The current melanoma 'epidemic' is primarily affecting older men and women in our Veteran population due to age, sun and chemical exposure. During melanoma tumor progression amplification of aurora kinases A and B and/or the deregulation of NF-:B lead to aneuploidy, enhanced cell proliferation, escape from apoptosis, enhanced production of inflammatory mediators and tumor progression. We have preliminary data showing that xenografts of some human melanoma tumors are growth inhibited when aurora A kinase is blocked, while xenografts from other melanoma lesions respond to an IKK2 inhibitor. We hypothesize that constitutive activation of IKK2 and/or aurora kinase (AIK) amplification can contribute to melanoma tumor progression and that inhibition of these pathways will inhibit tumor growth. Moreover, we hypothesize that human melanoma gene expression profiles can predict which tumors will respond to AIK inhibitors and which will respond to IKK2 inhibitors. There are three specific aims for this project: 1) to characterize the expression of aurora kinase A, B, C during melanoma tumor progression using immunohistochemical analysis of tissue microarrays and to determine how the over-expression of IKK/ AIK kinases affect melanocytes and tumor growth; 2) to determine whether inhibiting both IKK and AIK pathways may prove to be more efficacious for treatment of melanoma tumors than by targeting each individual kinase alone and to determine how inhibition of IKK and AIK affect the anti-tumor host defense; 3) to characterize the gene expression profiles for human melanoma tumors that respond or do not respond to AIK or IKK2 inhibitors. Using immunohistochemical analyses of tissue microarrays we will examine the expression pattern of aurora kinases and phosphorylated (RelA/p65) of nevi, dysplastic nevi, primary and metastatic melanoma lesions during tumor progression. We will utilize an inducible expression system to alter the expression of AurA and IKK2 in melanocytes and melanoma cells in vitro to determine the consequences of over-activation of these two pathways. We will examine the response of melanoma tumors to inhibitors of IKK2, AIKs, and combinations thereof in a murine xenograft model. Finally, using gene expression microarray analysis, we will determine the expression profiles that distinguish between drug responders versus non-responders. The data derived from this proposal will provide key insights for better design of clinical trials for melanoma patients which should positively impact our Veteran population.
Melanoma is one of the fastest growing tumor types in the US. The melanoma 'epidemic' is largely confined to older men. Our Veteran population is increasingly affected due to age, sun and chemical exposure. We would like to learn how blocking kinases that regulate cell growth and escape from death [aurora kinases and/or inhibitor of kappa-beta kinase (IKK )] are expressed during melanoma progression, how they function in tumor growth, cell division processes, and cell death. We also will assess the effects of these kinases and their inhibitors on normal cells during preclinical studies. We would like to characterize the gene expression profile for melanoma patients that respond or do not respond to aurora kinase inhibitors and IKK inhibitors, or a combination of these two inhibitors. Results from this study will provide key information for better design of future clinical trials which will hopefully indicate improved treatment for Veterans experiencing malignant melanoma-or other cancer types.
|Vilgelm, Anna E; Cobb, Priscilla; Malikayil, Kiran et al. (2017) MDM2 Antagonists Counteract Drug-Induced DNA Damage. EBioMedicine 24:43-55|
|Vilgelm, Anna E; Pawlikowski, Jeff S; Liu, Yan et al. (2015) Mdm2 and aurora kinase a inhibitors synergize to block melanoma growth by driving apoptosis and immune clearance of tumor cells. Cancer Res 75:181-93|
|Liu, Yan; Hawkins, Oriana E; Vilgelm, Anna E et al. (2015) Combining an Aurora Kinase Inhibitor and a Death Receptor Ligand/Agonist Antibody Triggers Apoptosis in Melanoma Cells and Prevents Tumor Growth in Preclinical Mouse Models. Clin Cancer Res 21:5338-48|
|Yang, Jinming; Hawkins, Oriana E; Barham, Whitney et al. (2014) Myeloid IKK? promotes antitumor immunity by modulating CCL11 and the innate immune response. Cancer Res 74:7274-84|
|Hockemeyer, K; Janetopoulos, C; Terekhov, A et al. (2014) Engineered three-dimensional microfluidic device for interrogating cell-cell interactions in the tumor microenvironment. Biomicrofluidics 8:044105|
|Su, Yingjun; Vilgelm, Anna E; Kelley, Mark C et al. (2012) RAF265 inhibits the growth of advanced human melanoma tumors. Clin Cancer Res 18:2184-98|
|Yang, Jinming; Kantrow, Sara; Sai, Jiqing et al. (2012) INK4a/ARF [corrected] inactivation with activation of the NF-?B/IL-6 pathway is sufficient to drive the development and growth of angiosarcoma. Cancer Res 72:4682-95|