A key event in the development of malignant melanoma is the disregulation of NF-kappa B which results in constitutive production of inflammatory mediators and chemokines and escape from apoptosis. NF-kB is regulated by an inhibitory protein-IkB which sequesters the NF-kappaBp65/p50 complex in the cytoplasm, preventing its translocation into the nucleus. When this IkappaB protein is phosphorylated by the IkappaB kinase (IKK), it subsequently becomes ubiquitinated and degraded by the 26S proteasome. We have demonstrated that human melanoma cell lines exhibit constitutive activation of IKK, enhanced phosphorylation and degradation of IkappaB, and elevated levels of activated the NF-kappaB p65/p50 complex in the nucleus. This results in enhanced NF-kappaB mediated gene transcription, resulting in constitutive expression of chemotactic cytokines (chemokines), VEGF, IL-6, and other regulatory factors that augment the growth of the tumor cells, promote tumor angiogenesis and metastasis. Our hypothesis is that during tumor progression the disregulation of NF-kappaB in melanocytes and/or stromal cells leads to enhanced production of inflammatory mediators and melanocyte tumor progression. Moreover, we propose that blocking NF-kappaB will interfere with tumor growth and/or metastasis. Our preliminary data suggest that blocking NF-kappaB in human melanoma cells growing on nude mice targets the cells for apoptosis and inhibits tumor growth. To further clarify the potential of inhibition of NF-kB for melanoma therapy in an immunocompetent setting, we propose the following specific objectives: la) To determine the effects of knocking down IKKa and IKKb on the growth and metastasis of melanoma tumors in vitro and in vivo; Ib) To determine the effect of expressing a constitutively active IKKb in melanocytes on incidence of melanoma and the effect of melanocyte specific expression of a super repressor form of IkappaB on resistance to tumor induction by oncogenic Ras; 2) To determine the effects of the IKKb specific inhibitor, BMS-345541, alone and in combination with the DNA alkylating agent, temozolamide, on the growth and metastasis of melanoma tumors and the immune response to the tumor in immunocompetent mice; 3) To determine the mechanism for the induction of apoptosis in melanoma tumor cells by inhibiting IKKb. Significance: Melanoma is one of the fastest growing tumor types in the US and aging persons are increasingly affected due to sun and chemical exposure. Surgical intervention prior to the time of tumor invasion is the key factor in reduction in fatality for this form of cancer. For metastatic disease, immunotherapy, often combined with chemotherapy, is one of the most promising approaches. Our data indicate that targeting NF-kappaB may target tumor cells for apoptosis, inhibit tumor angiogenesis, tumor growth and metastasis. However, we need to determine the effects of blocking NF-kappaB on the host response to the tumor and on the incidence of melanoma tumor formation. The studies designed here will help design better clinical trials using inhibitors like VELCADE or IKK inhibitors in combination with chemotherapy.
| Yang, Jinming; Kumar, Amrendra; Vilgelm, Anna E et al. (2018) Loss of CXCR4 in Myeloid Cells Enhances Antitumor Immunity and Reduces Melanoma Growth through NK Cell and FASL Mechanisms. Cancer Immunol Res 6:1186-1198 |
| Pellom Jr, Samuel T; Dudimah, Duafalia F; Thounaojam, Menaka C et al. (2017) Bortezomib augments lymphocyte stimulatory cytokine signaling in the tumor microenvironment to sustain CD8+T cell antitumor function. Oncotarget 8:8604-8621 |
| Vilgelm, Anna E; Cobb, Priscilla; Malikayil, Kiran et al. (2017) MDM2 Antagonists Counteract Drug-Induced DNA Damage. EBioMedicine 24:43-55 |
| Leelatian, Nalin; Doxie, Deon B; Greenplate, Allison R et al. (2017) Single cell analysis of human tissues and solid tumors with mass cytometry. Cytometry B Clin Cytom 92:68-78 |
| Nichols, Erin E; Richmond, Ann; Daniels, Anthony B (2016) Tumor Characteristics, Genetics, Management, and the Risk of Metastasis in Uveal Melanoma. Semin Ophthalmol 31:304-9 |
| Richmond, Ann; Yang, Jinming (2016) The role of NF-kB in modulating antitumor immunity. Oncoimmunology 5:e1005522 |
| Vilgelm, Anna E; Johnson, C Andrew; Prasad, Nripesh et al. (2016) Connecting the Dots: Therapy-Induced Senescence and a Tumor-Suppressive Immune Microenvironment. J Natl Cancer Inst 108:djv406 |
| Johnson, Douglas B; Estrada, Monica V; Salgado, Roberto et al. (2016) Melanoma-specific MHC-II expression represents a tumour-autonomous phenotype and predicts response to anti-PD-1/PD-L1 therapy. Nat Commun 7:10582 |
| Vilgelm, Anna E; Johnson, Douglas B; Richmond, Ann (2016) Combinatorial approach to cancer immunotherapy: strength in numbers. J Leukoc Biol 100:275-90 |
| Nichols, Erin E; Richmond, Ann; Daniels, Anthony B (2016) Disparities in Uveal Melanoma: Patient Characteristics. Semin Ophthalmol 31:296-303 |
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