Despite new cancer therapies, the majority of cancer patients with advanced disease still do not survive following diagnosis. A major reason for this is the ineffectiveness of cancer therapy due to chemotherapy resistance. Two types of chemotherapy resistance have been described: preexisting/acquired, where the constitutive expression of drug resistance genes or the loss of pro-apoptotic genes inhibits chemosensitivity; and inducible, whereby chemotherapy induces a transient resistance in the cancer cells blocking the cell death response. We have shown that the transcription factor NF-kappaB is activated in cancer cells in response to exposure to certain chemotherapies and radiation. The induction of NF-kappaB suppresses the ability of the cancer therapy to induce cell death in both cancer cell lines and in xenograft tumors. Inhibition of NF-kappaB by virally-delivered expression of a modified form of IkappaB or by an FDA-approved drug, PS-341, strongly potentiates the efficacy of the cancer therapy. Additionally, we and others have observed that NF-kappaB activity is elevated in tumors, raising the possibility that NF-kappaB contributes to pre-existing chemoresistance. Our hypothesis is that the activation of NF-kappaB in cancer, whether constitutive or inducible in response to cancer therapy, is the underlying major cause of chemotherapy resistance. In order to test our hypothesis, we propose the following set of goals: (1) determine which forms of chemotherapy activate NF-kappaB; (2) determine how chemotherapy activates NF-kappaB; (3) determine the mechanisms whereby NF-kappaB blocks apoptosis (focusing on NF-kappaB-regulated antiapoptotic genes); and determine if p53 is required or involved in the enhanced response to chemotherapy when NF-kappaB is inhibited. This proposal has the potential to completely alter chemotherapy strategies based on our understanding of the role of NF-kappaB in chemotherapy resistance.
|Potts, B C; Albitar, M X; Anderson, K C et al. (2011) Marizomib, a proteasome inhibitor for all seasons: preclinical profile and a framework for clinical trials. Curr Cancer Drug Targets 11:254-84|
|Sloss, C M; Wang, F; Palladino, M A et al. (2010) Activation of EGFR by proteasome inhibition requires HB-EGF in pancreatic cancer cells. Oncogene 29:3146-52|
|Sloss, Callum M; Wang, Fang; Liu, Rong et al. (2008) Proteasome inhibition activates epidermal growth factor receptor (EGFR) and EGFR-independent mitogenic kinase signaling pathways in pancreatic cancer cells. Clin Cancer Res 14:5116-23|
|Wang, F; Liu, R; Lee, S W et al. (2007) Heparin-binding EGF-like growth factor is an early response gene to chemotherapy and contributes to chemotherapy resistance. Oncogene 26:2006-16|
|Wang, Fang; Sloss, Callum; Zhang, Xiaobo et al. (2007) Membrane-bound heparin-binding epidermal growth factor like growth factor regulates E-cadherin expression in pancreatic carcinoma cells. Cancer Res 67:8486-93|
|Cusack Jr, James C; Liu, Rong; Xia, Lijun et al. (2006) NPI-0052 enhances tumoricidal response to conventional cancer therapy in a colon cancer model. Clin Cancer Res 12:6758-64|