Designing Polyamide Inhibitors of TWIST 1 for Prosenescence Therapy
Final rept. 1 July 2013-30 Jun 2014
JOHNS HOPKINS UNIV BALTIMORE MD
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Lung cancer is the most common cause of cancer mortality in the United States. The majority of human lung cancers are adenocarcinoma histology and have been found to have somatic mutations in the genes that encode the EGFRKRASBRAF signaling pathway. KRAS mutant adenocarcinomas of the lung are refractory to targeted agents and have been labeled undruggable . The identification of additional molecular targets in KRAS mutant lung tumors that when inhibited result in a clinical response are needed. Twist1 is a basic helix-loophelix bHLH transcription factor that usually is undetectable in adult tissues, but has been shown to be overexpressed in some cancers. Interestingly, Twist1 could also contribute to early tumorigenesis through inhibition of oncogene-induced senescence associated with KrasG12D. Therefore, Anti-TWIST1 agents could be useful against KRAS mutant lung cancer. We identified from a bioinformatics-chemical screen a candidate agent, harmine, that appears to target TWIST1-dependent pathways of tumor maintenance. Harmine decreased cell viability of lung cancer cells in a concentration dependent fashion that was correlated with increased markers of apoptosis and decreased TWIST1 protein levels in vitro. Harmine also decreased lung tumor growth rates in a genetically engineered mouse model of Twist1-induced lung adenocarcinoma that was correlated with increased markers of apoptosis and decreased TWIST1 protein levels in vivo.
- Medicine and Medical Research