Multiple myeloma is a clinically and genetically heterogeneous disease. One half of patients havehyperdiploidy and the other half have one of five recurrent immunoglobulin gene translocations. In bothcases these are felt to represent primary genetic events, with the consequence of dysregulation of theexpression 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 apromiscuous array of mutations that activate primarily the non-canonical NFkB pathway. The most commonis inactivation of TRAF3 in -13% of MM patients that appears to identify patients with a low response toglucocorticoids, and a high response to proteasbme inhibitors. The tumor acquisition of so many mutationsfocused on this single pathway highlights its critical importance to the MM cell. We hypothesize that in themajority of patients the pathway is activated as a result of ligand-dependent interaction in the bone marrowmicroenvironment, 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 NFkBpathway in MM patients. We hypothesize that both in the presence of ligand-dependent, as well as ligandindependentactivation of this pathway, there will be a favorable therapeutic index to its inhibition. Wepropose to study the functional consequence of specific targeted inhibition using small molecule inhibitors inrelevant pre-clinical models. Finally, we propose to introduce into clinical trials targeted NFkB pathwayinhibitors showing promise in pre-clinical studies.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Specialized Center (P50)
Project #
2P50CA100707-06
Application #
7507317
Study Section
Special Emphasis Panel (ZCA1-GRB-I (M1))
Project Start
2008-07-01
Project End
2013-06-30
Budget Start
2008-07-01
Budget End
2009-08-31
Support Year
6
Fiscal Year
2008
Total Cost
$211,553
Indirect Cost
Name
Dana-Farber Cancer Institute
Department
Type
DUNS #
076580745
City
Boston
State
MA
Country
United States
Zip Code
02215
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