P3: deregulated nrf2-keap1 pathway as a critical regulator of chemoresistance

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Project Title: P3: deregulated nrf2-keap1 pathway as a critical regulator of chemoresistance
Project Number: 5P50CA058184-17-8045
Project web address: Follow on NIH
Parent Project: 5P50CA058184-17
 
Project Description:
Chemoresistance remains the greatest challenge in improving survival of lung cancer patients. Lung cancer cells have greater expression than normal cells of proteins involved in detoxification of electrophiles and drugs detoxification and efflux pumps [Glutathione and Thioredoxin system and Multidrug resistance proteins] that provides intrinsic resistance against chemotherapy. Studies in project 3 have established that activation of the redox-sensitive transcription factor, Nuclear factor erythroid-2 related factor 2 (NRF2), in response to xenobiotic stress, positively regulates the expression of electrophile, xenobiotic detoxification enzymes and efflux pumps which confer cytoprotection against oxidative stress and apoptosis in normal cells. Kelch-like ECH-associated protein (KEAP1) negatively regulates NRF2 activity by targeting it for proteasomal degradation. Increasing NRF2 activity by small molecule activators might protect the lung epithelium of high risk subjects from oncogenic damage due to carcinogens. However, a surprising finding has emerged in the project that provoked re-thinking about the NRF2 pathway in terms of lung and other cancers. We have recently discovered that dysfunctional KEAP1 activity is a frequent alteration in lung adenocarcinomas which results in greater nuclear accumulation of NRF2 and enhances the transcriptional induction of electrophile, drug detoxification, and efflux proteins. Thus, unlike normal cells, lung cancer cells have unrestrained high NRF2 activity leading to therapeutic resistance. KEAP1 in the adenocarcinomas has deletions, insertions, and missense mutations in functionally important domains of the protein, and a very high percentage of loss of heterozygosity at 19p13.2, suggesting that biallelic inactivation of KEAP1 in these cancers is a common event. Mutations were detected in all stages of adenocarcinomas (including stage IA). Decreased KEAP1 activity, in-vitro, causes radio- and Chemoresistance. We have also identified mutations in KEAP1 in prostate tumors and recently similar mutations were reported in breast tumors.The new aims of this proposal are: Specific Aim 1: To determine the association between high NRF2 activity and Chemoresistance in non-squamous non-small cell lung cancer (NSCLC); Specific Aim 2: To determine whether targeted NRF2 inhibition can diminish Chemoresistancein preclinical models; and Specific Aim 3: To determine whether pharmacologically decreasing NRF2 activity in lung cancer can reverse Chemoresistance. Relevance to Public Health: The studies in this project have potential for both identifying biomarkers to predict drug sensitivity in patients with lung adenocarcinomas and to devise new means to reverse Chemoresistance in patients with drug-resistant tumors.
 
Project Terms:
19p13.2 adenocarcinoma amino acids antioxidants apoptosis base bevacizumab biological assay biological markers biopsy biopsy specimen cancer cell cancer cell line cancer patient carboplatin carcinogens cell line cell survival cells chemosensitization chemotherapy clinical clinical data clinical research clinical trials clinical trials design cohort collaborations combination drug therapy combinatorial common neoplasm cytoprotection cytotoxic chemotherapy cytotoxicity data deletion mutation diagnostic dose drug efflux drug metabolic detoxication drug resistance drug sensitivity efflux pump eligibility determination enzymes epithelium event excision fda approved funding genomics glutathione goals high risk improved in vitro activity in vivo inhibitor/antagonist insertion mutation insertion/deletion mutation large cell lung carcinoma lead loss of heterozygosity lung lung adenocarcinoma malignant neoplasm of lung malignant neoplasms mammary neoplasms methodology missense mutation mouse cell line multicenter trials mutation non-small-cell lung carcinoma normal cell novel nuclear nuclear factor-erythroid 2 oncogenic operative surgical procedures oxidation-reduction oxidative stress p-glycoproteins paclitaxel pathway interactions patients pharmaceutical preparations pharmacodynamics phase ii clinical trials pre-clinical pre-clinical model preclinical study prostatic neoplasms proteins public health radio randomized reporting research study resected resistance response sampling schedule series small hairpin rna small molecule small molecule libraries staging staining method stains stress success system tertiary protein structure testing therapeutic thinking thioredoxin tissue sample toxic effect transcription factor tumor tumor tissue tumorigenicity work xenobiotic metabolism xenobiotics xenograft model xenograft procedure cancer hiv/aids lung cancer
Project Title: P3: deregulated nrf2-keap1 pathway as a critical regulator of chemoresistance
Project Number: 5P50CA058184-17-8045
Project web address: Follow on NIH
Parent Project: 5P50CA058184-17
Organization: Johns Hopkins University, United States, Maryland, BALTIMORE
Principal Investigators (PI): Biswal Shyam, US
 
Project Categories:
Natural Sciences
 
Other Information:
Fiscal Year: 2011
Project Start Date: 1 December 2011
Project End Date: 30 November 2012
Project program: Specialized Center
 
Project Funding Information:
Funding Mechanism: Research Centers
Year Funding Organization Total Funding, $
2012 NIH - National Cancer Institute $239,171
Project Title: P3: deregulated nrf2-keap1 pathway as a critical regulator of chemoresistance
Project Number: 5P50CA058184-17-8045
Project web address: Follow on NIH
Parent Project: 5P50CA058184-17
 
Title FY Funding
There are no results for this project in database.
Project Title: P3: deregulated nrf2-keap1 pathway as a critical regulator of chemoresistance
Project Number: 5P50CA058184-17-8045
Project web address: Follow on NIH
Parent Project: 5P50CA058184-17
 
Project Title Organization FY Funding
Project Title: P3: deregulated nrf2-keap1 pathway as a critical regulator of chemoresistance
Project Number: 5P50CA058184-17-8045
Project web address: Follow on NIH
Parent Project: 5P50CA058184-17
 
Title Journal Year Country Rel
Project Title: P3: deregulated nrf2-keap1 pathway as a critical regulator of chemoresistance
Project Number: 5P50CA058184-17-8045
Project web address: Follow on NIH
Parent Project: 5P50CA058184-17
 
Title Year
Project Title: P3: deregulated nrf2-keap1 pathway as a critical regulator of chemoresistance
Project Number: 5P50CA058184-17-8045
Project web address: Follow on NIH
Parent Project: 5P50CA058184-17
 
Title Phase Year