Aurora kinases are a family of serine/threonine (S/T) kinases (Aurora A, B, C) that function predominantly in the mitotic-phase of the cell cycle. All 3 Auroras possess a highly conserved C-terminal kinase domain with a variable length N-terminal extension. These kinases regulate the completion of centrosome separation, bipolar spindle assembly, chromosome segregation and cytokenesis. Aberrant over-expression of Aurora A and B are oncogenic as they over-ride the mitotic and spindle check points leading to aneuploidy and genomic instability. Previously, we utilized small interference RNA (RNAi) techniques to validate Aurora A as an oncogenic target. We then evaluated the lymphoma, leukemia molecular profiling project (LLMPP) gene expression profile of ~100 mantle cell lymphoma (MCL) patients and demonstrated that over-expression of Aurora A and B, as 'signature genes for proliferation', predicts for an inferior overall survival and hence is a poor prognostic factor. Further, we showed that Aurora A is over-expressed in several of human MCL and DLBCL cell lines, Therefore, targeting Aurora with a specific small molecular inhibitor (SMI) might be of therapeutic value in aggressive B-cell non-Hodgkin's lymphomas (NHL). Hence, we utilized a structurebased drug discovery approach to design and synthesize a specific ATP-competitive Aurora SMI (SGI-498). Treatment of MCL and DLBCL cell lines with SGI-498 led to reduced cell viability and apoptosis in the 5- 10|aM IC50 range. Large animal safety studies have been conducted and an IND application is in progress (in collaboration with Supergen). Collectively these data show that Aurora is an excellent oncogenic drug target in aggressive subsets of B-cell NHL. Despite encouraging data in cell lines, there has not been a comprehensive study evaluating the expression of Aurora kinases in fresh tumor specimens of aggressive B-cell NHL nor a clinical test of efficacy in lymphoma patients. Therefore, the hypotheses to be tested in this Project 1 are: (1). Aurora A and B are over-expressed in fresh human aggressive B-cell NHL (mantle cell lymphoma (MCL), diffuse large B-cell lymphoma (DLBCL) and transformed follicular lymphoma (TFL)) tissues, (2). Aurora inhibitor SGI-498 is effective in promoting apoptosis in cell culture and tumor regression in a mouse xenograft model(s) of NHL and (3). SGI-498 will be safe and effective in treating patients with relapsed aggressive B-cell NHL in a early Phase clinical trial.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Specialized Center (P50)
Project #
5P50CA130805-05
Application #
8381185
Study Section
Special Emphasis Panel (ZCA1-GRB-I)
Project Start
Project End
2014-08-31
Budget Start
2012-09-01
Budget End
2013-08-31
Support Year
5
Fiscal Year
2012
Total Cost
$279,261
Indirect Cost
$47,347
Name
University of Rochester
Department
Type
DUNS #
041294109
City
Rochester
State
NY
Country
United States
Zip Code
14627
Holkova, Beata; Zingone, Adriana; Kmieciak, Maciej et al. (2016) A Phase II Trial of AZD6244 (Selumetinib, ARRY-142886), an Oral MEK1/2 Inhibitor, in Relapsed/Refractory Multiple Myeloma. Clin Cancer Res 22:1067-75
Akhenblit, Paul J; Hanke, Neale T; Gill, Alexander et al. (2016) Assessing Metabolic Changes in Response to mTOR Inhibition in a Mantle Cell Lymphoma Xenograft Model Using AcidoCEST MRI. Mol Imaging 15:
Holkova, Beata; Kmieciak, Maciej; Bose, Prithviraj et al. (2016) Phase 1 trial of carfilzomib (PR-171) in combination with vorinostat (SAHA) in patients with relapsed or refractory B-cell lymphomas. Leuk Lymphoma 57:635-43
Zhou, L; Zhang, Y; Chen, S et al. (2015) A regimen combining the Wee1 inhibitor AZD1775 with HDAC inhibitors targets human acute myeloid leukemia cells harboring various genetic mutations. Leukemia 29:807-18
Kiebala, Michelle; Skalska, Jolanta; Casulo, Carla et al. (2015) Dual targeting of the thioredoxin and glutathione antioxidant systems in malignant B cells: a novel synergistic therapeutic approach. Exp Hematol 43:89-99
Jaramillo, Melba C; Briehl, Margaret M; Batinic-Haberle, Ines et al. (2015) Manganese (III) meso-tetrakis N-ethylpyridinium-2-yl porphyrin acts as a pro-oxidant to inhibit electron transport chain proteins, modulate bioenergetics, and enhance the response to chemotherapy in lymphoma cells. Free Radic Biol Med 83:89-100
Chen, Liu Qi; Howison, Christine M; Spier, Catherine et al. (2015) Assessment of carbonic anhydrase IX expression and extracellular pH in B-cell lymphoma cell line models. Leuk Lymphoma 56:1432-9
Kelly, Jennifer L; Salles, Gilles; Goldman, Bryan et al. (2015) Low Serum Vitamin D Levels Are Associated With Inferior Survival in Follicular Lymphoma: A Prospective Evaluation in SWOG and LYSA Studies. J Clin Oncol 33:1482-90
Chen, Shuang; Zhang, Yu; Zhou, Liang et al. (2014) A Bim-targeting strategy overcomes adaptive bortezomib resistance in myeloma through a novel link between autophagy and apoptosis. Blood 124:2687-97
Lee, Kristy; Hart, Matthew R; Briehl, Margaret M et al. (2014) The copper chelator ATN-224 induces caspase-independent cell death in diffuse large B cell lymphoma. Int J Oncol 45:439-47

Showing the most recent 10 out of 112 publications