Recent advances in tumor biology have led to the identification of a variety of intracellular oncogenic pathways as potential targets for cancer therapy. Specifically, many studies have found that activation of the JAK/STAT pathway promotes tumor cell proliferation and survival in various types of leukemia and lymphoma. Our preliminary data demonstrate aberrantly activated JAK2 and STAT3 in more than 50% of diffuse large B-cell lymphoma patient samples. In vitro inhibition of JAK2 with the novel JAK2 inhibitor TG101348 (TG) inhibited JAK2 and STAT3 phosphorylation and induced apoptosis in a variety of lymphoma cell lines and patient samples. In this proposal the overall goal is to identify the molecular mechanisms underlying activation ofthe JAK/STAT pathway in lymphoma and to learn if inhibitors of this pathway can produce clinical benefit. We have identified several novel missense mutations in JAK2 and STAT3 genes.
In Aim 1 we will characterize the biological and therapeutic significance of these mutations with a site-directed mutagenesis approach. Suppressors of cytokine signaling (S0CS1) and protein tyrosine phosphatases (SHP1) are known key negative regulators of the JAK/STAT pathway. Our preliminary data demonstrate silencing of SHP1 and S0CS1 genes in 33% and 86%, respectively, of DLBCL lymphoma samples.
In Aim 2, we will delineate the mechanisms of silencing and how this regulates JAK/STAT pathway activation. The JAK/STAT signaling pathway is utilized by a number of growth factors and cytokines. We have identified increases in several JAK/STAT pathway-specific cytokines (IL-2, IL-6, IL-10 and EGF) in serum samples from patients with lymphoma compared to normal controls. In vitro we found in lymphoma cells that JAK2 and STAT3 are rapidly activated in response to IL-10.
Aim 3 will investigate the role of signaling for these interieukins mediated through their receptors with a focus on IL-10. This project is based on solid preliminary data demonstrating that the JAK/STAT pathway is a key mechanism for lymphoma growth and survival. These data have guided the design ofthe phase II trial in Aim 4 that will test TG in patients with relapsed lymphoma. Correlative research using patient samples pre- and posttherapy with JAK/STAT pathway inhibitor will increase our understanding ofthe mechanisms of how this pathway is regulated at the molecular and genetic level. These basic and clinical studies, working together, aim to offer a new therapeutic approach for patients with lymphoma.
Preliminary data from our lab indicate that the JAK/STAT pathway is frequently activated in lymphoma. Our studies are designed to understand the mechanism(s) of that activation and to study a new JAI<2 kinase inhibitor in a clinical trial for relapsed lymphoma. Our goal with these studies is to open up a new area of signal transduction therapy for lymphoma patients.
|Makkouk, Amani; Weiner, George J (2015) Cancer immunotherapy and breaking immune tolerance: new approaches to an old challenge. Cancer Res 75:10-May|
|Xing, Xiaoming; Flotte, Thomas J; Law, Mark E et al. (2015) Expression of the chemokine receptor gene, CCR8, is associated With DUSP22 rearrangements in anaplastic large cell lymphoma. Appl Immunohistochem Mol Morphol 23:580-9|
|Workalemahu, Grefachew; Wang, Hong; Puan, Kia-Joo et al. (2014) Metabolic engineering of Salmonella vaccine bacteria to boost human V?2V?2 T cell immunity. J Immunol 193:708-21|
|Witzig, Thomas E; Maurer, Matthew J; Stenson, Mary J et al. (2014) Elevated serum monoclonal and polyclonal free light chains and interferon inducible protein-10 predicts inferior prognosis in untreated diffuse large B-cell lymphoma. Am J Hematol 89:417-22|
|Hu, Guangzhen; Lou, Zhenkun; Gupta, Mamta (2014) The long non-coding RNA GAS5 cooperates with the eukaryotic translation initiation factor 4E to regulate c-Myc translation. PLoS One 9:e107016|
|Cerhan, James R; Berndt, Sonja I; Vijai, Joseph et al. (2014) Genome-wide association study identifies multiple susceptibility loci for diffuse large B cell lymphoma. Nat Genet 46:1233-8|
|Skibola, Christine F; Slager, Susan L; Berndt, Sonja I et al. (2014) Medical history, lifestyle, family history, and occupational risk factors for adult acute lymphocytic leukemia: the InterLymph Non-Hodgkin Lymphoma Subtypes Project. J Natl Cancer Inst Monogr 2014:125-9|
|Aschebrook-Kilfoy, Briseis; Cocco, Pierluigi; La Vecchia, Carlo et al. (2014) Medical history, lifestyle, family history, and occupational risk factors for mycosis fungoides and Sézary syndrome: the InterLymph Non-Hodgkin Lymphoma Subtypes Project. J Natl Cancer Inst Monogr 2014:98-105|
|Morton, Lindsay M; Slager, Susan L; Cerhan, James R et al. (2014) Etiologic heterogeneity among non-Hodgkin lymphoma subtypes: the InterLymph Non-Hodgkin Lymphoma Subtypes Project. J Natl Cancer Inst Monogr 2014:130-44|
|Vajdic, Claire M; Landgren, Ola; McMaster, Mary L et al. (2014) Medical history, lifestyle, family history, and occupational risk factors for lymphoplasmacytic lymphoma/Waldenström's macroglobulinemia: the InterLymph Non-Hodgkin Lymphoma Subtypes Project. J Natl Cancer Inst Monogr 2014:87-97|
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