Major finding: CDK4/6 inhibition reduces tumor metabolism and proliferation in MCL.
Approach: A phase Ib study treated relapsed MCL patients with a CDK4/6 inhibitor.
Impact: Cell-cycle inhibition achieves a clinical response in a subset of patients with MCL.
Mantle cell lymphoma (MCL) is a poor-prognosis subtype of B-cell lymphoma molecularly characterized by an oncogenic t(11;14) translocation that causes aberrant cyclin D1 expression. Mechanistically, cyclin D1 complexes with cyclin-dependent kinases (CDK) 4 and 6 to phosphorylate the retinoblastoma protein (RB) and drive cell-cycle progression. Leonard and colleagues performed a multicenter phase Ib study of the CDK4/6 inhibitor PD0332991 in 17 relapsed MCL patients, using positron emission tomography (PET) and immunohistochemical assessment of RB phosphorylation in lymph node biopsies to measure pharmacodynamic tumor responses at baseline and during the first month of treatment. PD0332991 treatment resulted in an objective response rate of 18%, with 1 complete response and 2 partial responses. Seven additional patients achieved stable disease, and 5 patients achieved more than 1 year of progression-free survival. PET scanning with 2-deoxy-2-[18F]fluoro-D-glucose showed a metabolic response in 7 patients, and 3-deoxy-3[18F]fluorothymidine-PET scanning demonstrated a proliferative response in 15 patients, supported by substantial reductions in Ki-67 and RB phosphorylation at a CDK4/6-specific site. Although treatment led to a significant reduction in the pharmacodynamic markers, these changes did not predict treatment response or long-term disease stability. However, patients who remained on treatment for longer than 1 year demonstrated more than a 70% reduction in tumor proliferation and approximately 90% reductions in phospho-RB and Ki-67 staining. Together, the findings provide evidence that PD0332991 hits its target in cancer patients. Additional studies will be needed to further correlate pharmacodynamic measures with clinical outcome.
Note: Research Watch is written by Cancer Discovery Science Writers. Readers are encouraged to consult the original articles for full details. For more Research Watch, visit Cancer Discovery online at http://CDnews.aacrjournals.org.
