Abstract 3163: Tissue-micro array based IHC analysis of mTOR activity in DLBCL

Abstract

Abstract Diffuse large B-cell lymphoma (DLBCL) is a heterogeneous group of diseases with several subtypes with differing responses to therapy. The standard initial therapy for DLBCL continues using regimens like R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine and prednisone), regardless of the subtypes. Targeted therapy offers a new approach to improve clinical responses. mTOR signaling has been shown to be activated in several lymphomas. mTOR inhibitors are being developed and are in clinical use in mantle cell lymphoma (MCL) therapy and clinical trials are ongoing in other high grade lymphomas as well. However, there is limited data about mTOR activity in different DLBCLs. We evaluated immunohistochemical (IHC) results in biopsy materials from 79 DLBCL patients (42 females and 37 males, mean age 61 years), who were conventionally treated with R-CHOP, R-CEOP or CHOP therapy. Several antibodies (phospho-S6, phospho-p70S6K, phospho-mTOR, p-4EBP1, Mum1, CD10, bcl-6, bcl-2) were used and more than 700 IHC stainings were evaluated on TMA slides. Mum1, CD10 and bcl-6 staining helped to distinguish between germinal center (GC) and non-germinal center B-cell derived DLBCL cases. Approximately 30% of cases were characterized as GC-derived DLBCL, which showed virtually no mTOR activity, as determined by phosphorylated S6 (p-S6) expression, the most sensitive marker (only weak p-S6 expression was detected in 2 cases). However, in about 80% of non-GC lymphoma cases, p-S6, p-mTOR, p-p70S6K and p-4EBP1 positivity was observed, which alludes to mTOR activity. Although the importance of mTOR activity is well demonstrated by mTOR mediated cyclinD1 expression in MCL, no statistical correlation was found between mTOR activity and the expression of pro-proliferative or anti-apoptotic factors (such as bcl-2 and bcl-6) in the examined DLBCL cases. These results suggest that mTOR activity is characteristic in most non-GC derived DLBCLs. Similarly to MCL patients, those patients with poor survival may benefit from rapamycin derivatives or other treatments targeting mTOR. These rapalogs or other novel anti-mTOR agents may be used in addition to the regular R-CHOP therapy, however, patient selection criteria should be carefully considered. Supported by OTKA-K68341 and OTKA-K81624 Projects. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 3163. doi:10.1158/1538-7445.AM2011-3163