A high-risk group of patients with follicular lymphoma could benefit from a novel drug combination, according to a new study published in the Journal of Experimental Medicine (2014;doi:10.1084/jem.20132120).
Follicular lymphoma, a B-cell lymphoma, is an incurable form of non-Hodgkin lymphoma that is diagnosed in 120,000 people each year worldwide. Follicular lymphoma is characterized by slow and relentless tumor growth with inevitable relapses despite intense chemotherapy.
Follicular lymphomas are driven by mutations that activate the BCL2 protein, which prevents cancer cells from dying, but additional genetic changes are also required. These could include mutations resulting in loss of cell cycle control, which is a hallmark of cancer and has a well-established role in aggressive B cell malignancies.
To find out more, Hans-Guido Wendel, MD, and colleagues from Memorial Sloan Kettering Cancer Center in New York, New York, analyzed genomic data from two large groups of slow-growing follicular lymphomas. The research team seeks to define the biological functions of the most common genetic abnormalities seen in leukemia and lymphoma.
The team identified a pattern of linked genetic mutations mainly in genes expressing cyclin-dependent kinases (CDKs), which impair the tumor-suppressing retinoblastoma pathway in nearly 50% of follicular lymphomas. The changes are associated with high-risk disease according to the prognostic index for follicular lymphoma.
The pathogenic role of these mutations was also confirmed in vivo in a mouse model of follicular lymphoma. Increased CDK4 activity is readily measured in tumor samples. Wendel and colleagues showed that a combination therapy of CDK4 and BCL2 inhibitors is safe and effective against available mouse models of follicular lymphoma.
The authors concluded that frequent lesions in the retinoblastoma pathway offer an untapped therapeutic opportunity in indolent, high-risk follicular lymphomas.