Pilot Project 5 - Pancreas

Development and Testing of a Novel Biospecific Using Modified Gemcitabene to target and treat Pancreatic Cancer

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. Thrid 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.

Meet the Pilot Project Team


Edward Agyare


Sherise Rogers


Bo Han


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