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.

Public Health Relevance

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.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Specialized Center (P50)
Project #
2P50CA097274-11
Application #
8395823
Study Section
Special Emphasis Panel (ZCA1-RPRB-7 (M1))
Project Start
2002-09-11
Project End
2017-06-30
Budget Start
2012-09-12
Budget End
2013-06-30
Support Year
11
Fiscal Year
2012
Total Cost
$291,843
Indirect Cost
$26,203
Name
University of Iowa
Department
Type
DUNS #
062761671
City
Iowa City
State
IA
Country
United States
Zip Code
52242
Link, Brian K (2017) Early Relapse in Follicular Lymphoma: High Risks and High Stakes. J Oncol Pract 13:810-811
Ding, Wei; LaPlant, Betsy R; Call, Timothy G et al. (2017) Pembrolizumab in patients with CLL and Richter transformation or with relapsed CLL. Blood 129:3419-3427
Ammann, Eric M; Shanafelt, Tait D; Larson, Melissa C et al. (2017) Time to Second-line Treatment and Subsequent Relative Survival in Older Patients With Relapsed Chronic Lymphocytic Leukemia/Small Lymphocytic Lymphoma. Clin Lymphoma Myeloma Leuk 17:e11-e25
Wafa, Emad I; Geary, Sean M; Goodman, Jonathan T et al. (2017) The effect of polyanhydride chemistry in particle-based cancer vaccines on the magnitude of the anti-tumor immune response. Acta Biomater 50:417-427
Paulus, A; Akhtar, S; Yousaf, H et al. (2017) Waldenstrom macroglobulinemia cells devoid of BTKC481S or CXCR4WHIM-like mutations acquire resistance to ibrutinib through upregulation of Bcl-2 and AKT resulting in vulnerability towards venetoclax or MK2206 treatment. Blood Cancer J 7:e565
Tanaka, Yoshimasa; Iwasaki, Masashi; Murata-Hirai, Kaoru et al. (2017) Anti-Tumor Activity and Immunotherapeutic Potential of a Bisphosphonate Prodrug. Sci Rep 7:5987
Wang, Xueju; Dasari, Surendra; Nowakowski, Grzegorz S et al. (2017) Retinoic acid receptor alpha drives cell cycle progression and is associated with increased sensitivity to retinoids in T-cell lymphoma. Oncotarget 8:26245-26255
Scott, David W; Abrisqueta, Pau; Wright, George W et al. (2017) New Molecular Assay for the Proliferation Signature in Mantle Cell Lymphoma Applicable to Formalin-Fixed Paraffin-Embedded Biopsies. J Clin Oncol 35:1668-1677
Tracy, S I; Maurer, M J; Witzig, T E et al. (2017) Vitamin D insufficiency is associated with an increased risk of early clinical failure in follicular lymphoma. Blood Cancer J 7:e595
Law, Philip J; Berndt, Sonja I; Speedy, Helen E et al. (2017) Genome-wide association analysis implicates dysregulation of immunity genes in chronic lymphocytic leukaemia. Nat Commun 8:14175

Showing the most recent 10 out of 337 publications