Over a half century ago, Charles Huggins demonstrated the response of prostate cancer to androgen deprivation therapy. Subsequently, many discoveries and evolving findings continued to support a research rationale focused on the androgen receptor (AR) as a key target for prostate cancer. More recently, preliminary trials have suggested that other targets could also be useful in the treatment of prostate cancer, and the proposed strategies for treatment have ranged from targeted toxins to immunotherapeutic agents. We provide an overview of some of these approaches, with an emphasis on those that employ prostate specific membrane antigen (PSMA) as a target.

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High-resolution small animal single photon emission computed tomography (SPECT) with pinhole collimation has become well-established in preclinical research. Conventional scanner designs use custom fixtures that precisely attach and align pinholes to dedicated detectors. As a lower-cost alternative, we have developed a compact small animal SPECT device with integrated pinholes that is physically detached from gamma camera detectors and uses real-time calibration. The device consists of a shielded lead box with multiple integrated tungsten pinholes on the sides and with a rotating platform at the bottom. The animal or phantom to be imaged is positioned within a hollow cylinder mounted to the platform, with point source markers attached to the cylinder's outer surface. The entire device is placed on the patient table of a standard dual-head gamma camera system with collimators removed. Projection data are acquired with multiple energy windows to separate the point source data from the emission data. The complete geometric calibration is derived through analysis of the point source data. The system matrix is computed based on the calibration parameters and then applied to reconstruction of the emission data. Real-time calibration was found to be robust and accurate, even in the presence of downscatter from 99m Tc emission data or dual-isotope 99m Tc/ 111 In emission data. Successful calibration was consistently achieved in all pinhole configurations tried (up to seven pinholes per detector). Accuracy of real-time calibration was demonstrated in phantom studies and animal studies, where structures as small as 0.8 mm could be resolved in reconstructed images. Images appeared to be free of artifacts, and no cross-contamination from the calibration point sources was observed. Real-time calibration is feasible for pinhole SPECT, thus enabling standalone pinhole devices to be used without special alignment fixtures. The calibration accuracy is sufficient for high-resolution small animal studies. The hardware is compatible with nearly all gamma camera models and represents a lower-cost entry-level solution to the field of small animal SPECT.Index Terms-Calibration, pinhole, single photon emission computed tomography (SPECT), small animal.

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Introduction and Objectives: The Natural Products Branch of the National Cancer Institute examined extracts from a number of plants from South Africa. One extract in particularly, from the Phyllanthus engleri plant exhibited selective toxicity towards renal cancer cells in the NCI panel of 60 cell lines. The active ingredient from the plant extract has been recently isolated and identified as Englerin A (Beutler, J., et al). Renal cancers are notorious for their resistance to various therapies. Therefore, the potential for any agent that has selective anti-tumor activity is attractive. In additions, renal cancers are associated with a variety of metabolic changes, regardless of the tumors VHL status (wild type vs. mutant). Using the synthetic, optically active compound to Englerin A, we have examined its impact on global metabolism in the sensitive human renal carcinoma cell line A498. Methods: Using the synthetic material of Englerin A (Applichem Co., Germany) and A498 renal cancer cell line (ATCC, Baltimore MD), we tested for cytotoxicity and growth inhibition using the CellTiter-Glo® assay (Promega). Cell Titer-Glo measures the number of viable cells in culture based on quantitation of the ATP present, an indicator of metabolically active cells. Cell cycle was determined with the aid of flow cytometry following propidium iodide staining. Global metabolism was determined by GC and LC/mass SPEC in the A498 cells receiving treatment with Englerin A (30nM and 150nM) at 0, 2, 4, 8 and 24 hour time points (Metabolon, Durham, N.C.). Statistical analysis of the 2,000 standard metabolites (and unknown metabolites) is compared between treated/non-treated cells, at the various time periods, utilizing the commercial package JMP (SAS). Following log transformation and samples in which the metabolite was detected within at least two/thirds of the specimens will be included in the analysis. Results: In the A498 cells, we observed an IC50 of 3nM, comparable to reported studies for Englerin A. Flow cytometry data revealed a delayed cell cycle progression through S phase. In the metabolic studies, the most sensitive aspect of the Englerin A toxin was the alteration of carnitine metabolism. Conclusion: Englerin A is a newly isolated molecule that has selective toxicity towards renal cancer cell lines, but also inhibits other types of tumor lines and cancers. Renal cell cancers are notorious for their insensitivity to treatment with a variety of therapies. The low dose of Englerin A required producing selective toxicity towards renal cell cancers, suggests that this newly identified toxin is likely to be impacting a novel signaling pathway. Identification of that signaling pathway may provide additional means for targeted tumor therapies. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 983. doi:10.1158/1538-7445.AM2011-983

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