is activated as a result of ligand-dependent interaction in the bone marrow microenvironment, and only a fraction (~20%) of patients acquire mutations causing constitutive activation. We propose to dissect out the mechanisms causing activation of the canonical and non-canonical NFkB pathway in MM patients. We hypothesize that both in the presence of ligand-dependent, as well as ligandindependent activation of this pathway, there will be a favorable therapeutic index to its inhibition. We propose to study the functional consequence of specific targeted inhibition using small molecule inhibitors in relevant pre-clinical models. Finally, we propose to introduce into clinical trials targeted NFkB pathway inhibitors showing promise in pre-clinical studies.

National Institute of Health (NIH)
National Cancer Institute (NCI)
Specialized Center (P50)
Project #
Application #
Study Section
Special Emphasis Panel (ZCA1-GRB-I)
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
Dana-Farber Cancer Institute
United States
Zip Code
Zhang, L; Tai, Y-T; Ho, M et al. (2017) Regulatory B cell-myeloma cell interaction confers immunosuppression and promotes their survival in the bone marrow milieu. Blood Cancer J 7:e547
Jain, Salvia; Washington, Abigail; Leaf, Rebecca Karp et al. (2017) Decitabine Priming Enhances Mucin 1 Inhibition Mediated Disruption of Redox Homeostasis in Cutaneous T-Cell Lymphoma. Mol Cancer Ther 16:2304-2314
Gullà, A; Hideshima, T; Bianchi, G et al. (2017) Protein arginine methyltransferase 5 has prognostic relevance and is a druggable target in multiple myeloma. Leukemia :
Harada, T; Ohguchi, H; Grondin, Y et al. (2017) HDAC3 regulates DNMT1 expression in multiple myeloma: therapeutic implications. Leukemia 31:2670-2677
Cholujova, Danka; Bujnakova, Zdenka; Dutkova, Erika et al. (2017) Realgar nanoparticles versus ATO arsenic compounds induce in vitro and in vivo activity against multiple myeloma. Br J Haematol 179:756-771
Bouillez, A; Rajabi, H; Jin, C et al. (2017) MUC1-C integrates PD-L1 induction with repression of immune effectors in non-small-cell lung cancer. Oncogene 36:4037-4046
Das, Deepika Sharma; Das, Abhishek; Ray, Arghya et al. (2017) Blockade of Deubiquitylating Enzyme USP1 Inhibits DNA Repair and Triggers Apoptosis in Multiple Myeloma Cells. Clin Cancer Res 23:4280-4289
Tagde, Ashujit; Markert, Tahireh; Rajabi, Hasan et al. (2017) Targeting MUC1-C suppresses polycomb repressive complex 1 in multiple myeloma. Oncotarget 8:69237-69249
Ray, A; Das, D S; Song, Y et al. (2017) Combination of a novel HDAC6 inhibitor ACY-241 and anti-PD-L1 antibody enhances anti-tumor immunity and cytotoxicity in multiple myeloma. Leukemia :
Song, Y; Li, S; Ray, A et al. (2017) Blockade of deubiquitylating enzyme Rpn11 triggers apoptosis in multiple myeloma cells and overcomes bortezomib resistance. Oncogene 36:5631-5638

Showing the most recent 10 out of 388 publications