238,000 prostate cancers (PCA) are diagnosed annually in the US, and about 80% of them are early enough in their progress to consider radical resection of ablation, which carries a high risk of impotence and incontinence. But 30-50% of early prostate cancers are indolent, and are therefore over treated creating a highly significant medical problem. Active Surveillance (AS) is offered to a small percentage of men with the earliest and lowest risk disease as candidates, but younger, healthier men are excluded. Even the best AS candidates are left with a choice of a radical, life-changing surgery, and a psychologically stressful, frequent and expensive surveillance regimen. For these reasons, image-guided focal therapies are evolving to ablate the tumors and spare the normal gland, but focal therapy by any method will not treat foci too small to image, nor will it treat muti-focal disease. Our goal is to provide a gland-sparing alternative to radical prostate surgery/ablation that will work in place of, with and as follow up to focal therapy, and that will treat multifocal disease. We will develop and test the hypothesis that image-guided super-selective microcatheterization of the prostate arteries can be used with novel Peptide Receptor Radionuclide Therapy (PRRT) to treat prostate cancer confined to the gland, and that dosimetry and monitoring of receptor expression by a unique digitally detected PET/CT imager will follow and predict outcome. To test the hypotheses, we created a novel canine prostate cancer cell expressing a human Gastrin Releasing Peptide Receptor, and implanted them in the prostate gland of immune compromised dogs to grow cm sized tumors. We will target a 177Lu GRPr-targeting peptide directly to the diseased gland and follow the progress of the radiation induced cell death by receptor imaging with 68Ga GRPr-targeting peptide. We will refine all of the methods and models in Aim 1, and test a validated existing agonist and an antagonist peptide in cells and mice radiotherapy trials in Aim 2.
In Aim 3 we will conduct a 20 dog clinical trial to assess three endpoints: therapeutic outcome with pathologic verification, and sexual and urinary side effects. At the conclusion we will know the effectiveness of a new image-guided therapeutic approach to early prostate cancer that spares gland function to an extent sufficient to proceed with direct translation into human patient clinical testing.
This project intends to demonstrate a new function sparing therapeutic approach for patients with early prostate cancer (Stage I, over 80% of patients), for which existing standard treatment and monitoring is rapidly evolving due to growing knowledge that overtreatment results in over 40 prostate glands being removed or disabled to save one life. This causes unnecessary risk of surgery, brachytherapy, or hormone therapy that cause life- changing side effects including impotence and incontinence. We will test the hypothesis that image-guided delivery of a drug directly through a prostatic artery can eradicate prostate cancer that is localized to the gland, sparing normal gland function, avoiding gland removal and the serious side effects that come with it. If successful, this therapy could replace radical gland removal in Stage I patients to avoid functional loss, and complement or supplement all newly emerging forms of focal therapy, providing a follow-up therapy analogous to whole breast radiation following breast lumpectomies.
|Ghosh, Arijit; Woolum, Karen; Knopp, Michael V et al. (2018) Development and optimization of a novel automated loop method for production of [11C]nicotine. Appl Radiat Isot 140:76-82|
|Ghosh, Arijit; Raju, Natarajan; Tweedle, Michael et al. (2017) In Vitro Mouse and Human Serum Stability of a Heterobivalent Dual-Target Probe That Has Strong Affinity to Gastrin-Releasing Peptide and Neuropeptide Y1 Receptors on Tumor Cells. Cancer Biother Radiopharm 32:24-32|
|Menendez, Maria I; Hettlich, Bianca; Wei, Lai et al. (2017) Preclinical Multimodal Molecular Imaging Using 18F-FDG PET/CT and MRI in a Phase I Study of a Knee Osteoarthritis in In Vivo Canine Model. Mol Imaging 16:1536012117697443|
|Menendez, Maria I; Hettlich, Bianca; Wei, Lai et al. (2017) Feasibility of Na18F PET/CT and MRI for Noninvasive In Vivo Quantification of Knee Pathophysiological Bone Metabolism in a Canine Model of Post-traumatic Osteoarthritis. Mol Imaging 16:1536012117714575|