My research interests are in developing novel biomarkers and therapeutic strategies in thoracic cancers (malignant mesothelioma, thymic epithelial tumors, non-small cell lung carcinoma, etc.). These clinical objectives are achieved by integrating a better understanding of tumor biology with testing of new experimental anti-cancer agents.
Malignant Pleural Mesothelioma (MPM)
Project I - Oncogenesis Modeling
The precise molecular steps leading to MPM remain obscure and, in part, underlie why this recalcitrant surface tumor is difficult to diagnose and treat. Our goal is to construct next-generation model(s) of MPM that can provide insights on tumor initiation, promotion and progression. We developed a novel method to generate new mesothelial cells, those which give rise to MPM, directly from patient tissue biopsy of pleural membranes. Utilizing 3D bioprinting, we incorporate these genetically defined mesothelial cells into building artificial human pleural membranes arranged in a multi-well, high-throughput pipeline. This ex-vivo equivalent of human pleura represents a novel and robust experimentation platform to conduct cell-based, real-time analyses into the origin and mechanism of MPM.Project II - miRNA-based Therapy
A major clinical bottleneck in MPM therapy is lack of efficacious, specific drugs that can be effectively delivered to the pleura space where this cancer is sheathed over vital organs. Since traditional chemotherapeutics and numerous small-molecule targeted drugs have yet to appreciably impact outcomes in MPM management, we are focused on identifying and testing novel agents. Currently we are investigating microRNA, short non-coding RNA, that are a class of epigenetic regulators interacting with transcription factors, as a promising type of cancer drug. miRNA exert anti-cancer effects by coherent simultaneous targeting of gene pathways, many of which are pathogenic in MPM and contain “undruggable” transcription factors like p53 or KRAS. We (in collaboration with the Chemical Biology Lab, NCI-Frederick) have innovated a thin-film, biodegradable, nano-scale, peptide hydrogel composite material as a locoregional delivery system (patent pending) that can deliver miRNA payloads more selectively to cancer cells. Using both unbiased high-throughput functional screens of miRNA and knowledge-based bioinformatic analysis, we are developing candidate therapeutic miRNA, e.g. miR-215 which targets p53 to induce apoptosis when applied to MPM xenografts. In addition to locoregional miRNA therapy for MPM as a monoagent, we are exploring novel combinatorial regimens with multiple classes of new drugs. Ultimately, we seek to complete preclinical studies in order to conduct future human trials assessing the clinical utility of miRNA with anti-MPM effects.
