Pilot Project 4 - Pancreas

Target pancreatic cancer mitochondrial redox to enhance chemotherapy efficacy in Blacks

Pancreatic ductal adenocarcinoma (PDAC) has one of the highest mortality rates of all malignancies. The
incidence rate of PDAC among Blacks has been 30% to 70% higher than other racial groups in the United States. The pathological dense extracellular matrix in the PDAC tumor microenvironment (TME) induces cancer cell metabolic adaptation and develops resistance to chemotherapy. Unfortunately, most cancer models are unable to recapitulate these tumor characteristics to study drug responses. In this proposal, the MPI team includes a medicinal chemist from FAMU (Dr. Agyare), a medical oncologist from UF (Dr. Rogers), and a
biochemist from USC (Dr. Han) combine their innovative resources to tackle PDAC in general and focus on disparity in different racial groups. We hypothesize that possible race mitochondrial GST (GSTK) polymorphisms and PDAC desmoplasia resulting in PDAC disparities in tumor progression and drug responses. Our preliminary studies demonstrate that PDAC patient-derived organoids (PDOs) are more resistant to gemcitabine drug treatment when cultured in stiffer matrices, and gemcitabine conjugated with fatty acid stearate (Gem-S) attenuate this inhibition through the increase of reactive oxidative stress (ROS). Motivated by these results and exploiting the unique tunable matrix, we propose Aim 1 to characterize and identify correlations between GSTK and drug sensitivity in Black and White patient-derived specimens. We have collected 20 Blacks and 20 Whites PDAC histology samples and conducted exosome DNA sequencing. We will use this dataset with the TCGA dataset to analyze GSTK polymorphism, copy number variation, DNA methylation, gene expression, and mutation-derived protein changes in racially different groups. We expect to demonstrate the relationship between mitochondrial GSTK evolution and induction of drug resistance through multiple approaches. In Aim 2, we will dissect the mechanism of Gem-S in relationship to GSTK genetic and epigenetic features in Black and White PDO and PDX models. First, we will examine the Gem-S mechanism by studying GSTK related redox pathways at gene, protein, and metabolic levels. Second, we will evaluate the therapeutic efficacies of ONC201 and fatty acid-modified gemcitabine analogs in PDOs. Third will use small interfering RNA (siRNA) to silence GSTK to determine any additive or synergistic effects. Lastly, we will confirm drug sensitivities in Black and White PDAC PDX mouse models and the relationship between GSTK expression in vivo. The proposed studies will provide insights into mechanisms of treatment resistance in PDAC in different racial groups. Moreover, our observations will provide information to define the mechanistic correlation of intrinsic and acquired resistance that can be exploited therapeutically for effective therapeutics. These two independent yet synergistic aims will provide preliminary data that will lay the foundation for an R01 application by this team.

Meet the Pilot Project Team


Edward Agyare


Sherise Rogers


Bo Han


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