Scientific Rationale: Distinguishing between indolent (non-fatal) and aggressive (fatal) prostate cancer (PC) in the 250,000 new PC cases each year in the United States has immense implications, both for individual patients and for the costs the overburdened healthcare system must bear. In this project, we propose a new concept for the management of PC using a nanoparticle platform labeled with the new radiotracer Zirconium-89. We take advantage of the fact that prostate cancer cells express prostate specific membrane antigen (PSMA), and the more aggressive the tumor, the more PSMA is expressed. Tumors with strong PSMA expression have a higher risk of recurrence and worse prognosis. By targeting PSMA with our nanoparticles, we can significantly improve PC management in two ways: (i) noninvasively characterize PC by positron emission tomography (PET) imaging to distinguish indolent from aggressive tumors and (ii) monitor antiandrogen therapy with the new drug MDV3100. MDV3100 is a novel antiandrogen, which demonstrated in a five-center trial on 140 patients substantial antitumor activity in men with castration-resistant prostate cancer. An exciting aspect of our approach is that the nanoparticle can be easily loaded with a drug to deliver a therapeutic agent directly to the PC, thus increasing the local dose. Importantly, new insights into the biology of PSMA have shown that the expression of PSMA increases once the androgen receptor is blocked by MDV3100. Thus, we can actually harness this effect of MDV3100 to augment the targeting efficacy of our nanoparticles to PC. In a virtuous cycle, this improved binding of our drug-loaded nanoparticle to PC can enhance the effectiveness of various and future PC drug therapies.

Applicability: Our concept is highly applicable to all PC patients. Specifically, it will provide improved risk stratification by identifying more aggressive tumors through imaging of molecular changes with PET, which will allow for appropriate selection and tailoring of therapy for the patients. In the case of anti-androgen therapy, noninvasive imaging of therapy efficacy will provide the managing physician and the patient information on the therapy response in an expedited manner. Current techniques can only provide an update on therapy response with a significant delay of weeks. For hormone-sensitive tumors, the delivery of drugs can be improved through the diagnostic as well as therapeutic (i.e., theragnostic) nanoparticle, especially when combined with MDV3100 therapy. This will improve the drug concentration in the tumor and thus therapy efficacy and decrease systemic side effects. Since the nanoparticles are clinically approved and biodegradable, no significant side effects are expected. We project a timeframe of about 5 years for a clinical translation of this approach.

Advancing the Field of Research: Considering that our approach utilizes a clinically approved nanoparticle platform and medical PET imaging, our work serves as a direct path for translation to the clinic. We propose a novel concept of using MDV3100 to enhance the targeting and thus drug delivery to the tumor while reducing the risk of treatment- and diagnosis-related side effects. This same concept can be explored with different drugs and ultimately in other biological pathways to improve therapy of other tumors as well.