Highly Expressed SIRT-1 in Hodgkin Lymphoma and the Therapeutic Implications
Andres E Quesada, Christine E Jabcuga, Robert E Brown, Adan Rios, Nghia D Nguyen. University of Texas at Houston, Houston, TX; University of Vermont, Burlington, VT
Background: Increasing knowledge of the molecular biology of Hodgkin lymphomas (HL) has begun to identify relevant molecular circuitries implicated in driving their malignant growth and biological behavior. The immunohistochemical characterization of key cellular proteins participating in these pathways provides surrogate markers of biological activity and identifies potential cellular targets with clinical therapeutic potential. Thus, the potential for individualized and targeted chemotherapy grows. SIRT-1 is a histone/protein deacetylase which has been shown to be strongly expressed in cases of Hodgkin lymphoma in a recent study by Frazzi et al. Panabinostat is a pan-deacetylase inhibitor which was shown by Lemoin et al. to have activity against HL derived cell lines, inducing cell death. Using a previously collected set of classical HL (cHL) patients, we evaluated the expression of SIRT-1 in each case given the therapeutic potential of this protein as a target for treatment.
Design: Nineteen cases of cHL, 10 with nodular sclerosis (NS) type and 9 with mixed cellularity (MC) type, were retrospectively examined between 2008 and 2011 in a previous study conducted at our institution. These same cases were selected for further investigation. Immunohistochemical analysis of paraffin embedded tissue was used to detect the SIRT-1 antigen. Using brightfield microscopy, high protein expression was defined as more than 50% of Reed Sternberg cells with nuclear staining for SIRT-1.
Results: SIRT-1 demonstrated high nuclear expression in 17 out of 19 Hodgkin Lymphoma cases analyzed (89%).
Conclusions: The overexpression of SIRT-1 in HL found in our study is in agreement with previous studies and may be considered as a possible target for modulation which may contribute to existing standard chemotherapy for cHL. Conceivably, histone deacetylase inhibitors may increase the efficacy of existing therapies by inhibiting the SIRT-1 signaling pathway, which appears to participate in the pathophysiology of Hodgkin lymphoma. This may include downstream molecules such as c-Myc expressed in 72% of patients with HL. Our previous study demonstrates overexpression of the FASN/c-Met Kinase pathway which could potentially be inhibited by Metformin. Taken together with the results in the current study, the combination of Panabinostat and Metformin could exhibit therapeutic effect on Hodgkin lymphoma.
Monday, March 4, 2013 1:00 PM
Poster Session II # 210, Monday Afternoon