The goal of this proposal is to develop a platform technology for detection and therapy of prostate cancer (PCa) based on induced cancer-specific expression of target proteins. In the US active surveillance is being reconsidered as an option for local disease due to the increasing recognition that many men undergo unnecessary prostatectomies. The idea behind active surveillance is that there is an indolent form of PCa that will never metastasize and will therefore not pose a major threat to the patient. There is no way to differentiate indolent from aggressive disease - no marker or panel of markers, no imaging agent to follow the course of the disease in vivo reliably. One approach is that, since it is nearly impossible to determine which tumors will progress, they should all be treated, and preferably when they are small, before they further de-differentiate and begin to metastasize. But they should not all be treated surgically, due to the well-known co-morbidities for resection of PCa, even with modern, nerve-sparing techniques. Recently the US Preventive Services Task Force issued a draft recommendation statement against prostate-specific antigen (PSA) screening for all age groups. The recommendation states that "PSA-based screening results in small or no reduction in PCa-specific mortality and is associated with harms related to subsequent evaluation and treatments, some of which may be unnecessary." That underscores the need for new, sensitive biomarkers for PCa, which can be used along with PSA history to provide suitable, tailored therapy. We propose a radical new method for detecting and treating PCa, whether it is localized, just beyond the capsule or widespread and metastatic to bone. The method relies on the discovery of a gene promoter, known as the progression elevated gene-3 (PEG-Prom), which is up-regulated in cancer and only cancer, i.e., it remains quiescent within normal or even immortalized normal tissue. When cloned in front of an imaging reporter or a therapeutic gene, these latter genes become activated only in the presence of malignancy - including PCa. We will deliver PEG-Prom systemically in a non-viral vector to relevant experimental models of PCa to delineate and concurrently eradicate it, specifically.
Compared to other cancers, prostate cancer is notoriously difficult to image. It is also impossible to know which tumors will be indolent or which will be aggressive and metastasize, necessitating treatment of all lesions detected - if such treatment is not harmful. By specifically activating imaging reporter and therapeutic genes within prostate cancer, we will be able to detect and treat it safely, irrespective of location.
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