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
Ravi, Praful; Kumar, Shaji K; Cerhan, James R et al. (2018) Defining cure in multiple myeloma: a comparative study of outcomes of young individuals with myeloma and curable hematologic malignancies. Blood Cancer J 8:26
Thanarajasingam, Gita; Minasian, Lori M; Baron, Frederic et al. (2018) Beyond maximum grade: modernising the assessment and reporting of adverse events in haematological malignancies. Lancet Haematol 5:e563-e598
Pophali, Priyanka A; Ip, Andrew; Larson, Melissa C et al. (2018) The association of physical activity before and after lymphoma diagnosis with survival outcomes. Am J Hematol 93:1543-1550
McMaster, Mary L; Berndt, Sonja I; Zhang, Jianqing et al. (2018) Two high-risk susceptibility loci at 6p25.3 and 14q32.13 for Waldenström macroglobulinemia. Nat Commun 9:4182
Maurer, M J; Habermann, T M; Shi, Q et al. (2018) Progression-free survival at 24 months (PFS24) and subsequent outcome for patients with diffuse large B-cell lymphoma (DLBCL) enrolled on randomized clinical trials. Ann Oncol 29:1822-1827
Shenoy, Niraj; Creagan, Edward; Witzig, Thomas et al. (2018) Ascorbic Acid in Cancer Treatment: Let the Phoenix Fly. Cancer Cell 34:700-706
Ammann, Eric M; Shanafelt, Tait D; Wright, Kara B et al. (2018) Updating survival estimates in patients with chronic lymphocytic leukemia or small lymphocytic lymphoma (CLL/SLL) based on treatment-free interval length. Leuk Lymphoma 59:643-649
Wang, Sophia S; Carrington, Mary; Berndt, Sonja I et al. (2018) HLA Class I and II Diversity Contributes to the Etiologic Heterogeneity of Non-Hodgkin Lymphoma Subtypes. Cancer Res 78:4086-4096
Chapuy, Bjoern; Stewart, Chip; Dunford, Andrew J et al. (2018) Molecular subtypes of diffuse large B cell lymphoma are associated with distinct pathogenic mechanisms and outcomes. Nat Med 24:679-690
Leal, Alexis D; Allmer, Cristine; Maurer, Matthew J et al. (2018) Variability of performance status assessment between patients with hematologic malignancies and their physicians. Leuk Lymphoma 59:695-701

Showing the most recent 10 out of 387 publications