Thalidomide consolidation improves progression-free survival in myeloma with normal but not up-regulated expression of fibroblast growth factor receptor 3: analysis from the Australasian Leukaemia and Lymphoma Group MM6 clinical trial.
As a part of these translational efforts, novel drugs that inhibit oncogenic proteins overexpressed in defined molecular subgroups of the disease, such as FGFR3 and MMSET in t(4;14) MM, are currently being developed.
Combination of seliciclib with flavopiridol effectively reduced CCNE1 and CCND1 protein levels, increased subG1 apoptotic fraction and promoted MM cell death in BMSCs co-culture conditions, therefore over-coming stroma-mediated protection.
Increased expression of cyclin-D1 on trephine bone marrow biopsies independently predicts for shorter overall survival in patients with multiple myeloma treated with novel agents.
From a clinical standpoint, it is critical to identify MM patients carrying the t(4;14) translocation, which is present in 15% of myelomas and is associated with dysregulation of WHSC1/MMSET and often FGFR3.
The ectopically expressed fibroblast growth factor receptor 3 (FGFR3) and its constitutively active mutations have been detected in patients with multiple myeloma (MM).
These data demonstrate that PD173074 and sunitinib are inhibitors of FGFR3 in MM cell lines, and that sunitinib has in vivo activity in a human MM tumour xenograft model.
Our study is the first to suggest that overexpressed CCND1 in MM is an independent prognostic marker associated with a more durable response to bortezomib.
Sox11 was then examined in plasma cell myeloma and hairy cell leukemia as a subset of plasma cell myeloma carry t(11;14) and overexpress cyclin D1, and cyclin D1 is overexpressed in a subset of hairy cell leukemia independent of t(11;14).
This suggests that dysregulated FGFR3 expression is likely to be essential at least for the early stages of pathogenesis of MM tumors that have a t(4;14) translocation.
To test the tumorigenic potential of cyclin D1b in vivo, we generated cell clones derived from the non-CCND1 expressing MM LP-1 cell line, synthesizing either cyclin D1b or cyclin K, a structural homolog and viral oncogenic form of cyclin D1a.
Reciprocal IGH/14q32 translocations are detectable in 55-70% of patients with plasma cell myeloma; e.g., the adverse t(4;14)(p16;q32) fusing the IGH and FGFR3 genes (immunoglobulin heavy chain/fibroblast growth factor receptor 3).
The identification of these overlapping sets of co-modulated tyrosine phosphorylations presents an outline of an FGFR3 network in the MM model and demonstrates the potential for pharmacodynamic monitoring by label-free quantitative phospho-proteomics.
These data suggest that an endogenous negative regulatory role for the p85-FGFR3 interaction on the Ras/ERK/MAPK pathway may exist in response to FGFR3 activity and identifies a novel therapeutic target for MM.