David Brian Shackelford, PhD

Non-small cell lung cancer (NSCLC) claimed the lives of an estimated 135,000 in the U.S. in 2021. Despite recent breakthroughs in targeted and immunotherapy, most patients with advanced NSCLC develop therapy-resistant disease, leading to a 5-year survival rate of approximately 6%. Subsets of lung tumors with mutations in the KRAS and LKB1 genes have proven to be highly resistant to immune-based therapeutic approaches. Patients with KRAS/LKB1 mutant lung tumors represent a large lung cancer population for whom effective therapies are greatly needed. As such, there is a critical need to identify novel therapeutic and diagnostic approaches to treat this deadly disease. We have discovered a novel compound that selectively kills KRAS/LKB1 mutant lung tumors that we will test in this study. This drug represents an effective and novel class of compound that we aim to develop for the treatment of therapy resistant KRAS/LKB1 mutant lung cancer. 

Update:
This past year we have made substantial progress. We have created a library of novel small molecule mitochondrial inhibitors and screened 95 of these compounds, identifying over 20 top candidate drugs. Additionally, we have identified a potential biological target of our drug(s), which is a calcium transporter that resides within the mitochondria at high levels in lung adenocarcinomas (LUAD). This represents a novel discovery and potential therapeutic target that has not been deeply explored in lung cancer. Currently, we are testing and validating our top candidate drugs to identify 2-3 lead compounds that we aim to test in pre-clinical efficacy studies in year two  of the award.