According to the American Cancer Society, prostate cancer will account for an estimated 180,890 new cases and 26,120 deaths in 2016, continuing to be the most commonly diagnosed cancer and second-leading cause of cancer death in men in the United States. This research application provides rationale toward the design and development of new diagnostic agents based upon two well-validated biomarkers for early and late-stage detection of prostate cancer and is central to the research mission of the United States Department of Veterans' Affairs of seeking fundamental knowledge to enhance health, lengthen life, and reduce illness and disability of American veterans. The primary objective of this research application is to develop a metabolically stable, bivalent (dual receptor targeting), gastrin releasing peptide receptor/prostate-specific membrane antigen (GRPR/PSMA) targeting radioligand for Single Photon Emission Computed Tomography (SPECT) imaging of GRPR- and PSMA- positive prostate tumors. The GRPR and PSMA are well-validated prostate cancer biomarkers that are expressed in very high numbers on the surfaces of most prostate cancers. Because prostate cancer cells seem to differentially express specific receptors depending upon factors that may include chronicity and metastatic nature, it logically follows that a compound capable of targeting more than one biomarker would have the potential of binding to both early and chronic/metastatic stages of prostate cancer, enabling a more prompt and accurate diagnostic profile for both stages of disease. This application contains four discrete and well-delineated specific objectives: 1. Synthesis, purification, and characterization of new bivalent GRPR/PSMA-targeting radioligands. 2. To validate the cell targeting capacity of the GRPR/PSMA-targeting probes in vitro in GRPR/PSMA- expressing cells. 3. To evaluate the pharmacokinetics, pharmacology, stability, and SPECT imaging potential of the targeting probes in GRPR/PSMA-expressing prostate tumors in mice. 4. Quantitative pharmacokinetic tumor modeling and single dose acute toxicity study of the most viable molecular imaging candidate.
to Veterans' Health: The mission of the United States Department of Veterans' Affairs states is to serve the needs of American veterans and their families ?with dignity and compassion and to be their principal advocate in ensuring that they receive the care, support, and recognition earned in service to this Nation?. To achieve these goals, the VA recognizes its need to be a comprehensive, integrated system that also provides excellence in education and research, fostering fundamental creative discoveries and innovative research strategies to ultimately protect and improve veterans' health. This research application describes the synthesis and characterizaton of novel agents, their biological evaluation in vitro and in vivo, molecular imaging and modeling investigations in vivo, and toxicity evaluation in mouse models of human prostate cancer. Translation of these novel agents into nuclear medicine clinics would provide a mechanism for non-invasive detection of primary and chronic/metastatic stages of prostate cancer disease in human patients.
|Bandara, Nilantha; Stott Reynolds, Tamila J; Schehr, Rebecca et al. (2018) Matched-pair, 86Y/90Y-labeled, bivalent RGD/bombesin antagonist, [RGD-Glu-[DO3A]-6-Ahx-RM2], as a potential theranostic agent for prostate cancer. Nucl Med Biol 62-63:71-77|