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CPRIT awards high-impact, high-risk seed grant to fight pancreatic cancer

Rice University, MD Anderson researchers use CRISPR tool and immunotherapy to deliver one-two punch

By Shawn Hutchins
Rice BIOE News

New collaborative research between Rice University bioengineers and physician-scientists at the University of Texas MD Anderson Cancer Center combines genome editing and immunotherapy intervention techniques to treat pancreatic cancer.

The work, which is co-led by Gang Bao, Rice’s Foyt Family Professor and a CPRIT Scholar in Cancer Research, and oncologist and immunotherapy expert Cassian Yee of UT MD Anderson, is possible through a High-Impact/High-Risk (HIHR) Research Award by the Cancer Research and Prevention Institute of Texas (CPRIT).

Also on the research team are Junghae Suh, an associate professor of bioengineering at Rice, and physician Anirban Maitra, a professor of pathology and scientific director of the Center for Pancreatic Cancer Research at UT MD Anderson.

Pancreatic ductal adenocarcinoma (PDAC), one of the most lethal types of cancer, is a notoriously silent disease. Most patients already have advanced disease or metastasis at the time of diagnosis, and only about seven percent of all patients diagnosed with PDAC remain alive five years after diagnosis. Complete surgical removal of the tumor remains the only chance for cure, however 80 to 90 percent of patients have the disease that is surgically incurable at the time of clinical presentation.

To address these challenges, the Rice-UT MD Anderson team brings extensive expertise in pancreatic cancer research, cancer immunotherapy, genome editing and viral vector engineering to create a high efficiency gene-disruption technique using CRISPR-Cas9 systems and immunotherapy interventions.

Gene disruption  
An illustration of a high efficiency gene-editing technique developed by Gang Bao’s laboratory at Rice’s BioScience Research Collaborative that uses CRISPR-Cas9 systems to target and disrupt the mutant KRAS gene in pancreatic ductal adenocarcinoma tumor cells. (Illustration by the Bao lab)  

CRISPR stands for clustered regularly interspaced short palindromic repeats. It is a new genome-engineering tool used by the Bao group to target the mutant KRAS gene in PDAC tumor cells.

Normally, the KRAS gene and associated K-Ras proteins are important in the transmission of signals that promote healthy cell differentiation and growth. A mutation in KRAS that disrupts the normal K-Ras signaling pathway and leads to cancer development, is one of the most common genetic causes found in PDAC, occurring in 90 percent of cases.

Bioengineering researchers Suh and Bao will work to package optimized CRISPR/Cas9 systems into benign adeno-associated virus (AAV) vectors engineered in the Suh lab. The engineered vectors will be designed to specifically target primary tumors and metastasis sites, gain access to the cell’s nucleus where gene expression occurs, and unload the CRISPR-Cas9 systems to disrupt the mutant KRAS gene in tumor cells. These events are expected to cause cancer cell death and release factors that will alter the immunosuppressive PDAC tumor microenvironment, thus enhancing cancer immunotherapy.

The Rice efforts will set the stage for the pre-clinical cancer immunotherapy studies by the physician-scientists at UT MD Anderson, with the goal of using a patient’s own adaptive immune system to recognize and attack PDAC tumor cells. Once validated, the combined strategies will be further tested in clinical trials.

CPRIT HIHR Research Awards seek to provide short-term funding to explore the feasibility of high-risk projects that, if successful, would contribute major new insights into the etiology, diagnosis, treatment, or prevention of cancers.