As a physician-scientist in gastrointestinal oncology, there is a clear unmet need to better understand and overcome mechanisms of therapeutic resistance. Current techniques define an average clinical outcome for a given population defined by disease type. My lab studies hepatobiliary and pancreatic cancer, because chemotherapy alone remains a mainstay for these cancer types. Pancreatic and cholangiocarcinoma have a 5 year survival of 10% across all patients, highlighting a critical unmet need for these cancer types. For the primary liver cancer hepatocellular carcinoma, it remains uncertain the key drivers in helping patients understand prognosis or intervene with precision-based cancer therapies. The goal of my laboratory is to develop ex vivo tools for the prediction of targeted therapeutic response and overcome secondary mechanisms of resistance. Patient-derived cancer organoids (PCOs) provide a platform to understand the mechanism of therapeutic selection. These technologies interface with broad advances in next-generation sequencing, broad expression profiling, high-throughput screening, advanced microscopy, and animal models. By focusing efforts from patient-derived tissues, the goal of my laboratory is to characterize pathways with the greatest opportunity to translate to effective therapies in early phase clinical trials.
Patient-derived Cancer Organoid Banking
There are few RNA-based biomarkers available for clinical diagnostics. We are working to bank fresh frozen tissues to better understand the distinct subtypes and molecular profiles of pancreatic and liver cancers at diagnosis. We are evaluating if patient-derived cancer organoids can accurately predict clinically relevant transcriptional signatures to tailor effective RNA and epigenetic targeted strategies. While current techniques classify cancers largely by driver DNA alterations, amplifications or gene fusions, my lab will focus on distinct expression profiling at the level of transcriptional regulation.
Fully Synthetic Organoid Cultures
The current standard for organoid cultures requires the use of animal-derived products that are highly variable proving a formidable barrier to clinical translation. Using a variety of tagged growth factors and synthetic hydrogels, we are working to develop technologies for synthetic culture propagation. The goal of this project is to evaluate if such techniques provide a more faithful model for predicting clinical response or effective agents from therapeutic screening. Using a combination of patient-derived models these are being compared against prospective clinical outcomes of therapeutic response.
Targeting RNA Transcription
Few precision strategies in pancreatic or liver cancer can be developed, despite years of research focused on common pathologic driver alterations such as RAS and TP53. The breadth of clinical development requires consideration of both pathologic DNA alternations AND the control of RNA transcription. Our laboratory is building therapeutic screening platforms examining combinations of agents that target regulation of RNA expression. Utilizing a variety of phenotypic assays, coupled to array based expression profiling, we are refining combination therapeutics to overcome resistance at the level of transcription. These methods are being applied against organoids in both tissue culture and patient-derived xenografts.