Project 1: Investigating the role that NQO1 plays in the survival of lung cancer cells
Cancer cells are exposed to elevated levels of reactive oxygen species that can lead to increased oxidative stress within their tumor microenvironment. Thus, cancer cells must regulate this increased oxidative stress exposure in order to prevent cell death. One strategy employed by cancer cells to enhance their survival in the presence of increased oxidative stress is to hijack the normal expression patterns of specific genes that regulate oxidative stress. One such gene, NADPH quinone oxidoreductase-1 (NQO1) has been found to be overexpressed in lung tumors as compared to its low expression levels in normal lung tissue. In this ongoing project we are comparing stable shRNA knockdown of NQO1 to CrispR/Cas9 genome-editing of NQO1 to determine if reducing NQO1’s expression or completely removing its expression alters the tumors ability to survive.
Project 2: NQO1 depletion and its role in cancer stem cell biology
Cancer stem cells are purportedly the primary culprit in therapeutic resistance and metastatic spread. We recently discovered that loss of NQO1 expression in lung tumors reduces the expression of an important lung cancer stem cell marker (aldehydye dehydrogenase, ALDH). Previous studies have shown that lung cancer patients whose tumors have elevated ALDH (aka, ALDHhigh expression levels) have a worse prognosis as compared to patients whose tumors have low expression levels of ALDH. Thus, the reduction of NQO1’s expression in lung tumors may also reduce the prevalence of this ALDHhigh subpopulation of cancer cells (AKA cancer stem cells) which are thought to be responsible for tumor recurrence and metastasis. In this ongoing project we have designed a nanoparticle (in collaboration with Dr Werner Geldenhuy’s Laboratory) to target NQO1 expression and we are currently working to test its efficacy in reducing the expression of NQO1 in tumors in vivo.
Project 3: Developing in vivo metastasis models to investigate novel therapeutics
Metastasis from the lung to the central nervous system (CNS) is a major problem in the management of lung cancer patients. CNS tumors are often found to exist in patients presenting with primary lung cancer disease that is beyond stage 1. Thus, the development of novel therapeutics is desperately needed. In this project we are utilizing luminescent cells to study the biology of metastatic disease spread from lung to brain. This model is also utilized to test therapeutics that have the potential to cross the blood brain barrier and efficaciously reduce tumor burden in the CNS.
Project 4: Developing synergistic treatment modalities for lung cancer
The survival of lung cancer patients whose tumors can’t be resected relies primarily on developing effective individualized treatment strategies. To date stand-alone therapies for lung cancer patients often fail due to chemoresistant tumors that then go on to metastasize and cause death. In this project we explore the synergistic potential between normal therapeutics and ionizing radiation. Our intent is to lower the effective dose of each agent in order to decrease tumor burden and systemic toxicity issues. One strategy currently under investigation (in collaboration with investigators at UTSW) is the use of polyADP-ribose polymerase (PARP) inhibitors in combination with therapeutics that inhibit DNA-repair, such as ARQ-761. PARP inhibitors inhibit a cancer cells ability to facilitate repair of their DNA. While ARQ-761 causes extensive double stranded DNA breaks when combined with ionizing radiation wreaks havoc on the cancer cells ability to perform repair functions. Thus, the cancer cell is forced to undergo cell death. In the current project we are investigating whether the combination of PARP inhibitors and the NQO1- bioactivated quinone ARQ-761 are efficacious in vivo.