Kelley M. Harsch

Targeted treatment of prostate cancer

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. J. Cell. Biochem. 102: 571–579, 2007.

The Role of 18F-FDG PET/CT for Initial Staging of Nasal Type Natural Killer/T-Cell Lymphoma: A Comparison with Conventional Staging Methods

The utility of 18F-FDG PET/CT in patients with nasal-type natural killer (NK)/T-cell lymphoma has not been established. Therefore, we evaluated the role of 18F-FDG PET/CT for determining cancer staging by comparing its results to those of conventional staging methods (CSMs) (physical examination, CT with intravenous contrast, biopsies from primary sites, and bone marrow examinations) in patients with nasal-type NK/T-cell lymphoma. Methods: In this study, 52 consecutive patients (34 men, 18 women; mean age, 49.4 y) with newly diagnosed nasal-type NK/T-cell lymphoma were studied. Anatomic regions (n = 1,300; 16 nodal and 9 extranodal regions per patient) were assessed with an 18F-FDG PET/CT scan and with CSMs, and each anatomic region was classified as positive or negative for malignancy. Biopsy and clinical follow-up, including additional imaging studies, were used as the gold standard for diagnosis. Results: Of the 59 nodal and 71 extranodal anatomic regions that were truly positive for malignancy, 18F-FDG PET/CT detected 58 nodal and 69 extranodal. CSMs, however, detected only 44 of the nodal and 61 of the extranodal anatomic regions that were positive for malignancy (nodal comparison of PET/CT vs. CSMs, P < 0.001; extranodal comparison of PET/CT vs. CSMs, P = 0.008). PET/CT scans exhibited a significantly better sensitivity (97.7% vs. 80.7%, P < 0.001) than CSMs for the detection of malignant lesions. PET/CT findings altered the original staging category for 12 patients (21.2%) and affected treatment planning in 23 cases (44.2%). Conclusion: Our study demonstrated that 18F-FDG PET/CT scanning is a valuable modality for staging and treatment planning in patients with nasal-type NK/T-cell lymphoma.

Robotic Real-time Near Infrared Targeted Fluorescence Imaging in a Murine Model of Prostate Cancer: A Feasibility Study

OBJECTIVE To evaluate the detection of near-infrared fluorescence from prostate tumors stained with a prostate-specific membrane antigen (PSMA)-targeted tracer developed in our institution with a novel robotic imaging system. METHODS Prostate cancer cell lines PC3-pip (PSMA positive) and PC3-flu (PSMA negative) were implanted subcutaneously into 6 immunodeficient mice. When tumors reached 5 mm, a PSMA-targeted fluorescent conjugate was injected intravenously. The first 3 mice underwent near-infrared imaging immediately and hourly up to 4 hours after injection to determine the time necessary to obtain peak fluorescence and were killed. The last 3 mice were imaged once preoperatively and were euthanized 120 minutes later. Excision of the tumors was performed by using a novel robotic imaging system to detect near-infrared fluorescence in real time. Specimens were submitted for pathology. RESULTS In the first 3 mice, we found 120 minutes as the time needed to observe peak fluorescence from the PSMA-positive tumors. We identified discrete near-infrared fluorescence from 2 of 3 PSMA-positive tumors with the robotic imaging system. Surgical margins were negative for all excised specimens except for one PSMA-negative tumor. CONCLUSIONS Real-time near-infrared fluorescence imaging of prostate cancer is feasible with a novel robotic imaging system. Further research is needed to optimize the signal intensity detectable from prostate cancer with our tracer. Toxicologic studies are needed before its clinical use.

Abstract 983: Effect of optically active Englerin A on global metabolism of A498 renal cell cancer: Impact on carnitine metabolism

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 IC 50 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