Researchers Find Barriers to Multiple Myeloma Drugs and Keys to Unlock Them
MD Anderson researchers have identified molecular factors that erode the effectiveness of two important drugs for multiple myeloma. For each mechanism of resistance, the scientists also pinpointed both a drug that overcame that resistance in cell line experiments and a potential biomarker that could guide combination therapy.
Lenalidomide, known as Revlimid®å, and bortezomib, known as Velcade®å, are usually used in combination with other drugs both in frontline therapy and for treatment of recurrent or resistant myeloma.However, they don't work for every patient and when they are effective can lose their punch over time as the disease develops defenses against them.
There are multiple mechanisms of drug resistance, so identifying which ones are at work in a given patient and targeting them specifically is critical, said Robert Orlowski, M.D., Ph.D., professor and head of the Multiple Myeloma Section in MD Anderson's Department of Lymphoma and Myeloma.
"Science is more important than ever now in multiple myeloma, because we can't just use the same combinations to treat refractory disease," Orlowski says.
Orlowski and colleagues reported their results at the 53rd Annual Meeting of the American Society of Hematology earlier this month.
Blocking IGF-1 restores sensitivity to bortezomib
ASH Abstract 925
They found that the insulin-like growth factor (IGF-1) pathway is active in myeloma cell lines that are resistant to bortezomib.Knocking down the IGF-1 receptor with small hairpin RNA (shRNA) restored sensitivity to the drug.
Treating with the experimental IGF-1 receptor inhibitor OSI-906 alone killed bortezomib-resistant myeloma cells but had little effect against cells that had not been treated with bortezomib.Combining the two drugs increased myeloma cell death.
"So we have cell surface expression of the IGF1 receptor as a potential biomarker for treating bortezomib-refractory multiple myeloma with an IGF1 inhibitor," Orlowski says.Instructor Deborah Kuhn, Ph.D., presented this research at ASH.
Orlowski's lab previously showed this pathway causes resistance to lenalidomide and implicated one pathway component in particular, the cell surface protein CD44.
Adding the drug all-trans-retinoic acid (ATRA), which is known to inactivate beta-catenin signaling, to lenalidomide treatment killed lenalidomide-resistant cells and reduced the presence of CD44 by up to 60%.
The team then combined lenalidomide with the experimental small-molecule drug FH535, which disrupts beta-catenin activity.The combination also increased cell death in resistant multiple myeloma cell lines.
They also found that lenalidomide treatment increases levels of CD44 and that knocking down CD44 with shRNA made lenalidomide-resistant cells vulnerable to lenalidomide.
An extensive analysis of gene expression data from myeloma samples at the Multiple Myeloma Research Consortium showed that high CD44 levels are significantly associated with poor prognosis.
CD44, therefore, is a potential biomarker for combining ATRA or another beta-catenin targeting drug with lenalidomide to overcome lenalidomide-resistant multiple myeloma. Post-doctoral fellow Chad Bjorklund, Ph.D., presented this research at ASH.