Despite recent targeted- and immune-therapies that have benefitted other cancer types, pancreatic and lung tumors develop therapy resistance. Therefore, there is an urgent clinical need to better understand the molecular biology of this disease to enable the improvement of therapeutic strategies.Activating mutations in KRAS and p53 co-occur in 40% of pancreatic and lung and other tumors. We recelty addressed the long-standing question of how these most common co-occurring mutations in human cancers cooperate to cause tumors, hoping to identify a meaningful therapeutic opportunity. We demonstrated that altered RNA splicing by mutant p53 activates and maintains oncogenic KRAS signaling. These paradigm shifting studies led to discovering that oncogenic KRAS is susceptible to inactivation, a novel finding in the field, and suggested the likelihood that inhibiting RNA splicing represents a valuable therapeutic strategy for mutant KRAS/p53 tumors (Cancer Cell 2020).
Therefore, our research focuses on understanding how aberrant RNA splicing contributes to the maintenance, establishment, and impairment of anti-tumor immune response in tumors. Additionally, we aim to test our novel developed therapy, called Splicing-Hit Oligonucleotide Therapy (SHOT), which corrects the RNA splicing errors selectively killing PDAC and LUAD cells of our own genetically engineered mouse models (GEMM) to recapitulate the human PDAC background and to validate our findings. Compared to traditional targeted therapies where it takes years to generate a compound or antibody to inhibit mutant proteins, SHOT enables rapid and precise therapy development. SHOTs are adaptable and scalable, to be used against second-line therapy resistant cancers or to target more than one cancer type.
Our laboratory collaborates actively with laboratories at Yale University, Stony Brook University, and Memorial Sloan Kettering Cancer Center. Our team involves experts within backgrounds spanning oncology, immunology, bioinformatics, drug delivery, and microbiology. We believe that through this collaborative environment, we will achieve our ultimate goals in hopes of developing new efficient therapies that can ultimately lead to the cure of this devastating malignancy.