Advances in genomics and proteomics drive
precision medicine by providing actionable genetic alterations and molecularly targeted
therapies, respectively. While genomic analysis and medicinal chemistry have advanced patient stratification with treatments tailored to the genetic profile of a patient's
tumor, proteomic targeting has the potential to enhance the therapeutic index of drugs like
poly(ADP-ribose) polymerase (
PARP) inhibitors.
PARP inhibitors in breast and
ovarian cancer patients with BRCA1/2 mutations have shown promise. About 10% of the patients who received
Olaparib (
PARP inhibitor) showed adverse side effects including
neutropenia,
thrombocytopenia and in some cases resulted in
myelodysplastic syndrome, indicating that off-target effects were substantial in these patients. Through proteomic analysis, our lab previously identified
plectin, a cytolinker
protein that mislocalized onto the cell surface during malignant transformation of healthy ovarian tissue. This
cancer specific phenotype allowed us to image
pancreatic cancer successfully using
plectin targeted
peptide (PTP) conjugated to nanoparticles or displayed on
capsid protein of adeno-associated virus (AAV) particles. Objective: The goal of this study was to integrate the available pharmacogenomics and proteomic data to develop effective anti-
tumor therapies using a targeted
drug delivery approach. Methods:
Plectin expression and localization in human ovarian
tumor specimens were analyzed followed by in vitro confirmation of cell surface
plectin localization in healthy and
ovarian cancer cell lines. PTP-conjugated
liposomes were prepared and their specificity for plectin+ cells was determined in vitro and in vivo. A remote loading method was employed to encapsulate a
PARP inhibitor (AZ7379) into
liposomes. An ideal
buffer exchange method and remote loading conditions were determined based on the amount of
lipid and
drug recovered at the end of a remote loading process. Finally, in vivo
tumor growth studies were performed to determine the efficacy of PTP
liposomes in preventing PARP activity in mice bearing OVCAR8 (high grade
epithelial ovarian cancer (EOC))
tumors. Results: PTP liposomal AZ7379 delivery not only enhanced PARP inhibition but also resulted in decelerated
tumor growth in mice bearing subcutaneous and intraperitoneal OVCAR8
tumors. In mice bearing subcutaneous or intraperitoneal
tumors, treatment with PTP
liposomes resulted in a 3- and 1.7-fold decrease in
tumor volume, respectively, compared to systemic
drug treatment. Conclusion: Targeted
drug delivery assisted by genomic and proteomic data provides an adaptable model system that can be extended to effectively treat other
cancers and diseases.