Diffuse large B-cell lymphoma (DLBCL) is characterized by marked biological and clinical heterogeneity. In the CHOP-era, it was demonstrated that survival of DLBCL patients can be predicted by measurement of expression of a limited number of genes. However, the standard treatment has evolved to include the rituximab with CHOP. Initial studies suggest that addition of rituximab changes the predictive power of specific molecular biomarkers and it is possible that new biomarkers associated with the anti-tumor effects of rituximab may become prognostically significant. Therefore, there is an urgent need to establish reliable biomarker-based prognostic models for DLBCL patients treated with the current standard regimen of R-CHOP, which will potentially change the way we practice medicine. In addition, all the previous models were based on RNA measurement in frozen specimens, which availability is limited thus restricting applicability of the proposed prognostic models. Construction of prognostic models based on widely available paraffin embedded samples using either RNA or immunohistochemistry for analysis of gene expression would allow immediate and widespread applicability of these models in daily clinical practice. This project is based on a new methodology of RNA extraction from formalin-fixed, paraffin-embedded tissues, developed in our laboratory, which allows reliable measurement of gene expression by either real-time PCR or oligo-microarrays. This methodology will be used to accomplish the goals of this project that include: 1. Identify a list of genes which expression correlates with survival of DLBCL patients treated with R-CHOP by array-based gene expression profiling;2. Construct and validate a paraffin-based real-time PCR gene expression prognostic mode based on RNA derived from paraffin specimens;3. Examine the survival predictive power of biomarkers associated with the anti-tumor effects of rituximab in DLBCL patients treated with R-CHOP;4. Construct a prognostic model for DLBCL patients treated with R-CHOP based on the expression of a limited set of genes measured at the protein level by immunohistochemistry. These studies should define paraffin-based molecular prognostic models for most common type of lymphoma that will be used in clinical practice and will add to the prognostic power of the current clinical prognostic indexes. Routine application of the prediction models will enable identification of patients at high risk for standard therapy failure and may form the basis for risk-adjusted therapies for DLBCL. Furthermore, identification of genes-proteins comprising the predictive models will point to distinct pathogenesis mechanisms of DLBCL subtypes and potentially lead to recognition of new molecular therapeutic targets. Further, establishment of a paraffin-based RNA prognostic model using the new methodology of RNA extraction could serve as a paradigm for other lymphomas and tumors.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA122105-04
Application #
7880670
Study Section
Cancer Biomarkers Study Section (CBSS)
Program Officer
Jessup, John M
Project Start
2007-09-24
Project End
2012-07-31
Budget Start
2010-08-01
Budget End
2012-07-31
Support Year
4
Fiscal Year
2010
Total Cost
$318,726
Indirect Cost
Name
University of Miami School of Medicine
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
052780918
City
Coral Gables
State
FL
Country
United States
Zip Code
33146
Ramachandiran, Sampath; Adon, Arsene; Guo, Xiangxue et al. (2015) Chromosome instability in diffuse large B cell lymphomas is suppressed by activation of the noncanonical NF-?B pathway. Int J Cancer 136:2341-51
Chapman-Fredricks, Jennifer; Sandoval-Sus, Jose; Vega, Francisco et al. (2014) Progressive leukemic non-nodal mantle cell lymphoma associated with deletions of TP53, ATM, and/or 13q14. Ann Diagn Pathol 18:214-9
Lossos, Chen; Bayraktar, Soley; Weinzierl, Elizabeth et al. (2014) LMO2 and BCL6 are associated with improved survival in primary central nervous system lymphoma. Br J Haematol 165:640-8
Bhatt, Shruti; Ashlock, Brittany M; Toomey, Ngoc L et al. (2013) Efficacious proteasome/HDAC inhibitor combination therapy for primary effusion lymphoma. J Clin Invest 123:2616-28
Zhu, Daxing; Ikpatt, Offiong F; Dubovy, Sander R et al. (2013) Molecular and genomic aberrations in Chlamydophila psittaci negative ocular adnexal marginal zone lymphomas. Am J Hematol 88:730-5
Zhu, Daxing; Lossos, Chen; Chapman-Fredricks, Jennifer R et al. (2013) Biased immunoglobulin light chain use in the Chlamydophila psittaci negative ocular adnexal marginal zone lymphomas. Am J Hematol 88:379-84
Bhatt, Shruti; Ashlock, Brittany M; Natkunam, Yasodha et al. (2013) CD30 targeting with brentuximab vedotin: a novel therapeutic approach to primary effusion lymphoma. Blood 122:1233-42
Romero-Camarero, Isabel; Jiang, Xiaoyu; Natkunam, Yasodha et al. (2013) Germinal centre protein HGAL promotes lymphoid hyperplasia and amyloidosis via BCR-mediated Syk activation. Nat Commun 4:1338
Dagan, Liat Nadav; Jiang, Xiaoyu; Bhatt, Shruti et al. (2012) miR-155 regulates HGAL expression and increases lymphoma cell motility. Blood 119:513-20
Azambuja, D; Natkunam, Y; Biasoli, I et al. (2012) Lack of association of tumor-associated macrophages with clinical outcome in patients with classical Hodgkin's lymphoma. Ann Oncol 23:736-42

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