Chronic treatment with certain MKIs in NSCLC may activate cancer associated fibroblasts (CAFs), which could in turn reduce drug penetration into the tumor and render NSCLC cells less responsive to long-term MKI therapy. Our ongoing study is concerned with the quantitative assessment of the impact of activated CAFs on the distribution of MKI using subcutaneous and orthotopic murine models of human NSCLC and the identification of the key molecular factor that regulates the activation of CAFs in MKI-treated NSCLC xenografts.

Given that the activation of “bypass signaling” appears to be an inevitable consequence of cancer treatment with all existing small molecule targeted therapeutic agents and it takes extremely long time for small molecule therapeutic agents to be approved by the FDA, we are prompted to test a different treatment approach that have the potential to target any gene of interest. In this project, we aimed to test the intratumoral gene knockdown efficiency of the  focal adhesion kinase (FAK)-targeting siRNA that is delivered to the lung tumor using a peptidic nanoparticle platform. Results of this study will provide the framework to develop RNA interference-based therapies to silence genes involved in the pathogenesis of lung cancer.

Although deregulation of cellular metabolism is long believed to play a key role in tumorigenesis, targeting cancer metabolism for therapeutic purposes remains challenging. Since our preliminary data showed that deletion of Tat-interacting protein 30 (TIP30) in A549 human lung adenocarcinoma cells resulted in the upregulation of genes involved in suppressing mitochondrial metabolism, we hypothesize that activation of TIP30 increases mitochondrial metabolism, production of ROS and oxidative stress, eventually leading to tumor growth arrest. The aim of this ongoing project is to examine the association between TIP30 expression levels and mitochondrial metabolisms in tumors and tumorigenic potential and to explore the mechanism underlying the effect of TIP30 on cellular metabolic pathways.

Combination therapy is considered a better strategy over monotherapy to target different mechanisms of blood pressure control. However, there is limited clinical data available to guide the selection of combination regimens in part due to the fact that clinical testing of new drug combinations is prohibitively expensive. As a result, the initial choice of drugs and dosing schedules is largely empirical, and whether the various degrees of improved therapeutic outcome with combination therapy are due to additive, synergistic or antagonistic effects remains undefined. We proposed to develop an isobolographic analysis-based approach to determine the nature and degree of interactions between two antihypertensive drugs used in combination. This approach has the potential to examine the impact of age on the patterns of synergistic or antagonistic interactions between two antihypertensive agents across doses, thereby assisting in the rational selection of promising drug combinations for further clinical development and providing clues for the investigation of underlying mechanisms.