SPOREs
Myeloma
Projects
Projects
The Myeloma SPORE consists of six projects:
Project 1: Proteasome-directed novel myeloma therapies
Leader: Kenneth Anderson, MD (DFCI)
Co-Leader: A. Keith Stewart, MB, ChB (Ontario Cancer Institute)
During the previous funding period, project one translated laboratory findings into the FDA approval of Bortezomib for relapsed refractory and relapsed MM. Although Bortezomib represents a major advance, not all patients respond, those that respond relapse, and no patients are cured. Project one will focus on using oncogenomics to define mechanisms of Boretezomib resistance. This new paradigm to overcome proteasome inhibitor resistance in MM has great promise not only to change the natural history of this disease, but to serve as a model for targeted therapeutics directed to improve the outcome of patients with other hematologic malignancies as well as solid tumors.
Project 2: Targeting telomere expansion mechanism in MM
Leader: Nikhil Munshi, MD (DFCI)
Co-Leader: Ronald DePinho, MD (DFCI)
Project two will initiate a phase I study of GRN163L in MM and identify agents that are synergistic with telomerase inhibition in preclinical in vitro and in vivo models. The molecular correlation of response versus resistance identified in the single agent clinical study, coupled with preclinical identification of combinations with synergistic anti-MM activity, will provide the framework for combination clinical trials.
Project 3: Targeting the Wnt pathway for treatment of MM
Leader: Donald Kufe, MD (DFCI)
Co-Leader: Teru Hideshima, MD, PhD (DFCI)
Project three will target the Wnt/β-catenin pathway as a rational appoach for the treatment of MM. The proposed studies focus on the role of MUC1-C in activating Wnt/β-catenin signaling in MM cells and on the development of agents that disrupt this pathway. The project will also define the involvement of MUC1-C integrating Wnt/β-catenin signaling with activation of the IKKβ->NF-κB pathway and Hsp90-dependent targeting of MUC1-C to mitochondria for the development of rationally based combinations. Agents that target the Wnt/β-catenin pathway will be studied alone and in combination for effects on myeloma cell growth and survival in the bone marrow microenvironment and in xenograft models. The results of these studies will be used to design clinical trials of Wnt/β-catenin inhibitors alone and in combination for the treatment of patients with refractory MM.
Project 4: Targeting activation of NFκB pathways in MM
Leader: P. Leif Bergsagel, MD (Mayo Clinic)
Co-Leader: Dharminder Chauhan, JD, PhD (DFCI)
Half of MM 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, a promiscuous array of mutations that activate the non-canonical NFκB pathway. The hypothesis for project four is that in the majority of MM patients the NFκB is activated as a result of ligand-dependant interaction in the bone marrow microenvironment, and only ~20% of patients acquire mutations causing constitutive activation. The proposed studies will dissect out the mechanisms causing activation of the canonical and non-canonical NFκB pathway and explore the functional consequence of specific targeted inhibition using small molecule inhibitors in relevant pre-clinical models. The results of these studies will be to introduce into clinical trials promising targeted NFκB pathway inhibitors.
Project 5: Molecular markers of plasma cell neoplasm evolution
Leader: Rafael Fonseca, MD (Mayo Clinic)
Co-Leader: S. Vincent Rajkumar, MD (Mayo Clinic)
By performing in situ single cell analysis on previously collected slides and samples from a reference cohort of patients, and utilizing our expertise using the oligo based array comparative genomic hybridization (aCGH), project five will continue the search for markers causative and predictive of progression from monoclonal gammopathy of unknown significance (MGUS) to MM.
Project 6: Identifying high-risk genotypes for MM: a collaborative multi-ethnic case-control study
Leader: Wendy Cozen, DO, MPH (Univ. of Southern California)
Co-Leader: David Conti, PhD (Univ. of Southern California)
Prior SPORE studies have found evidence linking polymorphisms in genes that control two important plasma cell growth factors, interleukin (IL)-6 and insulin-like growth factor (IGF)-1, with susceptibility to MM. In addition, there are positive associations between polymorphisms of certain DNA repair genes and MM risk. These studies had strong prior hypothesis but small sample sizes and disproportionably affects African-Americans and to a lesser degree, Hispanics. Project six will confirm these findings in a large multi-ethnic sample of 559 cases and 885 controls from five separate studies with existing DNA samples. This project will ultimately contribute to the understanding of the genetic susceptibility to MM needed for the development of both treatment and prevention strategies.
