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.

Final Project Update: 
Despite advancements in targeted therapies and immunotherapy, many patients with advanced non-small cell lung cancer (NSCLC) develop resistance to these treatments, resulting in a low 5-year survival rate of about 6%. In order to identify more effective treatments for this large group of patients, we sought to identify novel therapeutic and diagnostic approaches in which we identify distinct metabolic signatures that can be exploited and therapeutically targeted in therapy resistant lung tumors. 

Here, we proposed a therapeutic strategy that focuses on precisely targeting mitochondria within tumor cells, which are essential to the tumor cell’s energy production. By targeting the mitochondria, we aim to disable the energy supply of cancer cells, leading to their death. In our study, we developed a class of compounds that selectively target the mitochondria of lung tumor cells and kill them at very low doses, while not harming normal healthy cells. During the course of our study, we identified an ion channel within the mitochondria as a potential molecular target for our compounds, revealing its potential role in cancer. This finding opens up new avenues of investigation into understanding how ion regulation within the mitochondria regulates tumor cell survival.  

Additionally, we are working on a diagnostic tool to predict whether a patient’s tumors will respond to our compounds. Our goal is to advance this new treatment into phase I clinical trials for lung cancer patients who have not responded to traditional therapies. This approach aims to transform how we diagnose and treat lung cancer by developing personalized strategies that target the mitochondria and metabolism. By creating a companion diagnostic alongside our therapy, we hope to help doctors quickly identify which patients might benefit from our treatment, ultimately improving their chances of survival.