Project Details
Description
ABSTRACT
The lack of validated molecular profiles clearly distinguishing aggressive phenotypes of prostate cancer, and
the absence of suitable intermediate endpoints make this tumor difficult to manage rationally. We have
pioneered and developed an in vivo screening system in which peptide-targeted particles capable of homing
to tumors are recovered from a phage display random library following intravenous administration. In an
unbiased screening of an established patient-derived xenograft (PDX) with several biological attributes
reminiscent of human metastatic prostate cancer, we first isolated and validated tumor-homing peptides
targeting the cell surface-associated glucose-regulated protein-78 kD (GRP78); we also screened a patient
directly to isolate and validate ligands targeting the interleukin-11 receptor (IL11R). We next inserted cis-
genetic elements from adeno-associated virus (AAV) within the phage genome and established that hybrid
ligand-directed AAV/phage (AAVP) particles enable systemic tumor targeted delivery and molecular-genetic
imaging of reporter transgene in preclinical models of prostate cancer. We hypothesize that promoters of
upregulated transgenes in prostate cancer should enable transcription-driven suicide gene expression for
tumor imaging with in tandem growth suppression. Work from our group (among others) shows that
overexpression of GRP78 and IL11R is related to disease progression. As such, promoters for these genes
will be evaluated in new AAVP constructs. In Aim 1, we will validate GRP78 and IL11R, in addition to
promoters of other genes identified by transcriptome analysis of prostate cancer patient-derived samples.
These promoters will be cloned into reporter plasmids to initially assess their properties relative to a standard
CMV promoter in prostate cancer cells and 3-dimensional patient-derived osteogenic prostate cancer cultures
in vitro. In Aim 2, the constructs will be evaluated in animal models. Our strategy relies on intravenously
injected GRP78-targeting AAVP engineered to deliver a Herpes Simplex Virus thymidine kinase (HSVtk)
transgene. Promoter-driven TK expression will be imaged with [18F]-FEAU by PET/CT and quantified by
qPCR. Tumor growth inhibition after ganciclovir treatment will be assessed in vivo by imaging, and tumor
sections will be evaluated by immunohistochemistry. The integration of transcriptional profiling, prostate
cancer cell targeting and molecular-genetic imaging within a single platform will potentially allow for the
monitoring of progression and response to therapy in pathologically indistinguishable, yet biologically diverse
patient cohorts with different disease outcomes. Given that the previous body of work has established GRP78
and IL11R as bona fide molecular targets in human prostate cancer, our methodological approach and
findings bear mechanistic and translational significance.
Status | Finished |
---|---|
Effective start/end date | 3/15/20 → 2/28/25 |
Funding
- National Cancer Institute: $356,850.00
- National Cancer Institute: $323,224.00
- National Cancer Institute: $323,224.00
- National Cancer Institute: $358,185.00
- National Cancer Institute: $351,955.00
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