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.
|Sharma, Ayush; Oishi, Naoki; Boddicker, Rebecca L et al. (2018) Recurrent STAT3-JAK2 fusions in indolent T-cell lymphoproliferative disorder of the gastrointestinal tract. Blood 131:2262-2266|
|Fama, Angelo; Xiang, Jinhua; Link, Brian K et al. (2018) Human Pegivirus infection and lymphoma risk and prognosis: a North American study. Br J Haematol 182:644-653|
|Jalali, Shahrzad; Price-Troska, Tammy; Paludo, Jonas et al. (2018) Soluble PD-1 ligands regulate T-cell function in Waldenstrom macroglobulinemia. Blood Adv 2:1985-1997|
|Bachy, Emmanuel; Maurer, Matthew J; Habermann, Thomas M et al. (2018) A simplified scoring system in de novo follicular lymphoma treated initially with immunochemotherapy. Blood 132:49-58|
|Franqui-Machin, Reinaldo; Hao, Mu; Bai, Hua et al. (2018) Destabilizing NEK2 overcomes resistance to proteasome inhibition in multiple myeloma. J Clin Invest 128:2877-2893|
|Ghahramani, Grant K; Goetz, Kirsten E; Liu, Vincent (2018) Dermoscopic characterization of cutaneous lymphomas: a pilot survey. Int J Dermatol 57:339-343|
|Hu, G; Dasari, S; Asmann, Y W et al. (2018) Targetable fusions of the FRK tyrosine kinase in ALK-negative anaplastic large cell lymphoma. Leukemia 32:565-569|
|Moss, Jennifer L; Xiao, Qian; Matthews, Charles E (2018) Patterns of cancer-related health behaviors among middle-aged and older adults: Individual- and area-level socioeconomic disparities. Prev Med 115:31-38|
|Luchtel, Rebecca A; Dasari, Surendra; Oishi, Naoki et al. (2018) Molecular profiling reveals immunogenic cues in anaplastic large cell lymphomas with DUSP22 rearrangements. Blood 132:1386-1398|
|Oishi, Naoki; Brody, Garry S; Ketterling, Rhett P et al. (2018) Genetic subtyping of breast implant-associated anaplastic large cell lymphoma. Blood 132:544-547|
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