ZIA BC 011164 (ZIA) | |||
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Title | Expression profiles in ATL Patients | ||
Institution | NCI, Bethesda, MD | ||
Principal Investigator | Brady, John | NCI Program Director | N/A |
Cancer Activity | N/A | Division | CCR |
Funded Amount | $130,701 | Project Dates | 10/01/2009 - N/A |
Fiscal Year | 2009 | Project Type | Intramural |
Research Topics w/ Percent Relevance | Cancer Types w/ Percent Relevance | ||
Cancer (100.0%) Herpes - Other (10.0%) |
Leukemia (90.0%) Ovarian Cancer (10.0%) |
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Research Type | |||
Cancer Initiation: Oncogenes and Tumor Suppressor Genes Interactions of Genes and/or Genetic Polymorphisms with Exogenous and/or Endogenous Factors |
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Abstract | |||
Human T-lymphotropic virus type 1 (HTLV-1) is a complex delta-retrovirus that infects fifteen to twenty million individuals worldwide. HTLV-1 is the etiological agent of adult T-cell leukemia (ATL), an aggressive and fatal disease. Although several therapeutic approaches have been used, ATL continues to carry a very poor prognosis. With the advent of DNA microarray technology, expression profiles of HTLV-1-infected cells and Tax-expressing cells have allowed a more complete list of HTLV-1/Tax regulated genes. In collaboration with Tom Waldmann's group, we examined 32 ATL patients with smoldering, chronic, lymphoma and acute leukemia using the Affymetrix HG-U133A2.0 array containing probe sets for 14,500 genes. Expression patterns revealed distinct clustering of leukemia, lymphoma and control samples. Using BRB array and PathwayStudio programs, we identified genes differentially expressed in leukemia and lymphoma cells compared to normal donor lymphocytes. Leukemia cells were characterized by a striking increase in genes linked to CDC2/cyclin B1, RANKL, SYK/LYN tyrosine kinases and BIRC5. BIRC5 expression, increased in 12 of 14 leukemia samples, was decreased in Zenapax or bortezomib treated patients which demonstrated a decrease in leukemic cell number. This suggests its potential use as a biomarker for malignant cell growth. Examination of PBMCs from lymphoma patients indicate changes in CSPG2 and immune response pathways characterized by high levels of genes including TLR2, CCR1, CD14, CD33, ICAM1 and MHC Class II molecules. This study represents a comprehensive microarray analysis of ATL patient samples and provides insight into ATL genesis and potential targeted therapies. Using the information we gained from the microarray studies on ATL, we have established several collaborations investigating gene expression patterns in a variety of human cancers. Our collaboration with Dr. Michael Birrer has yielded important results on ovarian cancer. Despite the existence of morphologically indistinguishable disease, patients with advanced ovarian tumors display a broad range of survival end points. To resolve survival-associated loci, gene expression profiling was completed for an extensive set of 185 (90 optimal/95 suboptimal) primary ovarian tumors using the Affymetrix human U133A microarray. The prognostic signature successfully classified the tumors according to survival for suboptimally but not optimally debulked patients. The suboptimal gene signature was validated using the independent set of tumors. To elucidate signaling events amenable to therapeutic intervention in suboptimally debulked patients, pathway analysis was completed for the top 57 survival-associated probe sets. For suboptimally debulked patients, confirmation of the predictive gene signature supports the existence of a clinically relevant predictor, as well as the possibility of novel therapeutic opportunities. In conjunction with Dr. Giovanna Tosatos laboratory, we examined the contribution of ORFK13/vFLIP to the Kaposi's sarcoma (KS) phenotype and potential for therapeutic targeting. Retroviral transduction of ORFK13/vFLIP into primary human endothelial cells induces the spindle morphology distinctive of KS cells and promoted the formation of abnormal vascular networks; upregulated the expression of proinflammatory cytokines, chemokines, and interferon-responsive genes; and stimulated the adhesion of inflammatory cells characteristic of KS lesions. Expression profiles revealed that the cellular enzyme thymidine phosphorylase (Pd-Ecgf) was markedly induced by ORFK13/vFLIP. Pd-Ecgf can metabolize the prodrug 5-fluoro-5-deoxyuridine (5-dFUrd) to 5-fluouridine (5-FU), a potent thymidine synthase inhibitor, which blocks DNA and RNA synthesis. When tested for cytotoxicity, 5-dFUrd (0.1 to 1 microM) selectively killed ORFK13/vFLIP-expressing endothelial cells while sparing control cells. These results demonstrate that ORFK13/vFLIP directly and indirectly contributes to the inflammatory and vascular phenotype of KS and identify 5-dFUrd as a potential new drug that targets KSHV latency for the treatment of KS and other KSHV-associated malignancies. |